Northeast Florida Medicine - Winter 2012 - Rheumatology by Duval County Medical Society

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Inside this issue of

VOLUME 63, NUMBER 3 Rheumatology Winter 2012 EDITOR IN CHIEF Raed Assar, MD (Chair) MANAGING EDITOR Leora Legacy ASSOCIATE EDITORS Abubakr Bajwa, MD Steven Cuffe, MD Ruple Galani, MD Kathy Harris (Alliance) Sunil Joshi, MD (Vice Chair) James Joyce, MD Daniel Kantor, MD Neel Karnani, MD Mobeen Rathore, MD James St. George, MD

EXECUTIVE VICE PRESIDENT Bryan Campbell DCMS FOUNDATION BOARD OF DIRECTORS Malcolm T. Foster, Jr., MD, President Ashley B. Norse, MD, President Elect Eli Lerner, MD, Vice President Mobeen Rathore, MD, Vice President Neel Karnani, MD, VP & Treasurer Daniel Kantor, MD, Secretary Benjamin Moore, MD, Im. Past President Bouli Amoli, MD, Resident Raed Assar, MD Elizabeth Burns, MD J. Bracken Burns, DO Kelli Deese, MD, Resident Ruple Galani, MD Jeffrey M. Harris, MD LCDR James Hodges, MC, USN, Resident Mark L. Hudak, MD TraChella Johnson, MD Sunil N. Joshi, MD James Joyce, MD Harry M. Koslowski, MD Stephen Mandia, MD Jesse P. McRae, MD Jason D. Meier, MD Amit Grover, MD, Resident Nathan P. Newman, MD Sanjay Swami, MD David L. Wood, MD Northeast Florida Medicine is published by the DCMS Foundation, Jacksonville, Florida, on behalf of the County Medical Societies of Duval, Clay, Nassau, Putnam, and St. Johns. Except for official announcements from the County Medical Societies, no material or advertisements published in NEFM are to be seen as representing the policy or views of the DCMS Foundation or its colleague Medical Societies. All advertising is subject to acceptance by the Editor in Chief. Address correspondence and advertising to: 555 Bishopgate Lane, Jacksonville, FL 32204 (904-355-6561), or email: leora@dcmsonline.org. COVER: Khafre's Pyramid in Giza, Egypt. Tomb of the fourth Dynasty Pharaoh Khafre. Cover designed by Marigrace Doran.

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Northeast Florida Medicine

Features

Rheumatology: A Specialty with Ancient Roots Requires New Approaches

Ghaith Mitri, MD, MMM, CPE, FACR, Guest Editor

Rheumatologic Serologies and Inflammatory Markers: A Review

Ronald R. Butendieck, Jr., MD; Florentina Berianu, MD and Andy Abril, MD

Rheumatoid Arthritis: Optimizing Clinical Outcomes in Primary Care Benjamin W.E. Wang, MD, FRCPC

Systemic Lupus Erythematosus: A Simplified Guide

Erick Bournigal, MD, FACR and Ghaith Mitri, MD, MMM, FACR

Classification of Juvenile Idiopathic Arthritis

Paget's Disease of the Bone: Review for Clinicians

Severe Neutropenia in the Setting of Rheumatoid Arthritis and Hepatitis C: A Review and Case Report

Maria Leonor Noboa, Medical Student and Mohammad Ilyas, MD

Emad Naem, MD and Sandra Mesliniene, MD

Karishma Ramsubeik, MD and Ghaith Mitri, MD, MMM, FACR

Thirty Years of HIV in Women (CME) Laura Armas-Kolostroubis, MD

Insert 2012 Sports Concussion Guidelines

Northeast Florida Sports Concussion Task Force

Departments

4 From the Editor’s Desk 5 From the President’s Desk 8 Philip H. Gilbert Invited Editorial 9 From the EVP's Desk 11 Residents' Corner 12 Patient Page Insert Trends in Public Health Northeast Florida Medicine Vol. 63, No. 3 2012 3

From the Editor’s Desk

Celebrating Our Great Medical Society's History

Physicians learn early in their careers an important lesson: if you don’t document what you have done, it didn’t happen. How many cultures and their resulting achievements were lost because that history was not documented? The Duval County Medical Society (DCMS) has a tremendous heritage beginning in 1853 with physician leaders who thoroughly integrated with the community and were a great inspiration and driving force for its progress and health. How can future generations find a reliable source on what the DCMS’s physicians have done to serve their community, their accomplishments, and their sacrifices? All this and more may be found in Florida’s Pioneer Medical Society: A History of the Duval County Medical Society & Medicine in Northeast Florida. (Legacy Publishing, $53.50 + $6.00 SH) This 287 page coffee table-sized book with hundreds of photographs and illustrations recounts the trailblazing history of DCMS and medicine in Northeast Florida. Published and received in late summer, this book heralds the pioneer initiatives of DCMS and records how its members have been medical trailblazers and forerunners in Jacksonville as well as Northeast Florida for 159 years. Starting with the Timucua Indians and early French and English settlers in Northeast Florida, the book’s content covers Yellow Fever outbreaks of the 1800s, early physicians in Jacksonville, the founding of DCMS, pioneer Society presidents like Dr. Francis P. Wellford, Dr. Abel S. Baldwin and Dr. R.P. Daniel to other trailblazers like Dr. James Borland, Sr., Dr. Robert McIver and Dr. E. Thomas Sellers, the development from historic medical institutions such as St. Vincent’s, Brewster Hospital and St. Luke’s to Jacksonville’s current medical community, gender and racial diversity breakthroughs, influential partnerships with groups such as the University of Florida , Blue Cross & Blue Shield of Florida (now Florida Blue) and the U.S. Navy, the military involvement and volunteer efforts of Society members, key DCMS leaders and Society initiatives, future plans and visions, plus practice profiles. The longevity of the DCMS mirrors the history of Jacksonville through plagues, wars, fires, a Depression, and racial tensions as well as partnerships with the military, hospitals, corporations and community groups. Raed Assar, MD, MBA Editor-in-Chief Northeast Florida Medicine

Physicians mentioned in this book, as well as their colleagues, are shining examples of the medical profession. One cannot help but be thoroughly impressed by the sacrifice of physicians, their risk taking to help their patients, their financial sacrifices during dire times of economic stress, their philanthropic actions, and their unshakable belief in the goodness of their community as detailed in this historic volume. The book is an excellent reference and great source of inspiration for future generations.

Compliments about the book have come from among others: Emily Lisska of the Jacksonville Historical Society, Charles Tingley of the St. Augustine Historical Society, Baldwin’s Mayor Stan Totman, Raymond Neal of the Jacksonville Public Library System, Gretchen Kuntz of the Borland Health Sciences Library, and numerous DCMS members including Dr. Yank Coble, Jr; Dr. Guy Selander, Dr. John Lovejoy, Dr. Robert VanCleve, Dr. James Borland, Jr, and Dr. Kay Gilmour who said, “I admire and appreciate the book. It is masterful. What a great project and what a great effort.” Readers of this DCMS history, regardless of their relation to DCMS, ought to be impressed with the great contributions physicians have provided to their patients and beloved community. For the Society members, it is more so. The book is well written by Leora Legacy, DCMS staff member and this journal’s Managing Editor, and is organized in a manner that makes it easy for the reader to review, understand, and appreciate the leadership role of DCMS physicians in Northeast Florida for 159 years. This book is a must buy for North Florida physicians. It will be a treasured resource in a physician home or a medical facility. This is a historic attempt to capture and document the rich history of this society. It will serve to educate all who read it whether current or future generations. It instills a sense of pride and belonging among the physicians, their families, and friends. It builds bonds among the physicians of this community and creates a great resource of DCMS history; Florida’s Pioneer Society. Copies of the book may be purchased from the DCMS by calling 904-355-6561 or by ordering online at dcmsonline.org. Limited copies are also available at Chamblin’s Book Mine locations and San Marco Bookstore. At right is Baldwin's Mayor Stan Totman receiving a book from Leora Legacy. The town, named after DCMS' Second President Dr. Abel S. Baldwin, has dedicated a room in the restored Coleman House in Dr. Baldwin's honor. Dr. Assar is Aetna’s Medical Director for North Florida. Articles or opinions provided by Dr. Assar do not necessarily reflect the views of Aetna.

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From the President’s Desk

A Year Filled with Uncertainty and Change I can’t believe a year has already gone by and what a year it has been. I took over as DCMS president last November from Dr. Malcolm Foster in the midst of a lot of uncertainty about what changes healthcare reform would bring to the medical society as well as practicing physicians. A year later the uncertainty still exists. By the time this editorial reaches your desk the November elections will be over. Whether President Obama is re-elected or Governor Romney becomes our new President, healthcare in the U.S. and the practice of Medicine will undergo sweeping changes in the coming years. Currently we are facing big changes in Medicare reimbursement as two elements of the 2010 Affordable Care Act kick in: Value-Based Purchasing and Re-admissions Reductions. Hospitals and Physicians are scrambling to create ACOs. The changes in payment models towards bundled payments and away from fee for service have resulted in many physicians leaving private practice in favor of becoming employees. What these changes mean for US medicine remains to be seen. Besides uncertainty at the national level, there have been quite a few changes locally at DCMS. Shortly after taking over as president, I found out that our EVP of 7 years, Jay Millson, was resigning. My first hurdle was hiring a new Executive Vice President. Bryan Campbell joined DCMS as the EVP in February of this year. Bryan brought a background in public relations, media and television with him to DCMS and as a result DCMS has had a lot of media exposure this year. Shortly after joining DCMS, Bryan hired a new Communications Coordinator Laura Townsend. Bryan and Laura are making DCMS a “go-to” resource for media, both television and print, for issues related to healthcare and public health in Northeast Florida. DCMS now has a column, “Doctors On Call” in the Florida Times-Union in which DCMS members write about various healthcare related topics that are of interest to the public. While DCMS’s media exposure has increased this year, membership is still on the decline and is a major issue. The cause seems to be multifactorial. The change to an employee model for more physicians has definitely had an impact. The answer to membership decline is memAshley Booth Norse, MD 2012 DCMS President ber benefit and value. DCMS has to have value for its members. To that end, we have begun having membership meetings around Jacksonville including one aimed specifically at residents and fellows. These meetings are a way for our members to obtain CME, network, and just socialize with their peers. We hope these gatherings have been a valuable resource for our members, but DCMS needs your help. We need to know what you, our members, need DCMS to provide to add value and benefit. Barabara Braddock, DCMS’s membership director for more than 20 years, retired in September of this year. Barbara’s retirement was a huge loss for DCMS. She has been with DCMS for so long and will be greatly missed. Karen Pan has joined DCMS as our new membership director. She was previously with the American Association of Clinical Endocrinologists, and we are very excited that she has joined DCMS. Please email Karen (karen@dcmsonline.org) with any ideas or suggestions on how DCMS can provide added member benefit. This has been a wonderful and challenging year but no one does this job alone. DCMS has a wonderful and dedicated staff that drives this organization forward and I would be remiss if I didn’t take this opportunity to thank them for all they do. In addition to those already mentioned above, Patti Ruscito our Director of Operations celebrated her 20th anniversary with DCMS this year. Leora Legacy continues to keep the Northeast Florida Medicine journal in the forefront of medical publications in our area. Special thanks to Bookkeeper Deana Hadden, as well, for all she does. Deana has been with DCMS for over 30 years and will also be retiring at the end of this year. In closing, I have to say thank you to my husband, Ron Norse, for all he has done this year. I took over as DCMS president only four months after having our first child, so he has had a lot of daddy duty this year. I couldn’t have done it without him. Finally, thank you to you, our members, for making DCMS a great organization. At right is DCMS EVP Bryan Campbell (center), with new Membership Director Karen Pan (left) and Communications Coordinator Laura Townsend (right). Welcome to the DCMS staff!

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Northeast Florida Medicine Vol. 63, No. 3 2012 5

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6 Vol. 63, No. 3 2012 Northeast Florida Medicine

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JACKSONVILLE America’s Health Center Northeast Florida Medicine Vol. 63, No. 3 2012 7

Philip H. Gilbert Invited Editorial

Caring for the Indigent in Florida Christopher R. Cogle, MD President, Alachua County Medical Society Editor's Note: Philip H. Gilbert served as the Executive Vice President of the Duval County Medical Society (DCMS) from 1984 until his unexpected death in 2004. During those decades, he was an outspoken advocate for the physicians he served and for the needs of their patients. With no fear of retribution, Phil shared his honest informed opinions with his DCMS colleagues and with the community they served. In his honor, the DCMS Board of Directors established the Philip H. Gilbert Invited Editorial to celebrate his spirit for addressing issues that he championed such as advocacy, tort reform, community activism and caring for the underserved. The “Request for the 2011 Philip H. Gilbert Invited Editorial” invitation was sent in July to local, state, and national leaders (physician or layperson). All editorials received were reviewed by the DCMS Journal and Communications Committee and two were chosen for publication. One is published in this issue and one appeared in the fall journal.

One of the greatest embarrassments of our medical profession is that people in our communities suffer and die of diseases due to lack of money. In the world’s wealthiest country, lack of wealth and inability to afford health insurance is an independent risk for death.1,2 Even adjusting for level of education, income is a strong predictor for mortality.3 To most of us physicians, this ringing indictment is not new or surprising. We know that the uninsured suffer outside the walls of our outpatient clinics and inpatient units as we struggle to keep up with caring for people with money and insurance. Our hospitals shore up what they can, and some providers in the medical profession have responded to this call to arms with various donations of our time and resources. I remember the first time I volunteered in the University of Florida College of Medicine’s Equal Access clinic, which is a long-running indigent clinic run by medical students. It wasn’t my first exposure to abject poverty. But it was the first Christopher R. Cogle, MD President, Alachua County time I tried to help scared and needy individuals climb Medical Society impossibly formidable walls of basic medicine: a man with a severe case foot rot and no access to expensive, systemic anti-fungal therapy, let alone dry socks and shoes; a woman on the verge of malignant hypertension and a genuine fear of annihilating her family’s meager savings in one trip to the emergency department; a child with new-onset diabetes mellitus and two parents with four jobs that legitimately didn’t have time to enroll the child in a clinic and commit to frequent follow-up. In the richest nation, we have a poorly constructed and unreliable system to access care, resulting in both personal and societal costs.4-6 In 1984, Alachua County physicians created the first and largest charity care network in Florida, called We Care Physician Referral Network. In its first year, We Care recruited several hundred physicians who donated their time and approximately $400,000 in resources to take care of about 80 individuals. Because of the success of this indigent care charity program, We Care has expanded to over 900 Alachua County physicians and dentists who annually treat between 400–600 indigent patients at an estimated total of $4,500,000.00 8 Vol. 63, No. 3 2012 Northeast Florida Medicine

in care. Not only has the We Care network improved the health of Alachua County, it has also served as a template for physician-directed charity care networks statewide, including the Marion We Care network and a dozen other counties. At the national and state level, health care is poised for a seismic shift based on recently passed health insurance reforms and the Supreme Court ruling. In the trenches, our charity care networks are beginning to strain under the weight of increased demand and decreased donations. Unfortunately, who gets squeezed in this Smithian economic formula are our patients according to size of their bank account. Yet to be seen is whether our Florida state government will rise to the occasion and expand Medicaid so that it covers millions of poor and disabled Floridians unable to afford high-cost insurance. Charity care was never meant to be the answer to the class-based prejudice in our health care “system.” It is merely a bandaid, at best. In some ways charity care is a peroxide, unroofing previously unappreciated ailments that need equal or greater attention. The answer to indigent care is simple and the first step is to admit to our health care system’s flaws. Putting aside greed, ego and politics, the simple answer is that no one should suffer or die because of lack of money. Every physician I know has a heart-wrenching story of a patient encounter sullied by lack of money.7 No matter how analytical we choose to be about the situation, we can’t escape the inhumanity of turning away a person in need on the basis of their cash value. The rich and powerful will always have a voice. More than helping physicians practice medicine, we also have the responsibility to care for our neighbors in need.

Sources:

1)Franks P, Clancy CM, Gold MR. Health insurance and mortality. Evidence from a national cohort. JAMA. Aug 11 1993; 270(6):737-741; 2) Wilper AP, Woolhandler S, Lasser KE, McCormick D, Bor DH, Himmelstein DU. Health insurance and mortality in US adults. Am J Public Health. Dec 2009;99(12):2289-2295; 3) Sabanayagam C, Shankar A. Income is a stronger predictor of mortality than education in a national sample of US adults. J Health Popul Nutr. Mar 2012;30(1):8286; 4) Institute of Medicine (U.S.). Committee on Monitoring Access to Personal Health Care Services., Millman ML. Access to health care in America. Washington, D.C.: National Academy Press; 1993; 5) U.S. Dept. of Health and Human Services, U.S. Agency for Healthcare Research and Quality. 2005 national healthcare disparities report. Rockville, Md.: USDHHS, Agency for HRQ; 2005; 6) Bierman AS, Magari ES, Jette AM, Splaine M, Wasson JH. Assessing access as a first step toward improving the quality of care for very old adults. J Ambul Care Manage. Jul 1998;21(3):17-26; and 7) Markham MJ. The Inadequacy of 20 Dollars. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jun 4 2012.

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From the EVP's Desk

Leaves of Change Autumn is my favorite time of year. The changing of the leaves, the crisp fall air… OK, so I’m not in Nebraska anymore. But autumn is still a season of change. Kids are back in school, stores are getting ready for the holiday season, and DCMS gets ready to welcome its new President, Dr. Eli Lerner. This has been a year of change at the Duval County Medical Society. In January, Executive Vice President Jay Millson left to join the Florida Academy of Family Practitioners. After nearly 25 years of service, Membership Director Barbara Braddock retired in September. Not to be outdone, Bookkeeper Deana Hadden is retiring on November 29. Deana has been a faithful employee of the DCMS for 30 years! We miss Barbara and Deana and the experience they brought to the Society. As I have navigated my year one as the Executive Vice President for the Society, I am personally grateful for their help every day and for the wisdom and guidance provided by Mr. Millson. Thankfully, not everything is about change. This year, we celebrated the 20th Anniversary of DCMS Director of Operations Patricia Ruscito. Patti is an integral part of the success of DCMS, and I am so proud to work with her every day. We are working on some exciting projects at the DCMS right now. Some you may have already seen and others are still in development stages: • DCMS Strategic Plan – For the first time, the DCMS has a Strategic Plan which will help guide the Society into the future. The mission statement “Helping physicians care for the health of our community” will be something that you see reflected in all DCMS Communications moving forward. • Membership Meetings – We have resurrected general membership meetings for the DCMS. So far we have had events with topics such as marketing your practice and retirement planning. We’ve even had social events for Residents. This is a great new member benefit, and we’d love to hear your ideas for meeting topics. • Social Media – DCMS is active on Facebook and Twitter, connecting physicians and patients with important and timely information important to better healthcare. • Local Media – DCMS has partnerships with several local media outlets for regular content from physicians for patients. Check on Wednesdays in the Florida Times-Union for our Bryan Campbell “Doctors on Call” segment, or tune in to Action News (FOX 30) on the fourth Monday of DCMS Executive Vice President the month between 7:30 and 9a.m. when a DCMS physician answers questions live online and presents some of the most compelling information on the air. • Updated Website – We are striving to make your membership experience better every day. That includes a major update to the DCMS Website scheduled to go live in the first quarter of 2013. Autumn is a time of change, and there is plenty of change to be excited about at DCMS. But the fundamental basics of why we are here have not changed. DCMS is dedicated to being the voice of organized medicine in Northeast Florida. We remain committed to strong advocacy efforts and continue to provide access to free CME opportunities. You, the member, remain the most important element of DCMS. Please let me know how we can help to better serve you in 2013.

(L to R) Bookkeeper Deana Hadden with 30 years of service at DCMS. She is retiring in late November; Former Membership Director Barbara Braddock, retired in September with almost 25 years at DCMS. Director of Operations Patti Ruscito recently celebrated 20 years at DCMS. Thanks to them for their dedication to DCMS.

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Northeast Florida Medicine Vol. 63, No. 3 2012 9

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Residents’ Corner: Mayo Clinic Graduate School of Education Editor’s Note: In an effort to connect more Duval County Medical Society members with residents, in each 2012 issue there will be a “Residents’ Corner” with information about a residency program in the area, details about research being done and/or a list of achievements/accomplishments of the program’s residents. This “Residents’ Corner” features the Mayo Clinic Graduate School of Education.

Overview of Residency Program

Mayo School of Graduate Medical Education was one of the first medical specialty teaching programs in the world, with more than 23,000 alumni of residencies and fellowships programs across all medical and surgical specialties. Opened in 1986, Mayo Clinic in Jacksonville, Fla., was the first extension of Mayo Clinic beyond Rochester, Minnesota. The new Mayo Clinic Hospital, which opened in April 2008, has 214 beds and 22 operating rooms and offers care in 20 medical and 15 surgical specialties, and also includes a full-service Emergency Department. In May 2012, Mayo Clinic announced a $100 million expansion that includes $80 million for two additional floors to be added to the main Mayo Clinic Hospital building, increasing the number of patient beds from 214 to 304, with completion expected in 2014. An additional $16.7 million will be used to finance the construction of a new primary care clinic, expected to open in the summer of 2013 that will house approximately 24 physicians and their supporting staff. Currently at Mayo Clinic Jacksonville, there are more than 160 residents and fellows in training, with the number increasing to greater than 300 to include pharmacy, medical and students from other fields. Residents and fellows are allotted further clinic opportunities at nearby institutions including Nemours Children’s Clinic, Wolfson Children’s Hospital, University of Northern Florida, Shands Jacksonville Medical Center and the Naval Hospital in Jacksonville, FL.

Resident Research

Medical research is highly encouraged and supported by the institution and staff physicians. Trainees are deeply involved in research that not only advances medical knowledge that leads to new therapies, but also quality improvement projects that enhance the efficiency of delivery of patient care. Below are just a few examples of ongoing research. • Gastroenterology Fellow, Victoria Gomez, MD, is currently evaluating bipolar frequency ablation & stenting as palliative measures to treat patients with malignant biliary obstructions. • General Surgery Co-Chief Resident, Cameron Adkisson, MD, is contributing to research studies involving pancreatic resection in MEN-1 and trans-cystic biliary duct placement in liver transplants. • Radiology resident, Ashishkumar Parikh, MD, presented a case report on Ovarian Hyperstimulation Syndrome at the Florida Radiological Society Conference in June 2012. • Family Medicine Co-Chief Resident, Sara Filmalter, MD, evaluated factors associated with long distance race-related lower extremity injuries in marathon runners. • Internal Medicine resident, Jennifer Horsley-Silva, MD, is evaluating knowledge and adherence to Hepatitis B vaccination guidelines in Diabetic patients among primary care physicians.

Resident Community Outreach

Mayo Clinic residents have also pursued endeavors in the local community by providing their time and clinical expertise to those in need. • Family Medicine resident, Annellys Hernandez, MD, has lead the Family Medicine residents to volunteer at the Sulzbacher Center Beaches clinic, with residents having an opportunity to provide outpatient clinic procedure services to an under privileged population. • Family Medicine residents Heidi Hepp, MD & Sara Filmalter, MD, have performed sports physicals for athletes at the Florida School for the Deaf & Blind. With support of organizations like the Duval County Medical Society, trainees at the Mayo Clinic in Jacksonville, FL are afforded limitless opportunities in medicine, education and research.

Mayo History and Focus

From its humble beginnings as a family venture between a father and his two sons, Mayo clinic eventually became America’s first integrated group practice; a model that is now standard in the United States. The Mayo Clinic logo represents three primary focuses; first and primary to the organization is the patient care practice, represented by the central shield & primary statement of the organization that “the needs of the patient always come first.” The other two shields represent the areas of education and research. Dr. Amit Grover is a PGY-3 Resident in the Department of Family Medicine at Mayo Clinic. He is scheduled to graduate in June 2013 and has plans to relocate to the Pacific Northwest to join a multi-specialty outpatient practice with interest in chronic disease management and outpatient clinic procedures.

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Northeast Florida Medicine Vol. 63, No. 3 2012 11

Patient Page* - Rheumatology

Rheumatology: An Inverted Pyramid Approach Rheumatology is a relatively new specialty and covers over 120 rheumatic diseases. These result in fatigue and pain and affect patients of all ages. Although pain and arthritis are the major reasons for most doctors’ visits, the causes could be mechanical, immunological, or neurological. Besides arthritis and its causes, other organs involved could lead to significant disease and even death if not detected early and treated aggressively. Many of the internal organ involvements might go undetected until a very late stage if the evaluating physician was not aware of such a possibility. Clearly we must go beyond diagnosing and treating patients just with “arthritis”, which equals “joint failure”. Rheumatology is holistic in its approach to diseases. The focus is on the immune system dysfunction as a major cause for many diseases regardless of how many organs are involved and at different stages. A revolutionary mind shifting idea in Rheumatology is the Inverted Pyramid Approach. Today, rheumatologists prefer to start with aggressive treatment (tip of the pyramid) because that approach has been found to work best. Then treating these diseases can be lessened toward the end of the treatment period (the broad base of the pyramid); Aggressive and focused to less intense and broader focus like an upside down pyramid. This new approach and all others in this specialty are about the patients. They are the center and focus. This “out-of-the-box” thinking is best for the patients.

Some key statements from Jacksonville rheumatologists show how many diseases are part of the Rheumatology pyramid. • There are many blood (serological) tests available to assist clinicians in the evaluation and diagnosis of patients suspected to have a systemic (affecting the whole body) autoimmune disease (an immune reaction produced by white blood cells or antibodies) process. Understanding the advantages and limitations of each test is crucial to properly assessing the benefits of ordering a particular test for a specific patient…While advances in technology have allowed us to test for multiple serum markers (watery fluid) that have been associated with rheumatic disease, utilization of these tests are most beneficial when ordered in the appropriate clinical setting. (Ronald R Butendieck, Jr., MD; Florentina Berianu, MD; & Andy Abril, MD)

• We have made significant strides over the last decades in the care of lupus patients and have many newer biological drugs and treatments in the research pipelines. (Erick Bournigal, MD and Ghaith Mitri, MD)

•

Chronic arthritis in children is one of the most common rheumatic diseases of childhood. It is also one of the more frequent chronic illnesses of children and an important cause of short and long term disability. (Medical Student Maria Leonor Noboa and Mohammad Ilyas, MD)

•

With better understanding of the biological mechanisms of disease and early introduction of biologic therapy, we are re-writing the books about the natural history and pathogenesis of certain chronic diseases such as Rheumatoid Arthritis. (Karishma Ramsubeik, MD and Ghaith Mitri, MD)

•

Paget’s disease is a nonmalignant disease of the bone. The most common symptom is pain in the affected bones. Neurologic, hearing, vision, cardiac, and oncologic complications may occur. (Emad Naem, MD and Sandra Mesliniene, MD)

•

The last 15 years have seen significant advances in the treatment of Rheumatoid Arthritis (RA)… Although we are encouraged by the present therapeutic developments in rheumatoid arthritis, which represent true advances to benefit patients, vigilance is still necessary by all parties in order to provide early identification of active disease or potentially complicating factors. (Benjamin Wang, MD)

For more detailed information, go to the following websites:

1. 2. 3. 4.

American College of Rheumatology Patient Information at http://www.rheumatology.org/practice/clinical/patients/index.asp Arthritis Foundation at http://www.arthritis.org/what-is-juvenile-arthritis.php Paget’s Disease at http://www.medicinenet.com/pagets_disease/article.htm Lupus Foundation of America, Inc. http://www.lupus.org/newsite/index.html

*Copy and distribute to patients or go to dcsmsonline.org, click "NEFM" and download for patient use.

12 Vol. 63, No. 3 2012 Northeast Florida Medicine

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This Issue’s Focus: Rheumatology

Rheumatology: A Specialty with Ancient Roots Requires New Approaches Rheumatology, despite its ancient roots, is a relatively new specialty. The term “rheuma” appeared in the 1st century as a reference to “a substance that flows”. Rheumatism was first introduced by Dr. G. Baillou in 1642. The terms rheumatology and rheumatologist were coined by Dr. J.L. Hollander and Dr. B.I. Comroe, respectively, in the 1940s. But one of the revolutionary mind shifting ideas in Rheumatology occurred just a couple decades ago. Rheumatologists realized the importance of treating rheumatic diseases with significant morbidities and mortalities aggressively very early in the course of the disease since less aggressive treatment at the beginning only led to a more intense approach later with the results being less effective and more toxic for patients. So we inverted the pyramid and started treating these diseases aggressively at the beginning (tip of the pyramid) and then easing off toward the end of the treatment period. (broad base of pyramid) The cover of this journal, illustrates this inverted pyramid concept. This new approach and all others in this specialty are about the patients. They are the center and focus of all that we do. I learned my best skills from my patients; the art of listening and observing. With advances in IT and sciences coupled with greater life expectancies and more demand for efficiencies, our healthcare system should not be boxed in with logistics, liabilities and old traditions. Instead, we should rethink the message and focus on delivery and outcomes.

Ghaith Mitri, MD, MMM, CPE, FACR Medical Director, PPD

There are over 120 rheumatic diseases and all could manifest with fatigue, pain and are typically multi-systemic. Such conditions could affect patients of all age groups. Although pain and arthritis are the major reasons for doctors’ visits, the causes could be mechanical, immunological, or neurological, etc. Although arthritis could result in significant morbidity, other organs involved could lead to significant morbidity and mortality if not detected early and treated aggressively. Many of the internal organ involvements might go undetected until a very late stage if the evaluating physician was not aware of such a possibility.

Clearly we are beyond diagnosing and treating patients just with “arthritis”, which equals “joint failure”. Rheumatology is holistic in its approach to diseases as multi-systemic with a focus on the immune system dysfunction as a major cause for many diseases regardless of how many organs are involved and at different stages. Inflammation and inflammatory cells and cytokines are essential to all body functions. Not all inflammation is bad, and it is essential for many other non-rheumatic disease processes and health. Rheumatology was one of the pioneering sub-specialties of internal medicine in employing biological therapies with remarkable results in many aggressive diseases. However, despite newer advanced therapies and increased numbers of training programs throughout the country, according to estimates by the American College of Rheumatology, the specialty will see its biggest shortage in the year 2016 due to a much higher number of retiring rheumatologists combined with an aging population. In Jacksonville, Florida we are very fortunate to have some of the best rheumatologists in the country. In 2011 through years of collaborative and collegial efforts, The Mayo Clinic and UF & Shands, launched the two rheumatology fellowship training programs. Some of the faculty in those programs have contributed to this issue. They include: “Rheumatologic Serologies & Inflammatory Markers” by Ronald Butendieck, Jr., MD, Florentina Berianu, MD and Andy Abril, MD; “Rheumatoid Arthritis” by Benjamin Wang, MD; “Systemic Lupus Erythematosus” by Erick Bornigal, MD and myself; “Classification of Juvenile Idiopathic Arthritis”, by Maria Moboa, medical student, and Mohammad Ilyas, MD, “Paget’s Disease” by Sandra Mesliniene, MD, and Emad Naem, MD; and “Severe Neutropenia in the Setting of Rheumatoid Arthritis and Hepatitis C: A review and Case Report” by Karishma Ramsubeik, MD, and myself. While our aging population will require more costly healthcare, we are seeing some diseases, such as allergic conditions and autoimmune like Multiple Sclerosis, Type 1 Diabetes, and Crohn’s disease rising sharply in civilized countries in younger people, while others are declining. There is clearly more focus on the complex interactions between the environment, our genes, and personal choices or habits, which is reshaping our immune system’s experience and tolerance. This is leading to more sophisticated understanding of health, illness, prevention, and early treatment and education. The evolution of medicine will be critical in addressing rising healthcare costs and improving the well-being of our societies. We must embrace new approaches, focus on patients, and be true to our healing profession. www . DCMS online . org

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Rheumatologic Serologies and Inflammatory Markers: A Review Ronald R. Butendieck, Jr., MD; Florentina Berianu, MD and Andy Abril, MD Abstract: There are many serological tests available to assist clinicians in the evaluation and diagnosis of patients suspected to have a systemic autoimmune disease process. Understanding the advantages and limitations of each test is crucial to properly assessing the benefits of ordering a particular test for a specific patient. Commonly ordered tests, such as antinuclear antibodies for lupus and rheumatoid factor for rheumatoid arthritis, have been shown to be relatively nonspecific as they can be seen in a variety of rheumatic and nonrheumatic conditions. Serologic testing in individuals with nonspecific clinical exam findings or other underlying diseases that are known to be associated with a positive test may result in false positives, lead to unnecessary additional evaluation, and cause increased anxiety to patients. While advances in technology have allowed us to test for multiple serum markers that have been associated with rheumatic disease, utilization of these tests are most beneficial when ordered in the appropriate clinical setting.

Acute Phase Reactants The acute phase response occurs in a wide variety of inflammatory conditions, including infections, trauma, malignancies, inflammatory rheumatic conditions and reactions to different drugs. It may accompany both acute and chronic inflammatory states. An acute phase protein is one in which there is a change in plasma levels by 25% during inflammation. Many acute phase proteins are synthesized in the liver via stimulation by cytokines such as interleukin 6, interleukin 1, and tumor necrosis factor (TNF). During inflammation, the serum concentration of proteins such as C-reactive protein (CRP), fibrinogen, alfa1-antitripsine, haptoglobin, ceruloplasmin, and ferritin are elevated and therefore are called positive reactants.1 Some of the proteins have a decreased serum level such as albumin and transferrin and are subsequently called negative reactants. Currently, the most widely used tests to monitor inflammation are CRP and erythrocyte sedimentation rate (ESR). ESR is the rate (mm/hour) at which the erythrocytes fall through plasma when placed in a vertical tube (most used is a Westergren tube). The ESR is an indirect measurement of acute phase protein concentration, especially fibrinogen and it varies with serologic immunoglobulin levels. Any condition that causes an increase in serum concentration of acute phase proteins or hypergamaglobulinemia will cause an elevation of ESR. This occurs by dissipating the inter-red blood cells (RBC) repulsive forces causing RBCs to aggregate together and sediment faster. The RBCs fall more rapidly in anemia and thus increase the ESR. In patients with polycythemia, Address correspondence to: Andy Abril, MD, Chair & Program Director, Division of Rheumatology, Mayo Clinic Jacksonville, Jacksonville, FL. Email: Abril.Andy@mayo.edu.

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the increase in RBC count results in a lower ESR. It also increases with age and in pregnant women. ESR is elevated in patients with kidney disease and this may be due to underlying renal inflammation. A direct relationship between ESR and degree of proteinuria has been noted in patients with glomerular pathology.2 CRP was first identified in patients with streptococcus pneumonia.3 It is synthesized and secreted by hepatocytes when stimulated by a variety of inflammatory cytokines, especially interleukin-6. Under inflammatory conditions, serum CRP levels can rise up to 100-fold over baseline levels.4 CRP is increased during inflammation but the rise and fall in plasma levels is much more abrupt then the ESR. The basal level of CRP is higher among women and increases with age, but it varies less with race and ethnicity.5, 6 Both ESR and CRP can be mildly elevated in obesity, due to increased secretion of IL-6 by adipose tissue.4 There is a widespread use of the terms high-sensitivity CRP [hs-CRP] and low grade inflammation. Low grade inflammation refers to subclinical inflammation that occurs in many conditions, such as obesity, metabolic syndrome and insulin resistance. High-sensitivity CRP levels refer to plasma concentrations of CRP between 3 and 10 mg/L and is regarded as a marker of low grade inflammation. In large prospective studies, increased hs-CRP levels in metabolic syndrome confer greater cardiovascular risk. CRP has been shown to contribute to atherothrombosis and it has been proposed that hsCRP be added for assessment of the risk of future cardiovascular event.7, 8 The measurement of ESR and CRP is useful in assessing the presence and intensity of inflammation, but the results are not specific to any particular disease. In patients with polymyalgia rheumatica (PMR)/giant cell arthritis (GCA), a marked elevation of ESR/CRP is the hallmark of disease. However, studies showed that up to 20% of patients with PMR and 5% of patients with GCA were found to have normal value of ESRs before glucocorticoid therapy was started. A normal ESR in the appropriate clinical context should not delay glucocorticoid therapy if other criteria for GCA are present, since serious complication of GCA such as blindness or stroke may occur.9, 10 In rheumatoid arthritis (RA) patients, ESR and CRP are used to monitor disease activity and are valuable in assessing disease progression and prognosis. Some patients with inflammatory disorders such as RA, PMR and GCA, may demonstrate symptoms of active disease, but have normal ESR and CRP. Conversely, asymptomatic patients without signs of active disease may have elevated values of ESR and CRP. In these situations, the clinical picture should dictate the decision regarding therapy.1 www . DCMS online . org

Table 1 Recommendations for ANA Use

(adapted 18, 20)

ANA is very useful for the diagnosis: SLE (sensitivity 93%), Systemic sclerosis (sensitivity 85%) ANA is somewhat useful for the diagnosis: Sjogren’s syndrome (sensitivity 48 %), Polymyositis-Dermatomyositis (sensitivity 61%) ANA is a critical part of the diagnostic criteria for: Drug-associated lupus (sensitivity 100%), Mixed connective tissue disease ( diagnosis requires positive ANA), Autoimmune hepatitis ANA is very useful for monitoring or prognosis: Juvenile chronic arthritis (sensitivity 57%), Raynaud’s phenomenon (sensitivity 64%) ANA is not useful or have no proven value for diagnosis, monitoring or prognosis: Rheumatoid arthritis, Multiple sclerosis, Thyroid disease, Infectious disease, Idiopathic thrombocytopenic purpura, Fibromyalgia.

In systemic lupus erythematosus (SLE) patients, ESR may be a useful marker of disease activity and predictor of organ damage, but it is very non-specific. More specific tests to assess disease activity such as anti-double stranded DNA and C3 and C4 levels are preferable. It has long been observed that many patients with active lupus display only modestly elevated or even normal CRP levels during periods of intense disease activity. The lower levels of CRP in lupus patients may result from the ability of interferon-α, which is highly expressed in lupus patients, to inhibit the CRP production in hepatocytes. A number of studies have noted marked elevation of CRP levels (more than 60 mg/L) in patients with active lupus and serositis. Otherwise, marked CRP elevation in patients with lupus may suggest a bacterial infection.11 It has been suggested that CRP itself may contribute to the pathogenesis of SLE. CRP binds apoptotic cell membranes and presumably promotes their phagocytosis. Consistent with the waste-disposal hypothesis, impaired apoptotic-cell clearance in SLE results in accumulation of necrotic cell material with many of the intracellular antigens displayed on the surface of apoptotic cells promoting auto antigens and autoimmunity. CRP, on the other hand, by increasing clearance and phagocytosis of apoptotic cells, may prevent auto-immunity. Parenteral CRP administration in SLE mouse models demonstrated that CRP may ameliorate SLE by delaying onset and progression of nephritis, prolong survival, and reduce level of autoantibodies to DNA.12-15

Antinuclear Antibodies Antinuclear antibodies (ANA) are seen in many rheumatologic conditions as well as in healthy people. ANAs can be found in SLE, Sjogren’s syndrome, mixed connective tissue disease (MCTD), scleroderma, undifferentiated connective tissue disease, and similar diseases. ANAs can also be found in patients with organ-specific autoimmune disease involving the thyroid, liver, or lungs such as Hashimoto’s thyroiditis, Graves’ disease, autoimmune hepatitis, primary biliary cirrhosis, primary autoimmune cholangitis, and idiopathic pulmonary arterial hypertension.1 Serum ANA levels can be elevated in chronic infectious disease such as mononucleosis, hepatitis C, subacute bacterial endocarditis, tuberculosis, and human immunodeficiency virus. ANA may be elevated www . DCMS online . org

in some lymphoproliferative diseases as well.16,17 A positive ANA test may be found in healthy individuals, especially if the patient is a woman, elderly, has a positive family history of connective tissue diseases, or takes medications such as sulfasalazine or isoniazid. Most of these patients never develop SLE or other connective tissue disease and therefore care must be taken when interpreting a positive test. High ANA titers increase the likelihood of antibodies being related to true disease. In these cases, further evaluation with more specific tests is indicated. In some patients with positive high titer ANAs but no clinical symptoms suggestive of an autoimmune disorder a watchful waiting is recommended.1 The American College of Rheumatology (ACR) published recommendations for ANA use (Table 1) after an extensive review of literature. The technique most widely used for ANA screening was the immunofluorescence (IF) test.18 Testing methodology for detection of ANA has changed over the years. Previous tests have included the LE cell prep and IF utilizing rodent organs (e.g. rat or mouse liver or kidney) or cell lines.19 The most commonly used test is human epidermoid carcinoma cell lines (HEp-2). More recently, many laboratories have switched to solid phase immunoassay called multiplex platform. This later technique can screen and process large volumes of clinical specimen more quickly and cheaper than the traditional IF test using fixed Hep-2 cells a substrate.18,20 Testing utilizing HEp-2 cells detect ANAs through IF. The advantage is that both nuclear pattern and titer can be described. In addition, it also displays a variety of autoantigens not present in multiplex ANA tests. However, studies have shown that the particular pattern of nuclear staining has a relatively low sensitivity and specificity for specific autoimmune disorders. Therefore, a positive ANA test in the right clinical setting should be further investigated by testing for extractable nuclear antigens (ENA).1, 21 HEp-2 cells may identify approximately 100-150 possible autoantigens. The sensitivity of the HEp-2 cells IF test for SLE at dilutions of 1:40 and 1:160 is reported as 97% and respectively 95%. A review of literature suggested that 2530 % of healthy controls were reported to have ANA titer of 1:40 and 5% at 1:160 or greater. This frequency increases Northeast Florida Medicine Vol. 63, No. 3 2012 15

with age. Because of high sensitivity of the ANA for SLE, almost all patients with SLE will have a positive ANA test. A negative ANA test helps to rule out lupus.20-25 A literature review of ANA-negative lupus cases showed that in many of the reported patients, the ANA assay substrates were antigenically inadequate, particularly lacking the Ro antigen. It was observed that in the same group of patients, apparently ANA-negative patients became ANA-positive following a change in substrate from rodent tissue to the human epidermoid cell line.26 The solid phase screening kit (multiplex) uses a range of 6 to 15 antigen combinations. The most common antigens tested for include SSA (Ro), SSB (La), Smith, double stranded DNA, topoisomerase I (Scl-70), centromere, Jo-1, and U3-ribonucleoprotein (U-3 RNP). In addition to specific antigens, some kits contain a material extracted from HEp-2 cell nuclei to allow for increased sensitivity. A serum sample is reported as positive if it contains autoantibodies directed against any of the specific antigens. Recent reports suggest that the sensitivity for SLE of the new screening ANA test, is lower compared to IF tests and new cases of ANA negative lupus has been reported.23-25 ACR recommends that laboratories should specify the method utilized for detecting ANAs when reporting their results. If ANA test is negative in a patient with high clinical suspicion for SLE or other connective tissue disease, an indirect IF HEp-2 test should be performed. The indirect IF test remains the gold standard for ANA detection. A thorough history and physical exam remains the best screening test.

Extractable Nuclear Antigens Once a patient is noted to have a positive antinuclear antibody (ANA) test, further investigation to determine the subtype of antigens responsible for the positive ANA titer can be performed by extractable nuclear antigens (ENA) testing. Different subtypes of antigens are associated with different autoimmune diseases and can be supportive in making a diagnosis. The six main antibodies that are tested for in clinical practice include anti-SSA (Ro), anti-SSB (La), anti-smith (Sm), anti-U1-ribonuclear protein (RNP), anti-topoisomerase I (Scl-70), and antisynthetase (Jo-1). Additional antibodies that can be useful in the appropriate clinical setting include testing for anticentromere and myositis-specific antibodies are discussed later. The anti-Sm antibody (Ab) was the first nuclear protein antigen to be described in SLE.27 Although highly specific, it is only seen in only about 25-30% of patients with SLE and is therefore not very useful in ruling out SLE.28 It is often seen with anti-U1-RNP since they both bind similar antigens. Anti-SSA antibodies are associated with Sjogren’s syndrome, SLE, and neonatal SLE. They are found in approximately 70-97% of individuals with primary Sjogren’s syndrome and high titers have shown to be associated with the development of more extraglandular features such as purpura, cutaneous vasculitis, and a demyelinating syndrome resembling multiple sclerosis.28-30 In contrast, only about 10-15% of patients with 16 Vol. 63, No. 3 2012 Northeast Florida Medicine

secondary Sjogren’s syndrome associated with rheumatoid arthritis have positive anti-SSA antibodies. In neonatal lupus, anti-SSA antibodies are passively transferred from the mother and disappear in about 6 months. Anti-SSB antibodies are associated with SLE and Sjogren’s syndrome. Both anti-SSA and anti-SSB antibodies may infrequently be found in other conditions such as scleroderma, rheumatoid arthritis, polymyositis, and mixed connective tissue disease. Anti-U1-RNP is required for the diagnosis of mixed connective tissue disease. As mentioned earlier, it can be found in association with anti-Sm. Anti-Scl-70 is associated with diffuse cutaneous systemic scleroderma (dcSSc). Patients positive for this antibody have been shown to be at higher risk for developing severe interstitial lung disease.31,32 While anti-Scl-70 is a very specific test for dcSSc, its sensitivity is only 28%.9,31 Anti-centromere antibodies are associated with limited scleroderma, formerly referred to as the CREST syndrome (calcinosis, Raynaud’s, esophageal dysmotility, and telangiectasias). While the specificity of the test is very high, approximately 99.9%, sensitivity is low. Anti-Jo-1 antibody is the most common myositisspecific antibody. Their presence has been shown to have a strong association with interstitial lung disease, Raynaud’s phenomenon, arthritis, and a type of dermatitis called “mechanic’s hands”.33,34 Patients who present with a relatively acute onset of classic dermatomyositis with erythroderma and shawl sign may have Anti-Mi-2 antibody positivity.33,35

Rheumatoid Factor In 1940, Waaler and Rose described serum antibodies in patients with rheumatoid arthritis (RA) that possessed the intriguing ability to agglutinate sheep red blood cells. These antibodies are known today as rheumatoid factor (RF) and have been shown to target the Fc portion of IgG. Although the RF IgM subtype is most commonly tested in clinical practice, IgA and IgG subtypes have also been described. The etiology of RF is not fully understood.36,37 RF can be found on the surface of B lymphocytes in healthy human lymphoid tissue; however, it is thought that an antigenic stimulus is required for the selection of high-affinity RF from the host’s natural antibody repertoire as RF.36 Elevation in RF has been described in patients with chronic antigenic exposure, such as in subacute bacterial endocarditis, suggesting that an antibody response to antibodies that have been in contact with microbes may be a stimulus for RF production. Modified IgG may also play a role in RF production and pathogenesis.39,40 Production of RF has also been seen in association with the shared epitope of HLA DRB1*0401 and cigarette smoking.41,42 Although RF has become the routine diagnostic test for evaluating a patient with possible RA, it is not highly specific for RA and can be found in other rheumatic as well as nonrheumatic diseases. Rheumatic diseases that can have a positive RF include Sjögren’s syndrome, mixed connective tissue disease, mixed cryoglobulinemia (types II and III), systemic www . DCMS online . org

lupus erythematosus, and polymyositis/dermatomyositis. Non-rheumatic disorders that can have a positive RF include indolent or chronic infection, such as subacute bacterial endocarditis and hepatitis B or C; inflammatory or fibrosing pulmonary disorders, such as sarcoidosis; malignancy; and primary biliary cirrhosis.43 RF can also be found in up to 4% of young, healthy individuals and its prevalence increases with age despite the absence of a rheumatic disease.44-46 The exact role RF plays in the pathogenesis of RA or other rheumatic diseases is not clear. Identical twins with RA have a high correlation of RF positivity, suggesting a link between the development of RA and RF production.47 However, studies have shown that both patients who have RF-negative RA and RF-positive RA express similar HLA susceptibility alleles, suggesting an RF-independent immunogenetic predisposition to RA in these patients.48,49 Curiously, IgG and IgA RFs are occasionally present in patients with RA in the absence of IgM RF and there is evidence suggesting that IgG, IgA, and 7S IgM RFs are associated with more severe disease independent of HLA alleles that are typically associated with severe disease.50-57 Population studies have suggested that asymptomatic individuals with positive RF may develop RA over time.58,59 However, the utility of testing for RF in a patient without stigmata for rheumatic disease is low and RF has been shown to be a poor screening tool for the future development of rheumatic disease in asymptomatic patients as most will never develop a rheumatological disease.60 The sensitivity of RF for RA has been shown to be as high as 90%, although much lower (26-60%) in population studies including patients with mild disease.61-64 Specificity of RF for RA is reported to be 85%.65 Both, however, are significantly affected by pre-test probability and one should take into account the likelihood that the patient may have another rheumatic or non-rheumatic disease that may result in production of RF. The true positive predictive value of RF testing is unclear. While one study describes a modest positive predictive value among unselected patients with arthralgia and arthritis, it was noted that symptom duration of more than 12 weeks had a higher predictive value than RF.66 In addition, an earlier study did not show positive predictive value of RF in the same type of patients.67 The negative predictive value of RF, however, appears to be relatively high and in one study was shown to be 89 and 85 percent for RA and for any rheumatic disease, respectively.68The RF titer can be useful in assessing a patient. The higher the titer, the higher the specificity of the test; however, the sensitivity of the test decreases. As previously noted, care should be taken in patients with underlying chronic inflammatory disorders as these individuals may have a positive RF as well. Several studies have shown that determining RF status in patients can be helpful when used in the proper context. Patients with RF-positive disease tend to have more aggressive erosive disease and are more likely to develop extra-articular manifestation.69,70 However, studies also note that it is the www . DCMS online . org

combination of RF and the presence of specific HLAsusceptibility genes that have higher correlation with a more severe disease state and therefore RF alone cannot be predictive of disease severity.71 In patients with RF-positive Sjögren’s disease, some clinicians periodically check RF as there is suggestion that the disappearance of RF in these previously RF-positive patients may be a precursor to the development of lymphoma.72 The validity of this practice, however, has not been critically reviewed. The use of rituxumab, a CD-20 B-cell depleting agent, may be less effective than in those with RF-positive RA and may steer a clinician to the use of other agents.73

Anti-citrullinated Peptide Antibodies Testing for Anit-citrullinated peptide antibodies (ACPA) has become common in clinical practice to assist with evaluating individuals with findings suspicious for RA. While anti-cyclic citrullinated peptide antibodies were discovered in the 1960s, high expense and technical complexities prevented its widespread use. Fortunately, advances in technology have facilitated the development of accurate, commercially-available standardized enzyme-linked immunosorbent assay (ELISA) for testing.74 While its sensitivity is similar to RF, studies have demonstrated that ACPA is a more specific test for RA, with specificity usually greater than 90%.75,76 Despite higher specificity, ACPA has been noted to be positive in other rheumatic diseases such as SLE, Sjogren’s, and psoriatic arthritis; however, it is usually present in deforming or erosive disease.77-83 ACPA has also been noted in active tuberculosis and chronic obstructive pulmonary disease.84-86 ACPA is rarely found in patients with HCV infection or cryoglobulinemia and therefore may be more useful than RF in evaluating these types of patients for concomitant RA. Testing for ACPA may be helpful in the workup of early polyarthritis in light of its high specificity for RA.76,87 Detecting ACPA early is especially important as these patients have been shown to be at increased risk for progressive joint damage and it may a reliable marker for the future development of erosive disease and greater radiographic damage.88-92 ACPA testing may also be helpful in evaluating a patient with evolving symptoms that may overlap with other rheumatic diseases such as polymyalgia rheumatic.93 Although both RF and ACPA may precede symptoms of arthritis in individuals who eventually develop rheumatoid arthritis for over a year, there is no data to suggest that there is benefit in testing asymptomatic individuals.59, 94-96

Conclusion Rheumatologic serologies and measurement of inflammatory markers are tools that can be helpful during investigation of certain systemic autoimmune inflammatory diseases in the appropriate clinical setting. Inflammatory markers Northeast Florida Medicine Vol. 63, No. 3 2012 17

may help gauge disease activity in patients with established rheumatic disease, but are nonspecific and can be elevated by other processes including malignancy, infection, trauma, drug reactions, advancing age, pregnancy, and obesity. A high titer ANA is suggestive of true rheumatic disease such as SLE, but if found in isolation without other clinical manifestations, watchful waiting is recommended. The presence of a positive ANA test is nonspecific and may be found in healthy individuals, especially women and the elderly; individuals with a family history of autoimmune disease; and in patients with cancer, organ-specific autoimmune disease, and chronic infections. Once a patient is noted to have a positive ANA and there are clinical manifestations suggestive of an underlying rheumatic disease, testing for extractible nuclear antigens may be helpful in evaluating for specific rheumatic diseases although markers have varying sensitivities and specificities. Rheumatoid factor has commonly been used for the diagnosis of RA, however, it has a low specificity and a positive test can be found in other rheumatic diseases, nonrheumatic processes, and even healthy individuals. Testing for ACPA may be more helpful, therefore, in the workup of a patient with polyarthritis as it has a high specificity for RA. Clinically, the presence of RF and ACPA has been shown to be reliable markers for the development of more aggressive disease. While there are a variety of rheumatologic markers available to the clinician, many are nonspecific and the usefulness of a positive test is based upon the pretest likelihood that the patient has an underlying rheumatic disease. Ordering rheumatologic serology, therefore, should be performed in a judicious manner in the appropriate clinical setting to optimize expected benefit.

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29. Harley JB, Alexander EL, Bias WB, et al. Anti-Ro (SS-A) and anti-La (SS-B) in patients with Sjögren’s syndrome. Arthritis Rheum. 1986;29(2):196.

47. MacGregor AJ, Bamber S, Carthy D, et al. Heterogeneity of disease phenotype in monozygotic twins concordant for rheumatoid arthritis. Br J Rheumatol. 1995;34(3):215.

30. Hummers LK, Krishnan C, Casciola-Rosen L, et al. Recurrent transverse myelitis associates with anti-Ro (SSA) autoantibodies. Neurology. 2004;62(1):147. 31. Reveille JD, Solomon DH, American College of Rheumatology Ad Hoc Committee of Immunologic Testing Guidelines. Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum. 2003;49(3):399. 32. Hu PQ, Fertig N, Medsger TA, et al. Correlation of serum antiDNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis. Arthritis Rheum. 2003;48(5):1363. 33. Love LA, Leff RL, Fraser DD, et al. A new approach to the classification of idiopathic inflammatory myopathy: myositisspecific autoantibodies define useful homogeneous patient groups. Medicine (Baltimore). 1991;70(6):360. 34. Plotz PH, Rider LG, Targoff IN, et al. NIH conference. Myositis: immunologic contributions to understanding cause, pathogenesis, and therapy. Ann Intern Med. 1995;122(9):715.

48. Vehe RK, Nepom GT, Wilske KR, et al. Erosive rheumatoid factor negative and positive rheumatoid arthritis are immunogenetically similar. J Rheumatol. 1994;21(2):194. 49. al-Jarallah KF, Buchanan WW, Sastry A, et al. Seronegative rheumatoid arthritis and HLA-DR4.J Rheumatol. 1994;21(2):190. 50. Gioud-Paquet M, Auvinet M, Raffin T, et al. IgM rheumatoid factor (RF), IgA RF, IgE RF, and IgG RF detected by ELISA in rheumatoid arthritis. Ann Rheum Dis. 1987;46(1):65. 51. Bonagura VR, Wedgwood JF, Agostino N, et al. Seronegative rheumatoid arthritis, rheumatoid factor cross reactive idiotype expression, and hidden rheumatoid factors. Ann Rheum Dis. 1989;48(6):488. 52. van Leeuwen MA, Westra J, van Riel PL, et al. IgM, IgA, and IgG rheumatoid factors in early rheumatoid arthritis predictive of radiological progression? Scand J Rheumatol. 1995;24(3):146. 53. Coughlan RJ, Gordon Y, Clark B, et al. 7S IgM in the sera of patients with arthritis. Br J Rheumatol. 1987;26(2):108.

35. Nimelstein SH, Brody S, McShane D, et al. Mixed connective tissue disease: a subsequent evaluation of the original 25 patients. Medicine (Baltimore). 1980;59(4):239.

54. van Zeben D, Hazes JM, Zwinderman AH, et al. Clinical significance of rheumatoid factors in early rheumatoid arthritis: results of a follow up study. Ann Rheum Dis. 1992;51(9): 1029.

36. Sutton B, Corper A, Bonagura V, et al. The structure and origin of rheumatoid factors. Immunol Today. 2000;21(4):177. 37. Westwood OM, Nelson PN, Hay FC. Rheumatoid factors: what’s new? Rheumatology (Oxford). 2006;45(4):379.

55. Eberhardt KB, Truedsson L, Pettersson H, et al. Disease activity and joint damage progression in early rheumatoid arthritis: relation to IgG, IgA, and IgM rheumatoid factor. Ann Rheum Dis. 1990;49(11):906.

38. Carayannopoulos MO, Potter KN, Li Y, et al. Evidence that human immunoglobulin M rheumatoid factors can Be derived from the natural autoantibody pool and undergo an antigen driven immune response in which somatically mutated rheumatoid factors have lower affinities for immunoglobulin G Fc than their germline counterparts. Scand J Immunol. 2000;51(4):327.

57. Mattey DL, Hassell AB, Dawes PT, et al. Independent association of rheumatoid factor and the HLA-DRB1 shared epitope with radiographic outcome in rheumatoid arthritis. Arthritis Rheum. 2001;44(7):1529.

39. Das H, Atsumi T, Fukushima Y, et al. Diagnostic value of antiagalactosyl IgG antibodies in rheumatoid arthritis. Clin Rheumatol. 2004;23(3):218. 40. Newkirk MM, Goldbach-Mansky R, Lee J, et al. Advanced glycation end-product (AGE)-damaged IgG and IgM autoantibodies to IgG-AGE in patients with early synovitis. Arthritis Res Ther. 2003;5(2):R82. 41. Mattey DL, Dawes PT, Clarke S, et al. Relationship among the HLA-DRB1 shared epitope, smoking, and rheumatoid factor production in rheumatoid arthritis. Arthritis Rheum. 2002;47(4):403. 42. Padyukov L, Silva C, Stolt P, et al. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 2004;50(10):3085. 43. Shmerling RH, Delbanco TL. The rheumatoid factor: an analysis of clinical utility. Am J Med. 1991;91(5):528. 44. Newkirk MM. Rheumatoid factors: what do they tell us? J Rheumatol. 2002;29(10):2034. www . DCMS online . org

56. Cabral D, Katz JN, Weinblatt ME, et al. Development and assessment of indicators of rheumatoid arthritis severity: results of a Delphi panel. Arthritis Rheum. 2005;53(1):61.

58. Halldórsdóttir HD, Jónsson T, Thorsteinsson J, et al. A prospective study on the incidence of rheumatoid arthritis among people with persistent increase of rheumatoid factor. Ann Rheum Dis. 2000;59(2):149. 59. Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004;50(2):380. 60. Symmons DP. Classification criteria for rheumatoid arthritis-time to abandon rheumatoid factor? Rheumatology (Oxford). 2007;46(5):725. 61. Lichtenstein MJ, Pincus T. Rheumatoid arthritis identified in population based cross sectional studies: low prevalence of rheumatoid factor. J Rheumatol. 1991;18(7):989. 62. Mikkelsen WM, Dodge HJ, Duff IF, et al. Estimates of the prevalence of rheumatic diseases in the population of Tecumseh, Michigan, 1959-60. J Chronic Dis. 1967;20(6):351. 63. Cathcart ES, O’Sullivan JB. Rheumatoid arthritis in a New England town. A prevalence study in Sudbury, Massachusetts. N Engl J Med. 1970;282(8):421. Northeast Florida Medicine Vol. 63, No. 3 2012 19

64. Kellgren JH. Epidemiology of rheumatoid arthritis. Arthritis Rheum. 1966;9(5):658. 65. Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007;146(11):797. 66. Green M, Marzo-Ortega H, McGonagle D, et al. Persistence of mild, early inflammatory arthritis: the importance of disease duration, rheumatoid factor, and the shared epitope. Arthritis Rheum. 1999;42(10):2184.

peptide antibodies in primary Sjögren syndrome may be associated with non-erosive synovitis. Arthritis Res Ther. 2008;10(3):R51. 82. Chan MT, Owen P, Dunphy J, et al. Associations of erosive arthritis with anti-cyclic citrullinated peptide antibodies and MHC Class II alleles in systemic lupus erythematosus. J Rheumatol. 2008;35(1):77. 83. Bogliolo L, Alpini C, Caporali R, et al. Antibodies to cyclic citrullinated peptides in psoriatic arthritis. J Rheumatol. 2005;32(3):511.

67. Hülsemann JL, Zeidler H. Undifferentiated arthritis in an early synovitis out-patient clinic. Clin Exp Rheumatol. 1995;13(1):37.

84. lkayam O, Segal R, Lidgi M, et al. Positive anti-cyclic citrullinated proteins and rheumatoid factor during active lung tuberculosis. Ann Rheum Dis. 2006;65(8):1110.

68. Shmerling RH, Delbanco TL. How useful is the rheumatoid factor? An analysis of sensitivity, specificity, and predictive value. Arch Intern Med. 1992;152(12):2417.

85. Kakumanu P, Yamagata H, Sobel ES, et al Patients with pulmonary tuberculosis are frequently positive for anti-cyclic citrullinated peptide antibodies, but their sera also react with unmodified arginine-containing peptide. Arthritis Rheum. 2008;58(6):1576.

69. van der Heijde DM, van Riel PL, van Rijswijk MH, et al. Influence of prognostic features on the final outcome in rheumatoid arthritis: a review of the literature. Semin Arthritis Rheum. 1988;17(4):284. 70. Pruijn GJ, Wiik A, van Venrooij WJ. The use of citrullinated peptides and proteins for the diagnosis of rheumatoid arthritis. Arthritis Res Ther. 2010;12(1):203. 71. Cats A, Hazevoet HM. Significance of positive tests for rheumatoid factor in the prognosis of rheumatoid arthritis. A follow-up study. Ann Rheum Dis. 1970;29(3):254. 72. Gough A, Faint J, Salmon M, et al. Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome. Arthritis Rheum. 1994;37(8):1166. 73. Anderson LG, Talal N. The spectrum of benign to malignant lymphoproliferation in Sjögren’s syndrome. Clin Exp Immunol. 1972;10(2):199. 74. Edwards JC, Cambridge G. Prospects for B-cell-targeted therapy in autoimmune disease. Rheumatology (Oxford). 2005;44(2):151. 75. Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007;146(11):797. 76. Avouac J, Gossec L, Dougados M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review. Ann Rheum Dis. 2006;65(7):845. 77. Qing YF, Zhang QB, Zhou JG, et al. The detecting and clinical value of anti-cyclic citrullinated peptide antibodies in patients with systemic lupus erythematosus. Lupus. 2009;18(8):713. 78. Kakumanu P, Sobel ES, Narain S. Citrulline dependence of anti-cyclic citrullinated peptide antibodies in systemic lupus erythematosus as a marker of deforming/erosive arthritis. J Rheumatol. 2009;36(12):2682. 79. Gottenberg JE, Mignot S, Nicaise-Rolland P, et al. Prevalence of anti-cyclic citrullinated peptide and anti-keratin antibodies in patients with primary Sjögren’s syndrome. Ann Rheum Dis. 2005;64(1):114. 80. Mohammed K, Pope J, Le Riche N, et al. Association of severe inflammatory polyarthritis in primary Sjögren’s syndrome: clinical, serologic, and HLA analysis. J Rheumatol. 2009;36(9):1937. 81. Atzeni F, Sarzi-Puttini P, Lama N, et al. Anti-cyclic citrullinated

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86. Wood AM, de Pablo P, Buckley CD, et al. Smoke exposure as a determinant of autoantibody titre inα₁-antitrypsin deficiency and COPD. Eur Respir J. 2011;37(1):32. 87. Whiting PF, Smidt N, Sterne JA, et al. Systematic review: accuracy of anti-citrullinated Peptide antibodies for diagnosing rheumatoid arthritis. Ann Intern Med. 2010;152(7):456. 88. de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Verpoort KN, et al. Progression of joint damage in early rheumatoid arthritis: association with HLA-DRB1, rheumatoid factor, and anti-citrullinated protein antibodies in relation to different treatment strategies. Arthritis Rheum. 2008;58(5):1293. 89. Lindqvist E, Eberhardt K, Bendtzen K. Prognostic laboratory markers of joint damage in rheumatoid arthritis. Ann Rheum Dis. 2005;64(2):196. 90. Rönnelid J, Wick MC, Lampa J, et al. Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression. Ann Rheum Dis. 2005;64(12):1744. 91. Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007;146(11):797. 92. Meyer O, Labarre C, Dougados M, et al. Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage. Ann Rheum Dis. 2003;62(2):120. 93. Lopez-Hoyos M, Ruiz de Alegria C, Blanco R, et al. Clinical utility of anti-CCP antibodies in the differential diagnosis of elderly-onset rheumatoid arthritis and polymyalgia rheumatica. Rheumatology. (Oxford) 2004; 43:655-657. 94. Aho K, Heliövaara M, Maatela J, et al. Rheumatoid factors antedating clinical rheumatoid arthritis. J Rheumatol. 1991;18(9):1282. 95. Rantapää-Dahlqvist S, de Jong BA, Berglin E, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48(10):2741. 96. Berglin E, Padyukov L, Sundin U. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLADRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res Ther. 2004;6(4):R303. www . DCMS online . org

Rheumatoid Arthritis: Optimizing Clinical Outcomes in Primary Care Benjamin W.E. Wang, MD, FRCPC Abstract: The last 15 years have seen significant advances in the treatment of rheumatoid arthritis (RA). As a result, patients’ short-term symptoms, long-term functional status, as well as comorbidity and even mortality have improved. With the advances in rheumatoid arthritis treatment, the clinician should be aware of several key clinical points that will assist to optimize clinical outcomes. This paper seeks to provide physicians with a practical overview of these points with the goal of improving the patient’s long-term prognosis. The key points include the early diagnosis and referral of patients with suspected RA, clearly defining treatment goals, recognizing infections under the influence of immunosuppression, preventing the development of significant comorbidities that frequently accompany rheumatoid arthritis as a chronic inflammatory disease, and recognizing extra-articular manifestations which may develop later on in the course of RA and may signify the need of modification of therapy.

Early Diagnosis and Referral In 2010, the American College of Rheumatology (ACR) revised classification criteria for rheumatoid arthritis.1 As seen in Table 1, (p. 22) these revised criteria include a scoring system in order to classify patients as having definite rheumatoid arthritis. Factors important in identifying rheumatoid arthritis include the presence of multiple joint swelling. In particular, swelling is more specific and contributes to a higher score. In addition, antibody positivity with rheumatoid factor and anti-citrullinated peptide antibody (ACPA, formerly called anti-CCP antibody) are also important. Elevation of the acute phase inflammatory reactants such as C-Reactive Protein (CRP) or erythrocyte sedimentation rate are considered, as are the duration of symptoms. A time period of 6 weeks is an important cut off to delineate potentially self-limited inflammatory forms of arthritis (such as viral-induced arthritis) with chronic inflammatory arthritis. The clinician should also recognize the presence of systemic features which may suggest the onset of a chronic inflammatory condition. Fatigue, anorexia, weight loss, weakness, a generalized sensation of aching and stiffness, and low-grade fever often appear as a prodrome to clinical disease onset and are frequently worse with increases in disease activity. Other signs and symptoms of active rheumatoid arthritis may include the prolongation of morning stiffness of the joints. Though arbitrary, 30 minutes is usually a reliable limit to determine whether someone has true joint inflammation versus noninflammatory joint involvement. Osteoarthritis, a noninflammatory condition, frequently is associated with Address Correspondence to: Benjamin W.E. Wang, M.D., FRCPC, Assistant Professor of Medicine and Consultant, Division of Rheumatology, Mayo Clinic, Jacksonville, FL. Email: wang. benjamin@mayo.edu. www . DCMS online . org

morning joint stiffness lasting just 5 or 10 minutes, while active rheumatoid arthritis may produce stiff joints lasting for hours, or even all day. Certainly, swelling, warmth, and erythema around the joint should alert the clinician to the presence of inflammation, and if available, a synovial fluid analysis which demonstrates inflammatory properties such as reduced viscosity or an elevated number of white cells in the absence of infection is certainly implicative of active disease. The pattern of joint involvement in rheumatoid arthritis is typically symmetrical, and in the early stages may involve only large joints, such as the shoulders and knees, but will typically later involve small joints. Joints of the wrists and hands, most notably the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints are hallmarks of rheumatoid arthritis involvement. Over time, chronic inflammation in the joints may weaken adjacent supporting structures. This weakening, under the force of normal muscular contraction, may cause chronic deformities seen in rheumatoid arthritis, such as the swan-neck or boutonniere deformity. It is hoped that with early identification of disease, and prompt, appropriately aggressive treatment, these long-term deformities and other signs of damage will be a thing of the past. Laboratory studies helpful in the identification of rheumatoid arthritis include a positive rheumatoid factor. Although not uniquely positive in rheumatoid arthritis, moderate to high levels may be a validation of the diagnosis. The clinician should recall that entities such as hepatitis C infection, Hashimoto’s thyroiditis, and other rheumatic connective tissue diseases such as systemic lupus erythematosus, and primary Sjogren’s syndrome may also be associated with a positive rheumatoid factor.2 The use of the anti-cyclic peptide antibody (ACPA) has been a very useful later development in the serologic testing for rheumatoid arthritis. ACPA are produced in the inflamed synovium and are much more specific to the diagnosis of rheumatoid arthritis than the rheumatoid factor. While the rheumatoid factor has been approximately 60-70% specificity for the disease, a greater than 90% specificity has been reported in most studies of ACPA antibodies.3 One should be aware that the CCP antibody may be positive in select other autoimmune diseases, most notably primary Sjogren’s syndrome.4 Antinuclear antibodies (ANA) are positive in approximately 20% of patients with rheumatoid arthritis.2 The clinician should be aware that this does not necessarily mean that the patient has concomitant systemic lupus erythematosus, which is actually a rare development. However, moderate to high levels of antinuclear antibody in a patient with purported Northeast Florida Medicine Vol. 63, No. 3 2012 21

Table 1 2010 ACR/EULAR Criteria for Rheumatoid Arthritis Classification (adapted1) Category

Criteria

Score

A) Joint involvement

1 large joint (shoulders, elbows, hips, knees, and ankles)

2-10 large joints

11-3 small joints (with or without involvement of large joints) (Small joints include MCP (metacarpophalangeal), PIP (proximal interphalangeal), second through fifth MTP (metatarsophalangeal), thumb IP (interphalangeal), and wrists. DIP (distal interphalangeal), first CMC (carpometacarpal), and first MTP are excluded)

4-10 small joints (with or without involvement of large joints)

>10 joints, including at least 1 small joint

Negative RF (rheumatoid factor) and negative ACPA (anti-citrullinated protein antibody)

Low positive RF or low positive ACPA (less than 3x ULN [upper limit of normal])

High positive RF or high positive ACPA (greater than 3x ULN)

Normal CRP (C-reactive protein) and normal ESR (erythrocyte sedimentation rate)

Abnormal CRP or abnormal ESR

<6 weeks

â&#x2030;Ľ6 weeks

B) Serologic findings (at least one test result is needed for classification)

C) Acute phase reactants (at least one test result is needed for classification) D) Duration of symptoms

rheumatoid arthritis should prompt the clinician to do a full serologic and clinical evaluation for the possibility that an alternative connective tissue disease is present, such as Sjogrenâ&#x20AC;&#x2122;s syndrome or lupus.

measurements.6, 7 It is a model that is akin to the treatment of a newly diagnosed malignancy; aggressive combination therapy with a goal of remission has been shown to lead to the best long-term outcomes.8

Other laboratory tests such as the presence of a normocytic anemia, the anemia of chronic inflammation, may be present. Elevation of inflammatory markers such as the erythrocyte sedimentation rate, C-reactive protein, and other acute phase reactions such as thrombocytosis, or elevations of ferritin may also be present.

Treatment Goals

As listed in Table 2, (p. 23) there are a number of clinical and laboratory factors that portend to a worse prognosis with rheumatoid arthritis.5 If these are present, prompt referral to a specialist with the aim of instituting aggressive therapy should take place in order to salvage joint structure and function and long-term physical function. Some adverse prognostic factors include lower socioeconomic status and educational levels, high level of disease activity, disability at disease onset and smoking. Immunologic factors such as the presence of rheumatoid factor or ACPA at high levels are also indicators of a worse prognosis or the early presence of radiographic joint erosions. It is now known that early treatment that is aggressive, often using combinations of disease modifying antirheumatic drugs, combined with close monitoring of response, leads to a better long-term outcome than more conservative 22 Vol. 63, No. 3 2012 Northeast Florida Medicine

There are a number of treatment goals in the management of rheumatoid arthritis, both in the short term and in the long-term. Certainly, the reduction of pain, stiffness, and swelling is an important short-term goal in order for the patient to maintain physical function, employability, and quality of life. However, there are a number of important long-term treatment goals. These include the long-term preservation of joint structure and function, as well as a reduction in comorbidities such as cardiovascular disease and malignancies, which will be discussed later. It is recognized that remission should be an achievable treatment goal in rheumatoid arthritis.9, 10 Using the present armamentarium of available therapeutic agents, including traditional oral disease-modifying antirheumatic drugs (DMARDs) or newer biologic DMARDs, the patient should be treated as aggressively as possible in order to achieve a clinical remission. Studies have shown that there is a definite window of opportunity in which treatment should be initiated if at www . DCMS online . org

Table 2 Adverse Prognnostic Factors in RA (adapted20) • • • • • •

Delay in diagnosis and initiation of treatment with DMARDs Environmental factors - Socioeconomic status, Education, Age at disease onset, Gender, Lifestyle factors (eg, smoking) Disease activity and disability at onset - Number of swollen joints, Particularly high ESR and CRP level, High Health Assessment Questionnaire disablity index scores, HLA-DRB1*04 SE alleles Immunological factors - Presence of RF or ACPA antibodies Radiologic factors - Early radiographic evidence of joint damage Genetic factors - HLA-DRB1*04 SE alleles

all possible, leading to the best long-term results. In most clinical trials, patients with 3 or less years of symptoms are considered in the window of early rheumatoid arthritis. Those patients that have never been exposed to disease modifying treatments such as methotrexate are the best responders to these drugs, and the early use of biologic DMARDs such as tumor necrosis factor (TNF) inhibitors also have been shown to effect a prompt, significant reduction in inflammatory signs and symptoms, thereby leading to better functional outcomes, less structural joint damage, less work disability, and lower rates of premature death.11 Under the care of a rheumatologist, the patient may be first prescribed traditional oral DMARDs, such as those listed in Table 3. Of these, the most commonly used, for reasons of better durability, tolerability, and efficacy, include methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine.12 Other oral drugs have fallen into disfavor, mainly because of a lack of efficacy, and/or intolerable short-term side effects. These include parenteral or oral gold, azathioprine, penicillamine, and cyclosporine. Minocycline is still used as a weak disease modifying agent, but its effect as monotherapy is often inadequate to achieve good long-term control of disease.13

Table 3 Traditional Oral DMARDS in RA Treatment (adapted12)

In common use Methotrexate (MTX) Hydroxychloroquine Leflunomide Sulfasalazine

No longer favored Azathioprine Minocycline* D-penicillamine Parenteral/oral gold Cyclosporine

Methotrexate is still the gold standard in oral DMARD therapy. Doses may be gradually escalated in patients up to a maximum of 25 mg, most often taken once per week as a single oral or self-injected parenteral dose. The concomitant use of folate acid or folinic acid has been shown to reduce some of the common side effects of methotrexate, such as liver enzyme elevation, gastric intolerance, or mucosal ulcers. Patients on methotrexate therapy should be monitored every two months, according to ACR guidelines, for the development of any cytopenias in the blood counts, or for www . DCMS online . org

hepatic enzyme elevation. These are largely reversible changes that respond to dose lowering or temporary suspension of the drug. Leflunomide, a drug analogous to methotrexate, may be used if methotrexate is intolerable. Oral doses of 10-20 mg per day are typical. Diarrhea is a common side effect and sometimes dose or drug limiting.12 Hydroxychloroquine and sulfasalazine are both weaker DMARDs, and are often used in combination with methotrexate or leflunomide. The biologic DMARDs are a revolutionary therapeutic advance in rheumatoid arthritis treatment in the last 15 years. These now include nine approved drugs working through four distinct disease modifying mechanisms. Five are TNF inhibitors, acting to inhibit the action of this central cytokine in RA pathogenesis. Drugs of this family include infliximab, etanercept, certolizumab , adalimumab, and golimumab . The drug abatacept interferes with antigen presentation and T cell activation. Rituximab is an agent designed to deplete activated B cells and thus lower B cell-mediated antibody production, antigen presentation, and cytokine production. A newer agent is tocilizumab (Actemra), an inhibitor of the action of interleukin-6, another central cytokine in RA pathogenesis. Finally, interleukin-1 antagonism is also used, albeit with lesser clinical success, with agents such as anakinra (Kineret).

Identifying and Treating Infections With the biologic DMARDs, serious infections are the most worrisome complication in the practical management of RA patients. Others may include administration reactions with injections, malignancies, demyelinating diseases, hematologic abnormalities, worsening of congestive heart failure, and the induction of further autoimmunity. Fortunately, many of these latter complications are rare.14 While remissions are increasingly possible with contemporary treatment regimens, one must be acutely aware of the possibility of infection. As a precaution, all patients with rheumatoid arthritis who are candidates for biologic therapy should be screened for possible prior exposures to infectious agents of carrier states for infection. The ACR recommends that tuberculosis (TB) screening be carried out prior to drug initiation either by subcutaneous purified protein derivative testing, chest radiography, or one of the serum based interferon assays for TB. In addition, the TNF inhibitors have been associated with reactivation of viral hepatitis, and thus hepatitis B and C prescreening is recommended in these patients.15 It is recognized that the vast majority of infections with biologic DMARD are common and readily identified. These include pneumonia, cellulitis, urinary tract infections, wound infections, septic arthritis, diverticulitis, bronchitis, and herpes zoster infection.14 If the patient develops an infection, their next dose of biologic DMARD should be suspended and the patient investigated and treated with antimicrobial agents as necessary. Once the infection is cleared and the patient stabilized, biologic therapy may resume. However, Northeast Florida Medicine Vol. 63, No. 3 2012 23

should infections become recurrent or frequent, the patient should be advised to stop the biologic therapy and have their therapeutic regimen revised through their rheumatologist. Rare and fatal infections have been described with the use of several biologic agents, including progressive multifocal leukoencephalopathy with the use of rituximab in patients with connective tissue disease, systemic fungal infections, as well as rare forms of mycobacterial infection.14 From the perspective of primary care, equal vigilance is needed no matter which biologic drug is being used.

of joint pain and swelling, it is actually a disease of systemic inflammation and lymphocytic activation. Therefore, other tissues outside the synovium may be affected. Those patients with extra-articular manifestations of rheumatoid arthritis generally have a more severe form of the disease, warranting more aggressive treatment. The observation of the development of extra-articular manifestations over a patient’s disease lifetime is frequently at the hands of the primary care physician, who has the ability to follow the patient over the long-term, often at a greater frequency than the specialist physician.

Management of Comorbid Conditions

Rheumatoid nodules occur in approximately 30% of rheumatoid arthritis patients and are often located on the extensor surfaces in the extremities such as the olecranon process, proximal forearm, or the dorsum of the hands. They may also occur uncommonly in places such as the pleural membranes, meninges, or the pinna of the ear.

Another important advance in RA management is the identification of the high prevalence of certain comorbid conditions. One of these, coronary and cerebrovascular disease, is known to be increased and is a common cause of mortality in patients with rheumatoid arthritis. In the last decade, it has been recognized that patient mortality is increased from 25-40% due to cardiovascular disease in RA over the general population. It has been shown that rheumatoid arthritis is a cardiovascular risk factor in addition to the traditional Framingham risk factors.16 The relative risk of incident cardiovascular events has been reported as high as 3.96 associated with rheumatoid arthritis.16 Indeed, the molecular pathogenesis of atherosclerosis shares many of the inflammatory features that are seen in rheumatoid arthritis.17 The presence of chronic, untreated systemic inflammation serves to accelerate atherosclerosis. In addition to the identification of active rheumatoid arthritis as an important risk factor for cardiovascular disease, the clinician should also be knowledgeable of the patient’s modifiable risk factors overall. Thus, identification and treatment of glucose intolerance, overweight, hypertension, dyslipidemia and smoking should receive attention. In addition to cardiovascular disease, lymphomas are known to be more common in patients with rheumatoid arthritis. This is likely due to the fact of a chronic lymphocytic activation as part of rheumatoid arthritis pathogenesis. Over decades, observational studies have described standardize incidence of ratios of lymphoma increased approximately 2-2.5 in patients with rheumatoid arthritis compared to the general population.18 Indeed, several studies have correlated rheumatoid arthritis inflammatory activity with lymphoma risk, with a proportional increase in lymphoma being observed for those patients with persistently active disease. This makes the case again for the aggressive control of inflammation, not only for preservation of joint function, but also for the reduction in cancer incidence. The same implication has been verified in cardiovascular disease. Reduction of inflammatory activity is associated with a reduction in cardiovascular morbidity and mortality.19

Recognition of Extra-articular Features While rheumatoid arthritis is primarily a disease of the synovial membrane, leading to its principal manifestations 24 Vol. 63, No. 3 2012 Northeast Florida Medicine

Vasculitis is most often of the small vessel variety, causing cutaneous ulcerations, splinter hemorrhages, or infarctions of the periungual tissue. Frequently patients will have complaints of dry eyes and dry mouth or secondary Sjogren’s syndrome produced by lymphocytic infiltration into the lacrymal glands or the major or minor salivary glands. Again, the identification of such extra-articular manifestations usually is correlated with a more severe or uncontrolled form of rheumatoid arthritis, calling for more aggressive treatment. Uncommonly, with sometimes serious consequences, the ocular complications of episcleritis and scleritis may occur. In its most severe form, the scleral tissue may actually perforate, with herniation of the underlying choroid in a condition known as scleromalacia perforans. Neurologic complications include compressive neuropathies at the carpal tunnel, or at Guyon’s canal where ulnar nerve is potentially compressed. Cervical myelopathy from instability of the first and second cervical vertebrae can occur as a long-term consequence of uncontrolled inflammation. This potential complication should receive attention in any RA patient undergoing endotracheal intubation for surgical procedures or endoscopic examinations of the upper airway or gastrointestinal tract. In the lung, rheumatoid nodules may also occur, as may interstitial pulmonary fibrosis. Therefore, complaints of dyspnea should be investigated for the presence of extra-articular complications of rheumatoid arthritis. Rarely, the patient may present with pleural effusions or pericarditis. The finding of these extra-articular manifestations should alert the physician to contact the patient’s rheumatologist for consideration of changing or modifying therapy.

Summary In this article, five key points in the management of rheumatoid arthritis in the primary care setting are presented. With attention to these matters in coordination with the www . DCMS online . org

patient’s rheumatologist, the long short-term and long-term prognosis of the patient may be improved both in terms of musculoskeletal function, extra-articular complications, and major comorbid conditions. Although we are encouraged by the present therapeutic developments in rheumatoid arthritis, which represent true advances to benefit patients, vigilance is still necessary by all parties in order to provide early identification of active disease or potentially complicating factors. Doing so will allow for achieving optimal long-term outcomes for patients with this disease. 1.

References

Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/ European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-2581. Solomon DH, Kavanaugh AJ, Schur PH, American College of Rheumatology Ad Hoc Committee on Immunologic Testing Guidelines. Evidence-based guidelines for the use of immunologic tests: antinuclear antibody testing. Arthritis Rheum. 2002;47(4):434. Avouac J, Gossec L, Dougados M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review. Ann Rheum Dis. 2006;65(7):845. Atzeni F, Sarzi-Puttini P, Lama N, et al. Anti-cyclic citrullinated peptide antibodies in primary Sjögren syndrome may be associated with non-erosive synovitis. Arthritis Res Ther. 2008;10(3):R51. Visser K, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, et al. A matrix risk model for the prediction of rapid radiographic progression in patients with rheumatoid arthritis receiving different dynamic treatment strategies: post hoc analyses from the BeSt study. Ann Rheum Dis. 2010;69(7):1333-1337.

Verstappen SM, Jacobs JW, van der Veen MJ, et al; Utrecht Rheumatoid Arthritis Cohort study group. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis. 2007;66(11):1443-1449.

Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364 (9430):263-269.

Möttönen T, Hannonen P, Leirisalo-Repo M, et al; FIN-RACo trial group. Comparison of combination therapy with single drug therapy in early rheumatoid arthritis: a randomised trial. Lancet. 1999;353(9164):1568-1573.

Schoels M, Knevel R, Aletaha D, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search [published erratum in Ann Rheum Dis. 2011;70(8):1519]. Ann Rheum Dis. 2010;69(4):638-643.

10. Sokka T, Hetland ML, Mäkinen H, et al; Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis Group. Remission and rheumatoid arthritis: data on patients receiving usual care in twenty-four countries. Arthritis Rheum. 2008;58(9):2642-2651. 11. Smolen JS, Han C, van der Heijde DM, et al; Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) Study Group. Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade [published www . DCMS online . org

erratum in Ann Rheum Dis. 2011;70(8):1519]. Ann Rheum Dis. 2009;68(6):823-827. 12. Saag KG, Teng GG, Patkar NM, et al; American College of Rheumatology. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59(6):762-784. 13. O’Dell JR, Haire CE, Palmer W, et al. Treatment of early rheumatoid arthritis with minocycline or placebo: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1997;40(5):842. 14. Andrea Rubbert-Roth. Assessing the safety of biologic agents in patients with rheumatoid arthritis. Rheumatology 2012;51:v38-v47. 15. Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010;69:964-75. 16. del Rincón ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001;44(12):2737-45. 17. Pasceri V, Yeh ET. A tale of two diseases: atherosclerosis and rheumatoid arthritis. Circulation. 1999 Nov 23;100(21):2124-6. 18. Baecklund E, Ekbom A, Sparén P, et al. Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study. BMJ. 1998 Jul 18;317(7152):180-1. 19. Marks JL, Edwards CJ. Protective effect of methotrexate in patients with rheumatoid arthritis and cardiovascular comorbidity. Ther Adv Musculoskelet Dis. 2012; 4(3):149-57. 20. Morel J, Combe B. How to predict prognosis in early rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2005;19:137–146.

Kaufman Award Presented Dr. Linda Sylvester (center, below) received the Admiral Paul Kaufman Award from Dr. Paul Kaufman (left) and Cmdr. Kim Fry (right) at the DCMS/Navy Dinner, September 6, 2012.

DCMS Annual Meeting

The 2012 DCMS Annual Meeting is November 29, 2012 at the Hyatt Regency Jacksonville Riverfront. The 2013 Spring issue of the journal will have full coverage of the meeting: • Inauguration of Dr. Eli Lerner as DCMS President • Numerous awards and recognitions • Interesting Exhibit Hall

Don't miss the Annual Meeting issue!

Northeast Florida Medicine Vol. 63, No. 3 2012 25

Systemic Lupus Erythematosus: A Simplified Guide Erick Bournigal, MD, FACR and Ghaith Mitri, MD, MMM, CPE, FACR Abstract: Systemic Lupus Erythematosus (SLE) is the prototypical

autoimmune disease associated with autoantibody production and immune complex deposition. These syndromes (such as SLE, Sjogren’s, autoimmune myopathies, systemic sclerosis, and mixed connective tissue disease) are almost all associated with positive antinuclear antibodies (ANAs) and tend to affect mostly females of reproductive age with the blood vessels in multiple organs (such as the skin, joints, nervous system, kidney, muscles, etc.) as the primary target. Historically, any suppression of the immune system was helpful in treating flare-ups, but drug toxicities posed a significant problem. Despite the significant overlap among these syndromes, a more precise diagnosis became critical when using more targeted therapies and for better outcomes. SLE is not rare but tends to be over diagnosed. This is especially true in patients with other autoimmune conditions or in otherwise healthy individuals with vague symptoms of joint pain, fatigue, or atypical rashes especially when a screening ANA is positive, which could be due to multiple other causes. The goal for lupus improved treatment became more precise and earlier diagnosis to differentiate from other similar illnesses. The bright side is that both mortality and morbidity from SLE improved significantly with earlier and aggressive evidence based treatment, but the hunt is on for early and more precise remedies with improved outcomes. This guide is not to simplify the diagnosis and treatment of SLE, but it is intended to familiarize healthcare care providers with its challenges. Successful management of SLE emphasizes the importance of early, more directed referrals and treatments when indicated.

Epidemiology SLE is a prototypical autoimmune disease associated with autoantibodies (ANA) and immune complexes with strong evidence implicating autoantibodies in tissue damage mediation. However, multiple studies indicate that the most frequent cause of a positive ANA and pain is fibromyalgia rather than SLE. Lupus affects 1 in 2000 individuals with a peak between the ages of 15 – 40 years old and female to male ratio of 6 – 10/ 1. It is polygenetic with several environmental triggers. It is a major cause of morbidity and mortality among other connective tissue diseases. Based on CDC data (1979 – 1998), SLE accounts for 14.5% of all deaths from arthritis conditions, and for 44% for those aged less than 45-years-old with arthritis. The CDC data also suggested a 70% increase in death among black women aged 45 – 64 years old.1 Untreated disease was the number one cause of morbidity and mortality several decades ago, but cardiovascular disease is becoming the number one cause in recent decades. In the USA, death is three times higher in blacks compared to whites. Ethnic definition in the USA data is limited to black and white and based on personal reporting only. In a large prospective European study between 2000 and 2004 there Address Correspondence to: Ghaith Mitri, MD, MMM, CPE, FACR, Medical Director, PPD, Jacksonville, FL. Past Chief, Rheumatology & Clinical Immunology, University of Florida, College of Medicine, Jacksonville, FL. Email:ghaith.mitri@gmail.com. 26 Vol. 63, No. 3 2012 Northeast Florida Medicine

were 12 centers utilizing complex disease assessment tools; death occurred in one third of patients during remission, while two thirds had a mixture of active disease and accrued damage with cardiovascular disease and infections as the most direct causes.2 Non-compliance with treatment proved more likely than under treatment as cause of disease flare-ups. Patients with SLE may have overlap connective tissue diseases such as Sjogren’s syndrome, rheumatoid arthritis, and others. Other patients may not have enough criteria or pathology specific for one syndrome and will be classified as “undifferentiated connective disease.” This is not an “overlap” nor “mixed connective tissue disease”, the latter or which is a specific syndrome coined in 1972 by Sharp and colleagues.3 The survival for SLE patients has improved significantly over the past several decades from 50% at 5 years in 1955 to 85% at 10 years in recent studies. Improved survival can be attributed to better and earlier diagnosis and treatment coupled with better disease assessment and follow- up tools.4,5,6

Diagnosis The challenge of diagnosing Lupus lies in the variance of its presentation. The attempts to objectify the diagnosis has led to charts of criteria and then tables to break down each criteria until these tools can seem barriers to, rather than clarifications to ease, diagnosis. This phenomenon has been facilitated by the relatively common presence of a Antinuclear Antibody (ANA) in 5% of the normal population, coupled with the societal expectation that the doctor uncover the cause of a patient’s suffering, as well as the doctor’s desire to live up to that expectation. Then there have been cultural barriers to making the appropriate non-lupus diagnosis due to societal biases that will leave the appropriately diagnosed patient/family insulted by the non-lupus diagnosis such as fibromyalgia, a more common cause for chronic pain than arthritis, and more commonly associated with a positive ANA. Perhaps unexpectedly, most lupus patients prove to have concomitant fibromyalgia.7,8 In 1982, the American College of Rheumatology (ACR) defined 11 criteria for SLE, which were intended for clinical trials’ inclusion, with four needed to establish the diagnosis. These criteria were further refined by the ACR in 1997.9 After a thorough history and physical examination, the evaluation of a sick patient with chronic fatigue, arthralgia and other non-specific symptoms will require a complete blood count (CBC) with differential, liver and renal functions, urinalysis and indicators for inflammation such as a sedimentation rate and C-reactive protein. The presence of Raynaud’s phenomenon, especially new onset, in a female during her reproductive years should trigger an initial autoimmune evaluation including a screening ANA and further testing if positive. Deciding on how to expand the initial evaluation depends on further history and physical exam findings. www . DCMS online . org

Northeast Florida Sports Concussion Task Force: 2012 Sports Concussion Guidelines The Northeast Florida Regional Sports Concussion Task Force is a group of sports medicine professionals, including: physicians, athletic trainers, neuropsychologists and other clinicians interested in promoting a consensus on the care and management of sports related concussion in our region. This group was facilitated through the Jacksonville Sports Medicine Program (JSMP) and engaged by the Health Planning Council of Northeast Florida. The task force includes representatives of at least four counties surrounding the greater Jacksonville area. The Chair of the task force is Jennifer Roth Maynard, MD from the Mayo Clinic Florida. The work group associated with the following document included: Jennifer Roth Maynard, MD, Kristina DeMatas, DO, Russel Addeo, Ph.D., Michelle Boling, Ph.D., ATC, and Robert Sefcik, ATC. Other members of this document committee included: Leo Alonso, DO; Mary Soha, MD and Louise Spierre, MD. Participants of the Northeast Florida Sports Concussion Task Force included: Alex Moore, MD; Dick Bultmed, MD; Casey McClone, MD; Christopher Rossilli, PhD; Charity Payne, ATC; Dawn Emerick, EdD; Kristina Dematas, DO; Daniel Kantor, MD; Mary Soha, MD; Elsie Carrigan, ARPN; Jeffrey Goldhagen, MD; Jim Mackie, ATC; Jamie Kennedy, ATC; Joe Czerkawski, MD; Louise Spierre, MD; John Lucas, PhD; Michelle Boling, PhD, ATC: Madeline Joseph, MD; Jennifer Maynard, MD; Daniel Montero, MD; Paul Zawatsky, MD; Howard Weiss, DO; Robert Sefcik, ATC; Russell Addeo, PhD; Sina Kasraeian, MD; Walter Taylor, MD; and Tim Lucey, DO.

Introduction

Promoting safety in youth sports is of paramount importance. As many as 3.8 million sports and recreation-related concussions occur in the United States each year.1, 2, 3 A concussion is a brain injury that can occur in any sport, but is more frequently suffered in contact sports such as football, soccer, lacrosse, basketball and ice hockey. Sports concussions make up approximately 9% of all high school athletic injuries, but data is lacking in grade school and middle school athletes. Recent research shows that younger athletes are more susceptible to the detrimental effects of concussion and can take up to 7-10 days longer to recover than adults.4,5 Potential causes of increased dangers of youth concussion may be the plasticity of the immature central nervous system, increased head to neck ratio, thinner cranial bones, and decreased neck muscle strength which decreases the ability to dissipate the force of an impact.6 Studies also point toward a higher incidence of female concussion in comparable sports (eg. soccer, basketball). Females may also report a higher number of symptoms and neurocognitive changes may last longer than males. Reasons for the difference between sexes is still being evaluated, but possible causes include female sex hormones, higher cerebral flow rate and higher cerebral glucose demand.5 Potential long term detrimental effects of concussions sustained during youth sports and throughout the lifespan are still being investigated, but there appears to be a trend of increased risk of neurodegenerative dementia and depression particularly in professional football players.7,8 Expanding publicity of concussion in professional sports has filtered down to the school and community levels prompting recent legislation (HB291) in the state of Florida. This bill mandates school and club level athletics follow concussion guidelines set forth by the Florida High School Athletic Associationâ&#x20AC;&#x2122;s (FHSAA) Sports Medicine Advisory Committee (SMAC). The bill states that the SMAC must create guidelines for education of coaches, parents, athletes, and school teachers and administrators detailing the risks and dangers of concussion. Prior to the season, athletes and parents must sign an informed consent acknowledging receipt and understanding of this education. The FHSAA has also adopted bylaws that mandate any athlete suspected of a concussion must be immediately removed from play, be evaluated, and receive written clearance by a physician prior to return to play. Recognition of the unique dangers of youth sports related concussion inspired a utilization study by the Health Planning Council of Northeast Florida9. A major outcome of this review was the creation of a multidisciplinary team of health care providers, known as Northeast Florida Sports Concussion Task Force, whose objectives include; creation of standardized guidelines, and education and public awareness of youth sport related concussion. For the purpose of these guidelines, we focused on literature that reflected upon the evaluation and management of concussion in youth and adolescents.

Recognition of Concussion

It is imperative that all individuals associated with youth athletics be aware of the definition of concussion and be readily able to recognize the signs and symptoms in order to take appropriate action. As classically defined and upheld by the most recent 2008 International Consensus Statement on Concussion in Sport, a concussion is a functional/ physiologic disturbance in the brain caused by either direct or indirect traumatic force to the head, neck or face (ie direct blow to the head or body causing impulsive forces transmitted to the brain).10 This trauma results in a rapid onset of symptoms that may or may not involve a loss of consciousness, (less than 10% of concussion are associated with a loss of consciousness). However, it is necessary that there Insert

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Table 1 Signs and Symptoms of Concussion Physical

Cognitive

Emotional

Sleep

Headache

Fogginess

Irritability

Change in sleep pattern

Nausea

Difficulty concentrating

Sadness

Sleeping more/less than usual

Fatigue

Confusion

Nervousness

Difficulty falling asleep

Visual disturbances Sensitivity to light or noise

Memory loss Forgetfulness

Emotional lability Drowsiness

Difficulty staying asleep

Balance problems

Feeling slowed down

Dazed

Answers questions slowly

Amnesia

Repeats questions

is some degree of alteration of consciousness (ie dizziness, confusion, mental slowing). With rest, these symptoms usually resolve in a sequential fashion within 7-10 days. However, the latest research in children is showing that symptoms and or cognitive deficits often last longer than adults.4,5 Furthermore, a small subset of individuals who have sustained a concussion may have prolonged post-concussive symptoms that require specialty referral. Signs and symptoms of concussion can be divided into four subsets ; physical, cognitive, emotional, and sleep related (Table 1). Physical symptoms include headache, nausea, fatigue, visual disturbances, sensitivity to light or noise, and balance problems. Cognitive features include feeling mentally slowed down or foggy, difficulty concentrating, confusion, memory loss, or forgetfulness. Emotional changes such as irritability, sadness, or nervousness can occur. Patients may complain of changes in sleep patterns; sleeping more or less than usual or difficulty falling or staying asleep. Athletes may not always be forthcoming in reporting their symptoms for fear of missing play time; being perceived as weak, etc. Therefore, it is essential that parents, coaches, student athletes and other teammates be educated in recognizing these symptoms and understand the importance of notifying an appropriate health care provider if a concussion is suspected (ie certified athletic trainer, team physician, neuropsychologist, primary care or sports medicine physician).

Evaluation

On field evaluation and recognition of concussion is critical to the overall outcome of an athlete’s concussion. Once a concussion is suspected, immediately remove the athlete from play and do not allow him/her to return to play the same day. If there is any question about the nature of the injury, remember “When in doubt, sit them out!” Other key steps to take include: 1. Absolutely NO RETURN TO PLAY SAME DAY AS INJURY 2. Appropriate on-field trauma management is mandatory via CAB’s (Circulation, Airway, Breathing) and stabilization of suspected cervical spine injury (C-spine immobilization, spine board). a. Transportation via Emergency Medical Services (EMS) to the nearest Emergency Department (ED) for the following: 2 Vol. 63, No. 4 2012

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i. Suspected cervical spine injury ii. Prolonged loss of consciousness > 30 seconds iii. Inability of athlete to stand/walk iv. Any focal neurologic symptoms (ie dilated pupil, persistent weakness, numbness or paresthesia, slurred speech) v. Deteriorating symptoms/status vi. Severe or worsening headache vii. Repeated vomiting viii. Seizure activity ix. Unsteady gait 3. If a concussion is suspected, c-spine cleared and neurologic tests normal (ex. able to follow commands, move all 4 extremities, pupil equal); immediately remove the athlete from play and continue evaluation on the sideline. More in depth examination may be done in the training room or locker room to provide a quieter, more controlled environment. A suggested evaluation tool is the Sport Concussion Assessment Tool 2 (SCAT2, go to www.jaxsmp.com) a comprehensive sideline assessment tool that includes symptom scores, cognitive testing and balance evaluation. 4. It is important to educate the athlete, parents and coaches of the concussion injury and the importance of immediate physical and cognitive rest. a. Every effort should be made to contact the athlete’s parents if not present. Use the Concussion Information Sheet (go to www.jaxsmp.com ) to give to parents so they have this information on what to do/what to expect with a concussion. b. Discuss recommendations with the team physician, Certified Athletic Trainer (ATC), coach, athlete, and parent. Do not release information to the press. Reinforce that the athlete must be cleared by a physician (MD/DO) prior to any return to play. c. Do not let the player drive himself/herself home. d. If going home on a team bus, make sure to have the athlete observed by a responsible coach or adult to watch for deteriorating symptoms. e. Make sure the athlete has appropriate follow-up care; either with their primary care physician (PCP) or a Sports Medicine specialist. i. If recommending ED transport, emphasize Insert

importance of further follow-up with PCP. ii. ED physicians should NOT clear the athlete for return to play. iii. If a CT or MRI of the brain was performed and normal, this does NOT automatically clear the athlete to return to play. As concussions are a functional, not structural injury, it is expected that these standard neuroimaging studies will be normal.

Treatment

In accordance with the 2008 Consensus Statement on Concussion in Sports10, both immediate physical and cognitive rest are the keystones to recovery. We will discuss Northeast Florida Sports Concussion Task Force recommended guidelines for treatment, however it is important to reemphasize that each concussion is unique in its symptoms and recovery, thus an individualized approach must be employed to ensure safe return to play. There are several modifying factors that may impact the severity and duration of symptoms. These should be explored during history taking and be accounted for when developing recommendations for rest, academic accommodations and return to activity. 1. Chronic migraine 2. Attention deficit disorder (ADD or ADHD) 3. Learning disability 4. Depression or anxiety 5. History of multiple or prolonged concussion symptoms 6. History of subsequent concussions taking less force to occur It is recommended that physical rest occur until all concussion-related symptoms resolve. This, of course, includes refraining from practice or games of the sport in which they were injured. This also includes physical education class, recess and or physical horseplay at home with friends or siblings. Majerski and colleagues reported retrospective evidence that “athletes that engage in high levels of activity [post-concussion] demonstrate worse neurocognitive performance.”11 Concussions may also cause dysfunction in standard cognition such as verbal and visual memory, comprehension, processing speed, concentration and focus. In such cases, cognitive rest should occur until symptoms have resolved. This includes reading, using computer, video games, texting, watching television or any other activity that involves high demands on specific attentiveness. If an athlete reports “slowed” mentation (thinking) or reaction time is prolonged (>0.70 sec) on neurocognitive testing, restriction of driving should be considered. Often a concussion with symptoms exacerbated by concentration or focusing can adversely affect school performance; in particular reading comprehension, recall, history, math and science. During the acute phase of recovery, academic accommodations should be considered and communicated to school guidance counselors and teachers such as: 1. If the school environment is overwhelming for an athlete with severe symptoms, temporary removal from school or a half-day schedule may be considered. a. Prolonged absence from school may have unfavorable effects on a student athlete’s self-esteem, relationships Insert

2. 3. 4. 5. 6.

with peers and teammates, and mood due to isolation and view of the student athlete as “sick.” Thus titrated reintroduction, as soon as the athlete is able, is recommended. Testing, especially standardized tests, should be postponed until after symptom resolution. Pre-printed notes, open book or untimed testing Decreased work-load Decreased time on computer or on-line work Tutoring service

Academic accommodations should be tailored to the individual athletes needs and a plan should be discussed with parents, athlete, coach, guidance counselor and teachers. Most of our area schools do not have a specific plan for academic accommodations for concussed athletes, therefore, any recommendations suggested must be in writing. Sometimes it may be necessary to contact the individual school principal to determine the accepted procedures.

Neurocognitive Testing

The role of computerized neuropsychological testing continues to expand and be promoted as adding significant clinical value to the overall management of sports concussion.10 According to a survey of 192 ATCs reporting data from high schools throughout the United States, Meehan et al shows the use of computerized neurocognitive testing has increased among high schools from 25.7% in 2008-2009 school year to nearly 40% in 2009-2010.12 Ideally, athletes will have a baseline neurocognitive test (computerized or paper and pencil tests) performed before the athletic season begins to document their unique cognitive profile (ie. baseline brain function) prior to any concussion. This test can then be used as a comparison to a post-concussion test to determine if there has been a clinically significant change in cognitive function. Some of the computerized neuropsychological tests primarily focus on testing four distinct areas of cognition: verbal memory, visual memory, visual processing speed and reaction time. Research has shown that schools utilizing neurocognitive testing were often not interpreted by a neuropsychologist, and were more likely to have these tests interpreted by a physician or ATC with physician guidance.12 The physician interpreting the test must be appropriately trained in order to safely and effectively utilize the results for management of concussion and may be assisted by consultation with a neuropsychologist. Although some experts recommend testing a concussed athlete only after symptoms have cleared, there is ongoing research that may make it possible to gauge prognosis based on early results of computerized neurocognitive testing13. The interpreter must take into account the athlete’s history of learning disabilities or attention disorders. These more complex cases represent all the more reason to consult the neuropsychologist to determine how these variables affect interpretation. An athlete’s scores on neuropsychological testing should return to baseline within predetermined reliable change indices (or close to normative data if no baseline test is available) and have resolution of physical symptoms prior to consideration of return to play (RTP). It should be emphasized that neurocognitive assessment should never be used as a sole measurement to return an athlete to play, but rather Northeast Florida Medicine

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Table 2 Return to Play Protocol

Stage

(adapted from 10)

Functional Exercise

Objective

1. No activity

Complete physical and cognitive rest

2. Light aerobic exercise

Walking, stationary cycling, swimming. <70% maximum predicted heart rate. No resistance training

Increase heart rate

3. Sport-specific exercise

Skating drills, running drills. No head impact activities

Add movement

4. Non-contact training drills

More complex training drills, e.g. passing drills in football, lacrosse and ice hockey. May start progressive resistance training

Exercise, coordination, cognitive load

5. Full contact practice

Normal training activities

Restore confidence, assessment of functional skills by coaching staff

6. Normal game play a useful tool in the overall assessment of the athlete who has sustained a concussion.

Return to Play Protocols

A change from prior RTP guidelines is removal of arbitrary designation of days of rest until RTP (ie: 1 week, 1 month). Once an athlete has resolution of symptoms at rest, is off medications used to treat any symptoms associated with this concussive episode, and has resumed normal activities of daily living, including school participation, he/she may begin a supervised graded RTP protocol. (FHSAA form AT18, p. 1, go to www.jaxsmp.com ) If the athlete has the advantage of utilizing baseline neurocognitive testing, these scores must have returned to baseline or to normative data as interpreted by the designated clinician. Most experts now recommend a five step program beginning with light aerobic exercise and progressing to full return to play. Each step should take, at the minimum, 24 hours to complete. If the athlete remains asymptomatic, he/she may progress to the next step. Should any symptoms return during the RTP protocol, the athlete must stop immediately, rest at least 24 hours or until symptoms clear, then re-start at the prior symptom-free step. As advocated by the international Consensus statement on Concussion in Sport, we recommend the following RTP protocol.10 (Table 2) 1. No activity until symptom free at rest 2. Light aerobic exercise a. For example stationary bike, light jogging b. No resistance training at this point. 3. Sport-specific exercise a. Increased aerobic challenge 4. Non contact training drills a. May begin progressive resistance training 5. Full-contact practice 6. Return to play Final clearance of an athlete to return to play is the sole decision of a designated physician that has a firm understanding 4 Vol. 63, No. 4 2012

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Recovery

or training with sports concussion. Once the athlete has completed the above RTP protocol and the physician reviews the completed form, the physician must then complete FHSAA form AT18, p.2. (go to www.jaxsmp.com) stating the athletic is safe to return to full competition. Under no circumstances should the coach, athletic director, or other school official make the determination when the athlete is cleared to RTP with respect to concussion. If an athlete has sustained multiple concussions and/or subsequent concussions are occurring with less force, special consideration must be given when counseling the athlete and parents on safety and practicality of returning to play. These athletes are at higher risk for prolonged and more severe symptoms, possibly with lifelong detrimental cognitive effects. This discussion should involve the player, parent, coach, guidance counselor and physician.

Education & Prevention

Regarding the recognition and treatment of sport-related concussion, the value of an educational initiative cannot be overstated. Target audiences should include health care providers (medical doctors, doctors of osteopathy, certified athletic trainers, physician assistants, nurse practitioners, neuropsychologists), coaches, athletes, parents, teachers and the community at large. Without the recognition of concussion, an athlete may return to play prematurely possibly resulting in long term detrimental cognitive effects, or ultimately death.7 While rare and now considered controversial, second impact syndrome is thought to be the occurrence of a subsequent force to the brain before complete healing from an initial injury. This second impact can cause a cascade of rapid and severe brain swelling, herniation and possibly death.14 Health care providers will have the option to learn more about evaluation and management of concussion by attending courses or reading printed material that provides Continuing Education focusing on concussion. Local primary physicians and pediatricians should rest assured that there are Sports Insert

Medicine physicians, neurologists and neuropsychologists that have specialized training in concussion management. There should be no hesitation to refer to one of these providers should they feel uncomfortable treating an athlete with a concussion. Coaches, certified athletic trainers and team volunteers will have required annual education courses on concussion. The National Federation of High School Athletics video tutorial, “Concussion in Sports- What You Need to Know” is a free 20 minute course that can be accessed at www.nfhslearn.com. Proof of completion of this course should be given to the schools’ athletic director. The Florida High School Athletic Association will also be partnering with local sports medicine entities to provide interactive educational sessions. Each team or organization should have created, and reviewed annually, a team concussion policy in addition to their Emergency Action Plan. In order to participate in organized athletic programs, both parents/guardians and student athletes will be required to review educational information on sports concussions. This material will include a description of the symptoms and signs of a concussion, what to do in case of suspected concussion (“When in doubt, sit them out”), short and long-term risks of concussion, need for medical follow-up and formal written clearance by a physician prior to RTP. The parent/guardian and student-athlete will sign a statement acknowledging receipt and understanding above information.

Summary

Sports concussions will continue to be a significant public health concern. With the latest data showing higher risk and consequence of concussion in female and youth athletes, the Northeast Florida Sports Concussion Task Force has created this document to aid local health care providers, certified athletic trainers, and school officials in the recognition and management of concussion. First and foremost is still immediate removal of an athlete with a suspected concussion from play, with NO return to play the same day. Neuropsychological testing has added value in a comprehensive assessment of the concussed athlete, which includes a detailed history, neurologic exam, and balance testing. Rest, both physical and cognitive, is still the cornerstone of treatment. Resolution of symptoms and neuropsychological testing to baseline must occur before engaging in a closely monitored stepwise RTP protocol. As each concussion and recovery is unique, these guidelines should be tailored for an individualized approach to return the athlete safely to play.

5. Covassin T, Elbin RJ, Harris W, Parker T, Kontos A. The role of age and sex in symptoms, neurocognitive performance, and postural stability in athletes after concussion. Am J Sports Med 2012 Jun;40(6):1303-12. 6. Karlin, A. Concussion in the Pediatric and Adolescent Population: different Population, Different Concerns. PMR. 2011 Oct;3(10 Suppl 2):S369-79. 7. Lehman EJ, Hein MJ, Baron SL, Gersic CM. Neurodegenerative causes of death among retired National Football League players. Neurology 2012; 79:1-1. EPub 2012 Sept 5. 8. Kerr ZY, Marshall SW, Harding HP Jr, Guskiewicz KM. NineYear Risk of Depression Diagnosis Increases With Increasing SelfReported Concussions in Retired Professional Football Players. Am J Sports Med. 2012 Oct;40(10):2206-12. Epub 2012 Aug 24. 9. Health Planning Council of Northeast Florida. Emergency Department and hospital admission rates for youth sports-related concussions: A northeast Florida Utilization Study © Oct 20, 2011. http://www. neflorida counts.org/javascript/htmleditor/uploads/Youth_Sport_Related_ Concussion_Study_FINAL.pdf. Accessed October 7, 2012. 10. McCrory, P., W. Meeuwisse, et al. Consensus statement on concussion in sport - The 3rd international conference on concussion in sport held in Zurich, November 2008. PMR 2009 May;1(5): 406-420. 11. Majerski CW, Mihalik JP, Ren D, Collins MW, Reddy CC, Lovell MR, Wagner AK. Concussion in Sports: Postconcussive activity levels, symptoms, and neurocognitive performance. J AthleticTraining. 2008;43(3):265-274. 12. Meehan, W. P., d’Hemecourt, P. et al. Computerized Neurocognitive Testing for the Management of Sport-Related Concussions. Pediatrics 2012 Jan;129(1): 38-44. 13. Lau B, Collins M, Lovell M. Sensitivity and Specificity of Subacute Computerized Neurocognitive Testing and Symptom Evaluation in Predicting Outcomes After Sports-Related Concussion. Am J Sports Med. 2011:39(6), 1209-1216. 14. McCrory, P. Does second impact syndrome exist? Clin. J. Sport Med. 2001;11:144-9.

JSMP Athletic Screenings August 4 and 11, 2012, the Jacksonville Sports Medicine Program (JSMP) conducted free pre-athletic screenings for middle and high school athletes in Duval County. Over 1,000 students were screened. Some were cleared for sports participation while others were referred for further screening and testing by their primary care physicians. Many medical personnel, including DCMS physicians, volunteer their time and expertise to make sure student athletes are cleared to play sports. Volunteers (L to R) - Shawn McLane, PA student; Justin Hayne, PA student; Stephanie Collins, PA-C and Sasha Regan, PA student from Nova Southeastern University - Jacksonville.

References

1. Langlois JA., Rutland-Brown W., Wald MM. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil. 2006;21 (5):375-378. 2. Marar, M., McIlvain, NM., et al. Epidemiology of Concussions Among United States High School Athletes in 20 Sports. Am J Sports Med. 2012 Apr;40(4):747-55. Epub 2012 Jan 27). 3. Nonfatal traumatic brain injuries related to sports and recreation activities among persons aged ≤19 years: United States, 20012009. Centers for Disease Control and Prevention. Morb Mortal Wkly Rep. 2011 Oct 7;60(39):1337-42. 4. Field, M., Collins, MW., et al. Does age play a role in recovery from sports-related concussion? A comparison of high school and collegiate athletes. J Pediatrics. 2003 May;142(5):546-53. Insert

Students during the screening process with volunteers looking on. Far left and seated is Dr. Stephen Lucie, a founding JSMP member and former DCMS President.

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Fact Sheet on Sports Concussions - Patient Information As many as 3.8 million sports and recreation-related concussions occur in the United States each year. Sports concussions make up approximately nine percent of all high school athletic injuries. Recent research shows that younger athletes are more susceptible to the detrimental effects of concussion and can take up to seven to 10 days longer to recover than adults. Recent legislation (HB291) in the state of Florida mandates that school and club level athletic programs adopt concussion guidelines set forth by the Florida High School Athletic Association (FHSAA) Sports Medicine Advisory Committee (SMAC). The bill highlights the need for educational resources provided to parents, athletes and coaches regarding the risks and dangers of concussion. Prior to the season, athletes and parents must sign an informed consent acknowledging the risks of concussion associated with sports participation (FHSAA form EL3CH).

What is a concussion? Concussion is a brain injury. Concussions, as well as all other head injuries, are serious. They can be caused by a bump, a twist of the head, sudden deceleration or acceleration, a blow or jolt to the head, or by a blow to another part of the body with force transmitted to the head. You can’t see a concussion, and more than 90 percent of all concussions occur without loss of consciousness. All concussions are potentially serious and, if not managed properly, may result in complications including brain damage and, in rare cases, even death. Even a “ding” or a bump on the head can be serious. If your child reports any symptoms of concussion, or if you notice the symptoms or signs of concussion yourself, your child should be immediately removed from play, evaluated by a medical professional and cleared by a medical doctor.

What are the signs & symptoms of concussion? Concussion symptoms may appear immediately after the injury or can take several days to appear. Studies have shown that it takes on average 10-14 days or longer for symptoms to resolve and, in rare cases or if the athlete has sustained multiple concussions, the symptoms can be prolonged. Signs and symptoms of concussion can include: (not all-inclusive) 1. 2. 3. 4. 5. 6. 7. 8. 9.

Vacant stare or seeing stars Lack of awareness of surroundings Emotions out of proportion to circumstances Headache or persistent headache, nausea, vomiting Altered vision Sensitivity to light or noise Delayed verbal and motor responses Disorientation, slurred or incoherent speech Dizziness, including light-headedness, vertigo(spinning) or loss of equilibrium (being off balance or swimming sensation) 10. Decreased coordination, reaction time 11. Confusion and inability to focus attention 12. Memory loss 6 Vol. 63, No. 4 2012

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13. Sudden change in academic performance or drop in grades 14. Irritability, depression, anxiety, sleep disturbances, easy fatigability 15. In rare cases, loss of consciousness

What can happen if my child keeps playing with a concussion or returns too soon? Athletes with signs and symptoms of concussion should be removed from activity (play or practice) immediately. Continuing to play with the signs and symptoms of a concussion leaves the young athlete especially vulnerable to sustaining another concussion. Athletes who sustain a second concussion before the symptoms of the first concussion have resolved and the brain has had a chance to heal are at risk for prolonged concussion symptoms, permanent disability and even death (called “Second Impact Syndrome” where the brain swells uncontrollably). There is also evidence that multiple concussions can lead to long-term symptoms, including early dementia.

What do I do if I suspect my child has suffered a concussion? Any athlete suspected of suffering a concussion should be removed from the activity immediately. No athlete may return to activity after an apparent head injury or concussion, regardless of how mild it seems or how quickly symptoms clear, without written medical clearance from an appropriate health-care professional (AHCP). In Florida, an AHCP is defined as either a licensed physician (MD) or a licensed osteopathic physician (DO). Close observation of the athlete should continue for several hours. You should also seek medical care and inform your child’s coach if you think that your child may have a concussion. Remember, it’s better to miss one game than to have your life changed forever. When in doubt, sit them out.

When can my child return to play or practice? Following physician evaluation, the return to activity process requires the athlete to be completely symptom free, after which time they would complete a step-wise protocol under the supervision of a licensed athletic trainer, coach or medical professional and then, receive written medical clearance of an AHCP. Through the work of the Northeast Florida Regional Sports Concussion Task Force, local physicians who are supporting our youth athletes will have information available to them to help in the management of sports-related concussion. This task force has also prioritized expanding the availability of neuropsychological baseline testing across the region.

Information about the task force can be obtained through the Jacksonville Sports Medicine Program at 904.202.4332. Insert

Trends in Public Health

Injury Prevention and Duval County High School Students Radley Remo, MPH; Thomas Bryant III, MSW, and Robert G. Harmon, MD, MPH Seventy-two percent of deaths among 10-24 year olds in the United States are from motor vehicle crashes, other unintentional injuries, homicide and suicide.1 Public health experts group these four causes of injuries into two categories: unintentional and intentional. Unintentional injures are often wrongly referred to as accidents. The word “accident” implies that the injury/event could not have been prevented and was a result of chance or “an act of God.” Research has shown that accidents can be predictable and preventable.2

felt unsafe at school or on their way to or from school was lower than in 2011. However, when compared to the U.S., Duval County results were higher and significantly higher for students feeling threatened or injured and unsafe at school. Trending in the opposite direction, students who had “ever been bullied on school property” was 17.6%, slightly higher than in 2009 (16.3%) but lower than the U.S. (20.1%). Violence in and around Duval County high schools continues to flourish, placing students at great risk.4

Unintentional injuries include motor vehicle crashes, falls, fires and burns, drowning, poisonings and aspirations. Intentional injuries or “violence” can be defined as the use of physical force or power, threatened or actual, against oneself, another person, or against a group or community, that results in injury, death, psychological harm, mal-development, or deprivation.3 Both types of injuries take a major toll on the lives of our children and young adults.

Intentional risk behaviors related to suicide by high school students are most concerning. In 2011, the prevalence of high school students who “seriously considered attempting suicide” (14.9%) or “made a plan about how they would attempt suicide” (14.7%) increased from 2009, but not significantly. Most alarming was the 2011 statistic related to attempted suicides. Duval County’s prevalence was 12.7%, which was statistically higher than in 2009 (10.0%). It was also statistically significantly higher than for U.S. high school students (7.8%). Although the causes behind these increases are unknown, immediate action is needed to help Duval students.4

The Youth Risk Behavior Survey (YRBS) is a national study of the prevalence of risk behaviors among middle and high school students that contribute to unintentional injuries and violence. The Duval County Public Schools (DCPS), in partnership with the Centers for Disease Control and Prevention (CDC) and the Duval County Health Department (DCHD), conduct a local biennial YRBS as the primary means of monitoring these behaviors in Duval County, Florida. Risk behaviors that contribute to unintentional injuries are frequent among Duval County youth. In 2011, the percentage of Duval County high school students who rarely or never wore a bicycle helmet was 89.7%, virtually unchanged from 2009 with 88.9% but slightly higher than the 2011 U.S. prevalence of 88.8%. The Duval County prevalence of high school students who rarely or never wore a seat belt was 12.9% in 2011, significantly lower than in 2009 (16.1%), but higher than the U.S. (7.7%). When looking at the number of Duval County students who rode with a driver who had been drinking alcohol, there was no significant difference between 2011 and 2009. However, Duval County (28.2%) was statistically significantly higher than the U.S. (24.1%). Although the percentage of Duval County high school students who drove a car or other vehicle when they had been drinking alcohol was lower in 2011 (8.9%) than 2009 (11.1%), it was still higher than the U.S. (8.2%). In each instance, Duval students engage in risky behaviors at a higher percentage than students nationally.4 Risk behavior trends related to violence against another person by high school students were mixed. Locally, in 2011, the prevalence of high school students who were in a physical fight (32.3%), were threatened or injured with a weapon on school property(10.7%), or did not go to school because they Insert

These data are reviewed and shared locally with the community and DCPS’ partners to discuss strategies and programs to reduce risk behaviors. DCPS has a specific department, Safe and Healthy Schools, which addresses many of these issues. Several programs, such as Take a Stand, Lend a Hand, Stop Bully Now!, Zeroing In On Prevention (ZIP) and Health Education, seek to decrease risky behaviors related to injuries and other risky behaviors. Duval County high school students’ prevalence rates of risk behaviors that contribute to injuries and violence are generally higher than for U.S. students. Greater community awareness and action are necessary to impact the increased prevalence of injuries and violence. Public agencies cannot do it alone. The health and safety of our high school students are the responsibility of DCPS and DCHD in partnership with families and many organizations of Duval County. Reducing the rate of unintentional injuries and violence is a community problem. Sources:

MMWR Weekly Report June 8, 2012 Vol. 61, No. 4, pg 2 Accessed September 10, 2012. http://www.cdc.gov/mmwr/ pdf/ss/ss6104.pdf

CDC. Injury Prevention and Control http://www.cdc.gov/ injury/overview/ Accessed September 6, 2012

World Health Organization web-site, Accessed September 10, 2012. http://www.who.int/topics/violence/en/

Duval County YRBS-Violence, Suicide & Safety Behaviors Report. http://www.duvalschools.org. Accessed Sept. 10,2012.

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Insert

Any of the following SLE criteria would prompt the decision to add at least an ANA to the baseline lab evaluation.

Criteria 1-4

Note that 1-4 of the 11 criteria for lupus involve some form of rash or oral ulcers. 1- Malar rash, 2- discoid lesions, 3- photo (light) sensitivity and 4- oral ulcers. These skin manifestations don’t have to be memorized. Remember, lupus oral ulcers can be painless, so look for them. Lupus limited to the skin, though most cases will develop multi-system involvements later on, will often be diagnosed with a consistent biopsy and the lack of other criteria. It is important to note that SLE rash of the hands is typically in between the knuckles on the dorsum side of the fingers, pathologically and histologically identical to the rash of dermatomyositis, which is classically over the knuckles and termed “Gottron’s Papules”. Subacute cutaneous lupus erythematosus is an annular papulosquamous rash often associated with extreme photosensitivity and anti-Ro/SSA antibodies and is usually associated with drug induced lupus with limited systemic involvement and typically no renal involvement.

Criterion 5

Non-erosive arthritis is much more difficult to discern because a complaint of arthritis is synonymous with pain by patients. Certainly the presence of tender joints or their witnessed swelling would lock in this criterion clinically enough to order the ANA. In reality, distinguishing true arthritis from soft tissue pain is somewhat of an art. Many patients with osteoarthritis will have periods of pain in the enlarged PIP and DIP joints of the hand. Many patients with hyper flexible joints will have a generalized puffiness of the hands. The x-ray presence of erosive symmetrical arthritis usually suggests rheumatoid arthritis but may be seen in SLE.

Criterion 6

Pleurisy or pericarditis, which are rarely subtle. Of course, the presence of pleurisy or pericarditis mandates consideration of pulmonary embolus, more serious cardiac disease, possible infection, or malignancy.

Criterion 7

Renal disease: Persistent proteinuria or cellular casts with possibly deteriorating renal function. A new hypertension in the sick patient could be the first indication of lupus renal disorder and the only one that could be noted without labs and urinalysis.

Criterion 8

Seizures or psychosis are the clinical indicators for neuropsychiatric lupus which are attributed to organic dysfunction of SLE. Of course, a history of long standing psychosis or seizures prior to this illness would make a causal relationship more complicated.

Criterion 9

Hematologic disorders such as autoimmune hemolytic anemia, thrombocytopenia, leukopenia and lymphopenia, the last of which is the most typical of SLE. Petechiae are www . DCMS online . org

certainly clinical and suggest thrombocytopenia. Autoimmune hemolytic anemia could be seen in 10% of SLE patients with anemia, but the most common causes are anemia of chronic disease and iron deficiency.

Criteria 10

Immunologic Disorder: Positive anti-dsDNA, or Anti-SM, or antiphospholipid antibodies (IgG or IgM anticardiolipin antibodies or positive tests for lupus anticoagulant), or false positive syphilis testing for at least 6 months (FTA or Treponema Pallidum immobilization). This could be complicated for most non-rheumatologists and a consultation should be considered at this point.

Criteria 11

Positive ANA, which could be negative in SLE. The false negative ANA is less likely these days with more sensitive testing kits and methods. A screening ANA could be negative in SLE especially when testing labs use ELISA or bead assays rather than immunofluorescence tests which have proven more accurate. With the presence of other criteria and enough suspicion, the ANA negative patient should be repeat tested at another lab utilizing more accurate methods. Also, it is important to note that 40 – 50% of renal lupus patients will become ANA negative at end stage renal disease. However, for the majority of patients, the ANA is always positive and does not correlate with disease activity. In contrast the levels of anti-dsDNA, a subset of ANA, may correlate with renal disease activity. Other auto antibodies, ANA subsets, such as anti Ro/ SSA, La/ SSB and RNP and complement levels (C3, C4, and CH50 which usually decline in a lupus flare-up) are also informative. Biopsies of skin, kidney, and sometimes other organs such as lung, meninges, or nervous tissue could be critical for appropriate diagnosis and treatment. Not many other diseases could cause such a spectrum of organ involvement with typical history and clinical features especially when biopsies are highly suggestive or typical for SLE. The differentiation among ANA positive immune complex diseases is often challenging for the experienced clinician, even in the presence of biopsies or pathology reports, especially when specific ANA patterns are not present and the full clinical criteria is not fully established or present. Even in the case of SLE, having all 4 criteria out of 11 present at the same time is rare since some criteria will be gleaned from history and not all active at the time of assessment. Also we have to reaffirm that these criteria were intended for clinical research but are used for diagnosis. However a patient with early SLE documented by positive ANA and positive kidney biopsy most likely has SLE and should be treated based on complex staging despite having only 2 criteria out of the 11 mentioned earlier. Otherwise, the outcome could be severe or even fatal. Such patients should always be managed by a specialist. It is important to remind the reader that “undifferentiated connective tissue disease” is a disease still in evolution or could be Northeast Florida Medicine Vol. 63, No. 3 2012 27

in remission without prior significant pathology or evidence for a specific diagnosis. An “overlap” is when there is enough criteria satisfying more than one diagnosis, which is uncommon, while “mixed connective tissue disease” (MCTD) is a specific diagnosis that has been more completely characterized in recent years and is now recognized to consist of the following core clinical and laboratory features: Raynaud phenomenon, swollen hands, arthritis/arthralgia, acrosclerosis, esophageal dysmotility, myositis, pulmonary hypertension, high level of anti–U1-RNP antibodies, and antibodies against U1-70 kd small nuclear ribonucleoprotein (snRNP), which are specific ANA subsets. This condition shares features of SLE myositis and scleroderma.10,11

Treatment Recent data suggests that many SLE flares are due to noncompliance with treatment rather than aggressive or untreated disease.12,13 To date, treatment and immune suppression in SLE are selected according to the organs involved and pattern rather than the specific diagnosis, which is true for other ANA positive autoimmune connective tissue diseases. However, it is generally accepted and recommended by the entire American and international rheumatology authorities and societies that, unless contraindicated, all lupus patients should be treated with hydroxychloroquine for potential prevention of disease progression, treatment of mild disease, or as an adjunct to more aggressive treatments. An exception is Belimumab, which is the first and only FDA-approved drug for SLE in decades for ANA positive active SLE but not indicated for renal or neurological diseases. Belimumab has limited evidence in African Americans due to study design and lack of data. NSAIDs are also first line in patients with normal renal function. Corticosteroids are preferred first line in flare up. All efforts should be made to taper them off gradually but as quickly as possible, while adding more aggressive evidence based organ specific medications. NSAIDs, hydroxychloroquine, cytotoxic and immune suppressive drugs including corticosteroids require regular specific aggressive monitoring early-on, then periodically. With proper monitoring, the majority of lupus or drug related complications are reversible or prevented. Some complications are easily monitored with regular laboratory tests, but others could take years to develop, such as neuropathies, or several months, such as osteoporosis on high doses of prednisone if not preemptively treated with appropriate doses of bisphosphonates. Special consideration for retinal toxicity with hydroxychloroquine requires baseline and scheduled interval retinal examination by an ophthalmologist or optometrist every 6-12 months. The risk is increased after five years of use and in patients with existing ophthalmic pathology. Patients on high doses of corticosteroids or immune suppressive therapies should always be co-managed with one or more specialists such as rheumatology, neurology, pulmonary, cardiology, nephrology, ophthalmology and others if needed, not just for drug monitoring and risks vs. benefits assessments of current 28 Vol. 63, No. 3 2012 Northeast Florida Medicine

treatments, but also for organ specific disease assessments that might require expert interventions or opinions. Antimalarials such as hydroxychloroquine are the first line treatment especially for skin disease and mild arthritis. A critical point is cigarette smoking, which is associated with an increased risk for cutaneous lupus and decreased response to antimalarial therapy such as hydroxychloroquine.14 Smoking cessation should be encouraged for various reasons, including risk of cardiovascular disease and osteoporosis, increased with SLE and exacerbation of skin disease, among others15 There are several topical agents for cutaneous disease but corticosteroids should be used with extreme caution and very limited duration, no longer than two weeks without further consultation with a specialist. Unfortunately, many SLE patients are maintained on chronic maintenance corticosteroids for fear of unexpected flares despite the definite grim complications of such use, especially at higher doses. The majority of SLE patients with mild to moderate disease will only experience one flare-up per year.16 Such flares could be effectively aborted with short corticosteroids “bursts” of oral or intramuscular doses. The majority remain in remission without any maintenance corticosteroid doses according to the FLOAT study (Flares in Lupus: Outcomes Assessment Trial).17 Mycophenolate mofetil is the preferred drug for lupus nephritis due to its equivalent efficacy with cyclophosphamide and lower rate of adverse events.18,19 However, induction doses and sometimes maintenance with cyclophosphamide are still preferred in some patients with severe disease. Azathioprine is probably as good as mycophenolate mofetil as a remission drug in lupus nephritis.20 Methotrexate is the preferred agent in lupus arthritis especially with limited response to less aggressive treatments, and is a second line agent for cutaneous lupus.21 It is important to remember that many flares are due to noncompliance with treatment due to reasons such as side effects, complexity of disease and treatment plans among others. Many patients with SLE suffer dearly from untreated complications such as cardiovascular disease, chronic renal disease despite remission, or uncontrolled hypertension. Additionally, there is the risk of infection due to excessive immune-suppression, or simply from untreated osteoporosis, among multiple other common but ignored comorbidities or complications. It is very critical that lupus patients have good internists who can address such problems effectively and promptly before seeing the specialists.

Lupus in Pregnancy and Neonatal Lupus Patients with lupus have higher risk pregnancies, magnified if their disease is not well controlled for at least six months prior to conception. Also, some lupus medications are absolutely contraindicated with pregnancy. These patients should be screened and treated for the possibility of an overlap with antiphospholipid syndrome, well known to Continued p. 29

www . DCMS online . org

Continued from p.28

cause pregnancy and fetal complications. Another potential complication despite lack of any clinical disease in the mother is the possibility of neonatal lupus with the worst outcome of fetal heart block. The lupus rash is usually reversible but not the congenital heart block. This could develop in 1-2% of fetuses in mothers with positive anti-Ro/SSA or anti–La/ SSB antibodies with lupus, Sjogren’s syndrome, or no clinical disease at presentation. However, history of a previous fetus with such complication could raise the risk up to 20% in subsequent pregnancies. Those patients, once identified, require very close monitoring and serial fetal echocardiograms with appropriate specialty care and counseling before and during pregnancy.22,23 All lupus patients should consult their rheumatologist and possibly other specialists, if deemed necessary, before planning pregnancy since many flares could be silent during apparent remission.

Conclusion We hope that we were able to simplify some of the ambiguity or confusion around this seemingly simple but elusive, complicated, and silent killer. This review was never intended to simplify the diagnosis nor treatment of lupus patients, which should seldom or never be managed by primary care providers alone. All rheumatologists will require the expertise of other specialists based on organs involved and to coordinate their care with primary care providers as well. Despite the challenges, we have made significant strides over the last decades in the care of lupus patients and many newer biological drugs and treatment modalities are in the research pipelines.

References

Sacks JJ, et al. Report from the CDC. MMWR . May 3, 2002; 51(17):371-374

Nossent J, Cikes N, Kiss E, et al. Current causes of death in systemic lupus erythematosus in Europe, 2000--2004: relation to disease activity and damage accrual. Lupus 2007; 16(5):309-317.

Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. Feb 1972; 52(2):148-59.

Urowitz MB, Gladman DD, Abu-Shakra M, Farewell V. Mortality studies in SLE. III. Improved survival over 24 years. J Rheumatol 1997; 24:1061-5.

Merrell M, Shulman LE. Determination of prognosis in chronic disease, illustrated by SLE. J Chron Dis 1955; 1:12-32.

Bernatsky S, Boivin JF, Joseph L, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum 2006; 54:2550-7.

Akkasilpa S et al. Number of fibromyalgia tender points is associated with health status in patients with systemic lupus erythematosus. J Rheumatol 2005; 32(1)48-50

Taylor J et al. Lupus patients with fatigue: Is there a link with fibromyalgia syndrome? Rheumatology 2000; 39:620-623.

Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus [letter]. Arthritis Rheum 1997;40:1725.

11. Cappelli S, Bellando Randone S, Martinovic D, Tamas MM, Pasalic K, Allanore Y, et al. “To Be or Not To Be,” Ten Years After: Evidence for Mixed Connective Tissue Disease as a Distinct Entity. Semin Arthritis Rheum. Sep 27 2011. 12. Koneru S, Shishov M, Ware A, et al. Effectively measuring adherence to medications for systemic lupus erythematosus in a clinical setting. Arthritis Rheum. 2007; 57:1000-1006. 13. Koneru S, Kocharla L, Higgins GC, et al. Adherence to medications in systemic lupus erythematosus. J Clin Rheumatol. 2008; 14:195-201. 14. Jewell ML, McAuliffe DP. Patients with cutaneous lupus erythematosus who smoke are less responsive to antimalarial treatment. J Am Acad Dermatol. 2000; 42(6):983-987. 15. Miot HA et al. Association between discoid lupus and cigarette smoking. Dermatology 2005; 211:118-122. 16. Petri et al. Definition, incidence and clinical description of flare in systemic lupus erythematosus. A prospective cohort study. Arthritis Rheum 1991b; 34:937-944. 17. Danowski et al. Flares in Lupus: Outcomes Assessment Trial (FLOAT), a comparison between oral methylprednisolone and intramuscular triamcinolone. J Rheumatol 2006; 33(1):57-60. 18. Chan TM et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N Engl J Med. 2000; 343(16):1156-1162. 19. Ginzler EM et al. Mycophenolate mofitel or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005; 353(21):2219-2228. 20. Contreras G et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med. 2004; 350(10):971-980. 21. Sato EI. Methotrexate therapy in systemic lupus erythematosus. Lupus 2001; 10(3):162-164. 22. Jaeggi ET et al. Outcome of children with fetal, neonatal, childhood diagnosis of isolated congenital atrioventricular block. A single institution’s experience of 30 years. J Am Coll Cardiol 2002; 39(1):130-137. 23. Gladman G et al. Fetal echocardiographic screening of pregnancies of mothers with anti-Ro and/or anti-La antibodies. Am J Perinatol 2002; 19(2):73-80.

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10. Yoshida S. Pulmonary arterial hypertension in connective tissue diseases. Allergol Int. Nov 2011; 60(4):405-9.

www . DCMS online . org

Northeast Florida Medicine Vol. 63, No. 3 2012 29

Classification of Juvenile Idiopathic Arthritis Maria Leonor Noboa, Medical Studnet and Mohammad Ilyas, MD Abstract: Chronic arthritis in children is one of the most common

rheumatic diseases of childhood. It is also one of the more frequent chronic illnesses of children and an important cause of short and long term disability. Although it has been customary to refer to this disorder as a single disease, it almost certainly comprises a number of similar entities, characterized by arthritis of the appendicular joints, each of which has distinct modes of presentation and may have the same or different causes. In order to more accurately assess the childhood arthritis and to better understand its etiology, it is necessary to scrupulously define the diseases which cause arthritis in children. In general, criteria for the classification of the idiopathic arthritides of childhood are intended to subdivide childhood onset arthritides in a manner that allows better understanding of their pathogenesis and treatment. 1,2 The purpose of these strict and sometimes confusing subtypes is to stratify patients entered into studies into homogeneous groups.

Classification The classification of childhood arthritis has been problematic for decades.3, 4 In recent years, several changes in the terminology of juvenile arthritis have been proposed. The older terms juvenile rheumatoid arthritis (JRA), used commonly in the United States, and juvenile chronic arthritis (JCA), preferred in Europe, were replaced by the term juvenile idiopathic arthritis (JIA) at meetings of the International League of Associations for Rheumatology (ILAR) in the late 1990s. All nomenclature, including the JIA classification, has shortcomings. Systems will remain imperfect until enough is known to allow classification based upon pathophysiology and genetics rather than phenotypes.

JRA Classification Since the 1940s, juvenile rheumatoid arthritis (JRA) has been the preferred term in the US. This term was an attempt to distinguish between children with a more chronic arthritic course and those with the most common form of arthritis at that time, i.e. acute rheumatic fever. The component terms “juvenile” and “arthritis” are self-explanatory, but the term “rheumatoid” has been problematic.This term has been interpreted by many to imply adult rheumatoid arthritis (RA) occurring in children. This supposition is incorrect, since <10% of children with chronic arthritis have a disease that resembles adult RA from a clinical and immunogenetic perspective. The term “rheumatoid” in these cases simply means “swollen joint,” and antedates the discovery of the association of rheumatoid factor (RF) with RA.5 The criteria for JRA was developed by the American College of Rheumatology (ACR), and was revised as necessary.6 (Table 1). This classification describes three main subtypes of JRA based on clinical features at onset (systemic, polyarticular, and Address correspondence to: Mohammad Ilyas, MD, University of Florida, Shands - Jacksonville. Email: mohammad.ilyas@jax.ufl.edu. 30 Vol. 63, No. 3 2012 Northeast Florida Medicine

Table 1 ACR Revised Criteria/JRA Classification (adapted6) 1. Onset type defined by type of disease in first 6 mo:

a. Polyarthritis: ≥5 inflamed joints b. Oligoarthritis (pauciarticular disease): <5 inflamed joints c. Systemic-onset: arthritis with characteristic fever 2. Exclusion of other forms of juvenile arthritis

pauciarticular) with clearly defined inclusion and exclusion criteria. The requirement that age at onset of arthritis be less than 16 years was criterion based more on practice patterns than on age-related biologic variation in disease. This system was widely accepted and subsequently validated.7 However, these criteria do not account for children with spondylarthritis or psoriatic arthritis, many of whom were thought to have a late-onset form of pauciarticular JRA. The lack of criteria applicable to these patients, in addition to the use of the term “rheumatoid,” has generated most of the controversy.

JCA Classification In 1977 at the European League Against Rheumatism (EULAR) conference on the Care of Rheumatic Children in Oslo, the term juvenile chronic arthritis (JCA) was proposed for the heterogeneous group of disorders that present as chronic arthritis in childhood.8 (Table 2, p.31). The term “chronic” replaced the controversial term “rheumatoid”. This classification system contains similar onset types to the JRA classification, but JCA includes in addition the spondylarthritides and psoriatic arthritis. It does not, however, distinguish between the latter two groups. Within the JCA classification, the term JRA is still used for those patients with polyarticular disease who have positive RF, leading to considerable confusion. Nevertheless, the JCA classification gained wide acceptance in Europe in preference to the JRA classification, although it has never been validated by longitudinal studies.

JIA Classification In 1993 in an effort to overcome the limitations of earlier classification systems, the Pediatric Standing Committee of the ILAR proposed, revised, and further revised criteria for JIA.9-11. (Table 3, p.31). The term juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of several disease subtypes that are characterized by arthritis beginning before the age of 16 years with symptoms persisting for more than 6 weeks. Six diagnostic categories are defined using specific inclusion and exclusion criteria, with the aim of achieving homogeneity within disease and categories and to avoid overlap.12 These categories are similar to those used for the JCA classification www . DCMS online . org

Table 2 EULAR Criteria for a Diagnosis of JCA (adapted8) Type defined by characteristics at onset: a. Pauciarticular: <5 joints b. Polyarticular: >4, rheumatoid factor negative c. Systemic: arthritis with characteristic fever d. Juvenile rheumatoid arthritis: >4 joints, rheumatoid factor positive e. Juvenile ankylosing spondylitis f. Juvenile psoriatic arthritis

system, but with a clearer definition. Additionally, a seventh “undifferentiated” or “other” category is included for patients who do not fulfill criteria for any other category, or fit into more than one category. These JIA criteria still require validation and consensus and will almost certainly be modified further as new evidence for pathogenesis becomes available.13,14 It is the “other” category that has caused perhaps the greatest discussion about the JIA classification; one study of patients in Italy demonstrated that, with strict adherence to these criteria, up to 30% of the authors’ JIA population had to be classified as “other”.15 The frequency of “other” JIA as a diagnosis should be not surprising, however, since one goal of developing these new criteria was to define homogeneous groups in an effort to facilitate research on all JIA patients, especially those who might not meet more rigid classification criteria. Even so, some pediatric rheumatologists, uncomfortable with not being able to classify all patients, have suggested modifications to this classification system.15,16

JIA Subtypes The JIA is subdivided in to seven sub-groups. This classification scheme was developed to facilitate communication regarding epidemiology, therapeutics, and outcomes among physicians globally.17 They are recognized based on the clinical features during the first 6 months of disease. Systemic Arthritis – Systemic onset juvenile idiopathic arthritis (SOJIA) is the only subtype of JIA without a strong age, gender, or HLA association. The systemic signs of fever and rash can precede the arthritis for weeks or even months. For a clear diagnosis, the presence of arthritis is necessary, accompanied or preceded by double quotidian fever (two peaks daily), lasting at least 2 weeks. The febrile episodes are often accompanied by a characteristic discrete, circumscribed, Table 3 ILAR Criteria for JIA (adapted9-11) 1. Systemic 2. Oligoarthritis a. Persistent b. Extended 3. Polyarthritis (rheumatoid factor negative) 4. Polyarthritis (rheumatoid factor positive) 5. Psoriatic arthritis 6. Enthesitis-related arthritis 7. Undifferentiated arthritis: Fits no other category or more than one category

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macular, salmon-colored rash. The transient lesions are distributed most commonly over trunk and proximal extremities, including the axilla and inguinal areas, they are less than 10 mm in size that may be surrounded by a ring of pallor or may develop central clearing, and usually nonpruritic. Arthritis can initially be oligoarticular, but with persistence (within 6 months of systemic features) can result in the more severe polyarticular form, resulting in pronounced disability. Both large and small joints are affected.18 Growth failure is a peculiar feature of systemic-onset JIA, at least during the active course of the disease. Even in the absence of corticosteroid treatment, these patients experience impaired growth velocity. Dysregulated IL-6 production is likely partly responsible for this.19 Diagnosis of systemic JIA is always based on clinical observation, and the differential diagnosis usually includes all different causes of fever of unknown origin including viral and bacterial infections, septicemia, malignancies, Kawasaki syndrome, rheumatic fever, and connective tissue diseases. Laboratory evaluation reveals anemia (which may be severe), leukocytosis, granulocytosis, as well as thrombocytosis; erythrocyte sedimentation rate (ESR) and C-reactive protein levels are also elevated. The Anti-Nuclear Antigen (ANA) titer is rarely positive. However if Macrophage Activation Syndrome (MAS), which is one of the serious complications of juvenile rheumatoid arthritis (JRA) develops, leukopenia and thrombopenia can occur accompanied by highly elevated levels of ferritin, lactate hydrogenase and D-dimers. SOJIA patients have a variable course; the mean period of disease activity is approximately 6 years.20 Predictors of a poor prognosis include an age less than 6 years at diagnosis, disease duration longer than 5 years, IgA levels, and persistent systemic symptoms or the presence of thrombocytosis 6 months into the disease course. Oligoarthritis – The Oligoarthritis is defined as an arthritis that affects fewer than five joints during the first 6 months of the disease. Within this category are two subtypes: persistent oligoarthritis, which does not extend to more than four joints, and extended oligoarthritis, in which active arthritis extends to more than four joints after 6 months of disease.21 Risk factors for extended disease include ankle or wrist arthritis, hand disease, symmetric arthritis, arthritis of two to four joints, elevated erythrocyte sedimentation rate (ESR) and ANA titer.22 Extended disease confers a worse prognosis. Oligoarthritis is typically characterized by early onset, usually affecting children aged 2 to 3 years. The arthritis is asymmetric and predominantly involves the large joints of the lower extremities such as knees and ankles, excluding the hip. The most frequently affected joints in decreasing order are the knees, ankles, elbows and wrists. In approximately one third of patients, only a single joint is affected at disease onset. Monoarticular onset affecting only the knee is common. This is seen in half of all patients and these patients tend to function remarkably well. Diagnosis can be difficult since the signs of joint pain and swelling are not always recognized, and small children may not verbalize their complaints. Children, rather, present with easy fatigability with either cessation or regression in development. Northeast Florida Medicine Vol. 63, No. 3 2012 31

Sequelae include morning stiffness with warmth, painful motion or resisting the full range of motion. Muscle atrophy of affected extremities combined with accelerated growth may occur. A child with unilateral gonarthritis typically presents with a discrepancy in leg length resulting in a flexion and outward rotation of the affected knee. Acute phase reactants are normal or moderately increased, but a high Erythrocyte Sedimentation Rate (ESR) can also occur. Antinuclear antibodies (ANAs) are detected in about 60% of patients. Oligoarthritis predominately affects females; they are at high risk for developing uveitis. The presence of ANAs conveys a risk of iridocyclitis, an inflammation of the iris and ciliary body of the eye.23 Iridocyclitis affects approximately 30% of patients with oligoarthritis. Although iridocyclitis can precede arthritis, it usually manifests itself within the first few years after the onset of arthritis. Due to its insidious and often asymptomatic onset, children with JIA should be screened at regular intervals by slit-lamp examination. Rheumatoid Factor-Negative (RF-) Polyarthritis – This pathology is defined as an arthritis that affects five or more joints during the first six months of the disease.21 Patients often develop polyarthritis in early childhood. This subtype affects girls more frequently than boys and it has a variable prognosis. By definition, immunoglobulin-M rheumatoid factor (IgM-RF) is negative, and this subtype involves multiple large and small joints, very often in a symmetric fashion. The onset can be acute or insidious. Pain, confined movements and morning stiffness are the most prominent symptoms. Some patients with polyarthritis especially those who are ANA positive, could be classified as having oligoarthritis, except that more joints are involved. Other patients present with only slight small joint swelling, but have pronounced stiffness and flexion contractions and a normal ESR. These patients are especially hard to diagnose. Rheumatoid Factor-Positive (RF+) Polyarthritis – This subtype is probably identical to the rheumatoid arthritis seen in adults. RF+ polyarthritis occurs primarily in late childhood and adolescent girls as a symmetric small joint involvement and severe erosive disease. It affects the small joints of the hands and feet including the metacarpophalangeal, proximal interphalangeal and metatarsophalangeal joints. Rheumatoid nodules sometimes appear on the extensor surfaces of the elbows. By definition, the presence of IgM-RF is mandatory and probably represents the early expression of adult rheumatoid arthritis; however, anticyclic citrullinated peptide antibodies may also be of interest since they have been observed in adult patients with rheumatoid arthritis. Enthesitis-Related Arthritis (ERA) – Patients with juvenile ankylosing spondylitis and arthritis associated with inflammatory bowel disease are included in the ERA subtype. This is the only subtype of JIA that affects more males than females, older than 8 years of age, and it comprises approximately 10 to 15% of all patients with JIA. It is characterized by a combination of chronic arthritis of the axial and periphereal skeleton, enthesitis (tenderness at the insertion of a tendon, ligament, joint capsule or fascia to the bone), RF and ANA seronegatively. It has a strong genetic predisposition and most patients express HLA-B27, long known to be associated with arthritis; however, the etiology of enthesitis related arthritis is still unknown.24 32 Vol. 63, No. 3 2012 Northeast Florida Medicine

The hallmarks of the disease are pain, stiffness, and loss of mobility of the back. Involvement of the hip joint, an effect sometimes seen in this subgroup, can progress to include the sacroiliac joints and other joints of the axial skeleton, finally resulting in (juvenile) ankylosing spondylitis.25 Arthritis frequently affects the joints of the lower extremities, and the typical localization of the enthesitis is the calcaneal insertion of the Achilles tendon. Four or fewer joints are usually affected, but the disease can also take a polyarticular course. Extra-articular manifestations include anterior acute uveitis, aortic insufficiency, aortitis, muscle weakness, and low-grade fever. Laboratory data may show mild anemia, a normal to moderately elevated white blood cell count, thrombocytosis and elevated sedimentation rate.26, 27 Psoriatic Arthritis – Psoriatic arthritis is defined as a chronic inflammatory arthritis with psoriasis, with a peak age of onset in mid-childhood. In children, arthritis can precede psoriasis for many years. That is why this subtype is a difficult diagnosis. Often larger joints are affected in an asymmetric fashion, but small joints can have this arthritis, namely the knees and ankles and the small joints of the hands and feet. Proximal interphalangeal joints, distal interphalangeal joints, and the tendon sheath are often inflamed, resulting in the diffuse swelling of the digit known as the “sausage digit”.28 By definition, the presence of dactylitis, nail pitting, onycholysis or a positive family history supports the diagnosis; however, many children classified as having psoriatic arthritis according to the ILAR criteria might be better classified as having oligoarticular disease. Therefore, the definition of juvenile psoriatic arthritis is under scrutiny.25 Laboratory data show elevated acute-phase reactants, anemia of chronic disease, and thrombocytosis, ANA may be positive. Undifferentiated Arthritis – This subgroup includes patients who do not fulfill the criteria of any of the other categories or who would fit into two or more subgroups. This category, therefore, does not represent a separate clinical subgroup.

Conclusion Juvenile idiopathic arthritis is one of the most common rheumatic diseases of childhood and is a significant cause of short and long term disability. The classification of JIA has been modifies over the recent decades. Three primarily classification have been adopted in recent past; first by the American College of Rheumatology (ACR), second by the European League Against Rheumatism (EULAR) conference and third by the International League of Associations for Rheumatology (ILAR). These classification schemes were developed to facilitate communication regarding epidemiology, therapeutics, and outcomes among physicians globally. They are recognized based on the clinical features during the first 6 months of disease. The current JIA classification still has shortcomings and will remain imperfect until enough is known about pathophysiology and genetics of disease.

References

Fink CW. Proposal for the development of classification criteria for idiopathic arthritides of childhood. J Rheumatol 1995; 22:1566.

Petty RE, Southwood TR, Baum J, et al. Revision of the

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proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol 1998; 25:1991.

to improve the efficacy of the Santiago-Durban criteria. J Rheumatol 2001; 28: 456–9.

Cassidy JT: What’s in a name? Nomenclature of juvenile arthritis. A North American view. J Rheumatol Suppl 40:4-8, 1993.

Schneider R, Passo MH: Juvenile rheumatoid arthritis. Rheum Dis Clin North Am 28: 503-530, 2002.

16. Manners P, Lesslie J, Speldewinde D, Tunbridge D. Classification of juvenile idiopathic arthritis: should family history be included in the criteria? J Rheumatol 2003; 30: 1857–63.

Cassidy JT. What’s in a name? Nomenclature of juvenile arthritis: a North American view. J Rheumatol 1993; 20 Suppl: 4–8.

Brewer EJ Jr, Bass J, Baum J, et al. Current proposed revision of JRA criteria. Arthritis Rheum 1977;20 Suppl 2:195-9.

Cassidy JT, Levinson JE, Bass JC, et al. A study of classification criteria for the diagnosis of juvenile rheumatoid arthritis. Arthritis Rheum 1986; 29: 274–81.

European League Against Rheumatism: EULAR Bulletin No. 4: Nomenclature and Classification of Arthritis in Children. Basel, National Zeitung AG, 1977.

Fink CW, and the Taskforce for Classification Criteria. Proposal for the development of classification criteria for idiopathic arthritides of childhood, J Rheumatol 1995;22:1566-9.

10. Petty RE, Southwood TR, Baum J, et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol 1998; 25: 1991–4. 11. Petty RE, Southwood TR, Manners P, et al. International League of Associations of Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004; 31: 390–2. 12. Petty RE. Exclusivity versus the hierarchy, or fear and loathing of the undefined [editorial]. J Rheumatol 2003; 30: 8–9. 13. Fantini F: Classification of chronic arthritides of childhood (juvenile idiopatic arthritis): criticisms and suggestions to improve the efficacy of the Santiago-Durban criteria. J Rheumatol 28: 456-459, 2001. 14. Manners P, Lesslie J, Speldewinde D, et al: Classification of juvenile idiophatic arthritis: should family history be included in the criteria? J Rheumatol 30: 1857-1863, 2003. 15. Fantini F. Classification of chronic arthritides of childhood (juvenile idiopathic arthritis): criticisms and suggestions

17. Petty R E, Southwood TR, Baum J, et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban 1997. J Rheumatol 1998;25:1991-4. 18. Schaller JG. Juvenile rheumatoid arthritis. Pediatr Rev 1980;2(6):163-74. 19. Souza LS, Machado SH, Brenol CV, et al. Growth velocity and interleukin 6 concentrations in juvenile idiopathic arthritis. J Rheumatol 2008;35:2265-2271. 20. Svantesson H, Akesson A, Eberhardt K, et al. Prognosis in juvenile rheumatoid arthritis with systemic onset. A follow-up study. Scand J Rheumatol 1983;12(2):139-44. 21. Petty R E, Southwood TR, Manners P,et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31:390-392. 22. Al-Matar MJ, Petty RE, Tucker LB, et al. The early pattern of joint involvement predicts disease progression in children with oligoarticular (pauciarticular) juvenile rheumatoid arthritis. Arthritis Rheum 2002;46(10):2708-15. 23. Ravelli A, Felici E, Magni-Manzoni S, et al. Patients with antinuclear antibody-posiive juvenile idiopathic arthritis constitutes a homogeneous subgroup irrespective of the course of joint disease. Arthritis Rheum 2005;52:826-832. 24. Taurogg JD: The mystery of HLA-B27: if it isn`t one thing, it`s another. Arthritis Rheum 2007;56:2478-2481. 25. Ravelli A, Martini A: Juvenile idiopathic arthritis. Lancet 2007;369:767-778. 26. Burgos-Vargas R, Petty RE. Juvenile ankylosing spondylitis. Rheum Dis Clin North Am 1992;18(1):123-42. 27. Schaller J, Bitnum S, Wedgwood RJ. Ankylosing spondylitis with childhood onset. J Pediatr 1969;74(4):505-16. 28. Shore A, Ansell BM. Juvenile psoriatic arthritis-an analysis of 60 cases. J Pediatr 1982;100(4):529-35.

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Northeast Florida Medicine Vol. 63, No. 3 2012 33

Paget's Disease of the Bone: Review for Clinicians Emad Naem, MD and Sandra Mesliniene, MD Abstract Paget’s disease (also known historically as osteitis deformans)

is a nonmalignant disease of the bone. It is characterized by accelerated bone resorption followed by an abnormal bone formation and impaired integrity of the affected bone. Both genetic and environmental causes are thought to contribute to its pathogenesis. The majority of Paget disease patients are asymptomatic; however, some patients may present with symptoms depending on the bones involved. The most common symptom is pain in the affected bones. Neurologic, hearing, vision, cardiac, and oncologic complications may occur. Diagnosis is primarily made by bone turnover markers and radiographs. The nitrogen-containing bisphosphonates are currently the treatment of choice.

Definition Sir James Paget, the famous English surgeon and pathologist, was the first to describe five cases of the rare disease which he believed was the result of chronic inflammation of bones, causing mainly deformities of long bones and skull. Therefore, he suggested that “for brief reference, and for the present, it may be called, after its most striking character, Osteitis Deformans”.¹ A lot of new information has been discovered about this disease since 1877, however it retained the name of the Sir Paget’s. Paget’s disease (PD) is characterized by a focal alteration of bone remodeling with increased both resorption and formation in which the normal architecture is replaced by non-organized bone tissue, resulting in bone pain, deformities and fractures in the affected areas and arthritis in the adjacent joints.

Epidemiology PD is the second most common bone disease after osteoporosis. The overall prevalence of PD in the United States was estimated to be around 1% according to NHANES I data, which was derived from pelvic radiographs of general population. The disease had highest prevalence in the group of 65- to 74-year-old, reaching 2.3%, with slight male predominance. The regional distribution suggested the highest prevalence in the Northeast with the lowest prevalence in the South.² Worldwide, the highest prevalence of the disease was noted to be in the United Kingdom (UK) in the 1970s, when it reached 5%. High prevalence was also reported among British migrants to Australia, New Zealand and South Africa (up to 3%). Prevalence rates have fallen by 50% in several of the centers studied in UK, European countries and New Zealand. ³ Interestingly, the incidence of PD has remained fairly stable in the USA according to the database from Mayo Clinic in Rochester, MN, while an increase in severity and neoplastic degeneration of the disease has been noted recently in southern Italy.⁴,⁵ Address Correspondence to: Emad Naem, MD, 12894 Oxford Crossing Dr., Jacksonville, FL 32207. enaem@yahoo.com. 34 Vol. 63, No. 3 2012 Northeast Florida Medicine

Pathogenesis Primary abnormality in PD is increased localized bone resorption which is followed by intense bone formation, in particular, in the bones that are subject to mechanical forces. However, the bone that forms in the lesions is disorganized and has a mosaic pattern with loss of the usual lamellar structure; it has reduced mechanical strength, predisposing patients for developing deformities and pathological fractures. Main cells contributing to this process were believed to be multinucleated giant osteoclasts, which are also found in larger quantities in the pagetic bone lesions.⁶ Multiple studies show, that osteoclast precursors in peripheral blood and pagetic bone marrow are implicated in the pathogenesis. They have increased sensitivity to factors that stimulate bone resorption, such as active form of vitamin D (1,25 dihydroxyvitamin D) and receptor activator for nuclear factor κB (NFκB) ligand (RANKL).⁷,⁸ Moreover, there is data suggesting that osteoblast lineage cells are also abnormal in PD patients. They show increased expression of genes such as interleukin 1, interleukin 6, and dickkopf 1, which could stimulate bone resorption and result in focal abnormalities of bone turnover that are characteristic of the disease.⁹

Etiology The cause of PD is not completely understood, but two hypotheses, viral infection and genetic factors, have been developed to explain the etiology of this disease. Viral hypothesis – The concept of the viral pathogen to be the trigger of disease was brought by observation that osteoclasts from pagetic bone were shown to have nuclear inclusions that resemble viral nucleocapsides .¹⁰ Measles virus from paramyxovirus group was found in the hematopoetic cells of PD patients.¹1,¹² The expression of the measles virus nucleocapsid protein gene in osteoclast precursor cells was found to enhance the ability of these cells to form osteoclasts.¹³ However, this finding is not specific to paramyxovirus proteins since overexpression of the Human T-lymphotropic virus 1 Tax protein also induces a state of increased bone turnover in vivo.¹⁴ Moreover, other study did not find evidence of measles virus in the bone marrow from patients with PD.¹⁵ In addition, similar nuclear structures have been found in the osteoclasts of patients with unrelated illnesses.¹⁶ Due to these conflicting findings the role of paramyxovirus in pathogenesis of PD remains a subject of continued debate. Genetic hypothesis – Roughly 15% of patients have a positive family history.¹⁷ The risk of developing PD has been estimated to be approximately seven times as high in relatives of patients than in the general population.¹⁸ PD is a genetically heterogeneous condition that has been linked to at least eight different www . DCMS online . org

chromosome loci.¹⁹ The most frequently identified mutations are found in the sequestosome 1 gene (SQSTM1), which are believed to explain about 37% of familial forms and 8% of sporadic forms of PD.²⁰ Sequestosome 1 (SQSTM1) encodes p62—a scaffold protein that plays important role in NFκB signaling and is involved in forming signaling complexes that can affect osteoclast formation.²¹ Patients with SQSTM1 mutations have more extensive disease than do those who do not carry mutations, and penetrance has been reported to range between 79–100% by the age of 70 seventh decade of life.²² However, there is evidence that the penetrance is falling; in adults inheriting SQSTM1 mutations from affected parents the disease appears to manifest at least 10 years later and in less severe form compared to their parents.²³ This phenomenon suggests that SQSTM1 mutations may result in disease susceptibility, but not necessarily cause the disease. Moreover, environmental factors influence the disease onset. Several other potential environmental triggers for PD, that have been suggested on the basis of epidemiological studies are: low dietary calcium intake or vitamin D deficiency during childhood, zoonotic infections and occupational exposure to toxins.²²

bone resorption and formation processes are active, but the formation process eventually prevails. The radiographs have lytic and sclerotic appearance and bone formation markers are highly elevated. Replacement of the bone marrow with vascular and fibrous tissue is also seen in this stage. The third, late phase is called “burn out” phase, where osteoclastic activity is minimal and bone sites have osteosclerotic appearance in radiographs. In this stage bone turnover markers usually return to normal. (Figure 1)

Figure 1 Paget's Disease of the Tibia

This figure illustrates the lytic changes, the sclerotic changes and cortical thickening of long bones.

(Reproduced with permission from The Paget Foundation: Diagnosis and Management of Paget's Disease of the Bone. Courtesy of Dr. Pierre Delmas. 2012. New York, NY.)

Genetic testing is available in some European countries, but not widely used. A scenario in which this testing would be beneficial is the screening of asymptomatic first degree relatives of patients with known SQSTM1 mutations. However, one should keep in mind that finding SQSTM1 mutations is not needed for disease confirmation. On the other hand, absence of mutation does not rule out the PD due to heterogeneity of genetics of this disease.²⁴

Classification and Distribution of the Disease According to the number of pagetic lesions, PD is classified into monostotic, when only one bone site is involved and polyostotic, which involves multiple bone sites. A recent study reported overall average of 5.5 bone lesions per patient.²⁵ However, the monostotic form is becoming more common and is reported in 30-40 % of cases. Any bone may be involved in PD, but most common sites are the pelvis (up to 60%), followed by the vertebrae, femur (both up to 35%) and tibia, and skull (both up to 25%).²⁶

Diagnosis The most common presentation of PD is an incidental finding of an elevated serum alkaline phosphatase (AP) or an abnormal radiograph taken in patients who are undergoing investigation for other diseases. Depending on the phase of the pagetic bone activity, several presentations of laboratory and radiological findings could be detected. The initial active bone resorption phase corresponds to osteolytic appearance of the radiographs as well as elevated markers of bone resorption. It is usually followed by mixed phase, when both www . DCMS online . org

Laboratory Since PD is disease of bone remodeling, various bone turnover markers are used to estimate extent and activity of the disease. Bone formation marker AP is the most widely used marker. AP is an inexpensive test and has low inter-assay variability. In case of liver disease, when AP is also elevated for that reason, one should consider obtaining bone specific alkaline phosphatase (BAP). In the untreated state, AP correlates well with the proportion of the skeleton involved, as judged by scintigraphy, however extent of disease can explain only 50% of AP variance and the remaining 50% is explained by disease activity.²⁷ Other formation markers (type I procollagen peptides PINP and P1CP, osteocalcin) and resorption markers such as N (NTX) and C (CTX) telopeptides of type I collagen cross-links, tartrate resistant acid phosphatase 5b (TRAP5b) and cathepsin K provide little useful additional information as shown in several studies regarding diagnosis of PD.²⁷ Study on the performance of bone turnover markers in patients with PD undergoing ibandronate therapy concluded that the most reliable marker in monitoring the response of therapy is also AP and BAP. In addition, PINP showed good performance which exhibited the greatest changes with treatment and on relapse of disease. The best performing Northeast Florida Medicine Vol. 63, No. 3 2012 35

Table 1 Radiographic Findings in Paget's Disease

Phase

Findings

Initial, osteolytic

Long bones: Sharp wedge-shaped leading edge of osteolysis starting from metaphysis to diaphysis (“blade of grass”, “candle flame”) Skull: osteolysis has well defined, oval configuration (“osteoporosis circumscripta”)

Intermediate, mixed lytic-

Cortical thickening, osseous expansion, loss of corticomedullary differentiation and

sclerotic

coarse trabecular markings. Mixed foci are called “cotton-wool” pattern when affecting skull and “picture frame” when affecting the vertebrae.

Late, sclerotic

Diffuse increase in bone density, medullary sclerosis, markedly increased bone size.

resorption marker was NTX which showed abnormal values at baseline in >95% cases, followed by reduction by 15–30% with treatment. However, this reduction was not significant.²⁸

Radiology Conventional radiography and total bone scintigraphy represent the main radiological tests to be considered for PD skeletal localization and extension. PD is associated with wide variety of radiological findings in plain radiographs. (Figure 1) Typically they are distinct for each phase, however all three phases may occur at the same time. (Figure 1, p.35) They are summarized in the Table 1. Computed tomography (CT scan) may be helpful in PD cases when affected regions are difficult to assess with plain radiography such as when neural foramina or facial bones are involved. Also, CT should be considered when radiographic findings are not specific or neoplasm is suspected. MRI has limited utility in PD diagnosis since it may present a confusing picture, therefore its use should be reserved in evaluation neurological complications in PD patients such as spinal cord, spinal nerve roots or cranial nerves compression.²⁹ Radionuclide bone scans using a 99mTc-labelled bisphosphonate tracer are more sensitive than radiographs in detection of PD of bone lesions and are also helpful in defining the extent of the disease. Increased homogeneous tracer uptake is seen secondary to the high perfusion of pagetic bone and high affinity of the tracer to woven bone. In contrast, scintigraphy is less specific than plain radiography since high uptake may be seen in other diseases, including skeletal metastases. Therefore, correlation of bone scan images with radiographs of at least one site is always recommended.²⁹ Bone biopsy is rarely required for diagnosis of PD and may be useful in the presence of radiological figures not easily distinguished from osteosclerotic metastases (e.g. prostatic cancer or Hodgkin’s disease). Also it is needed when there is strong suspicion of the development of osteosarcoma in a PD affected bone. ³⁰ 36 Vol. 63, No. 3 2012 Northeast Florida Medicine

Clinical Features and Complications The majority of PD patients are asymptomatic and diagnosed incidentally during routine blood work or X-rays. They may remain so throughout their lives. On the other hand, many patients have symptoms for long periods before the disease is recognized. ²⁷ Bone pain is a common complaint. Typically it is worse at rest and relieved by movement. Other symptoms caused by complications include pain due to secondary arthritis, pathological fracture (typically in lytic disease in long bones), bone enlargement and deformity. PD in the skull can cause deafness and increasing hat size. In large community studies, PD was statistically associated with increased relative risks for back pain, osteoarthritis, hip arthroplasty, knee arthroplasty, fracture and hearing loss and with reduced quality of life.³¹-³³ Table 2 (p. 37) summarizes the complications of PD with their clinical manifestations.³⁰

Treatment Medical Treatment – The main indication for medical treatment of Paget’s disease of the bone is bone pain that is thought to be due to increased metabolic activity (as determined by bone turnover markers or bone scintigraphy). Treatment is also indicated in asymptomatic Paget patients with active disease at sites where complications could occur (eg, skull, spine, weight-bearing bones, and bone abutting a joint). ³⁴ Pagetic bone pain responds well to antiresorptive agents such as bisphosphonates and calcitonin but can also be managed symptomatically with analgesic drugs and nonsteroidal anti-inflammatory drugs. Evidence from randomized placebo-controlled clinical trials have shown that bisphosphonate therapy reduces bone turnover,improves bone pain, promotes healing of osteolytic lesions, and restores normal bone histology in PD. ³⁵-³⁸ The newer generation of nitrogen-containing bisphosphonates are best studied and currently recommended for the treatment of PD. They include two oral agents, Alendronate and Risedronate, and two administered by www . DCMS online . org

Table 2 Paget's Disease Complications30 Complication

Clinical Features

Skeletal-related complications

Malocclusion Interdental diastema (migration of teeth) Loss of teeth Enlarged sclerotic vertebrae (the most common finding in spinal PD) Vertebral compression and kyphosis

Joint-related complications

Spine Pain due to associated degenerative arthritis Nerve root or spinal cord impingement (less commonly) Pelvis Pelvic PD is associated with degenerative arthritis of the hips Hip Impairment of the mobility and autonomy to walking over time due to pain Arthritis of the hip

Neurological complications

Hearing loss Tinnitus Hydrocephalus Spinal stenosis Nerve compression syndromes Paraplegia(rare) Hydrocephalus (rare)

Eye’s fundus complications

linear opacity representing a crack in Bruch’s membrane, known as angioid streak.

Cardiovascular complications

(1) High-output chronic heart failure (CHF) (2) Arterial calcification in the aorta, iliac, femoral, gluteal and pelvic arteries. (3) Calcification of the aortic valve and the interventricular septum. (4) Generalized atherosclerosis. (5) Endocardial calcification.

GU complication

Peyronie’s disease has been found with a prevalence of 14.5% in PD patients.

Neoplasms

PD can be complicated by benign or rarely malignant giant-cell tumors (GCTs). The incidence of such tumors is low (probably <1%): osteosarcoma (86% of cases), fibrosarcoma (5%) and chondrosarcoma (2.5%)

intravenous infusion, Pamidronate and Zoledronic acid.³⁹,⁴⁰ Calcitonin is another antiresorptive agent that is now used infrequently. It is less potent than the newer bisphosphonates and unlikely to result in a sustained clinical remission. However, it is relatively safe and can be used in patients intolerant of bisphosphonates. Surgical Treatment – Surgical intervention is frequently required for the management of complications due to PD. The most common indication for surgical treatment is joint replacement for osteoarthritis, but others include fracture fixation, osteotomy to correct bone deformity, spinal decompression, resection of bone tumors, and prophylactic surgery in patients with painful pseudofractures.⁴¹,⁴² Bisphosphonate treatment is frequently given before elective orthopedic surgery to try to reduce operative bleeding.

Conclusion PD is a relatively common bone disease in elderly. It is often asymptomatic. However, some patients may present with pain and deformity depending on the bones involved. www . DCMS online . org

The diagnosis should be suspected in patient with an elevated serum alkaline phosphatase of bone origin or an imaging study that shows pagetic lesions in the bone. A baseline radionuclide bone scan is recommended to document the extent and locations of skeletal involvement. Symptomatic patients should be treated with bisphosphonates to relieve their pain and reduce the rate of bone remodeling. Asymptomatic patients can be observed. However, treatment should be considered if the disease is present at sites where complications could occur (eg, skull, spine, weight-bearing bones, abutting joint lines). Bone turn over markers and X- rays should be used to monitor patients during therapy. Osteosarcoma is a rare complication of PD and should be suspected in patient with persistent pain despite treatment, local swelling, pathologic fracture or atypical finding on X-rays. Referral to bone specialists should be considered in patients who fail or do not tolerate bisphosphonates, disease complications, or if osteosarcoma is suspected.

References 1.

Paget J. On a Form of Chronic Inflammation of Bones (Osteitis Deformans). Med Chir Trans. 1877; 60:37-64.9.

Northeast Florida Medicine Vol. 63, No. 3 2012 37

Altman RD, Bloch DA, Hochberg MC, Murphy WA. Prevalence of pelvic Paget’s disease of bone in the US. J Bone Miner Res. 2000 Mar;15(3):461-5.

Cooper C, Harvey NC, Dennison EM, van Staa TP. Update on the epidemiology of Paget’s disease of bone. Bone Miner Res. 2006 Dec;21 Suppl 2:P3-8.

Tiegs RD, Lohse CM, Wollan PC, Melton LJ. Long-term trends in the incidence of Paget’s disease of bone. Bone. 2000 Sep;27(3):423-7.

Rendina D, Gennari L, De Filippo G, et al.Evidence for increased clinical severity of familial and sporadic Paget’s disease of bone in Campania, southern Italy. J Bone Miner Res. 2006 Dec;21(12):1828-35.

Melmed S, Polonsky K, Larsen P, Kronenberg H. Williams Endocrinology Textbook ( 12th edition). Sounders Elsevier, Philadelphia, PA. Jun 10, 2011.

Menaa C, Barsony J, Reddy SV, et al. 1,25-dihydroxyvitamin D-3 hypersensitivity of osteoclast precursors from patients with Paget’s disease. J Bone Miner Res 2000;15:228–36.

Menaa C, Reddy SV, Kurihata N, et al. Enhanced RANK ligand expression and responsivity of bone marrow cells in Paget’s disease of bone. J Clin Invest 2000;105:1833–8.

Naot D, Bava U, Matthews B, et al. Differential gene expression in cultured osteoblasts and bone marrow stromal cells from patients with Paget’s disease of bone. J Bone Miner Res. 2007;22:298-309.

10. Rebel A, Bregeon C, Basle M, et al. Osteoclastic inclusions in Paget’s disease of bone. Rev Rhum Mal Osteoartic. 1975 Nov;42(11):637-41. 11. Reddy SV, Singer FR, Mallette L, Roodman GD. Detection of measles virus nucleocapsid transcripts in circulating blood cells from patients with Paget disease. Bone Miner Res. 1996 Nov;11(11):1602-7. 12. Friedrichs WE, Reddy SV, Bruder JM, et al. Sequence analysis of measles virus nucleocapsid transcripts in patients with Paget’s disease. J Bone Miner Res. 2002 Jan;17(1):145-51. 13. Kurihara N, Reddy SV, Menaa C, et al. Osteoclasts expressing the measles virus nucleocapsid gene display a pagetic phenotype. J Clin Invest. 2000;105:607-614. 14. Ruddle NH, Li CB, Horne WC, et al. Mice transgenic for HTLV-I LTR-tax exhibit tax expression in bone, skeletal alterations, and high bone turnover. Virology 1993; 197: 196–204. 15. Ooi CG, Walsh CA, Gallagher JA, Fraser WD. Absence of measles virus and canine distemper virus transcripts in longterm bone marrow cultures from patients with Paget’s disease of bone. Bone 2000; 27: 417–21. 16. Ralston SH. Pathogenesis of Paget’s disease of bone. Bone. 2008;43:819-825 17. Gennari L, Merlotti D, Martini G, Nuti R. Paget’s disease of bone in Italy: Characteristics and familial aggregation of Paget’s disease of bone in Italy. J Bone Miner Res. 2005 Aug;20(8):1356-64. 18. Siris ES, Ottman R, Flaster E, Kelsey JL. Familial aggregation of Paget’s disease of bone. 1991. J Bone Miner Res. 2005 Mar;20(3):542-7. 19. Michou L, Collet C, Laplanche JL, et al. Genetics of Paget’s disease of bone. Joint Bone Spine 2006;73:243–8 20. Morissette J, Laurin N, Brown JP. Sequestosome 1: mutation frequencies, haplotypes, and phenotypes in familial Paget’s disease of bone. J Bone Miner Res 2006;21(Suppl. 2):P38–44

38 Vol. 63, No. 3 2012 Northeast Florida Medicine

21. Roodman GD, et al; Insights into the pathogenesis of Paget’s disease; Ann N.Y. Acad. Sci. 1192 (2010) 176-180 22. Ralston SH, Langston AL, Reid IR. “Pathogenesis and Management of Paget’s Disease of Bone”. The Lancet. July 2008:( Vol. 372, Issue 9633, 155-163 ). 23. Bolland MJ, Tong PC, Naot D, Callon KE, Rutland MD, Cundy T. Delayed development of Paget’s disease in offspring inheriting SQSTM1 mutations. J Bone Miner Res 2007;22:411–5. 24. Michou L, Brown JP. Genetics of bone diseases: Paget’s disease, fibrous dysplasia, osteopetrosis, and osteogenesis imperfecta. Joint Bone Spine. 2011 May;78(3):252-8. 25. Haddaway MJ, Davie MW, McCall IW, Howdle S. Effect of age and gender on the number and distribution of sites in Paget’s disease of bone. Br J Radiol 2007; 80:532–536. 26. Gennari L, Merlotti D, Martini G, Nuti R. Paget’s Disease of Bone in Italy. J Bone Miner Res 2007; 21:14–21. 27. Cundy T, Reid RI. Paget’s disease of bone. Clinical Biochemistry 45 (2012) 43–48 28. Reid IR, Davidson JS, Wattie D, et al. Comparative responses of bone turnover markers to bisphosphonate therapy in Paget’s disease of bone. Bone 2004;35:224–30. 29. Cortis K, Micallef K, Mizzi A. Imaging Paget’s disease of bone-from head to toe. Clin Radiol. 2011 Jul;66(7):662-72. 30. Falchetti A, Masi L, Brandi ML. Paget’s disease of bone .Curr Opin Rheumatol. 2010 Jul;22(4):410-23. 31. Kanis JA. Pathophysiology and treatment of Paget’s disease of bone. London: Martin Dunitz Ltd; 1991. 32. Van Staa TP, Selby P, Leufkens HG, et al. Incidence and natural history of Paget’s disease of bone in England and Wales. J Bone Miner Res 2002;17:465–71. 33. Langston AL, Campbell MK, Fraser WD, et al. Clinical determinants of quality of life in Paget’s disease of bone. Calcif Tissue Int 2007;80:1–9. 34. Margaret Selton. Treatment of Paget disease of bone. Uptodate. com. 2012. 35. Altman RD, Johnston CC, Khairi MR, et al. Influence of disodium etidronate on clinical and laboratory manifestations of Paget’s disease of bone (osteitis deformans). N Engl J Med 1973; 289: 1379–84. 36. Reid IR, Nicholson GC, Weinstein RS, et al. Biochemical and radiologic improvement in Paget’s disease of bone treated with alendronate. Am J Med 1996; 101: 341–48. 37. Fraser WD, Stamp TC, Creek RA, et al. A double-blind, multicentre, placebo-controlled study of tiludronate in Paget’s disease of bone. Postgrad Med J 1997; 73: 496–502. 38. Ralston SH, Boyce BF, Cowan RA, et al. The effect of one alpha hydroxyvitamin D3 on the mineralisation defect in disodium etidronate treated Paget’s disease—a double-blind randomized study. J Bone Miner Res 1987; 2: 5–12. 39. Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med 2005; 353:898. 40. Hosking D, Lyles K, Brown JP, et al. Long-term control of bone turnover in Paget’s disease with zoledronic acid and risedronate. J Bone Miner Res 2007; 22:142. 41. Redden JF, Dixon J, Vennart W, Hosking DJ. Management of fissure fractures in Paget’s disease. Int Orthop 1981; 5: 103–06. 42. Parvizi J, Klein GR, Sim FH. Surgical management of Paget’s disease of bone. J Bone Miner Res 2006; 21 Suppl 2:P75.

www . DCMS online . org

Severe Neutropenia in the Setting of Rheumatoid Arthritis and Hepatitis C: A Review and Case Report Karishma Ramsubeik, MD and Ghaith Mitri, MD, MMM, CPE, FACR Abstract: Tumor necrosis factor-alpha inhibitors have emerged as a potent treatment for rheumatoid arthritis (RA), but not without significant risks. We describe a case of a 49-year-old man with chronic hepatitis C, chronic severe neutropenia, intermittent pancytopenia, history of recurrent fever and infections, and RA, who was successfully treated with TNF inhibitors. This case illustrates how a better understanding of disease mechanisms supported by strong review of the literature and assessment of risks vs. benefits ratios allowed us to give this patient a very tailored, albeit very risky treatment, a better quality of life than he had for the last several years of his life, and hope for a future cure in what otherwise seemed a very grim prognosis.

Case Presentation We present a 49-year-old Caucasian male with a past medical history of Hepatitis C, genotype 1a, without previous treatment who presented to our Rheumatology Clinic in April 2009 for evaluation of joint pain. The pain was located in his hands, shoulders, neck and upper back. It had been present for almost four years and today it was rated as 8 out of 10. It was persistent, worse in the morning, with morning stiffness >60 minutes, and alleviated by rest or non steroidal anti-inflammatory drugs (NSAIDS). There was associated swelling. Review of systems was positive for chronic weight loss, fatigue and chronic leucopenia for four years with neutropenia in the last two years complicated by multiple URI infections and repeated oral antibiotics courses. His joint pain was previously well-controlled with ibuprofen but since 2009 it got worse after an episode of fever, lower extremity erythematous maculopapular rash, and generalized pain. When he presented to the ER, he was found to be neutropenic and was treated with multiple courses of antibiotics. Since January 2009, he lost 25 lbs due to severe loss of appetite. There was no family history of arthritis or any autoimmune disease. He denied using tobacco, alcohol. He stopped using intravenous drugs 20 years ago. His home medications were Aleve and Diclofenac Sodium as needed. Vital signs were normal. The physical exam revealed tenderness of the metacarpophalangeal (MCP) joints of both hands. There was limitation of shoulder abduction secondary to pain. The patient had tonsillar exudates with associated erythema. There were areas of hyperpigmentation on the lower extremities suggested a resolving rash. The remainder of the exam was unremarkable. Patient’s laboratory data is shown in Table 1. Chest X-ray was normal. Imaging of hands showed symmetrical erosions of the base of the 5th metacarpal and discrete erosions on the ulnar aspect of the 4th MCP joint bilaterally consistent with a diagnosis of RA (Figure 1, p.40). Abdominal ultrasound dated February 2009, showed moderate splenic enlargement and normal echogenicity of the liver. Address Correspondence to: Ghaith Mitri, MD, Medical Director, PPD, Jacksonville, FL. Former Assistant Professor of Medicine, University of Florida College of Medicine, Jacksonville, FL. Email: ghaith.mitri@gmail.com. www . DCMS online . org

Table 1 Patient's Lab Values & Reference Range Laboratory data

Patient’s value

Normal value

White blood cell count

0.9

4.5-11 x 103/ uL

Absolute neutrophil count

0.18

1.5-7.8/103/ uL

10.9

12-16 gm/dL

Platelets

128

140-440 mL

110

<14 IU

AST

14-33 U/L

ALT

10-42 U/L

CCP

>60

<20 U

pANCA

1:40

<1: 20 titer

ESR

0-15/H

ANA

Normal

Cryoglobulins

Normal

cANCA,

Normal

Hepatitis B

Normal

HIV

Normal

B12

Normal

Iron stores

Normal

Kidney function

Normal

Ultrasound guided liver biopsy done in April 2009 showed evidence of chronic hepatitis necroinflammatory Grade ¼, chronic hepatitis fibrosis stage 0/4. There was no bridging fibrosis or cirrhosis. Hepatitis viral load was 1,894,600 (March 2009). He was sent to the ER to assess for sepsis given the presence of neutropenia and tonsillar exudates. Blood cultures were done and he was started on antibiotics. The patient was started on Prednisone 5 mg BID and Plaquenil 200 mg BID which did not control his symptoms. A decrease in the Prednisone dose below 7.5mg/day caused a worsening of his symptoms. Sulfasalasine was added in May. Two and four weeks later he developed worsening pancytopenia and sulfasalazine was stopped. In May 2009, Filgrastim, was started. To aid with arthritis control, a TNF inhibitor was started in June and prednisone was lowered to 5mg per day and Plaquenil was stopped. A bone marrow biopsy done in March 2009 showed hypercellular marrow (~70% cellular) with maturating trilineage hematopoiesis. The myeloid elements showed complete maturation to the neutrophilic band forms. After four weeks on a TNF-inhibitor and about seven weeks on GCSF, the patient had a dramatic response with resolution of his neutropenia and significant improvement in his symptoms. Despite the promising results, his TNF-inhibitor was stopped due to significant injection site discomfort. A trial of another TNF inhibitor was started in July 2009. After a few weeks, he had a dramatic response. He continued Northeast Florida Medicine Vol. 63, No. 3 2012 39

Figure 1 Hand Images of RA Erosions

in HCV infected patients compared to controls, with the circulating soluble TNF receptors levels showing significant correlation with aminotransferase levels and the histological severity of inflammation.3 These findings highlight the fact that TNF alpha has a crucial role in the inflammatory process of hepatitis C. The advent, of TNF inhibitors has revolutionized the management of RA. These potent immunomo-dulatory/ suppressive agents are not without risk and it is well recognized that infection is an important potential complications of therapy.4 Indeed, TNF is a pro-inflammatory cytokine which plays an important role in the host immune mediated inflammatory response to infectious pathogens and may increase susceptibility to infectious agents.

Imaging of hands shows symmetrical erosions of the base of the 5th metacarpal and discrete erosions on the ulnar aspect of the 4th MCP joint bilaterally consistent with a diagnosis of RA.

to receive weekly GCSF. His WBCs increased to 8,500 and the neutropenia resolved. However, he developed severe symmetrical polyarthritis with joint swelling, erythema, and warmth in his hands and knees which responded to prednisone 5 mg twice daily. Eventually the Prednisone and GCSF were weaned off in August of 2009. He was restarted on Sulfasalazine and Plaquenil which seemed to have coincided with elevation in his transaminases, (AST 101 U/L (normal 14-33) and ALT 200 U/L (normal10-42)) which resolved gradually over four weeks after discontinuing sulfasalazine. (AST 34 U/L (normal 14-33), ALT 43 U/L (normal10-42). His hepatitis viral load in November 2006 was 6,180,000 IU/ml, and 1, 894,600 IU/ml in March 2009 before any TNF-inhibitions. It dropped to 750, 000.IU/ml in November 2009 after five months of TNF-inhibition. Repeat pANCA was negative at this time. In January 2010, neutrophil antibodies were not detected using the flow cytometry method. Since February 2010 the patient has been off GCSF, prednisone and is being maintained on a TNF-inhibitor and Celebrex. His CBC has been normal for the last several months, he gained 20 lbs, reported feeling great and is working full time.

Discussion This is a very challenging case of a patient with neutropenia, intermittent pancytopenia, chronic hepatitis C and active inflammatory arthritis. The treatment of his arthritis with immunosuppressive drugs could gravely increase his risk of infection, bone marrow suppression, or increase the virulence of his hepatitis C. Treatment of his hepatitis C was greatly feared due to the risk of worsening his inflammatory arthritis. The use of TNF inhibitors is linked to infections and would generally be avoided in patients with neutropenia. It is now understood that the cytokine TNF alpha plays a key role in the pathogenesis of RA. By sustaining inflammation and promoting osteoclast formation it results in the classic radiographic findings seen in RA.1 HCV viremia also has a global effect on the immune system. Kottilil et al2 showed that the proinflammatory cytokine tumor necrosis factor (TNF) was found within a cluster of genes significantly up-regulated only in the group of HCV monoinfected individuals. Indeed, previous studies have shown that TNF alpha and its circulating soluble receptors are increased 40 Vol. 63, No. 3 2012 Northeast Florida Medicine

The coexistence of RA and hepatitis C is a clinical situation that is commonly encountered due to the increasing prevalence of HCV. At least 170 million people worldwide are estimated to have HCV.5 Joint involvement is a common manifestation of HCV infection. It is well established that HCV can induce a form of arthritis very similar to RA. It is now known that HCV related arthritis can be divided into two subsets, a more frequent symmetrical polyarthritis form and an intermittent mono-oligo-arthritis form. Our patient met 5 of the 7, 1987 American College of Rheumatology diagnostic criteria (Table 2, p.41)6 and also meet criteria for definite rheumatoid arthritis based on the 2010 American College of Rheumatology diagnostic criteria with a score of 8(Table 3, p.22 in Dr. Wang's article).7 In the hepatitis C population, rheumatoid factor (RF) does not aid in the diagnosis of RA. This is because in the general population the prevalence of HCV and RA are similar and RF is detected at similar frequencies in both.8 Girelli et al reported that RF was seen in 91% of RA and 86% of patients with HCV-related arthritis, whereas anti-CCP was seen in 71% and 0%, respectively.9 Anti-CCP may be useful to differentiate patients with RA from those with HCV related arthritis. The presence of CCP and erosive polyarthritis favor the diagnosis of RA in our patient. It is important to make the distinction as the treatment modalities would differ. Currently there are no guidelines for the use of TNF inhibitors in the treatment of patients affected by both conditions. Park and Reveille examined the safety of using anti-TNF therapy in patients with RA in the setting of HCV infection.10 In their study no patient displayed evidence of sustained elevation of serum aminotransferases during therapy with anti-TNF. One patient was observed to have a decreased HCV viral load after extended treatment with only anti-TNF. They concluded that anti-TNF-alpha agents are safe and efficacious in patient with RA and HCV. Ferri et al treated 31 HCV positive patients with RA with TNF alpha inhibitors.11 Their results supported the safety of TNF-Îą blockers in patients with HCV. A retrospective survey that examined the influence of treatment with TNF alpha antagonists on levels of HCV viremia and serum transaminases in patients with RA and HCV showed that TNF alpha blockade did not significantly change the mean concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, albumin or viral loads.12 Some authors suggested that TNF inhibition might boost the response of hepatitis C to interferon. A double-blinded, randomized, placebo controlled trial that investigated the efficacy and safety of Etanercept given for 24 weeks as adjuvant to interferon and ribavirin in treatment-naive patients with www . DCMS online . org

Table 2 1987 ACR Classification Criteria for Rheumatoid Arthritis6 Criterion

Definition

1. Morning stiffness

Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement

2. Arthritis of 3 or more joint areas

At least 3 joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints

3. Arthritis of hand joints

At least 1 area swollen (as defined above) in a wrist, MCP, or PIP joint

4. Symmetric arthritis

Simultaneous involvement of the same joint areas (as defined in 2) on both sides fo the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry)

5. Rheumatoid nodules

Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxtaarticular regions, observed by a physician

6. Serum rheumatoid factor

Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal control subjects

7. Radiographic changes

Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify)

HCV showed significantly improved virologic response at the end of the etanercept randomization period among patients with HCV, and was associated with decreased incidence of most adverse effects associated with interferon and ribavirin.13 Another interesting point of discussion is whether our patient’s pancytopenia was due to his hepatitis C or his RA or Felty’s syndrome (FS). Pancytopenia secondary to hepatitis viral infection is a rare although known clinical entity. It is more likely to occur in the context of acute rather than chronic hepatitis. In these cases bone marrow biopsy reveals hypo-cellular marrow.14 Bone marrow examination in FS usually reveals maturation arrest, left shift of granulopoiesis, hypercellularity and very rarely hypocellularity.15 In our patient, it seems that his hepatitis C was the initial insult 15-20 years ago. Subsequently, in the last four years Leucopenia developed. In the last two years, the patient had intermittent neutropenia and pancytopenia. The initial arthralgia/arthritis was easily relieved with NSAIDS. However, in the last year the symptoms have become more painful. It is chronologically and clinically unclear whether the HCV infection played any causative role in the development of his erosive symmetric polyarthritis, It is also not clear whether his neutropenia was due to the chronic hepatitis versus RA versus FS that could have developed at the same time or prior to his arthritis versus, as part of an autoimmune response to the chronic HCV infection. One might argue that the sustained response of his arthritis and resolution of his neutropenia while being maintained on a TNF inhibitor points towards an autoimmune mechanism for the neutropenia rather than hepato-splenomegaly. Pancytopenias are classified according to bone marrow cellularity. Pancytopenia may be due to impaired production, splenic pooling or increased destruction. There is also evidence that circulating immune complexes and autoantibodies associated with certain autoimmune disorders may produce growth factors that promote marrow fibrosis.16 In our patient, pancytopenia may have been due to splenic pooling secondary to his hepatitis and impaired produced due to sulfasalazine. Neutropenia may be caused by drugs, www . DCMS online . org

infections, nutritional deficiencies including B12 or folate deficiency, hematologic malignancies, hypersplenism or autoimmune disease. Autoimmune neutropenias (AIN) are characterized by autoantibodies directed against neutrophils, resulting in destruction of neutrophils. AINs are classified as primary when they are not associated with other detectable pathology or secondary, in cases in which there is another pathology, usually rheumatological such as FS, systemic lupus erythematosus (SLE), or haematological such as large granular lymphocyte syndrome.17,18 The diagnosis of AIN depends on the demonstration of autoantibodies directed against neutrophil-specific antigens. The Second International Granulocyte Serology Workshop suggested that a minimum of two methods be used to detect anti-neutrophil autoantibodies: the granulocyte agglutination test and the granulocyte immunofluorescence test.16 The neutropenia present in FS has a complex, multifactorial pathogenesis which includes destruction and peripheral margination by the antineutrophil autoantibodies and by immune complexes adhering to these cells and inhibition of bone marrow granulopoiesis by proinflammatory cytokines (interleukin-1, tumour necrosis factor-α, interferon-γ). 18 FS is a rare extra-articular manifestation of RA and refers to the clinical triad of arthritis, neutropenia and splenomegaly.19 FS affects approximately 1-3% of all patients diagnosed with RA. Many years of destructive RA usually precedes the onset of FS. On rare occasion, the two may coexist simultaneously. The prevalence of antinuclear antibody (ANA) was found to be less in RA than FS (37% versus 69%) and ANCA was detected in the sera of 33% of patients with FS and was absent in RA sera.20 The treatment of the neutropenia of FS is not well established due to its infrequency and the lack of proper prospective clinical trials. Low dose oral pulse methotrexate therapy usually results in improvement in most patients and currently this is the most well described efficient treatment.21 Experience with Etanercept was described in a case report by Ghavami et al but Etanercept had to be discontinued due to the development of neutropenia.22 Hellmich and Gross examined the efficacy and safety of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human granulocyte-macrophage colony-stimulating Northeast Florida Medicine Vol. 63, No. 3 2012 41

factor (rhGM-CSF) for the treatment of severe neutropenia due to FS or SLE. rhG-CSF effectively corrected neutropenia due to FS and SLE in 7 of the 8 patients.23 In 54 of 55 FS and SLE patients retrieved from the literature, G-CSF or GM-CSF, respectively, proved to be effective at elevating the neutrophil count. Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by recombinant DNA technology. In our patient, it seemed that Filgrastim caused his RA to flare up once his white blood cell counts were normalized and while he was on a TNF inhibitor, and improved once the G-CSF dose was lowered and eventually discontinued. Snowden et al conducted a double-blind, randomized placebo-controlled dose escalation study and showed that flare-ups of RA occur in a minority of patients on colony-stimulating factors and is more likely with 10 than 5 g/kg/day.24 Etanercept is a dimeric fusion protein produced by recombinant DNA technology and specifically binds to TNF and blocks its interaction with cell surface TNF receptors. Etanercept is currently FDA approved for use for RA.25 There are only a few cases of Etanercept use for FS, which showed no clinically relevant benefit.26,27 Methotrexate is the first line drug but is contraindicated in hepatitis C, however plaquenil and sulfasalazine can be used.28

To date, the risk-benefit ratio for the biologic agents remains favorable in rheumatology, and this case serves to highlight that appropriate caution should not preclude their use in the right clinical circumstances. Nevertheless a high level of suspicion of infection is necessary in patients under anti-TNF-α therapy. Approaches for the prevention, rapid recognition and pre-emptive therapy of such infections must be employed. Our patient continues to be treated with a TNF-Inhibitor with no complications and his neutropenia/ pancytopenia never recurred. His HCV viral load decreased persistently and progressively while TNF-inhibition, but we are not sure of the clinical relevance and the impact on any potential treatment of his chronic HCV in the future. Early treatment with DMARDs led to many previously known long-term complications of RA almost disappearing. With better understanding of the biological mechanisms of disease and early introduction of biologic therapy, we are possibly re-writing the books about the natural history and pathogenesis of certain chronic diseases.

3. 4. 5.

10. 11.

12.

13.

14. 15.

Conclusions

References

Weaver ALM. Differentiating the New Rheumatoid Arthritis Biologic Therapies. JCR: Journal of Clinical Rheumatology 2003; 9: 99-114. Kottilil S, Yan MY, Reitano KN, Zhang X, Lempicki R, Roby G, et al. Human immunodeficiency virus and hepatitis C infections induce distinct immunologic imprints in peripheral mononuclear cells. Hepatology. 2009; 50:34-45. Knobler H, Schattner A. TNF-alpha, chronic hepatitis C and diabetes: a novel triad. Q J Med. 2005; 98: 1-6 Desai SB, Furst DE. Problems encountered during antitumour necrosis factor therapy. Best Practice & Research Clinical Rheumatology 2006; 20: 757-90. Perz JF, Farrington LA, Pecoraro C, et al. Estimated global prevalence of hepatitis C virus infection. 42nd Annual Meeting of the Infectious Diseases Society of America; Boston, MA, USA; Sept 30–Oct 3, 2004. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31:315-324.

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16. 17. 18. 19. 20. 21. 22. 23.

24.

25. 26. 27.

28.

Aletaha D, Neogi T, Silman AJ, et al. The 2010 ACR-EULAR classification criteria for rheumatoid arthritis. Arthritis Rheum. 2010 Sep;69(9):1580-8 Wener MH, Hutchinson K, Morishima C et al. Absence of antibodies to cyclic citrullinated peptide in sera of patients with hepatitis C virus infection and cryoglobulinemia. Arthritis & Rheumatism 2004; 50: 2305-8. Girelli F., Foschi F.-G., Bedeschi E. et al. Is Anti Cyclic citrullinated peptide a useful laboratory test for the diagnosis of rheumatoid arthritis? European Annals of Allergy and Clinical Immunology 2004; 36: 127-30. Parke F, Reveille J. Anti-tumor necrosis factor agents for rheumatoid arthritis in the setting of chronic hepatitis C infection. Arthritis Care & Research 2004; 51: 800-4. Ferri C, Ferraccioli G, Ferrari D et al. Safety of Anti-Tumor Necrosis Factor-α Therapy in Patients with Rheumatoid Arthritis and Chronic Hepatitis C Virus Infection. The Journal of Rheumatology 2008; 35: 1944-9. Peterson JR, Hsu FC, Simkin PA et al. Effect of tumour necrosis factor {alpha} antagonists on serum transaminases and viraemia in patients with rheumatoid arthritis and chronic hepatitis C infection. Ann Rheum Dis 2003; 62: 1078-82. Zein N, Group TES. Etanercept as an adjuvant to interferon and ribavirin in treatment-naive patients with chronic hepatitis C virus infection: a phase 2 randomized, double-blind, placebo-controlled study. Journal of Hepatolology 2005; 42: 315-22. Young NS. Acquired Aplastic Anemia. Ann Intern Med 2002; 136: 534-46. Hellmich B, Pinals RS, Loughran JTP et al. New clues to accrue on neutropenia in rheumatoid arthritis. Clinical Immunology 2005; 117: 1-5. Durupt S, David G, Durieu I et al. Myelofibrosis in systemic lupus erythematosus: a new case. European Journal of Internal Medicine. 2000;11(2): 98-100. Capsoni F, Sarzi-Puttini P, Zanella A. Primary and secondary autoimmune neutropenia. Arthritis Res Ther. 2005; 7:208–214. Akhtari M, Curtis B, Waller EK. Autoimmune neutropenia in adults. Autoimmunity Reviews. 2009; 962-66. A.R. Felty, Chronic arthritis in adults with splenomegaly and leukopenia: a report of five cases of an unusual clinical syndrome, Bull Johns Hopkins Hosp 35 (1924), pp. 16–20. Juby A, Johnston C, Davis P et al. Antinuclear and antineutrophil cytoplasmic antibodies (ANCA) in the sera of patients with Felty’s syndrome. Br J Rheumatol. 1992 Dec;31(12):859-60. Wassenberg S, Herborn G, Rau R. Methotrexate treatment in Felty’s syndrome. Br J Rheumatol 1998;37:908–911. Ghavami A, Genevay S, Fulpius T, Gabay C. Etanercept in treatment of Felty’s syndrome. Ann Rheum Dis 2005;64 7: 1090-1091. Hellmich B, Schnabel A, Gross WL. Treatment of severe neutropenia due to Felty’s syndrome or systemic lupus erythematosus with granulocyte colony-stimulating factor. Semin Arthritis Rheum 1999;29:82–99. Snowden JA, Biggs JC, Milliken ST et al. A randomised, blinded, placebo-controlled, dose escalation study of the tolerability and efficacy of filgrastim for haemopoietic stem cell mobilisation in patients with severe active rheumatoid arthritis. Bone Marrow Transplantation 1998; 22: 1035-41. ENBREL® (etanercept) Prescribing Information, Imunex Corporation, Thousand Oaks, CA. Ghavami et al. Etanercept in treatment of Felty’s syndrome. Ann Rheum Dis (2005) 64 (7): 1090. Ravindran, J, Shenker, N, et al. Case report: Response in proteinuria due to AA amyloidosis but not Felty’s syndrome in a patient with rheumatoid arthritis treated with TNF-alpha blockade. Rheumatology (Oxford) 2004; 43:669. Zuckerman E, Yeshurun D, Rosner I. Management of hepatitis C virus-related arthritis. BioDrugs 2001; 15: 573-84.

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Northeast Florida Medicine Vol. 63, No. 3 2012 43

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44 Vol. 63, No. 3 2012 Northeast Florida Medicine

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Thirty Years of HIV in Women Background - Benefits that Matter!

The Duval County Medical Society (DCMS) attempts to provide its members with the benefits that consistently meet your professional needs. One example of how this is being accomplished is by providing to DCMS members free Continuing Medical Education (CME) opportunities in the subject areas mandated/and or suggested by the State of Florida Board of Medicine to obtain and retain medical licensure. The DCMS would like to thank the St. Vincent’s Healthcare (SVHC) Committee on CME for reviewing and accrediting this activity in compliance with the Accreditation Council on Continuing Medical Education (ACCME). Helena Karnani, MD, Chair of the CME Committee; Betsy Miller, Director, Medical Staff, Quality Management; and Cindy Williamson, CME Coordinator, from SVHC deserve special recognition for their work on behalf of DCMS. This issue of Northeast Florida Medicine includes an article, “Thirty Years of HIV in Women” authored by Laura Armas-Kolostroubis, MD (see pp. 46-49), which has been approved for 1.0 AMA PRA Category 1 credit(s).™ For a full description of CME requirements for Florida physicians (MD/DO), please visit the DCMS website (http://www.dcmsonline.org/cme_requirements.aspx).

Faculty/Credentials: Laura Armas-Kolostroubis, MD, is an Associate Professor at the University of Florida (UF) and CoMedical Director of UF Center for HIV/AIDS Research, Education and Service in Jacksonville, FL. Prior to coming to UF, she was a staff physician at the HIV Women's Specialty Center, Parkland Health and Hospital System HIV Services, Southeast Health Center, Amelia Court HIV/AIDS Clinic in Dallas, TX. Dr. Armas-Kolostroubis earned her MD from La Salle University in Mexico City. She did internships and fellowships in Mexico and the U.S. She is licensed to practice in Florida, Texas and in Mexico. Another prior assignment was as Clinical Director of the Texas/Oklahoma AIDS Education and Training Center in Dallas, TX. Her Boards and Certifications include the American Board of Internal Medicine and American Academy of HIV Medicine Specialist. Objectives for CME Journal Article 1. Describe current recommendations for HIV testing in women 2. Identify missed opportunities for prevention of HIV mother to child transmission 3. Discuss two interventions to prevent HIV transmission in women

Date of Release: November 26, 2012 Date Credit Expires: November 26, 2014. Estimated time to complete: 1 hr.

Methods of Physician Participation in the Learning Process

1. Read the “Thirty Years of HIV in Women” article pages 46-49. Complete the Post Test and Evaluation on page 50. 3. Members or non-members may fax the Post Test to DCMS (FAX) 904-353-5848 OR members can also go to www.dcmsonline.org & submit the test online. Non-members must arrange for the CME fee payment before submitting the post test by fax. Call 904-355-6561 x106 or fax.

CME Credit Eligibility

In order to receive full credit for this activity, a minimum passing grade of 70% must be achieved. Only one re-take opportunity will be granted if a passing score is not made on the first attempt. DCMS members and non-members have two years to submit the post test and earn CME credit. A certificate of credit/completion will be emailed or USPS mailed within 4-6 weeks of submission. If you have any questions, please contact the DCMS at 355-6561, ext. 103, or leora@dcmsonline.org.

Faculty Disclosure Information

Dr. Armas-Kolostroubis reports no significant relationships to disclose, financial or otherwise with any commercial supporter or product manufacturer associated with this activity.

Disclosure of Conflicts of Interest

St. Vincent’s Healthcare (SVHC) requires speakers, faculty, CME Committee, and other individuals who are in a position to control the content of this educational activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly evaluated by SVHC for fair balance, scientific objectivity of studies mentioned in the presentation and educational materials used as basis for content, and appropriateness of patient care recommendations.

Joint Sponsorship Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of St. Vincent’s Healthcare and the Duval County Medical Society. St. Vincent’s Healthcare is accredited by the Florida Medical Association to provide continuing medical education for physicians.The St. Vincent’s Healthcare designates this educational activity for a maximum of 1.0 AMA PRA Category 1 credit(s) .TM Physicians should only claim credit commensurate with the extend of their participation in the activity.

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Northeast Florida Medicine Vol. 63, No. 3 2012 45

Thirty Years of HIV in Women Laura Armas-Kolostroubis, MD Abstract: Women comprise half of the HIV infections worldwide. Prevention is possible through a variety of approaches, including routine testing and timely treatment, educating patients about barrier methods to prevent sexually transmitted disease, pre and post-exposure prophylaxis in at risk populations and through prenatal testing. Treatment with Highly Active Antiretroviral Therapy (HAART) is quite effective and through viral suppression life expectancy has greatly increased for people living with HIV/AIDS, particularly for women. But there are still gender and ethnic differences in the access to treatment due to different social and structural barriers making AIDS the leading cause of death for African American women. Perinatal exposure to HIV had a 30% increase in the last decade and despite great efforts to diagnose and treat mother and infants, infections still occur. Women may have higher rates for side effects and lower adherence rates to HAART. Degenerative diseases are an increasing concern for the HIV infected population, particularly, for women, and especially diseases related to cardiovascular disease and bone metabolism.1

Introduction In June of 1981, description of a cluster of cases with rare diseases presented in otherwise healthy homosexual individuals and hemophiliacs and were manifested by the presence of Kaposi’s sarcoma and opportunistic infections such as Pneumocystis Carinii Pneumonia (PCP).2 A few months later, accounts of the first cases of mother to child transmission cases and similar incidents in sexual partners of affected individuals followed. 3,4 After finally providing a name for the unusual disease, the Acquired Immunodeficiency Syndrome (AIDS) and its deadly nature, the Centers for Disease Control and Prevention (CDC) established surveillance and monitoring mechanisms, clearly establishing its transmission through intimate contact such as exchange of blood products and genital secretions. By 1984, a retrovirus, now known as the Human Immunodeficiency Virus (HIV) was identified as the causal agent that led to the devastating consequences of this disease. But in the United States and other developed countries, the proportion of women initially diagnosed were low, in the 2-6% range of the HIV infected population. Generally identified for belonging to what it was considered then a ‘High Risk Category’, they or their partners were injection drug users or promiscuous, such as commercial sex workers. This generated the misconception that female acquisition of the virus was selective to personal behavioral choices, heightening the stigma related to the infection.5

Epidemiology By the 1990s the spread of HIV infections reached the global level of pandemic. By the early years of the 21st century, over Address Correspondence to: Laura Armas-Kolostroubis, MD., Associate Professor, Co-Medical Director, UF CARES, University of Florida Center for HIV/AIDS, Research, Education & Service, Jacksonville, FL. Email: Laura. Armas-Kolostroubis@jax.ufl.edu. 46 Vol. 63, No. 3 2012 Northeast Florida Medicine

60 million people have been diagnosed with the disease. One third of them have succumbed to the disease, and globally half of them are women or adolescent girls. In the United States, by the end of 2008 there were 1,178,350 persons diagnosed with the disease and the proportion of women is lower but increased from 8% in the early 1990s to 25% nationally.6 In 2009, Florida ranked first among the states in new cases of HIV infections and second in estimated number of AIDS cases.7 Racial and ethnic minorities are disproportionally affected and despite significant advances in prevention and treatment, AIDS continues to be the 4th leading cause of death for African American women in the United States.8 Nationwide the AIDS case rate per 100,000 population is 20 times higher for black women and 5 times higher for Hispanic women, as compared to white women. Although these proportions are similar, Florida’s AIDS rates cases in women are significantly higher as compared to the rest of the nation. (Table 1) In Florida, AIDS is the leading cause of death for black women aged 25-44 years of age for the 15 consecutive years despite decrease in the number of new diagnosis in this population.9

Sex Differences in Pathophysiology The main mode of transmission worldwide is through sexual exposure. This and other co-factors such as circumcision and the presence of other sexually transmitted infections, particularly genital ulcerative disease, play a significant role when it comes to the risk associated with each encounter.10Male to female transmission is more effective than female to male, partly due to larger volume and time of semen exposure and the fact that semen contains greater concentrations of HIV particles.11 Sex steroid hormones play an important role on vaginal mucosa and ectocervical tissue, as well as exert an important influence in upper and lower female genital tract immune regulation. Furthermore, there is increasing evidence that oral contraceptive, particularly, progesterone based preparations may increase HIV acquisition.12 In addition, females have lower viral loads than men and higher CD4 counts at baseline than men, yet, disease

Table 1 2006 AIDS Case Rates

(per 100,000 in women 13-64 years old, by race) Race/Ethnicity U.S. Florida Black 40.4 89.4 Hispanic

9.5

14.6

White

1.9

5.1

Other

2.4

11.5

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progression does not differ and neither does their response to HAART. 13-15

Sex Differences in Diagnosis Despite the 2006 CDC recommendations to test every person who is sexually active between the ages of 13-64 at least once, with further testing based on risk and community prevalence, a pervasive lag in implementation leads to the persistent delay in diagnosis. 16,17 In July 2011, the Institute of Medicine included annual HIV testing and counseling for sexually active women as one of eight recommendations for preventive services for women, along with preconception and inter-conception visits, screening for gestational diabetes, lactation support and counseling, domestic violence screening and counseling, and others.18 Even more discouraging was the March 2012 announcement by the HIV Prevention Trials Network (HPTN), a National Institutes of Health (NIH) sponsored global network. In their HPTN 064 Women HIV sero-incidence Study (ISIS), investigators in areas with high prevalence rates, such as Atlanta, Georgia found 32 new infections at baseline (1.5%), 2 women had acute infection at baseline, with an annual incidence rate of 2.52 (95% CI 0.60 to 10.7) and 4 women acquired HIV in the 6 to 12 month follow-up, with an incidence rate of 0.24% (95% CI 0.09 to 0.65). These incidence rates are similar to those seen in women living in some Sub-Saharan countries like Congo and Kenya (0.28% and 0.53% respectively) and are five fold higher than the 0.05% estimate from the CDC.19 These findings highlight the fact that the HIV epidemic in women may be underrecognized and the recommended universal screening will uncover asymptomatic individuals, thus preventing further disease progression and new transmissions. Although the incidence of perinatally acquired HIV transmission has decreased over 95% since 1999, the estimated numbers of HIV-infected women of childbearing age who give birth has increased by 30% from 6,075-6,422 in 2000 to 8,650 to 8,900 in 2006, mostly due to an increased in women living with HIV/AIDS, extended life expectancy and expanded reproductive options.20

Sex Differences in Treatment In 1987, zidovudine, a nucleoside thymidine analogue agent was approved by the US Food and Drug Administration as a competitive inhibitor of the reverse transcriptase enzyme. This drug halts the production of pro-viral DNA and significantly reducing viral replication. Several drugs in this category were approved in the early nineties. But monotherapy soon proved to have limitations and failure, leading scientists to use combination of two of these drugs with improved but still limited outcomes.5 By 1995 a new class of drugs appeared in the market. Their mechanism of action targeted the protease enzyme, key in maturation of viral particles. Used in combination with two nucleoside reverse transcriptase inhibitors proved to be highly efficacious in achieving viral suppression and in turn, improved immune reconstitution, decreased mortality and decreased the development of viral resistance. This combinawww . DCMS online . org

tion therapy was then named Highly Active Antiretroviral Therapy (HAART).5 To date, 25 years since the first drug was discovered, 27 individual drugs, seven combination tablets, three of them with multi-class co-formulation have been approved.5 HAART has significantly increased life expectancy for those living with HIV and this is inclusive of those who have already have progressed to AIDS. An analysis of several cohorts in high-income countries shows life expectancy for women was better for women than men.21 Similarly other cohort studies around the world have shown that women have similar, and in some cases even better, immunologic and virologic response to HAART than men.22-24 This may be related to increased plasma concentrations of the drugs, but also, probably due to the fact they have higher discontinuation rates than men due to side effects.25-28 Side effects is an area in which gender differences are marked. For example, nevirapine, has shown to have greater severity of drug induced rash and even Stevens Johnson syndrome in women. Protease inhibitors produce higher rates of nausea and vomiting in women and diarrhea in men. This may be partially explained to the hormonal influence on gastrointestinal transit.24

Access In the United States, most antiretrovirals are covered by major insurers, including federal and state programs. Furthermore, for those who are unable to afford or do not qualify, medication is provided through a federal and state collaboration known as the AIDS Drug Assistance Program (ADAP). Unfortunately, despite this access to antiretroviral therapy, there still are gender and race disparities. Gebo, et.al showed that males were 1.23 more likely to access HAART than females, and being African American gave an Odds Ratio of 0.84 likelihood to receive this life-saving medication.29

Sex Differences in Aging with HIV After 25 years of antiretroviral therapy, HIV is now considered a treatable, chronic infection. However, with the increased lifespan, aging and the imminent non-infectious diseases such as cardiovascular, renal and hepatic disease have rapidly become a concern for the HIV-care provider. Furthermore, antiretroviral medications such as protease inhibitors are known for their effects on lipid metabolism leading to a higher risk for myocardial infarction and strokes. It has been noted that women have higher triglyceride levels than in men.24 Another concern is that HIV, especially if advanced disease has ensued, impairs bone metabolism in both men and women. It must then be considered as a risk factor for osteoporosis in postmenopausal women, especially if they are on a tenofovir containing regimen.30

Sex Differences in Prevention HIV is a highly preventable disease. Use of barrier methods such as male and female condoms and early diagnosis and treatment of sexually transmitted diseases and male circumNortheast Florida Medicine Vol. 63, No. 3 2012 47

cision all have proven to decrease transmission rates.31-33 In 2011, the HIV Prevention Network 052 trial demonstrated that among 1,763 heterosexual sero-discordant couples (one partner was infected and one not) if treatment was taken and viral suppression achieved at less than 400 copies/mL, transmission rates decreased by 96%. This suggests treatment of HIV infection is the most effective way of preventing new infections.34 For women of reproductive potential, the CDC preconception care proceedings recommends a separate visit to address health status, including infectious, metabolic, psychological and even social diagnosis that may impact maternal or fetal outcomes. These visits should occur regularly and between pregnancies.35 At those times, primary care providers can offer an array of contraceptive choices if the woman desires to avoid pregnancy or to delay it until her medical conditions related to HIV issues are optimal for pregnancy, as well as identify risks on the patient or her partner. This year the combination tablet of Emtricitabine/Tenofovir was approved by the FDA to be taken by those individuals who are at high risk for infection and the CDC published an interim guide for their use in heterosexual couples.36 It is recommended that those providers who are considering prescribing it for this purpose review the guide. Although resistance development in these situations is low, both medications are active against hepatitis B, and tenofovir may impair renal function and bone metabolism, which requires careful selection and monitoring of patients who may benefit. Prevention is not only achieved by individual health choices, but a series of co-factors such as poverty and homelessness place women in particularly vulnerable situations. They may not have control of the risks they are exposed to such as in cases of domestic violence in which the abused partner cannot negotiate condom use effectively or disclose HIV status. That is why high impact approaches to HIV prevention are needed at the individual, societal and system levels. This removes structural barriers that prevent individuals from accessing services.37-40

HIV and Pregnancy One of the most striking successes has been the prevention of perinatally acquired infection. Rates have fallen from an estimated 22.6% on those without treatment and breast-feeding to less than 2% on those who receive antiretroviral therapy during pregnancy and avoid lactation. 41,42 But more needs to be done since missed opportunities to prevent transmission of this lifelong infection continue to be identified. In a recent report, among 8,054 births from HIV-infected women, 179 (2.2%) infants were diagnosed with HIV infection. Odds of having an infected infant were higher for women who received late testing or no prenatal antiviral medications OR 2.5 ([95% confidence interval (CI) 1.5-4.0]) and 3.5 ([95% CI 2.0-6.4]), breastfed 4.6 (95% CI 2.2-9.8) and advanced disease, 2.4 (95% CI 1.4-4.2) in those with CD4 counts <200 versus those with >500 cells/microliter. Women who abused substances were twice as likely to transfer HIV to babies than those who did not.43 The sooner HIV is discovered and treated, the better.

48 Vol. 63, No. 3 2012 Northeast Florida Medicine

In an early report, Birkhead analyzed a cohort of 3,396 HIV-exposed neonates in New York State from 2000 to 2006. HIV transmission was presumed or confirmed in 65 neonates (2.1%) born to 63 mothers, after all factors analyzed, HIV acquisition during pregnancy had the highest odds of leading to a neonatal infection, lack of prenatal care, evidenced by a diagnosis during or after delivery or less than 2 prenatal care visits were also associated with higher rates of perinatal infection. 44

Conclusion HIV infection in women has been described since the beginning of the pandemic, and globally they account for half of the infections. Although highly preventable, women have intrinsic and extrinsic factors that increase their vulnerability to the infection. There are no significant gender differences in the response to HAART but in the access to these therapies. In Florida minorities are more affected and AIDS is the leading cause of death for young African American women. When diagnosed early, through routine screening, appropriate treatment is available and highly effective to halt disease progression to AIDS or death and to prevent new infections. Although mother to child transmission is low in the United States, pervasive rates remain an issue. As life expectancy continues to rise in the general population, HAART has made it possible for people living with HIV to reach a close to normal lifespan, yet with metabolic complications that should be addressed.

References

Centers for Disease control and Prevention; HIV SurveillanceUnited States, 1981-2008; Morbidity and Mortality Weekly Report, June 2011; 60(21): 689-699

Center for Disease Control and Prevention: A cluster of Kaposi’s Sarcoma aand Pneumocystis carinii pneumonia among homosexual male residents of Los Angeles and Orange Counties, California; Morb Mortal Wkly Rep. 1982 Jun; 31(23):305-7.

Center for Disease Control ad Prevention: Unexplained Immunodeficiency and Opportunistic Infections in infants –New York, New Jersey, California; Morb Mortal Wkly Rep. 1982 Dec; 31(49):665-7.

Center for Disease Control ad Prevention: Immunodeficiency among female sexual partners of males with Acquired Immunodeficiency Syndrome (AIDS) –New York; Morb Mortal Wkly Rep. 1983 Jan; 31(52):697-8.

Fauci A; HIV and AIDS: 20 years of science; Nature Medicine 2003; 9(7): 839-43.

Centers for Disease Control and Prevention: Diagnosis of HIV infection and AIDS in the United States and Dependent Areas, 2010; HIV Surveillance Rep. 2012 Feb; Vol 22.

Florida Department of Health: Florida’s 2012-2015 Statewide Coordinated Statement of Need and Comprehensive Plan; http://www.doh.state.fl.us/Disease_ctrl/aids/SCSN_ Comprehensive_Plan.pdf ; pp:3-13. Accessed October 8, 2012

Lieb S; HIV Incidence, Prevalence and Mortality Epidemic Snapshot, Florida; http://www.doh.state.fl.us/Disease_ctrl/ aids/Docs/HIV_Epidemic_Snapshot_FL_2010.pdf . Accessed October 7, 2012.

Lieb S, McKinley-Beach L, LaLota M, Ullah E, et.al; Florida

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Dept Health, Bureau of HIV/AIDS; Organizing to survive: The HIV/AIDS Crisis among Florida’s Women; http://www. floridashealth.com/Disease_ctrl/aids/Docs/HIV_AIDS_ Womens_Report_4_2008.pdf , October 7, 2012. 10. Coates T., Ritcher L., Caceres C.; Behavioural strategies to reduce HIV transmission:how to make them work better; Lancet 2008; 372(9639):669-84. 11. European Study Group on Heterosexual Transmission of HIV; Comparison of female to male and male to female transmission of HIV in 563 stable couples; BMJ 1992; 304:809-13. 12. Zdenek H, Stringer E, Mestecky J.; Sex steroid hormones, hormonal contraception and the immunobiology if huma immunodeficiency virus-1 infection; Endocr Rev 2012 Feb; 31(1)79-97. 13. Gandhi M., Bacchetti P., Miotti P., Quinn TC, et.al; Does patient sex affect human immunodeficiency virus levels?; Clin Infect Dis. 2002; 35(3)313-22. 14. Delmas MC, Jadand C, De Vicenzi I, et.al; Gender differencesin CD4+ cell counts persist after HIV-1 infection. SEROCO Study Group; AIDS 1997 Ju; 11(8): 1071-3. 15. Hewitt RG, Parsa N, Gugino L.; Women’s health. The role of gender in HIV progression; AIDS Read. 2001 Jan; 11(1):29-33. 16. Branson BM, Handsfield HH, Lampe MA, et.al; CDC MMWR Recomm Rep 2006 Sep22; 55(RR-14):1-17. 17. Shirreffs A, Lee DP, Henry J, et.al; Understanding barriers to routine HIV screening: knowledge, attitudes and practices of healthcare providers in King County, Washington. PLoS One. 2012; 7(9):e44417. 18. National Research Council. Clinical Preventive Services for Women: Closing the Gaps. Washington, DC: The National Academies Press, 2011, 79-156. 19. Hodder S, Justman J, Hughes J, et.al; The HPTN 064 (ISIS Study)- HIV incidence in women at risk for HIV: US; 19th Conference on Retrovirus and Opportunistic Infections (CROI), March 2012; Paper #1048. 20. Whitmore S., Zhang, X., Taylor A; Estimated number if births to HIV positice women, United States, 2006; 16th Conference on Retrovirus and Opportunistic Infections (CROI), February 2009; Paper #924. 21. The Antiretroviral Therapy Cohort Collaboration; Life expectancy of individuals on combination antiretroviral therapy in high income countries: a collaborative analysis of 14 cohort studies; Lancet 2008 Jul; 372(9635): 293-9. 22. Patterson K, Napravnik S, Eron J, et.al; Effects of age and sex on immunological and virological responses to initial highly active antiretroviral therapy; HIV Med. 2007 Sep; 8(6):406-10. 23. Jarrin I, Geskus R, Bhaskaran K, et.al; Gender differences in HIV progression to AIDS and death in industrialized countries: slower disease progression following HIV seroconversion in women; Am J Epidemiol 2008 Sep 1; 168(5): 532-40. 24. Nicastri E, Leone S, Angeletti C, et.al; Sex issues in HIV-1 infected persons during highly active antiretroviral therapy: a systematic review; J Antimicrob Chemother. 2007 Oct; 60(4): 724-32. 25. Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF; Sex differences in pharmacokinetics and pharmacodynamics; Annu Rev Pharmacol Toxicol. 2004; 44:499-523. 26. Ofotokun I, Chuck SK, Hitti JE; antiretroviral pharmacokinetic profile: a review of sex differences; Gen Med. 2007 Jun; 4(2):106-19. 27. Elzi L, Marzolini C, Furrer H, et.al; Treatment modification in human immunodeficiency virus-infected individuals starting www . DCMS online . org

combination antiretroviral therapy between 2005 and 2008; Arch Intern Med 2010 Jan 11; 170 (1):57-65. 28. Currier J, Bridge DA, Hagins D, Zorrilla CD, et.al; Sex-Based Outcomes of Darunavir–Ritonavir Therapy: The GRACE (Gender, Race, and Clinical Experience) Study; Ann Intern Med. 2010 Sep 21; 153(6): 349-357. 29. Agwu Al, Fleishman JA, Korthuis PT, et.al; Disparities in Antiretroviral Treatment: A Comparison of Behaviorally-HIVInfected Youth and Adults in the HIV Research Network. J Acquir Immune Defic Syndr. 2011 Sep 1; 58(1):100-107. 30. Arnsten JH, Freeman R, Howard AA, et.al; HIV infection and bone mineral density in middle aged women; Clin Infect Dis. 2006 Apr 1; 42(7):1014-20. 31. Carvalho FT, Goncalves TR, Faria ER, et.al; Behavioral interventions to promote condom use among women living with HIV; Cochrane Database Syst Rev. 2011 Sep 7; (9): CD007844. 32. Wilkinson D, Rutherford G.; Population-based interventions for reducing sexually transmitted infections, including HIV infection.Cochrane Database Syst Rev. 2001; (2):CD001220. Review. Update in: Cochrane Database Syst Rev. 2004;(2):CD001220. 33. Smith DK, Taylor A, Kilmarx PH, et.al; Male circumcision in the United States for the prevention of HIV infection and other adverse health outcomes: report from a CDC consultation. Public Health Rep. 2010 Jan-Feb;125 Suppl 1:72-82. 34. Cohen MS, Chen YQ, McCauley M, et.al; Prevention of HIV-1 infection with early antiretroviral therapy; N Engl J Med 2011 Aug 11; 365(6):493-505. 35. Kent H, Johnson K, Curtis M, et.al.; Proceedings of the preconception health and healthcare clinical, public health and consumer workgroup meetings; CDC June 2006. 36. CDC; Interim guidance for clinicians considering the use of preexposure prophylaxis fro the prevention of HIV infection in heterosexually active adults; Morb Mortal Weekly Rep. 2012 Aug 10; 61(31):586-589. 37. German D, Latkin CA; Social stability and HIV risk behavior: evaluating the role of accumulated vulnerability; AIDS Behav. 2012 Jan; 16(1):168-78. 38. Ober AJ, Iguchi MY, Weiss RE, et.al.; The relative role of perceived partner risks in promoting condom use in a threecity sample of high-risk, low income women; AIDS Behav. 2011 Oct; 15(7):1347-58. 39. Riley ED, Gandhi M, Hare C, et.al; Poverty, unstable housing, and HIV among women living in the United States; Curr HIV/ AIDS Rep. 2007 Dec; 4(4): 181-6. 40. Sormanti M, Shibusawa T; intimate partner violence among midlife and older women: a descriptive analysis of women seeking medical services; Health Soc Work. 2008 Feb; 33(1):33-41. 41. CDC; Zidovudine for the prevention of HIV transmission from mother to infant; Morb Mortal Wkly Rep. 1994 Apr 29; 43(16):285-7. 42. European Collaborative Study; Mother to child transmission of HIV infection in the era of highly active antiretroviral therapy; Clin Infect Dis. 2005; 40(3):458-65. 43. Whitmore SK, Taylor AW, Espinoza LR; Correlates of mother to child transmission of HIV in the United States and Puerto Rico; Pediatrics 2012; 129; e74-e81. 44. Birkhead GS, Pulver WP, Warren BL, et.al.; Acquiring human immunodeficiency virus during pregnancy and mother-to-child transmission in New York:2002-2006. Obstet Gynecol. 2010 Jun;115(6):1247-55. Northeast Florida Medicine Vol. 63, No. 3 2012 49

CME Questions & Answers (Circle Correct Answer) /Free-DCMS Members/$50.00 charge non-members*

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Thirty Years of HIV in Women

(Return by November 26, 2014 by FAX: 904-353-5848, by mail: 555 Bishopgate Lane, Jacksonville, FL 32204 OR online: www.dcmsonline.org) 1. Since surveillance started, approximately 1.2 million people have been diagnosed with HIV infection in the U.S, and according to the CDC, as of 2009, the proportion of infected women was: a. 8% b. 12% c. 18% d. 25% e. 33% 2.

In the NIH Women and HIV sero-incidence study, areas with high HIV prevalence (ie Atlanta, GA), the results reported: a. Incidence rates comparable with Sub-Saharan countries b. Lower rates than the CDC estimated c. No infections at baseline & only a couple at 1 year d. All of the above

In the last 10 years, the estimated number of HIV infected women giving birth: a. Decreased by 10% b. Remains stable (200-300 every year) c. Increased by 10% d. Increased by 30% (almost 9,000 giving birth in 2006)

Florida ranks where in the U.S. for new infections: a. Third b. Sixth c. First d. Twelfth e. Fourth

Most recent cases of perinatally transmitted HIV infections occur in pregnant women who: a. Receive no prenatal care b. Are tested late or not tested c. Do not receive Antiretroviral therapy d. Are infected during pregnancy e. All of the above

Which statement is false regarding women & HAART: a. No gender differences in immunologic & virologic response to HAART b. Women have higher plasma concentrations of several antiretrovirals c. Rash due to nevirapine is worse in women d. Women are more likely to receive antiretroviral therapy than men

A 36-year-old HIV infected herterosexual male has unprotected intercourse with his girlfriend. He has been in care 5 years & has a viral load of less than 200 c/ml. As his physician you advise: a. Sex partner should be tested ASAP. If negative, repeat in 3 months b. Reassure his viral load transmission might be rare c. Discuss barrier methods & advise using emtricitabine/ tenofovir for pre-exposure prophylaxis d. All of the above In Florida, AIDS is the leading cause of death for African American womens ages 25-44. a. True b. False c. Not sure

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50 Vol. 63, No. 3 2012 Northeast Florida Medicine

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Until there’s a cure, there’s hope. UF CARES is Northeast Florida’s only comprehensive pediatric and family-focused HIV and AIDS program. Services include: • Primary and Specialty Care Services • Family Centered Medical Case Management • Social Services Case Management • Free HIV Testing and Counseling • Health Education • Nutritional Evaluations • Family Planning and Gynecological Care • Psychological Evaluations • Access to Pediatric, Adolescent, and Adult Clinical Trials/Research Studies • Support Groups and Consumer Advisory Board/CAB • Perinatal Visits and Services for HIV-Infected Pregnant Women • Legal Aid Services

www . DCMS online . org

Mobeen H. Rathore, MBBS, CPE, FACPE, FIDSA, FAAP Director, UF CARES Associate Chair, Department of Pediatrics Chief, Division of Pediatric Infectious Diseases and Immunology

University of Florida Center for HIV/AIDS Research, Education and Services (UF CARES)

904-244-3051 • http://hscj.ufl.edu/ufcares

Northeast Florida Medicine Vol. 63, No. 3 2012 51

DCMS Membership Applications These physicians’ applications for membership in the Duval County Medical Society are now being processed. Any information or opinions you may have concerning the eligibility of the applicants listed here may be directed to Ashley Booth Norse, MD, DCMS President (904-244-4106) or Karen Pan, Membership Director (904-355-6561 x107).

Brooke N. Bair, DO Dermatology Gulf Coast Dermatology Medical Degree: Nova Southeastern University Residency: MSU/St. Mercy Hospital Larae C. Brown, MD OB-GYN UF Generation to Generation OB-GYN Medical Degree: University of Florida College of Medicine Residency: UFHSC/Jacksonville Shamsur Chowdhury, MD Pediatric Critical Care Medicine UF Pediatric Cardiovascular Center Medical Degree: Chittagong Medical College Residency: New York Methodist Hospital Fellowship: University of Chicago College of Medicine & Children’s Hospital of Pittsburgh Bharat K. Gummadi, MD Cardiology Shands at Lake Shore Medical Degree: St. George’s University Residency/Fellowship: University of Florida College of Medicine/JAX Jason Ho, MD Pediatric Cardiology UF Pediatric Cardiovascular Center Medical Degree: East Carolina University Brody School of Medicine Residency: East Carolina University Brody School of Medicine Fellowship: Indiana University School of Medicine & Vanderbilt University School of Medicine Gloria Hou, MD Physical Medicine & Rehabilitation Brooks Rehab Medical Group Medical Degree: Harvard Medical School Internship/Residency: McGaw Medical Center of Northwestern University Ross Eon Jones, MD Family Medicine Baymeadows Family Practice & Peds Center

Medical Degree: University of Florida College of Medicine Residency: St. Vincent’s Family Medicine Daniel Kessler, DO Family Medicine Family Care Partners Medical Degree: Nova Southeastern University Internship/Residency: Mayo Clinic Benjamin John Ludwig, MD Diagnostic Radiology/Neuroradiology Drs. Mori Bean & Brooks PA Medical Degree: Michigan State University College of Human Medicine Residency: Boston University Medical Center Fellowship: Duke University Medical Center Thomas J. Moon, Jr., MD Pediatric Cardiology UF Pediatric Cardiovascular Center Medical Degree: University of Texas at San Antonio Residency: University of North Carolina at Chapel Hill Fellowship: Children’s Hospital Boston Eduardo Oyola Torres, MD Diagnostic Radiology/Neuroradiology Drs. Mori Bean & Brooks PA Medical Degree: University of Puerto Rico School of Medicine Residency: St. Joseph’s Hospital & Medical Center Fellowship: Barrow Neurological Institute Andreea Poenariu, MD Nephrology UF Nephrology Medical Degree: University of Medicine & Pharmacy Carol Davila Residency: New York University Downtown Hospital Fellowship: Brown University Asma Salahuddin, MD Pediatrics UF Pediatric Service Medical Degree: University of Florida College of Medicine Residency: UFHSC/Jacksonville

52 Vol. 63, No. 3 2012 Northeast Florida Medicine

Sophia E. Sheikh, MD Emergency Medicine UF Emergency Medicine Medical Degree: University of Alabama Residency: UFHSC/Jacksonville Fellowship: Emory University Hospital Terrence Lee Soldo, DO Family Medicine St. Vincent’s Family Medicine Residency Medical Degree: Kirksville College of Osteopathic Medicine Internship/Residency: Naval HospitalCamp Pendleton Fellowship: UNC-Faculty Development Daryoush Tavanaiepour, MD Neurosurgery UF Neurosurgery Medical Degree: University of Otago Internship/Residency/Fellowship: Virginia Commonwealth University School of Medicine Fellowship: Brigham & Women’s Hospital Deborah J. Williams, MD Emergency Medicine UF Emergency Medicine Medical Degree: Wake Forest University School of Medicine Residency: UFHSC/Jacksonville RESIDENTS/FELLOWS/MAYO CLINIC Cardiology Andrew Kurklinsky, MD General Surgery Brooke Augustin, MD Wesley Dailey, MD John Dortch, MD Brian Reeves Giles, MD Minimally Invasive Surgery Marc Mesleh, MD Urology Andrew Davidiuk, MD Ram Pathak, MD RESIDENTS/FELLOWS/ UNIVERSITY OF FLORIDA JACKSONVILLE Anesthesiology Matthew Mello, MD Linda Young, MD Mary Zoccoli, MD

www . DCMS online . org

Cardiology Charles-Lwanga Bennin, MD Lydia Engwenyu, MD Jacinta Green, MD Wassim Jawad, MD Kamaldeep Singh, DO

Dhruv Panchal, MD Dhruvkumar Patel, MD Virin Ramoutar, MD Khurram Tariq, MD Sam Thomas, MD

Cardiology-Clinical Cardiac Electrophysiology Gabriel Mufuka, MD

Zaid Brifkani, MD Hasan Riaz, MD

Cardiology-Interventional Cardiology Stephen Chen, DO Diagnostic Radiology Amanda Kent, DO Abdur Khan, MD Daniel Roura, MD Alicia Schrader, DO Huynh Tran, MD Emergency Medicine Neal Aaron, DO Laurie Bryant, DO Gautam Dixit, MD Kelvin Harold, MD Karl Horn, MD Kate Justus, MD Melissa Mann, MD Alex Mathai, MD Ryan McKenna, DO Dena Mohnani, MD Chase Ranson, MD Jordan Smith, MD Matthew Thomas, MD Nitin Ubhayakar, MD Nicholas Wilkes, MD Endocrinology Salma Makhoul-Ahwach, MD Melanie Thomas, MD Gastroenterology Sujai Jalai, MD Infectious Disease Shobha Vootukuri, MD Internal Medicine Tracy Ashby, DO Amit Babbar, MD James Banks, MD Sharica Brookins, MD Bilkisu Gave, MD Saif Ibrahim, MD Constance Katsafanas, DO Haley Letter, MD Robert Mannel, MD Kaitlin McCurdy, MD Vinay Minocha, MD Bashar Mourad, DO Jesse Onyenekwe, MD Kavita Pal, MD www . DCMS online . org

Pathology-Cytopathology Alexandra Bovbel, MD Harish Goli, MD

Nephrology

Neurology

Ryan Crooks, MD Fahed Saada, MD Adil Zia, MD OB Anesthesiology Anita Vinjirayer, MD OB-GYN Daniel Benrubi, MD, MPH Christine Djapri, MD Charlene Hylton, MD Anesha Maxwell, MD Aaron Snyder, MD Tiffannie Walker, MD

Pediatrics Olumuyiwa Akerele, DO Stefani Altman, MD Allison Bechtel, DO Ashley Bennett, MD Joanna Ganczar, DO Tariq Gulzar, MD Krystin Harrison, MD Claire Lancaster, DO Sana Merchant, MD Jolie Ramesar, MD Elizabeth Ropp, DO Caitlin Wainscott, MD Yiting Yang, MD Pediatric Emergency Medicine Lorraine Mendez, MD Pediatric Endocrinology Monica Dussan Buitrago, MD

Oncology Louise Zhou, MD

Pediatric Infectious Disease Andres Alarcon, MD Kristie Bragg, MD

Ophthalmology Chad Hummel, MD

Rheumatology Priyanka Jalandhara, MD

Ophthalmology-Vitreo-Retinal Keyvan Koushan, MD

Surgery Todd Husty, MD Keya Locke, MD Noah Melikian, MD Song Pak, MD Rita Patel, MD Katherine Puckett, DO Idania Mejias Rodriguez, MD Priya Sharma, MD Christopher Villar, MD

Orthopaedic Surgery Kathryn Bentley, MD Cody Martin, MD Mark Wilson, MD Jacob Worsham, MD Pathology-Anatomic & Clinical Claudia Ormenisan, MD Yi Zhuang, MD Pathology-Breast Pathology Mark Laudenschlager, MD

Surgical Critical Care Mark Smith, MD

Thinking About...Selling a Practice? Buying a Practice? Terry Flanagan/Direct 877-988-0911 t.flanagan@murphybusiness.com

Murphy Business and Financial Services Northeast Florida Medicine Vol. 63, No. 3 2012 53

OCR Launches Full Scale HIPAA audits in 2013 Are you ready for a HIPAA Audit? The Office of Civi Rights (OCR) in the U.S. Department of Health and Human Services announced it plans to launch a full scale audit program in 2013. The results of the OCR's pilot audit program shows: • Small covered entities had more issues than larger ones. • Health care providers had more problems than plans or clearinghouses • Security is the biggest problem. Breath easier by letting the professionals of Secure Data Consortium with over 20 years experience guide you through the maze of HIPAA compliance.

Medical IT: ONE STOP SHOP These days a medical office typically uses products from multiple vendors. When there are problems, staff can have problems identifying exactly where the problem lies which can cause critical systems to be down for extended periods of time. These problems create frustration among staff and patients. · · · · · · · · ·

Virus/Spyware Infections Printer Problems Domain resources not available User(s) not able to access critical Healthcare data securely EMR/EHR not working properly PACS equipment not communicating properly Lab Equipment issues Servers/Workstations not properly maintained Dictation software/hardware malfunctioning

We also provide custom IT and software solutions for all types of practices. Whether you have a solo Physician practice or multiple Physicians/locations, Secure Data Consortium is your one stop shop for all your Technology needs.

At Secure Data Consortium, we understand that time is of the essence. We strive to identify and correct IT issues at Medical Practices expediently.

Call us today to take the headache out of Healthcare IT! 904-419-9SDC • ( 904-419-9732 )

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What's the new normal? Come to The Diamond Group dinner workshops "The New Normal - 6 Investment Strategies That Do Not Work in Today's Investment World" • January 22, 2013 - Duval County member event • February 5, 2013 - St. Johns County member event • March 5, 2013 - Duval County member event • March 14, 2013 - Clay County (monthly membership meeting)

For more information and to register, go to www.dcmsonline.org Attend these exclusive Society events designed specifically for physicians to learn strategies to protect their assets. These workshops are free to Society members and spouses. Come and learn about "The New Normal." Registered Representative of and securities offered through Berthel Fisher Company Financial Services (BFCFS, member FINRA/SIPC. The Diamond Group is independent of BFCFS.

54 Vol. 63, No. 3 2012 Northeast Florida Medicine

Financial Planning 9 Family Office You work hard. Your money should work harder.

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www . DCMS online . org

Count on our team any season Find out how Community Hospice, your hometown hospice team, is there for your patients and their families this season and any time of the year. Together, we can give them the gift of quality time with family and friends.

904.407.6500 • 866.253.6681 toll free • communityhospice.com Community Focused • Community Supported Serving Baker, Clay, Duval, Nassau and St. Johns counties since 1979

Duval County Medical Society Foundation 555 Bishopgate Lane Jacksonville, FL 32204 ADDRESS SERVICE REQUESTED

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We do what no other medical malpractice insurer does. We reward loyalty at a level that is entirely unmatched. We honor years spent practicing good medicine with the TributeÂŽ Plan. We salute a great career with an unrivaled monetary award. We give a standing ovation. We are your biggest fans. We are The Doctors Company.

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We created the Tribute Plan to provide doctors with more than just a little gratitude for a career spent practicing good medicine. Now, the Tribute Plan has reached its five-year anniversary, and over 22,700 member physicians have qualified for a monetary award when they retire from the practice of medicine. More than 1,300 Tribute awards have already been distributed. So if you want an insurer thatâ&#x20AC;&#x2122;s just as committed to honoring your career as it is to relentlessly defending your reputation, request more information today. Call (800) 741-3742 or visit us at www.thedoctors.com/tribute. Endorsed by

www.thedoctors.com/fpic Tribute Plan projections are not a forecast of future events or a guarantee of future balance amounts. For additional details, see www.thedoctors.com/tribute.

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