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Rheumatology Practice News

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May 2012

Special Edition

Expert Insights From Cleveland Clinic Rheumatologists

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hile visiting and interviewing several of the physicians who make up the Cleveland Clinic’s Department of Rheumatic and Immunologic Diseases (see article, p. 23), which is a part of the Orthopaedic and Rheumatologic Institute there, we asked a few

of the rheumatologists to comment on recent clinical studies that they felt were important. What follows are a few such commentaries. Note that we have written a summary of the study findings followed by commentary written by a Cleveland Clinic physician.

Osteocyte-Secreting Sclerostin Targeted by Novel Drug From the Journal of Bone and Mineral Research

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n a Phase I trial, researchers have demonstrated that targeting sclerostin, an osteocyte-secreted protein, using a sclerostin monoclonal antibody—in this case, the novel AMG 785 (manufactured as part of a partnership between UCB and Amgen)—is both safe and effective in the treatment of postmenopausal osteoporosis. UCB and Amgen have announced their intention to commence Phase III trials of this

EXPERT INSIGHT Chad Deal, MD Head, Center for Osteoporosis and Metabolic Bone Disease Department of Rheumatic and Immunologic Diseases Cleveland Clinic

novel antibody later this year.

It is believed that sclerostin negatively regulates osteoblasts and inhibits bone formation. In this first trial in 72 humans, healthy men and postmenopausal women received a single dose of either AMG 785 or placebo (ratio, 3:1). AMG 785 was administered in doses of 0.1, 0.3, 1, 3, 5, or 10 mg/kg subcutaneously or 1 or 5 mg/ kg IV, and patients in both groups were monitored for up to 85 days, depending on the dose amount. The study results were published in the

Journal of Bone and Mineral Research (2011;26:19-26).

The authors, a team of researchers from Amgen, found that AMG 785 was “generally … well tolerated.” Only one treatment-related serious adverse event—nonspecific hepatitis—was reported (and resolved).

No deaths or study discontinuations occurred. Interestingly, the researchers found that AMG 785 pharmacokinetics were “nonlinear” with respect to dose level. They observed dose-related increases in the bone

There currently is only one anabolic agent for osteoporosis, teriparatide.

This study is the first in-human trial of a new anabolic agent, AMG 785, a monoclonal antibody against sclerostin.

Sclerostin is an inhibitor of Wnt signaling, a major pathway in cells for osteoblast function. Sclerosteosis is a disease that results from a homozygous genetic defect that reduces sclerostin

secretion. These patients have extremely high bone mass with Z-scores of at least 5.0 in many cases. AMG 785 binds to sclerostin, removing an inhibitor of Wnt signaling resulting in increased osteoblast function and bone formation. In this trial the drug, given as one subcutaneous injection, increased bone mass in the lumbar spine of postmenopausal women by 5.3% in 85 days. If the

formation markers procollagen type 1 N-propeptide, bone-specific alkaline phosphatase, and osteocalcin, as well as a dose-related decrease in the bone resorption marker serum C-telopeptide, the latter of which resulted in a large anabolic window. Additionally, on day 85, there were statistically significant increases in bone mineral density of up to 5.3% in the lumbar spine and 2.8% in the total hip compared with placebo. Six patients, all in the higher-dose groups, developed anti-AMG 785 antibodies.

rate of increase continues with additional doses in continuing trials, the one-year increase in bone mass would be more than 20%.

This drug has the potential to be a game changer in treating osteoporosis. It is currently in Phase III trials for postmenopausal osteoporosis and for healing of hip and tibial fractures.

Bisphosphonates Carry Small Absolute Risk for Atypical Fracture From The New England Journal of Medicine

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population-based Swedish study has found that the absolute risk for atypical fracture of the femoral shaft associated with the use of bisphosphonates is small. The findings were published in The New England Journal of Medicine (2011;364:17281737, PMID: 21542743).

Previous studies yielded conflicting results about a possible association between atypical femoral fractures and the use of bisphosphonates for reducing overall fracture risk in patients with osteoporosis. The researchers

sought to clarify the issue with population-based nationwide analyses. In Sweden in 2008, 12,777 women aged 55 years or older sustained a fracture of the femur. Of these women, 1,271 had a femoral subtrochanteric or shaft fracture. Radiographs from 1,234 of these patients were reviewed, and 59 patients with atypical fractures were identified. Using national registries, the researchers obtained data on medications and coexisting conditions.

Both a nationwide cohort analysis and a case–control study, comparing the 59 case patients with 263 control patients who had ordinary subtrochanteric or shaft fractures, were conducted.

In the cohort analysis, the ageadjusted relative risk for atypical fracture with any use of bisphosphonates was 47.3 (95% confidence interval [CI], 25.6-87.3). The increase in absolute risk was five cases per 10,000 patientyears (95% CI, 4-7), corresponding to an average number needed to harm of 2,000 per year of use. The risk was higher with longer duration of use.

In the case–control study, 78% of the case patients received bisphosphonates compared with 10% of the controls, corresponding to a multivariable-adjusted odds ratio of 33.3 (95% CI, 14.3-77.8). The risk appeared to be independent of coexisting conditions,

age and concurrent use of systemic glucocorticoids or other drugs known to affect bone. There was a 70% reduction in risk for every year since the last use of bisphosphonates (odds ratio, 0.28; 95% CI, 0.21-0.38).

The researchers concluded that, despite the high prevalence of current bisphosphonate use in patients with atypical fractures, the absolute risk for atypical fracture associated with bisphosphonates was small compared with the benefits of the medication for patients at high risk for osteoporotic fracture. These analyses, they said, “should be reassuring for bisphosphonate users.”

May 2012

Rheumatology Practice News

Special Edition

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Causality of Anti-TNF Therapy and PML Remains Undefined From Arthritis & Rheumatism

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study that attempted to define the relationship between progressive multifocal leukoencephalopathy (PML) and immunosuppressive therapy with biologics for the treatment of autoimmune rheumatic disease (ARD) returned inconclusive results, owing in part to the relative paucity of cases during the study period, which stretched from late 1997 to early 2010. However, the study’s findings, the authors believe, are noteworthy because they seem to signal a possible association between the use of one biologic agent, rituximab (Rituxan, Genentech), and PML among patients with ARD. PML, an opportunistic infection,

EXPERT INSIGHT Leonard Calabrese, DO Head, Center for Clinical Immunology Department of Rheumatic and Immunologic Diseases Cleveland Clinic

PML is a devastating complication that has long been recognized in the setting of immunosuppressive therapy

EXPERT INSIGHT Chad Deal, MD Head, Center for Osteoporosis and Metabolic Bone Disease Department of Rheumatic and Immunologic Diseases Cleveland Clinic

Patients are concerned about bisphosphonate side effects, and

at the onset of PML, other than an antimalarial drug and/or low-dose glucocorticoids. They also noted that all but one biologic-treated patient had at least one potential confounding factor for the diagnosis of PML. The authors acknowledge that the paucity of cases demonstrates that a causal relationship between anti-TNF therapy and PML, in general, is unlikely. However, although it is clearly a rare adverse event, given the complex nature of PML, further study of the role of rituximab therapy in ARD is warranted, as is continued vigilance in the treatment setting, particularly in patients with current or prior exposure to an alkylating agent.

recently has been reported in the ARD setting, particularly among patients with rheumatoid arthritis and other diseases and who are administered biologic therapy. However, its exact cause is poorly understood and attributing its onset to the use of specific agents has proved challenging.

The study, which was published in the March 15 issue of the journal Arthritis & Rheumatism (Epub ahead of print), accessed the FDA’s Adverse Event Reporting System (AERS) database via a Freedom of Information Act request and identified 34 cases of PML in the ARD setting during the study period. Of these ARD cases, 17 had been diagnosed with systemic lupus erythematosus, which appears to have

a somewhat heightened susceptibility to PML; 10 with rheumatoid arthritis; four with vasculitis; and three with dermatomyositis. Genentech assisted in the research by providing the authors with some of the raw data.

Of the identified cases of PML in the ARD setting, 15 of the patients had undergone treatment with at least one biologic agent: 14 with rituximab and 6 with an anti-tumor necrosis factor (anti-TNF) agent (5 were treated with anti-TNF therapy prior to starting rituximab). The remaining patients were treated with synthetic diseasemodifying antirheumatic drugs. The authors found that 4 of the rituximabtreated patients were not receiving additional immunosuppressive therapy

but, given its rarity, it has not been the focus of clinical concern for most rheumatologists. With the introduction of biologic therapies and the recognition of the link between PML and drugs such as natalizumab (Tysabri), used in multiple sclerosis and inflammatory bowel disease, and efalizumab (Raptiva), once used in psoriasis, the situation has changed.

This study, of which I was a co-author, examined the long-term FDA AERS database and clearly demonstrated that PML can be seen in patients with rheumatic

disease who are undergoing various immunosuppressive therapies, including those that are both non-biologic and biologic-based. Fortunately, even for drugs like rituximab, which has been the biologic therapy most frequently associated with PML, it is an extremely rare event (estimated at less than 1 in 25,000 exposed patients).

Rheumatologists need to be vigilant for the development of PML and not ascribe new-onset focal or diffuse neurologic dysfunction to underlying disease (ie,

neuropsychiatric lupus or central nervous system vasculitis) and aggressively pursue the diagnosis with screening magnetic resonance imaging and, if abnormal, then lumbar puncture with polymerase chain reaction analysis for the John Cunningham (JC) virus. In rare situations, brain biopsy may be needed to confirm the diagnosis. Unfortunately, there is no specific therapy for PML, but decreasing or eliminating immunosuppressive treatments may be highly beneficial.

many are choosing not to start or to discontinue these medications. Bisphosphonates undoubtedly are effective for reducing fracture risk; as with all medications, the risks and benefits of medication need to be considered, and if the benefits outweigh the risks then the medications should be used. One reason patients are fearful about bisphosphonate therapy is the risk for atypical hip fracture. This study reviewed more than 12,000 hip fractures from Sweden, of which 1,271 occurred in the subtrochanteric region or femoral shaft.

Based on the American Society for Bone and Mineral Research case definition of atypical fracture, 59 of 1,271 were deemed atypical. An important point is that most femoral shaft fractures are not atypical and may be typical osteoporotic fractures; x-rays need to be reviewed to make this determination.

In patients with atypical hip fractures, there was an association with bisphosphonate use, with an odds ratio of 33.

However, the absolute risk in patients on bisphosphonates was five cases per 10,000 patient years—this is termed the

number needed to harm. In most trials, the number needed to treat to prevent a fracture is about 100. Thus the benefit, reduction of hip fracture, is much greater than the risk, atypical hip fracture. Interestingly, the risk for atypical fracture increased within one year of use and the risk decreased rapidly after discontinuation. This is at odds with the thinking on the presumed etiology of these fractures, adynamic bone accumulation of micro-damage.

Rheumatology Practice News

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May 2012

Special Edition

Increasing Allopurinol Dose Lowers Urate in Chronic Gout From Arthritis & Rheumatism

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ncreasing the dose of allopurinol above the proposed creatinine clearance–based dose results in a significant reduction in serum urate concentrations in patients with chronic gout, even in those with renal impairment. The increased dosing did not increase significant safety risks in this study.

Published in Arthritis & Rheumatism (2011;63:412-421), this study enrolled 90 chronic gout patients from the Christchurch, New Zealand area who had been receiving allopurinol for a EXPERT INSIGHT Brian Mandell, MD, PhD Department of Rheumatic and Immunologic Diseases Orthopaedic and Rheumatologic Institute Cleveland Clinic

For years it has been advised to reduce the dose of allopurinol in the

month or longer and whose dose was increased by 50 to 100 mg each month until the target serum urate level of <0.36 mmol/L (less than 6 mg/dL) was achieved. The proposed recommended dose of the drug is based on an individual patient’s creatinine clearance using a formula developed by Hande et al (Am J Med 1984;76:47-56). Patients were seen monthly until their serum urate level was less than 0.36 mmol/L for three consecutive months, after which they were seen at three-month intervals for a period of 12 months.

Doses were increased by as much as

400 mg over the creatinine clearance– based dose (the mean baseline dose was 221.4 mg per day); the mean final dose was 335.7 mg per day.

In all, 45 of the enrolled patients had a serum urate concentration of at least 0.36 mmol/L, and the dose of allopurinol was increased in these patients. Three of these patients developed rashes, and their treatment and/or dose escalation was discontinued. Another 7 patients were lost to follow-up or developed intervening medical problems. However, 31 of the 35 patients who completed

setting of chronic kidney disease (CKD) due to the increased prevalence of allopurinol hypersensitivity reactions in patients with CKD. However, despite the decreased renal clearance and resultant increased levels of oxypurinol in patients with CKD who receive allopurinol, it has not been prospectively demonstrated that reduction in allopurinol dosing in gouty patients with CKD will reduce the incidence of severe allergic reactions. What has been shown, however, is that dose reduction will NOT likely provide appropriate efficacy (lowering of

serum urate to <6.0 mg/dL).

Recent studies, including this one, demonstrate (in a small group of patients) that if allopurinol is started at a low dose and then slowly escalated to a dose that is able to lower the serum urate to <6 mg/dL, there is an acceptable and apparently not increased frequency of hypersensitivity reactions; and thus there is no need to utilize more expensive alternative therapies.

The sample size is certainly not large enough to be definitive when studying a rare side effect of a medication, but

Scleroderma Pulmonary Function Test Proposed From Arthritis & Rheumatism

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team of British researchers has developed what they describe as an “easily applied formula” for measuring pulmonary function in— and identifying potential candidates for right-sided heart catheterization (RHC) among—patients with systemic sclerosis.

The formula is designed to assess patient risk for pulmonary hypertension (PH) by measuring their mean pulmonary artery pressure (mPAP), and uses oxygen saturation (as measured by pulse oximetry; Spo2) and diffusing capacity for carbon monoxide (DLco%) as its key variables. In a retrospective study designed to assess the formula’s accuracy, the results of which were published in Arthritis

& Rheumatism (2011;63:3531-3539), the formula’s creators found that it proved to be a strong predictor of the presence of PH in 129 patients with systemic sclerosis (SSc).

Historically, RHC has been considered the gold standard for the diagnosis of PH; however, RHC is invasive, and pulmonary function tests alone are not always a reliable method for determining the need for the procedure—hence, the need for a new methodology. The Arthritis & Rheumatism study was supported through funding from the British National Health Service. Recent data has revealed that PH occurs in more than 10% of patients with SSc. The new formula can be stated as follows: mPAP = 136 – Spo2 – 0.25 x DLco%

In the SSc study, using a predictive mPAP threshold of 25 mm Hg (studies have shown that in a population of patients with scleroderma, those with mPAP less than 25 mm Hg are unlikely to have PH), the formula’s sensitivity was 90.1% and its specificity was 29.2%; the results were confirmed by echocardiography, the primary nominative test for pulmonary artery pressures. The London-based researchers, led by Benjamin Schreiber, found that a high formula-predictive mPAP was “strongly associated with the presence” of PH. They concluded, “Use of this simple formula may assist in the interpretation of results of pulmonary function tests performed as part of the routine screening protocol in patients with SSC as well as in better selection of patients for RHC.”

the study had serum urate levels of less than 0.36 mmol/L at 12 months.

In these patients, a significant reduction in the serum urate concentration (mean, 0.30 mmol/L) was observed for all allopurinol doses above the recommended dose. The mean time to target serum urate level was 3.9 months.

Among the 5 patients who continued to have serum urate levels of at least 0.36 mmol/L at the conclusion of the study period, 2 had undetectable levels of plasma oxypurinol, indicating likely noncompliance with allopurinol treatment.

since the initial recommendation for dose adjustment did NOT come from a controlled prospective trial, I believe that this paper (combined with the clinical experience of many rheumatologists) supports the use of allopurinol dose escalation in the setting of CKD—but certainly close observation, vigilance for the development of any “rash,” and patient education are absolutely required. Hopefully, this will improve the management of patients with gout and the frequent comorbidity of CKD.

EXPERT INSIGHT Soumya Chatterjee, MD, MS, FRCP Staff Physician Department of Rheumatic and Immunologic Diseases Cleveland Clinic

Pulmonary disease in scleroderma (ie, SSc) mainly comprises interstitial lung disease and PH. According to various series, PH occurs in about 7% to 12% of patients with SSc, and along with interstitial lung disease currently is one of the leading causes of death in this disease. Multiple studies have consistently demonstrated that PH in SSc has a much worse prognosis compared with idiopathic PH, and the response to current therapy also is not as favorable.

Doppler transthoracic echocardiography (TTE) can be quite unreliable for the screening and diagnosis of early

May 2012

Rheumatology Practice News

Special Edition

37

Pegloticase Proves Effective for Lowering Uric Acid Levels From the Journal of the American Medical Association

or refractoriness, and serum uric acid concentration of 8.0 mg/dL or higher.

They received 12 biweekly IV infusions of either pegloticase (8 mg), pegloticase alternating with placebo (thus, the monthly treatment group), or placebo only. The primary end point for both trials was plasma uric acid levels of less than 6.0 mg/dL at the conclusion of 3 and/or 6 months. Patient baseline characteristics were similar across the trials. The trials were funded by Savient, the manufacturer of the study drug.

According to the authors, the primary end point was achieved in 42% of the patients overall (in both trials) in the biweekly group, compared

with 35% of the patients in the monthly groups for both trials. No patients in the placebo group in either trial achieved the primary end point (P<0.001). Serious adverse events (AEs) were reported more frequently in patients treated with biweekly (24%) and monthly (23%) pegloticase than in patients receiving placebo (12%). The most common AE was gout flare, which was reported in approximately 80% of patients across the 3 pooled study groups. The second most common AE was infusion-related reaction, which was reported in 26% of the patients in the biweekly groups, 42% of the patients in the monthly groups, and 5% of the patients in

There are patients with clearly refractory tophaceous gout who

benefit from “debulking” of their significant uric acid burden. This paper summarizes the efficacy of pegloticase therapy. The side effects are described, which turn out to be manageable with a strategy of monitoring patients for the presence of anti-drug/pegylation antibodies. Although no serious anaphylactic episodes were described, infusion reactions do occur. However, if patients are monitored for the dramatic serum urate-lowering effect of this drug (levels often <1 mg/dL 2 weeks following infusion), then patients who have (or

who develop) neutralizing antibodies to the drug are identified by the lack of maintained hypouricemia over the 2 weeks following the prior infusion. It is these patients who are likely to develop infusion reactions. These antibodies commonly occur, may even precede drug therapy (!), but often happen early on in the course of chronic (every2-week) therapy. Patients who do not have these neutralizing antibodies do well and exhibit dramatic reductions or disappearance of tophi over time.

The ideal duration of therapy and

PH because of its inherent and operator-dependent limitations. The prevalence of PH often is overestimated when based on TTE. Therefore, it is inappropriate to initiate specific therapy based on TTE findings alone, and the diagnosis only can be based on the results of an RHC. However, RHC is an invasive procedure, with inherent risks, even in expert hands in a specialized PH center. It often is difficult to select patients for an RHC based on TTE findings alone, as a TTE frequently overestimates the prevalence of PH. When dictated by a TTE, many patients end up receiving an unnecessary RHC, which

often is reported as normal. Hence, the TTE-driven RHC does not change their management; yet the patients are exposed to the risk for an invasive procedure, and it results in an unnecessary waste of resources, manpower and health care dollars. It is clear that selecting patients for RHC more carefully will be cost-effective. The limitations of the “six-minute walk test” and plasma brain natriuretic peptide or N-terminal prohormone of brain natriuretic peptide levels in SSc patients limit their use as noninvasive screening tests. It also is not reliable to longitudinally follow these test results to evaluate response

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ompared with placebo, pegloticase (Krystexxa, Savient) lowers uric acid levels in patients with chronic gout refractory to conventional urate-lowering therapy, according to the results of 2 replicate, randomized, double-blind, placebocontrolled trials that were published in the Journal of the American Medical Association (2011;306:711-720).

The trials, which enrolled 225 patients from 56 rheumatology practices across North America, were conducted between June 2006 and October 2007. Patients included those with severe gout, allopurinol intolerance

EXPERT INSIGHT Brian Mandell, MD, PhD Department of Rheumatic and Immunologic Diseases Orthopaedic and Rheumatologic Institute Cleveland Clinic

to therapy or predict outcome.

In their study, Schreiber et al provide an excellent tool (based on a pulmonary function test, which is routinely recommended in SSc patients) that should help select patients for RHC more carefully, and will likely increase the yield for a positive RHC. The predictive value of this test seems quite high, and may help further streamline the patient selection process for RHC. The formula-derived mPAP also will help increase the predictive value for PH in patients with ambiguous TTE findings, and hence will more reliably justify the RHC.

the placebo groups. Serious infusionrelated reactions occurred in 5% of the biweekly patients and 8% of the monthly patients.

According to the authors, antibodies to pegloticase (typically immunoglobulins IgM and IgG isotopes) “appeared early in treatment and were detected” in 134 of 150 patients treated with the drug. Only one of the 52 pegloticasetreated patients with pegloticase antibody exceeding a titer of 1:2,430 at any time maintained a urate-lowering response to therapy.

the ideal time to introduce oral urate-lowering therapy remain to be defined. Although extremely expensive and a bit labor-intensive, this therapy should be strongly considered in patients with massive urate deposition, and I believe that it is being underutilized. Experience is growing with use in patients with chronic kidney disease and other comorbidities. Mobilization flares, occurring with the dramatic decrease in serum urate levels, must be anticipated and managed aggressively.