אלרגיה ואימונולוגיה update הרפואה

‫כתב העת של האיגוד הישראלי לאלרגיה ואימונולוגיה קלינית‬ ‫גיליון מס' ‪ | 1‬אוקטובר ‪ | 2009‬מבית ההסתדרות הרפואית בישראל‬

‫המודעות למחלות אלרגיה ‪-‬‬ ‫ואוטואימוניות ‪-‬‬ ‫קווים מנחים לאבחנה וטיפול ‪-‬‬ ‫בבצקת (אנגיואדמה) תורשתית ‪-‬‬ ‫תקצירים ועדכונים מהספרות ‪-‬‬ ‫העולמית והמקומית ‪-‬‬ ‫הכינוס השנתי של האיגוד ‪-‬‬ ‫לאלרגיה ואימונולוגיה קלינית ‪-‬‬ ‫‪ 31-29‬באוקטובר‪ ,‬צפת ‪-‬‬

‫גליון מס' ‪ | 1‬אוקטובר ‪2009‬‬ ‫כתב העת של האיגוד הישראלי לאלרגיה‬ ‫ואימונולוגיה קלינית‬

‫מבית ההסתדרות הרפואית בישראל‬

‫אלרגיה ואימונולגיה‬ ‫דבר היו"ר‬

‫תקצירים‬

‫‪ 04‬המודעות למחלות אלרגיה‬ ‫ואוטואימוניות‬

‫‪ 40‬אלרגיה‬

‫פרופ' אליאס טובי‬

‫עדכונים מהספרות העולמית‬ ‫‪ Xolair 06‬לחרלת כרונית‬ ‫ד"ר ננסי אגמון לוין‬

‫‪ 06‬אימונותרפיה כטיפול ברגישות‬ ‫לחלב פרה‬ ‫ד"ר אוריאל כץ‬

‫‪ 08‬תאי ‪ B‬לימפוציטים בתלבושת‬ ‫חדשה‬ ‫פרופ' אליאס טובי‬

‫‪ 10‬תמונה אחת שווה אלף מילים‬ ‫ד"ר שלמה בר סלע‬

‫קווים מנחים ‪ -‬אנגיואדמה‬ ‫‪ 12‬קווים מנחים לאבחנה‬ ‫וטיפול בבצקת (אנגיואדמה)‬ ‫תורשתית‬ ‫ד"ר אבנר רשף‪ ,‬פרופ' שמואל קיויתי‪,‬‬ ‫פרופ' אליאס טובי‬

‫תוכנית הכינוס השנתי ‪2009‬‬

‫‪ 35‬אימונולוגיה‬ ‫‪ 32‬מחלות אוטואימוניות‬ ‫‪ 27‬כשל חיסוני ואיידס‬

‫מהספרות המקומית‬ ‫‪Psoriatic Arthropathy: 50‬‬ ‫?‪Where Now‬‬ ‫‪Gleb Slobodin, Itzhak Rosner,‬‬ ‫‪Michael Rozenbaum, Nina‬‬ ‫‪Boulman, Aharon Kessel,‬‬ ‫‪Elias Toubi‬‬

‫‪The Predictive Value of 46‬‬ ‫‪Specific Immunoglobulin‬‬ ‫‪E on the Outcome‬‬ ‫‪of Milk Allergy‬‬ ‫‪Menachem Rottem,‬‬ ‫‪Daniela Shostak, Sylvia Foldi‬‬

‫‪The Role of Mast 43‬‬ ‫‪Cells in Non-Allergic‬‬ ‫‪Inflammation‬‬ ‫‪Adaya Weissler, Yoseph A. Mekori,‬‬ ‫‪Adam Mor‬‬

‫חברי מערכת‬ ‫עורכת‪:‬‬ ‫ד"ר ננסי אגמון לוין‬ ‫חברי מערכת‪:‬‬ ‫פרופ' אליאס טובי‬ ‫ד"ר אילן דלאל‬ ‫ד"ר מנחם רותם‬ ‫ד"ר ולרי טיפליצקי‬ ‫ד"ר אוריאל כץ‬ ‫ד"ר מונה כידון‬ ‫ד"ר שלמה בר־סלע‬ ‫מח' פרסום ושיווק‪ :‬מדיה פארם‬ ‫אמיר דורון‪050-5569003 :‬‬ ‫גולן פרץ‪050-3003304 :‬‬ ‫כתובת המערכת‪:‬‬ ‫רח' זבוטינסקי ‪ ,35‬בניין התאומים ‪,2‬‬ ‫ת"ד ‪ ,3566‬רמת גן‪ ,‬מיקוד ‪52136‬‬ ‫טל'‪ ,03-6100430 :‬פקס‪03-7519673 :‬‬ ‫דוא"ל‪harefuah@ima.org.il :‬‬ ‫כל המודעות המתפרסמות בעיתון הן על‬ ‫אחריות המפרסמים בלבד‪ .‬כמו־כן גם תוכן‬ ‫המאמרים הוא על אחריות הכותבים בלבד‪.‬‬ ‫לעורכי העיתון ולהסתדרות הרפואית‬ ‫בישראל אין כל אחריות לתוכן המודעות‬ ‫והמאמרים‪.‬‬

‫‪ 24‬תוכנית הכינוס השנתי‬ ‫של האיגוד לאלרגיה‬ ‫ואימונולוגיה קלינית‬

‫צילום השער (‪)istockphoto‬‬ ‫התבוננות מעמיקה בחלקיקי‬ ‫אבק ‪ -‬הזווית המיקרוסקופית‪.‬‬

‫דבר היו"ר‬

‫הרפואה‪ | update‬אלרגיה ואימונולגיה | אוקטובר ‪2009‬‬

‫המודעות למחלות אלרגיה ואוטואימוניות‬

‫ב‬

‫תחילת המאה הקודמת היה השימוש במושג "תגובה‬ ‫אוטואימונית" אסור בהחלט‪ .‬רוב האימונולוגים אז נמצאו‬ ‫תחת ההשפעה המדעית האדירה של חתן פרס נובל‪,‬‬ ‫המדען הגדול פול ארליך‪ ,‬שהאמין בכל מאודו שהמערכת החיסונית‬ ‫שלנו אינה מסוגלת להגיב‪/‬לתקוף את עצמה ולגרום לנזק דלקתי‬ ‫כלשהו כתוצאה מתגובה זו‪.‬‬ ‫באותה התקופה התקדם המחקר על מחלות ממאירות‪ .‬בשנות‬ ‫הארבעים של המאה הקודמת התפתחו אמצעי טיפול מתקדמים‬ ‫כגון הטיפול הקרינתי‪ .‬בשנים אלו נכנס הטיפול באמצעות פניצילין‪,‬‬ ‫שנתן מענה לרבבות שעד אז מתו ממחלות זיהומיות‪ ,‬ובלי להפחית‬ ‫מחשיבות ההתקדמות הזו בשטחי רפואה אלו‪ ,‬נותר הנושא של‬ ‫מחלות אוטואימוניות ואלרגיות באפלה‪.‬‬ ‫רק בסוף שנות החמישים העזו מדענים כמו נואל רוז מבאפלו‬ ‫שבארצות הברית להצהיר בפה מלא שאכן קיימת תגובה‬ ‫אוטואימונית כנגד מרכיבים עצמיים‪ ,‬ושהתגובה הזו גורמת לעתים‬ ‫למחלה אוטואימונית‪.‬‬ ‫בתקופה זו תוארה לראשונה מחלת ה־‪.Auto Immune Thyroiditis‬‬ ‫זו הייתה ההתחלה‪ ,‬אמנם מעט באיחור‪ ,‬אבל המסע לתוך התחום‬ ‫של אימונולוגיה קלינית ואלרגיה יצא אז לדרך וההמשך ידוע‪.‬‬ ‫כמה נקודות ציון‪:‬‬ ‫ההתקדמות הגדולה בתחום האלרגיה ובהבנת מנגנוני החיסון‬ ‫הביאו לשימוש רחב באימונותרפיה‪ ,‬דבר ששינה את פני הטיפול‬ ‫במחלות אלרגיות‪ .‬לאחרונה גוברת ההתעניינות בחיסון תת־לשוני‪,‬‬ ‫שאמנם ההסכמה לגביו עדיין אינה מגובשת‪ ,‬אך זו היא התקדמות‬ ‫נוספת וחשובה בתחום זה‪.‬‬ ‫בנוסף ראוי לציון הטיפול בתרופות חדשניות‪ ,‬כגון הנוגדן כנגד ‪IgE‬‬ ‫או מתן תרופות חוסמות ליקוטרינים‪ ,‬שהוסיפו הרבה לאיכות הטיפול‬ ‫באסתמה‪.‬‬ ‫בתחום המחלות העוריות‪ ,‬כגון הדרמטיטיס האטופית והחרלת‬ ‫הכרונית‪ ,‬ראוי לציין את פריצת הדרך במתן ציקלוספורין מקומי‬ ‫ופומי שנתנו מענה לחולים רבים הסובלים מביטוי קליני קשה של‬ ‫מחלות אלו‪.‬‬ ‫גם בתחום המדע הבסיסי מתבצעות ומתפרסמות עבודות‬ ‫המצביעות על התפקידים השונים של תאי הפיטום בתהליכי דלקת‬ ‫שאינם נובעים מתהליכים אלרגיים‪ .‬לאחרונה מתבהרים יותר‬ ‫מנגנונים חדשים המשתתפים בתהליכי דה־גרנולציה של תאים אלו‪.‬‬ ‫ממצאים אלו מבססים את חשיבותם של תאי הפיטום במחלות‬ ‫זיהומיות ובתהליכי דחיית שתל‪.‬‬ ‫באשר למחלות אוטואימוניות‪ ,‬הרי שגם כאן פורסמו עבודות‬ ‫מחקר השופכות אור על התפתחות מחלות אלו‪ .‬מחלות חדשות‬ ‫הוגדרו בעקבות הימצאותם של נוגדנים כנגד מרכיבים תוך תאיים‪,‬‬ ‫כגון ‪ ANCA, anti Cardiolipin‬ו־‪ .anti P-Ribosomal abs‬ממצאים‬ ‫אלו אפשרו הבנה וטיפול נכונים יותר במצבים של קרישיות יתר‬ ‫או וסקוליטיס במחלות האוטואימוניות השונות‪ .‬בעקבות התיאור‬ ‫של נוגדנים כנגד פוספוליפידים שונים תואר לראשונה המצב ‪Anti‬‬ ‫‪ ,Phospholipid Syndrome‬שבמהרה תואר כמצב האוטואימוני השכיח‬ ‫ביותר מבין כל המחלות האוטואימוניות‪.‬‬

‫‪4‬‬

‫הכנסת הטיפולים הביולוגיים השונים כגון נוגדנים כנגד ‪TNF‬‬ ‫או נוגדנים המסלקים תאי ‪ B‬מדם פריפרי הביאו אף הם עידן חדש‬ ‫בטיפול במחלות האוטואימוניות השונות‪.‬‬

‫•‬

‫•‬

‫•‬

‫האיגוד הישראלי לאלרגיה ואימונולוגיה קלינית קיים כבר עשרות‬ ‫שנים‪ .‬הוא כולל בתוכו רופאים מומחים‪ ,‬חוקרים ועובדי מעבדה‪.‬‬ ‫תפקידי האיגוד הם רבים‪ ,‬ואציין רק חלק מהם‪:‬‬ ‫ •לשמור על רמה גבוהה של ידע בסיסי ומעשי בתחומים אלה‪.‬‬ ‫ •לחנך דור חדש של אלרגולוגים ואימונולוגים קליניים‪.‬‬ ‫ •להפיץ את הידע והמודעות למחלות אלו בקרב רופאי הקהילה‬ ‫ולהדק את הקשר עמם‪.‬‬ ‫ •להגביר את המודעות של ציבור החולים למחלות אלה‪ ,‬דבר שיביא‬ ‫לאבחון מהיר יותר של חולים וטיפול מוקדם בהם‪.‬‬ ‫בימים אלה האיגוד עוסק בבניית תוכנית שיתוף פעולה עם איגודים‬ ‫אחרים‪ ,‬כגון איגוד הרופאים הראומטולוגיים‪ ,‬רופאי עור‪ ,‬ריאות ואא"ג‪.‬‬ ‫בעקבות שיתוף פעולה זה יתקיימו בקרוב כנסים משותפים ויחוברו‬ ‫ניירות עמדה משותפים‪ ,‬דבר שיהיה לתועלת לכלל ציבור הרופאים‬ ‫והחולים גם יחד‪.‬‬ ‫בימים אלו יוצא לאוויר אתר האינטרנט של האיגוד ב"לבושו החדש"‪,‬‬ ‫מעוצב ומלא חומר על אודות האיגוד‪ .‬כל הפעולות הללו מחזקות את‬ ‫מעורבותו של האיגוד בעשייה היומיומית בשדה הרפואה‪.‬‬ ‫זהו הגיליון הראשון של "עיתון העדכונים של האיגוד לאלרגיה‬ ‫ואימונולוגיה קלינית"‪ .‬עיתון זה עתיד לצאת לאור כארבע פעמים‬ ‫בשנה‪ ,‬בתמיכת ההסתדרות הרפואית בישראל‪ ,‬והוא ישמש במה‬ ‫לעדכונים שוטפים במגוון התחומים שבהם עוסק האיגוד‪ :‬אלרגיה‪,‬‬ ‫אימונולוגיה בסיסית‪ ,‬חסר חיסוני‪ ,‬מחלות אוטואימוניות ועוד‪.‬‬ ‫עיתון האיגוד יגיע לכל חברי האיגוד ולכל רופא המעוניין להתעדכן‬ ‫בתחומים אלו‪.‬‬ ‫במת העיתון פתוחה בפני כל חברי האיגוד הן לכתיבה והן להבעות‬ ‫דעה בנושאים המעסיקים את האיגוד‪.‬‬ ‫חוברת זו יוצאת לקראת הכנס השנתי של האיגוד‪ ,‬שיתקיים‬ ‫בתאריכים ‪ 31-29‬באוקטובר ‪ .2009‬בכנס זה יוצגו עבודות רבות‬ ‫שבוצעו במרכזים שונים בארץ‪ .‬כמו כן יתארחו בכנס חוקרים מחו"ל‪,‬‬ ‫דבר המצביע על הקשר ההדוק שאנו מקיימים עם איגודים נוספים‬ ‫בעולם‪.‬‬ ‫לסיום‪ ,‬ברצוני לברך את כל חברי האיגוד ומשפחותיהם בברכת שנה‬ ‫טובה‪.‬‬

‫פרופסור אליאס טובי‬ ‫יו"ר האיגוד הישראלי לאלרגיה ואימונולוגיה קלינית‬

‫עדכונים מהספרות העולמית‬

‫הרפואה‪ | update‬אלרגיה ואימונולגיה | אוקטובר ‪2009‬‬

‫‪ Xolair‬לחרלת כרונית‬ ‫‪ (Omalizumab) Xolair‬הוא נוגדן מונוקלונאלי רקומביננטי הקושר‬ ‫באופן סלקטיבי אימונוגלובולינים מסוג ‪ ,IgE‬ובכך מעכב את קישורם‬ ‫לרצפטור בעל האפיניות הגבוהה ל־‪ IgE‬המצוי על תאי פיטום ותאים‬ ‫בסופיליים‪ .‬ההתוויה הנוכחית ל־‪ Xolair‬היא טיפול בגנחת סימפונות‬ ‫אלרגית קשה‪ ,‬וטיפול זה אכן הוכח כיעיל בהפחתת תסמיני גנחת‬ ‫הסימפונות‪ .‬הטיפול ב־‪ Xolair‬בחולי גנחת הסימפונות גורם לירידה‬ ‫ברמות ‪ IgE‬חופשי‪ ,‬ועקב כך לירידה בכמות הרצפטורים ל־‪ IgE‬על‬ ‫פני התא‪ .‬במאמר אשר פורסם בשנה האחרונה בדקו אלן קפלן‬ ‫וחבריו (‪ )J Allergy Clin Immunl 2008:122; 569-73‬את השפעת‬ ‫הטיפול ב־‪ Xolair‬על תסמיני מחלה אחרת‪ ,‬חרלת אוטואימונית‬ ‫כרונית‪ .‬כ־‪ 45%‬מחולי החרלת הכרונית נושאים נוגדנים עצמיים מסוג‬ ‫‪ IgG‬אשר קושרים את שרשרת אלפא של הרצפטור בעל האפיניות‬ ‫הגבוהה ל־‪ ,IgE‬וגורמים בכך לאקטיבציה ולדגרנולציה של תאי פיטום‬ ‫ובסופילים בעור‪ .‬הנחת המחקר היתה כי טיפול ב־‪ Xolair‬עשוי להוריד‬ ‫את מספר הרצפטורים בעלי האפיניות הגבוהה‪ ,‬ובכך גם את חומרת‬ ‫תסמיני החרלת‪ .‬על מנת להוכיח רעיון זה בדקו קפלן וחבריו ‪ 12‬חולים‬ ‫(בגילאי ‪ 75-18‬שנים‪ 4 ,‬גברים ו־‪ 8‬נשים) אשר סבלו מחרלת כרונית‬ ‫אוטואימונית‪ .‬אבחנת המחלה נעשתה באמצעות שני מבחנים‪ :‬מבחן‬ ‫שחרור היסטמין מבסופילים‪ ,‬אשר היה חיובי בכל החולים‪ ,‬ומבחן‬ ‫עורי אוטולוגי‪ ,‬אשר היה חיובי ב־‪ 8‬מתוך ‪ 12‬החולים‪ .‬כל החולים‬ ‫סבלו מתסמיני המחלה מעל ‪ 6‬שבועות (בין ‪ 7‬שבועות ל־‪ 30‬שנה)‪,‬‬ ‫ונותרו תסמיניים למרות טיפול אנטי־היסטמיני במינונים המקסימליים‬ ‫המקובלים‪ .‬ערכי ‪ IgE‬לפני הטיפול נעו בין ‪ ,2-102IU/ml‬והטיפול‬

‫ב־‪ Xolair‬ניתן במשך ‪ 16‬שבועות‪ ,‬אחת לשבועיים או אחת ל־‪ 4‬שבועות‬ ‫בהתאם לרמת ‪ .IgE‬במקביל ניהלו החולים יומן יומי שעקב אחר תסמיני‬ ‫המחלה‪ .‬במהלך תקופת המעקב נצפתה ירידה משמעותית ((‪p=0.0002‬‬ ‫בפעילות המחלה (‪ .)UAS-Uriticaria Activity Score‬שבעה חולים‬ ‫החלימו לחלוטין‪ ,‬בארבעה נוספים נצפתה ירידה משמעותית סטטיסטית‬ ‫בחומרת התסמינים‪ ,‬ואילו חולה אחד לא הגיב לטיפול ב־‪ .Xolair‬כמו‬ ‫כן נצפתה ירידה משמעותית סטטיסטית בצורך בטיפול תרופתי נוסף‪,‬‬ ‫ועלייה משמעותית באיכות החיים (על פי שאלון ‪ .)DLQ1‬בארבעה‬ ‫חולים מתוך השבעה אשר החלימו מן המחלה הפך גם מבחן השחרור‬ ‫מבסופילים שלילי‪.‬‬ ‫מסקנות‪ :‬זהו מאמר ראשוני‪ ,‬אשר ייעודו בהוכחה ראשונית כי ‪Xolair‬‬ ‫עשוי להועיל לחולים הסובלים מחרלת אוטואימונית כרונית‪ .‬אף שהמחקר‬ ‫אינו כפול סמיות ומספר הנבדקים בו קטן‪ ,‬הוא מעלה אפשרות חדשנית‬ ‫לטיפול בחרלת אוטואימונית כרונית‪ ,‬מחלה הפוגעת באופן משמעותי‬ ‫באיכות החיים של החולים‪ ,‬ואשר הטיפול בה עדיין לוקה בחסר‪ .‬בנוסף‪,‬‬ ‫מאמר זה מרחיב את האופקים לשימוש ב־‪ Xolair‬לחולים אשר אינם‬ ‫לוקים בגנחת הסימפונות‪ ,‬אין להם רגישות מוכחת לאלרגן מסוים או‬ ‫עלייה ברמת אימונוגלובולינים מסוג ‪ .IgE‬מחקרים נוספים‪ ,‬גדולים יותר‬ ‫וכפולי סמיות‪ ,‬דרושים על מנת לבסס מסקנות אלו‪ ,‬ולהרחיב את ההתוויה‬ ‫הקימת לשימוש ב־‪ .Xolair‬במהלך הכינוס השנתי של האיגוד לאלרגיה‬ ‫ואימונולוגיה יוצגו מחקרים נוספים המרחיבים את האופק הטיפולי ב־‬ ‫‪ ,Xolair‬הן למחלות נוספות והן לגילאים צעירים‪.‬‬ ‫ד"ר ננסי אגמון־לוין‬

‫אימונותרפיה פומית לאלרגיה לחלב פרה‬ ‫הטיפול המקובל באלרגיה לחלב פרה המטווחת על ידי ‪ IgE‬הוא הימנעות‬ ‫מלאה‪ .‬עם זאת‪ ,‬שכיחות החשיפות לחלב פרה בשוגג בקרב הלוקים‬ ‫ברגישות יתר גבוה‪ ,‬ותוצאותיו יכולות להיות קשות ואף קטלניות‪ .‬בשנים‬ ‫האחרונות חלה התפתחות משמעותית בטיפול באימונותרפיה‪ ,‬הן‬ ‫בפיתוח שיטות שונות (למשל אימונותרפיה פומית‪/‬תת–לשונית) והן‬ ‫בהרחבת ההתוויות האפשריות לטיפול זה‪ .‬ואכן‪ ,‬ניסיונות להשרות‬ ‫סבילות (‪ )Tolerance‬ולהעלות את הסף לתגובה לאלרגן ספציפי‬ ‫(‪ ,)Desensitization‬ובכך למנוע "תאונות" שלאחר חשיפה בשוגג‪.‬‬ ‫במחקר שפורסם בשנה האחרונה הציגו ‪ Skripak‬וחבריו (‪Skripak‬‬ ‫‪ )JM et al. J Allergy Clin Immunol 2008 ;122:1154-60‬עבודה‬ ‫שבה נבדק הטיפול האימונותרפי בילדים הלוקים ברגישות לחלב פרה‬ ‫המטווחת על ידי ‪ .IgE‬טרם גיוסם למחקר נבדקו הילדים (‪ 20‬במספר)‬ ‫על ידי תבחינים עוריים עם מיהולים עולים של חלב פרה ותגר פומי על‬ ‫מנת לקבוע את סף התגובה‪ .‬במהלך תקופת המחקר טופלו ‪13‬ילדים‬ ‫באימונתרפיה לחלב פרה‪ ,‬זאת באמצעות מתן מינונים עולים של חלב‬ ‫פרה עד הגעה למינון החזקה‪ ,‬השווה ל–‪ 15‬מ"ל חלב פרה ביום‪ 7 .‬ילדים‬ ‫שימשו קבוצת בקרה וטופלו בפלצבו‪ .‬לאחר ‪ 13‬שבועות שבהם טופלה‬ ‫קבוצת המחקר במינון החזקה (‪ 15‬מ"ל חלב פרה ביממה)‪ ,‬עברו כל‬ ‫הילדים תבחינים עוריים ומבחן תגר חוזרים‪ .‬הסף ההתחלתי לתגובה‬

‫‪6‬‬

‫לאחר תגר פומי של חלב פרה היה ‪ 1.2‬מ"ל בממוצע בשתי הקבוצות‪ .‬עם‬ ‫סיום המחקר לא חל כל שינוי בקבוצת הבקרה‪ ,‬ואילו בקבוצת הניסוי אשר‬ ‫קיבלה אימונותרפיה לחלב פרה נרשם סף חדש של ‪ 153‬מ"ל (‪.)p=0.002‬‬ ‫בנוסף‪ ,‬הסף לתגובה עורית עלה בקבוצת המחקר מ–‪ 1:50‬ל–‪ .1:3‬סף‬ ‫זה לא השתנה בקבוצת הפלצבו (‪ .)p=0.03‬נוסף על כך נבדקו רמות‬ ‫אימונוגלובולינים ספציפיים לחלב‪ ,‬ובהם לא נמצא שינוי בריכוז ‪ IgE‬בדם‪.‬‬ ‫לעומת זאת‪ ,‬ריכוז ‪ IgG‬ו–‪ IgG4‬ספציפיים לחלב פרה עלו באופן משמעותי‬ ‫(יותר מ–‪ )p=0.0002 ,700%‬לאחר אימונותרפיה‪ ,‬ולא לאחר טיפול‬ ‫פלצבו‪ .‬עם סיום המחקר טופלו שבעת הילדים אשר שימשו קבוצת בקרה‬ ‫באימונותרפיה לחלב פרה‪ ,‬והתוצאות שנצפו בקבוצה זו היו זהות לאלה‬ ‫של קבוצת האימונתרפיה הראשונה‪ .‬יש לציין כי במהלך הטיפול נצפו‬ ‫לרוב תופעות לוואי קלות( גירוד סביב לפה‪ ,‬כאב בטן‪) .‬ב–‪ 1%‬מהטיפולים‬ ‫של אימונותרפיה נרשמו תופעות רב–מערכתיות‪ ,‬כולל מערכת העיכול‪,‬‬ ‫הנשימה והעור‪ ,‬ובארבעה מקרים היה צורך בטיפול באדרנלין( אפיפן‪.‬‬ ‫לסיכום‪ ,‬למרות המדגם הקטן במחקר זה‪ ,‬נראה כי אימונותרפיה‬ ‫פומית לחלב פרה יכולה לשמש כלי חשוב להעלאת סף לתגובה לאלרגן‬ ‫זה‪ .‬טיפול שכזה עשוי לסייע בעיקר לילדים העלולים להיחשף בשוגג לחלב‬ ‫פרה‪ ,‬חשיפה אשר תוצאותיה חמורות‪.‬‬ ‫ד"ר אוריאל כץ‬

‫הרפואה‪ | update‬אלרגיה ואימונולגיה | אוקטובר ‪2009‬‬

‫עדכונים מהספרות העולמית‬

‫תאי ‪ B‬לימפוציטים בתלבושת חדשה‬

‫ל‬

‫אורך שנים חשו החוקרים שעיקר עיסוקם הוא תאי ‪B‬‬ ‫לימפוציטים מידה מסוימת של נחיתות לעומת עמיתיהם‬ ‫העוסקים בלימפוציטים מסוג ‪.T‬‬ ‫בו־בזמן שהלימפוציטים מסוג ‪ T‬התאפיינו במגוון רחב של‬ ‫תפקידים‪ ,‬נותרו תאי ‪ B‬בפינת המגרש של התגובה החיסונית כאשר‬ ‫עיקר תפקידם הוא בייצור נוגדנים‪ .‬לעומת זאת‪ ,‬ללימפוציטים מסוג‬ ‫‪ T‬יש מגון רחב של תפקידים‪ .‬חלקם אחראים על הפרשת ציטוקינים‬ ‫דלקתיים הנוטלים חלק חשוב בתגובה לתהליכים זיהומיים‪ ,‬ואילו לתאי‬ ‫‪ T‬בעלי התכונה הציטו־טוקסית יש תפקיד חשוב במניעת תהליכים‬ ‫ממאירים‪ .‬סוג אחר של לימפוציטים מסוג ‪ T‬הוא תאי ‪ T‬מווסתים‬ ‫(‪ ,)T regulatory cells‬שהפכו בשנים האחרונות להיות הנושא העיקרי‬ ‫בהרבה מחקרים‪ .‬עיתונים רפואיים מובילים דנו בחשיבותם של תאי‬ ‫‪ T‬מווסתים במניעת התפתחותם של מחלות אוטואימוניות‪ .‬התברר‬ ‫כי חסר כמותי או תפקודי בתאים אלו הוא הבסיס הפתופיזיולוגי‬ ‫להתפתחות או להחמרה של מחלות אוטואימוניות כגון זאבת‬ ‫אדמנתית מערכתית‪ ,‬וכן דלקת שיגרונתית‪.‬‬ ‫בנוסף התברר כי תאי ‪ T‬מווסתים מעורבים במחלות זיהומיות‪,‬‬ ‫במחלות ממאירות‪ ,‬במחלות אלרגיות ובתגובת המערכת החיסונית‬ ‫להשתלות‪.‬‬ ‫עקב כך היה הגיוני לסמן את הקבוצה הזו של תאי ‪ T‬כתאי מטרה‬ ‫לטיפולים ביולוגיים שונים‪ .‬טיפולים כמו ‪ Rituximab‬או ‪anti-TNF therapy‬‬ ‫הוכחו כיעילים וכבעלי יכולת לשפר מהלך של מחלות אוטואימוניות או‬ ‫של קליטת שתל‪ .‬כל זה בחלקו עקב יכולתם של טיפולים אלו להשפיע‬ ‫על תפקודם המווסת של תאי ‪ T‬אלו או לשפרו‪.‬‬ ‫המחקר המתקדם בתחום תאי ‪ B‬לימפוציטים הביא לראייה‬ ‫רחבה יותר ולשדרוג מקומם של תאי ‪ B‬בתהליך התגובה החיסונית‪.‬‬ ‫בהדרגה התחזק מעמדם של תאי ‪ B‬כתאים המציגים אנטיגנים‬ ‫(‪ .)[APC's] Antingen Presenting cells‬בהיותם ‪ APC's‬יעילים‪ ,‬הפכו‬ ‫תאי ‪ B‬לכלי מוביל המפעיל את תאי ‪ T‬ושותף פעיל בהתהוות התהליך‬ ‫הדלקתי‪ .‬בהקשר זה נמצא כי תאי ‪ B‬מייצרים ציטוקינים דלקתיים‬ ‫במקביל ליצירת נוגדנים‪ .‬בנוסף התברר שתאי ‪ B‬מסוגלים‪ ,‬בתנאים‬ ‫מסוימים‪ ,‬להפריש גם ציטוקינים מדכאים כגון ‪ IL-10‬או ‪ TGF-β‬או‬ ‫שניהם ביחד‪ ,‬ואז לא מפתיע אם נתייחס לקבוצה זו של תאי ‪ B‬גם‬ ‫כתאי ‪ B‬מווסתים‪.‬‬ ‫בשנים האחרונות ניתן להדגים במודלים של עכברים שחסר בתאי‬ ‫‪ B‬היה מלווה במהלך קליני חמור יותר של ‪[EAE] Experimental‬‬ ‫‪ .autoimmune encephalitis‬במודלים אלו‪ ,‬החזרת תאי ‪ B‬שהיו בעיקר‬ ‫תאי ‪ B‬המפרישים ‪ IL-10‬או ‪ ,TGF-β‬גרמה לשיפור ניכר במהלך‬ ‫המחלה בעכברים אלו‪ .‬עבודות אלו ביססו את הרעיון שגם לתאי ‪B‬‬ ‫(בתנאים מסוימים) יש תפקיד מווסת‪ ,‬ולכן הוצע שבדומה לתאי ‪T‬‬ ‫מווסתים‪ ,‬גם תאי ‪ B‬יכולים להיות תאים מווסתים‪.‬‬

‫נושא זה עדיין נמצא בחיתוליו‪ .‬עדיין עומדות בפנינו שאלות‬ ‫חשובות‪ ,‬כגון‪:‬‬ ‫ •האם תאי ‪ B‬מווסתים הם חלק מהרפרטואר של תאי ‪ B‬או שהם‬ ‫מתפתחים בתנאים מיוחדים?‬ ‫ •מה או מי מפעיל אותם ועל מה במערכת החיסון הם משפיעים?‬

‫‪8‬‬

‫ •האם תאים אלו יזכו לחשיבות בדומה לתאי ‪ T‬מווסתים‪ ,‬ויהפכו‬ ‫לתא מטרה בעת טיפול במחלות אוטואימוניות כגון זאבת‬ ‫אדמנתית מערכתית?‬

‫תאי ‪ B‬הם יותר מאשר תאים המייצרים נוגדנים‬ ‫במחשבה הראשונה על התפקיד שנועד ללימפוציטים מסוג ‪ ,B‬רובנו‬ ‫יגדירו את התפקיד הזה כתא המייצר נוגדנים (ראה תרשים ‪1‬א')‪.‬‬ ‫תפקיד חשוב נוסף לתאי ‪ B‬הוא להיות ‪ .APC's‬בתפקיד זה הם‬ ‫מציגים אנטיגנים ספציפיים לתאי ‪ ,TH1‬וגורמים להפעלת המערכת‬ ‫התאית ולהפרשת ציטוקינים חשובים כגון ‪ TNF‬או ‪( IL-12‬ראה‬ ‫תרשים ‪1‬ב')‪.‬‬ ‫בשנת ‪ 2000‬פורסמו עבודות המצביעות על סוג אחר של תאי‬ ‫‪ ,B‬המסוגלים להפריש כמות גדולה יחסית של ‪ IL-10‬בדומה לתאי‬ ‫‪ T‬מווסתים (ראה תרשים ‪1‬ג')‪ .‬כאמור מעלה‪ ,‬הזרקתם של תאי ‪B‬‬ ‫אלו לעכברים שבהם הושרתה קודם לכן מחלה הדומה למחלת "כרון"‬ ‫גרמה לשיפור ניכר בתהליך הדלקתי החיסוני‪.‬‬ ‫העובדה שתאי ‪ B‬אלו הם מפרישי ‪ IL-10‬לא מספיקה לצורך‬ ‫האפיון של תאי ‪ B‬מווסתים‪ ,‬שאין להם סמן אופייני תוך או חוץ תאי‬ ‫בדומה ל־‪ Foxp3‬או ‪ CTLA-4‬האופייניים לתאי ‪ T‬מווסתים‪ .‬עדיין לא‬ ‫ברור מהם הסימנים החוץ תאיים שיכולים לאפיין את תאי ‪ T‬מווסתים‬ ‫ובאיזה סטטוס של פעילות נמצאים התאים האלו‪ ,‬וכן באילו מצבי חולי‬ ‫ל־‪ IL-10‬יש חשיבות ובאילו ל־‪ TGF-β‬כציטוקינים מדכאי פעילות‬ ‫חיסונית‪.‬‬

‫שאלות פתוחות‬ ‫חלק מהחוקרים משוכנע שחלק קטן מכלל תאי ‪ B‬מסומן מההתחלה‬ ‫כתאי ‪ B‬מווסתים‪ .‬אחרים סוברים שתאי ‪ B‬הופכים להיות תאים‬ ‫מווסתים בעקבות גירוי ספציפי‪ ,‬כך שכל תא ‪ B‬הופך בעצם להיות‬ ‫תא מווסת כאשר הוא נחשף לגירוי ספציפי‪ .‬בהקשר לכך יש לציין‬ ‫את המחקרים שהראו שההתמיינות של תאי ‪ B‬לכיוון ‪ B‬מווסתים‬ ‫היה תלוי בגירוי התאים דרך שפעול )‪Toll-like receptor (TLR‬‬ ‫מסוימים כגון ‪ TLR-9‬שפעול זה הפך חלק מתאי ‪ B‬אלו להיות תאים‬ ‫יצרני ‪ ,IL-10‬ומכאן תאים מווסתים‪ .‬במנגנון זה יהיה ניתן למנוע את‬ ‫התפתחותן של תגובות אוטואימונית על ידי הגברת תפקודם של תאי‬ ‫‪ B‬מווסתים‪.‬‬

‫תאי ‪ B‬מווסתים בבני אדם‬ ‫בשלב הזה לא ברור אם תת־קבוצה זו של תאים קיימת בצורה‬ ‫ראשונית בדם פריפרי בבני אדם‪ .‬הרמזים הקיימים לכך מצויים‬ ‫בעבודות המדגימות שתאי ‪ B‬לימפוציטים מחולי ‪ MS‬הדגימו יכולת‬ ‫פחותה בייצור ‪ .IL-10‬רמז נוסף לקיומם של תאי ‪ B‬מווסתים בבני‬ ‫אדם נובע מהעובדה שהטיפול ב־‪ Rituximab‬נחל כישלון בחלק‬ ‫מהמטופלים‪ .‬במקרים אלו יוחס הכישלון לעובדה שמתן ‪Rituximab‬‬ ‫חיסל גם את התאים המווסתים "הטובים" יחד עם תאי ‪ B‬הדלקתיים‬ ‫"הרעים"‪ .‬אם נדע לאפיין יותר טוב את תאי ‪ B‬המווסתים‪ ,‬אולי נוכל‬ ‫לכוון את הטיפול הביולוגי טוב יותר‪ ,‬ובכך לשמר תאים אלו ולגרום‬ ‫בעיקר לחיסולם של תאי ‪" B‬הרעים"‪.‬‬

‫הרפואה‪ | update‬אלרגיה ואימונולגיה | אוקטובר ‪2009‬‬

‫עדכונים מהספרות העולמית‬ ‫למרות הפרסומים הקיימים בנושא‪ ,‬עדיין רב הנסתר מהגלוי‬ ‫ •מהו טיב הקשר בין תאי ‪ B‬מווסתים לתאים אחרים במערכת‬ ‫החיסון?‬ ‫ •האם לנוגדנים המופרשים על ידי תאי ‪ B‬יש השפעה על התמיינותם‬ ‫של תאי ‪ B‬מווסתים?‬ ‫ •באילו מצבים תהיה ההפרשה של ‪ IL-10‬בעלת חשיבות רבה יותר‬ ‫מזו של ‪ TGF-β‬או שניהם ביחד בתהליך ויסותי זה?‬ ‫ •ומהו התפקיד של המגע הפיזי בין התאים השונים במערכת זו?‬ ‫ב־‪ 2007‬פורסמו כ־‪ 4‬עבודות הדנות בנושא של תאי ‪ B‬מווסתים;‬ ‫ב־‪ 2008‬עלה המספר ל־‪ 9‬עבודות‪ ,‬וב־‪ 2009‬פורסמו עד כה ‪ 6‬עבודות‬ ‫בנושא‪ .‬הנושא חשוב‪ ,‬מעניין‪ ,‬ומלא שאלות לא פתורות‪.‬‬ ‫פרופ' אליאס טובי‬

‫‪B cells play a major role in the pathogenesis‬‬ ‫‪of autoimmune diseases‬‬

‫‪Produce IgG, IgM‬‬ ‫)‪(autoantibodies‬‬

‫‪Present autoAg to T cells‬‬ ‫)‪(T cell activation‬‬

‫ביבליוגרפיה‬

‫‪Produce pro- and‬‬ ‫‪anti-inflammatory‬‬ ‫‪cytokines‬‬

‫‪charge B cells create a buzz. Science 2009; 325: 144-5.‬־‪1. Leslie, M. Take‬‬ ‫‪2. Fillatreau, S., Gray, D., Anderton, S.M. Not always the bad guys: B cells as regulators‬‬ ‫‪of autoimmune pathology. Nat Rev Immunol 2008; 8: 391-7.‬‬

‫‪TNF-α, IL-6‬‬

‫‪3. Bouaziz, J.D., Yanaba, K., Tedder, T.F. Regulatory B cells as inhibitors of immune‬‬ ‫‪responses and inflammation. Immunol Rev 2008; 224: 201-14.‬‬

‫‪APC‬‬

‫‪B cells‬‬

‫א‬

‫‪B cells‬‬

‫ב‬

‫‪B cells‬‬

‫ג‬

‫‪IL-10, TGF-β‬‬

‫־‪activated B cells suppress T cell‬־‪4. Lampropoulou, V., Hoehlig, K., Roch, T. et al. TLR‬‬ ‫‪mediated autoimmunity. J Immunol 2008; 180: 4763-73.‬‬

‫תמונה אחת שווה אלף מילים‬ ‫פרשת החולה‬ ‫חולה בת ‪ 58‬הגיע למרפאת אלרגיה לבירור רגישות לפניצילין‪.‬‬ ‫חמישה חודשים טרם ביקורה במרפאה טופלה באוגמנטין בשל‬ ‫פריודונטיטיס‪ ,‬והתפתחה פריחה מוקדית בכמה מקומות עם עקצוץ‬ ‫ניכר‪ .‬חמישה שבועות טרם קבלתה שוב התפתחה פריחה דומה‬ ‫)ראה תמונה(‪ ,‬והפעם ביום הראשון לטיפול באטופן‪ ,‬אך הפעם לא‬ ‫נטלה כל תכשיר אנטיביוטי‪ .‬בנוסף הסתבר כי גם חמישה חודשים‬ ‫קודם לכן טופלה באטופן במקביל לטיפול באוגמנטין‪.‬‬ ‫מה האבחנה ומה המלצתך?‬

‫לאור השימוש באטופן בשני המקרים‪ ,‬הועלתה ההשערה כי‬ ‫מדובר בתפרחת מקובעת שמתרופה (‪ ,)fixed drug eruption‬והומלץ‬ ‫לחולה לבצע תבחין מטלית עם התרופה (אטופן)‪ .‬אך לחולה אצה‬ ‫הדרך‪ ,‬והיא החליטה על דעת עצמה ליטול שוב אטופן‪ .‬כעבור שעות‬ ‫מספר החלה לסבול מעקצוץ קשה ביותר‪ ,‬והתפתחו כמה נגעים‬ ‫שלפוחיתיים גדולים כמו זה שבתמונה‪.‬‬

‫מסקנות‪:‬‬ ‫» »בלי נטילת אנמנזה היה אפשר לייחס את התופעה לאוגמנטין‪ ,‬כפי‬ ‫שחשבו כמה רופאים שראו אותה‪.‬‬ ‫» »נגעים שלפוחיתיים בתפרחת מקובעת מתרופה כבר תוארו‪ ,‬אך אין‬ ‫זה שגרתי לראותם‪.‬‬ ‫» »חשוב לזכור שתגר הוא ההוכחה לרגישות כזו‪ ,‬ואין צורך בתבחיני‬ ‫מטלית‪.‬‬ ‫ד"ר שלמה בר סלע‬

‫ספרות‪:‬‬ ‫‪• Ozkaya C: Fixed drug eruption: State of the art. J Deutsch Dermatol Ges, 6:181‬‬‫‪8, 2008.‬‬ ‫‪• Das J, Mandel AC: A study of drug eruption by provocative tests. Ind J Dermatol‬‬ ‫‪Venereol Leprol 67:238-9, 2001.‬‬ ‫‪• Atzori L, Pinna A, Pau M, Aste N, Zucca M, Ferreli C: Adverse cutaneous‬‬ ‫‪reactions to selective cyclooxygenase 2 inhibitors: experience of an Italian drug‬‬ ‫‪surveillance center. J Cutan Med Surg 10:31-5,2006.‬‬

‫‪10‬‬

‫קווים מנחים ‪ -‬אנגיואדמה‬

‫הרפואה‪ | update‬אלרגיה ואימונולגיה | אוקטובר ‪2009‬‬

‫האיגוד הישראלי לאלרגיה ואימונולוגיה קלינית‬

‫קווים מנחים לאבחנה וטיפול‬ ‫בבצקת (אנגיואדמה) תורשתית‬ ‫הוועדה‪:‬‬ ‫יו"ר‪ :‬ד"ר אבנר רשף ‪ -‬היח' לאלרגיה‪ ,‬אימונולוגיה ואנגיואדמה ‪ -‬המרכז הרפואי "שיבא" תל השומר‬ ‫חבר‪ :‬פרופ' שמואל קיויתי ‪ -‬היח' לאלרגיה ואימונולוגיה והמעבדה לאימונולוגיה ‪ -‬מ"ר ע"ש סוראסקי‪ ,‬תל אביב‬ ‫חבר‪ :‬פרופ' אליאס טובי ‪ -‬היחידה לאימונולוגיה קלינית ואלרגיה ‪ -‬המרכז הרפואי בני‪-‬ציון‪ ,‬חיפה‬ ‫אוגוסט ‪2009‬‬

‫‪ .1‬מבוא‬ ‫אנגיואדמה תורשתית (א"ת‪ )Hereditary Angioedema, HAE ,‬היא‬ ‫מחלה נדירה המתבטאת בחסר מלידה באנזים ‪C1-esterase‬‬

‫‪ .Inhibitor‬רמה נמוכה וירידה בפעילות האנזים בנסיוב מביאה‬ ‫להתקפים נשנים של בצקות באיברים שונים‪ .‬המחלה נדירה ומספר‬ ‫החולים בה קטן יחסית (נחשבת ל"מחלה יתומה")‪ .‬תוצאותיה‬ ‫גורמות למבוגרים ולילדים מצוקה יומיומית עקב התקפים המשבשים‬ ‫ומאיימים על חייהם‪.‬‬ ‫נייר העמדה מסכם את הידע העדכני על א"ת בשנת ‪ 2009‬ומציע‬ ‫דרכים לאבחנה וטיפול במחלה בישראל‪ .‬בכתיבת נייר העמדה‬ ‫הסתמכנו על ניסיוננו בטיפול בחולי א"ת בשלושה מרכזים רפואיים‬ ‫בישראל‪ ,‬על ניירות עמדה רשמיים שפורסמו בבריטניה ובקנדה ועל‬ ‫מאמרי סקירה שפורסמו בשנים האחרונות בספרות העולמית‪.‬‬

‫‪ .2‬הגדרה‬ ‫אנגיואדמה (בצקת) היא תהליך פתולוגי המביא להצטברות נוזלים‬ ‫ולנפיחות (‪ )Swelling‬ברקמות ובאיברים‪ .‬הבצקות בא"ת נגרמות‬ ‫בעיקר כתוצאה מהגברת חדירות דופן כלי הדם בהשפעת חומרים‬ ‫ואזואקטיביים‪ .‬אגירת הבצקות מתרחשת ברקמות הרכות ובאיברים‬ ‫עשירים באספקת דם (תת־עור‪ ,‬לשון‪ ,‬שפתיים‪ ,‬עפעפיים‪ ,‬דופן‬ ‫המעי)‪.‬‬

‫‪ .3‬היסטוריה‬ ‫התיאור הראשון והמפורט של תסמיני המחלה מיוחס להיינריך‬ ‫אירנאוס קווינֶקה‪ ,‬שעל שמו נקראו בעבר תסמיני הבצקת‪Quincke's :‬‬ ‫‪ .Edema‬הרופא הדגול ויליאם אוסלר הציע את השם‪Angio-neurotic :‬‬

‫‪ ,Edema‬מאחר שסבר כי מדובר במחלה על רקע נפשי‪ .‬קראודר‬ ‫הצביע על אופן התורשה של המחלה ב־‪ .1917‬דונאלדסון וחב' גילו‬ ‫לראשונה את החסר האנזימי במעכב המשלים ‪C1: C1esterase‬‬ ‫‪ Inhibitor‬בחולי א"ת‪ .‬פריצת דרך נוספת נעשתה על ידי נוסברגר‬ ‫וחב' אשר הוכיחו שהגורם העיקרי לבצקת בא"ת הוא המדיאטור‪:‬‬ ‫ברדיקינין (‪ .)Bradykinin‬דיוויס וחב' הראו לראשונה שבהיעדר‬ ‫קולטנים לברדיקינין (או חסימתם על ידי מעכב ייחודי) נבלמת‬ ‫התפתחות הבצקת‪.‬‬

‫‪12‬‬

‫‪ .4‬ביטויים קליניים‬ ‫א"ת מתבטאת בהתקפים חוזרים ונשנים של בצקת ברקמות‬ ‫הרכות באזורים שונים‪ .‬ההתקפים מופיעים בפתאומיות ומתפתחים‬ ‫בהדרגה תוך שעות מספר‪ ,‬והם כוללים‪ :‬פנים‪ ,‬פה ולוע‪ ,‬כפות‬ ‫הידיים והרגליים‪ ,‬זרועות‪ ,‬איברי מין‪ .‬בהיעדר טיפול‪ ,‬הבצקת עלולה‬ ‫להמשך ‪ 5-2‬ימים ולגרום לעיוותים ולהפרעות קשות בתפקוד‪.‬‬ ‫בצקת באזור הלשון‪ ,‬הלוע והענבל (‪ )Laryngeal Edema‬עלולה לגרום‬ ‫מחנֶ ק ומחייבת טיפול מיידי‪ .‬הסיכון למוות מחנק במהלך‬ ‫למוות ֶ‬ ‫החיים מגיע ללא טיפול מתאים לשיעור של ‪ .33-15%‬מעל ל־‪90%‬‬ ‫מהחולים סובלים מהתקפים של כאבי בטן קשים‪ ,‬המלווים לעתים‬ ‫בבחילות‪ ,‬בהקאות ובשלשולים‪ ,‬מאחר שבצקת של דופן המעי‬ ‫גורמת לחסימת מעי מכנית (‪ )Ileus‬ולעתים נדירות גם להתפשלות‬ ‫המעי (‪ .)Intussusception‬בניגוד לבצקות על רקע אלרגי‪ ,‬התקפי‬ ‫א"ת מתוארים כ"בצקת שקטה" ואינם מלווים בתפרחת חרלתית או‬ ‫גרד‪ ,‬אך חלק ניכר מהחולים מדווחים על הופעה של סימנים מבשרים‬ ‫("פרודרומה") הכוללים עקצוץ‪ ,‬תחושת לחץ באזור התהוות הבצקת‪,‬‬ ‫בחילות‪ ,‬חוסר תיאבון‪ ,‬עייפות ואי־שקט‪ .‬תפרחת ייחודית (‪Erythema‬‬ ‫‪ )marginatum‬מקדימה את ההתקף בשליש מהמקרים‪ .‬תכיפות‬ ‫ועוצמת תסמיני המחלה שונים ‪ -‬יש הלוקים בהתקפים תכופים‪,‬‬ ‫כמעט יומיומיים‪ ,‬ויש שאינם לוקים בהתקפים‪ ,‬למרות שקיים אצלם‬ ‫חסר משמעותי של האנזים בנסיוב‪.‬‬

‫‪ .5‬אפידמיולוגיה ותורשה‬ ‫א"ת היא מחלה תורשתית נדירה (‪ )OMIM #106100‬אוטוזומית־‬ ‫שולטנית הנגרמת עקב מוטאציות בגן המקדד לייצור ‪C1INH:‬‬ ‫‪ ,SERPING1‬המאותר על הזרוע הארוכה של כרומוזום מס' ‪11‬‬ ‫(לוקוס ‪ .)11q11-q13.1‬שכיחותה באוכלוסיה ‪ ,1:10-50,000‬ולכן‬ ‫אנו מעריכים שמספר החולים בישראל יכול להגיע ל־‪ .450‬המחלה‬ ‫מופיעה אצל ילדים ומבוגרים בכל הגילים‪ ,‬ובאופן שווה בנשים וגברים‪,‬‬ ‫ללא קשר למוצא אתני‪ .‬האבחנה מושהית במקרים רבים עד גיל‬ ‫‪ ,25-20‬עקב חוסר מודעות של הציבור‪ ,‬והרופאים ומעריכים‬ ‫שהאיחור הממוצע באבחנה מגיע ל־‪ 21‬שנה‪ 14% .‬מהחולים אינם‬ ‫לוקים כלל בהתקפים‪ .‬עד כה תוארו כ־‪ 238‬מוטאציות מסוגים שונים‪,‬‬ ‫ומאחר שאצל ‪ 30%-20%‬מהחולים מופיעות מוטאציות עצמוניות‪,‬‬ ‫היעדר סיפור משפחתי של א"ת אינו שולל לחלוטין אפשרות של א"ת‪.‬‬

‫הרפואה‪ | update‬אלרגיה ואימונולגיה | אוקטובר ‪2009‬‬

‫קווים מנחים ‪ -‬אנגיואדמה‬

‫‪ .6‬הבסיס הביוכימי‬

‫‪ .9‬טיפול בתרופות‬

‫האנזים ‪ C1INH‬חיוני לבקרה על כלי הדם ומשפיע על מערכת‬ ‫המשלים‪ ,‬הקרישה והפיברינוליזה‪ .‬המעכב הוא ‪SERine Protease‬‬ ‫‪ )INhibitor) SERPIN‬הנקשר לליגנדים שונים‪FXIIa, C1q, Kallikrein, :‬‬ ‫‪ Plasmin, Tissue Plasminogen Activator‬ועוד‪ .‬חסר או פגם באנזים‬ ‫גורם להפעלה בלתי־מבוקרת של מסלול המשלים‪ ,‬מערכת הקרישה‬ ‫והפיברינוליזה‪ .‬הפעלת קינינוגן גבה־מולקולתי ((‪HMW Kininogen‬‬ ‫בפלסמה גורמת לעלייה ברמת ברדיקינין (‪ )Bradykinin‬ברקמות‬ ‫ובדם‪ .‬מתווך כימי זה גורם להרחבת העורקים ההיקפיים והכליליים‬ ‫ולהגברת חדירות דופן כלי הדם במצבי חבלה ודלקת‪ .‬ברדיקינין פועל‬ ‫באמצעות קולטנים ייחודים בכלי הדם‪ ,‬וחסימתם היא אחד האמצעים‬ ‫החדישים לטיפול בהתקפי א"ת‪.‬‬

‫הערה ‪ -‬הטיפול בהתקפי בצקת אצל חולים עם חסר ב־‪C1INH‬‬

‫‪ .7‬אבחנה וקלסיפיקציה‬ ‫סיפור משפחתי של בצקות והתקפים חוזרים ונשנים של כאבי בטן‬ ‫יכול לתמוך באבחנה של א"ת‪ ,‬אך בדיקות המעבדה הן הבסיס לאבחנה‬ ‫מדויקת של המחלה‪ .‬אצל מרבית החולים רמת ‪ C4‬בנסיוב ירודה מאוד‬ ‫בעת התקף ובין ההתקפים (מתחת ‪ 30%‬מהרמה התקינה)‪ .‬כמו כן‬ ‫נמדדת רמה נמוכה של ‪ ))Antigenic C1esterase Inhibitor C1INH‬או‬ ‫תפקוד ירוד שלו בבדיקת ‪ .functional C1INH‬הפרופיל הביוכימי בחולי‬ ‫א"ת מאפשר את סיווג המחלה לכמה סוגים‪:‬‬ ‫ •‪( HAE Type I‬כ־‪ 85%‬מהחולים) ‪ -‬נובע מחסר כמותי של‬ ‫‪ .C1INH‬רוב החולים הם הטרוזיגוטים‪ ,‬אך האלל התקין מייצר רק‬ ‫‪ 30-25%‬מהרמה בדם‪ .‬כאשר רמת המעכב נמוכה מ־‪ 50%‬קיים‬ ‫סיכון מוגבר לבצקות‪.‬‬ ‫ •‪( HAE Type II‬כ־‪ 15%‬מהחולים) ‪ -‬רמת ‪ C1-INH‬תקינה‪ ,‬אך‬ ‫המעכב פגום ותפקודו לקוי (‪ .)Dysfunctional‬בבדיקות המעבדה יימדד‬ ‫‪ C4‬נמוך‪ ,‬רמה תקינה של ‪ Antigenic C1INH‬ורמה נמוכה של ‪C1-‬‬ ‫‪.INH Functional‬‬ ‫ •אנגיואדמה משפחתית (‪Hormone-dependent, "Type III",‬‬ ‫‪ .)HAE-FXII) (OMIM #610618‬תוארה לאחרונה בעיקר אצל נשים‬ ‫בעקבות טיפול הורמוני‪ .‬הביטוי הקליני זהה לא"ת‪ ,‬אך רמות המשלים‬ ‫והמעכב (אנטיגני ותפקודי) הן תקינות‪ .‬אין עדיין סמן ביוכימי ייחודי למחלה‪,‬‬ ‫אך אצל כשליש נמצאו מוטאציות לגורם הקרישה ‪.Factor XII-‬‬ ‫ •אנגיואדמה נרכשת (‪ - )Acquired Angioedema, AAE‬תסמונת‬ ‫נדירה אצל חולים מבוגרים עם ממאירות לימפטית (בעיקר לימפומה‬ ‫מסוג ‪ )B‬וגאמופתיות חד־שבטיות‪ ,‬או במחלות אוטואימוניות‪.‬‬ ‫אבחנה מבדלת של אנגיואדמה ‪ -‬ראה טבלה מס' ‪1‬‬ ‫אלגוריתם לאבחנה של א"ת ‪ -‬ראה איור מס' ‪1‬‬

‫‪ .8‬גורמי סיכון ומעוררים (‪)Triggers‬‬ ‫גורמים מעוררים להתקפים של אנגיואדמה קשורים בעיקר בנזק‬ ‫רקמתי‪ ,‬כמו חבלה או דלקת וכולל‪ :‬מכות‪ ,‬לחץ‪ ,‬זעזועים ורטט (כלי‬ ‫עבודה)‪ ,‬טיפולי שיניים‪ ,‬דלקות לוע‪ ,‬זיהומים ומחלות חום‪ ,‬ניתוחים‬ ‫והרדמה‪ .‬תרופות העלולות להשרות התקפים‪ :‬הורמונים‪ ,‬תכשירים‬ ‫לשיכוך כאבים (בפרט ‪ )NSAID‬ויתר לחץ דם (מעכבי ‪ .)ACE‬גם מתח‬ ‫נפשי ועקה נפשית (‪ )Stress‬מהווים גורמים מעוררים‪ .‬חולות א"ת‬ ‫סובלות מהחמרה משמעותית בתקופת גיל ההתבגרות‪ ,‬בעת המחזור‪,‬‬ ‫בשימוש בגלולות (בעיקר המכילות אסטרוגנים) ובמהלך היריון‪.‬‬

‫שונה מהטיפול בבצקות הנגרמות מתגובות אלרגיות (כגון חרלת‬ ‫ואנגיואדמה אלרגית)‪ .‬בצקות והתקפים בטניים של א"ת אינם‬ ‫מגיבים לטיפול באדרנלין‪ ,‬אנטי־היסטמינים וסטרואידים‪.‬‬ ‫ •טיפול תומך ‪ -‬הטיפול התומך יינתן לכל חולה בעת התקף‪.‬‬ ‫הוא כולל‪ :‬משככי כאבים (ובכלל זה תכשירים נרקוטיים בעת‬ ‫התקפי כאב בטן)‪ ,‬נוגדי בחילה והקאה ותרופות הרגעה‪ .‬אירועים‬ ‫בטניים מלווים לא פעם בירידה בלחץ הדם‪ ,‬ומחייבים מתן עירוי‬ ‫כדי לפצות על אובדן נוזלים ל"חלל השלישי"‪ .‬במקרים של בצקת‬ ‫של הלוע והענבל וסכנה לדרכי הנשימה‪ ,‬יש לאשפז את החולה‬ ‫להשגחה ולשקול אפשרות של פיום זמני של הקנה (טרכיאוטומיה)‬ ‫עד נסיגת הבצקת‪.‬‬ ‫ •תרכיזי ‪ - C1INH‬טיפול חלופי (‪)Replacement therapy‬‬ ‫המיועד להשלים את החסר ב־‪ .C1INH‬תרכיזים המופקים מנסיוב‬ ‫אנושי (‪ )C1INH concentrates‬נמצאים בטיפול מעל ‪ 30‬שנה‪,‬‬ ‫ויעילותם הוכחה במחקרים מבוקרים ובעשרות אלפי טיפולים‪.‬‬ ‫התרכיזים מיוצרים ממנות דם‪ ,‬עוברים תהליכי פסטור‪ ,‬סינון־על‬ ‫(‪ )Ultra, Nano-filtration‬ובקרת איכות קפדנית המפחיתה את‬ ‫הסיכון מנגיפים ומחיידקים‪ .‬התרכיזים מסופקים בצורת אבקה‬ ‫לשחזור (‪ )Reconstitution‬וניתנים בעירוי לווריד‪ .‬נכון לכתיבת נייר‬ ‫עמדה זה‪ ,‬תרכיזי ‪ C1INH‬עדיין אינם רשומים בישראל ויש לנפק‬ ‫אתם לחולים על ידי התוויה פרטנית (טופס ‪29‬ג')‪ .‬תרכיזי ‪C1INH‬‬ ‫יעילים הן לטיפול בהתקף חד ((‪ ,acute‬על פי הצורך (‪)on-demand‬‬ ‫או כטיפול מונע (‪ - )prophylactic treatment‬ראה פרק‪" :‬הגישה‬ ‫לטיפול" להלן‪ .‬תופעות לוואי‪ :‬תגובות אלרגיות (נדיר)‪ ,‬חום‪ ,‬כאבי‬ ‫מפרקים‪.‬‬ ‫ •תרכיזים מנסיוב אנושי המיובאים לישראל‪:‬‬ ‫‪ -(CSL-Behring, Germany) - Berinert-P‬נמצא בטיפול‬ ‫באירופה ובארצות נוספות זה שנים רבות‪ ,‬ומיועד לטיפול‬ ‫בהתקף חריף ולטיפול מונע‪ .‬קיים בסיס נתונים נרחב על יעילותו‬ ‫ובטיחותו של התכשיר‪ ,‬כולל טיפול מונע קבוע וטיפול עצמי (‪self-‬‬ ‫‪ .)administration‬לאחרונה‪ ,‬עם סיומו של מחקר רב־מרכזים‬ ‫(שכלל את ישראל)‪ ,‬הוגש התכשיר לאישור ה־‪ .FDA‬במחקר זה‬ ‫הוכח שמינון של ‪ 20‬יח' לק"ג יעיל באופן משמעותי יותר מאינבו‪.‬‬ ‫בטיחות‪ :‬חברת ‪ CSL-Behring‬עורכת מעקב אחרי אצוות של‬ ‫‪ Berinert-P‬מאז שנת ‪ 1985‬ועד היום‪ ,‬ולא נמצאה עדות לנוכחות‬ ‫נגיפים פתוגניים כגון ‪ HIV, HB‬ו‪.HC-‬‬ ‫)‪ - Sinryze (ViruPharma, USA‬מיוצר ממנות דם אנושיות‬ ‫בטכנולוגיה של ‪ .Nano-filtration‬התכשיר אושר לאחרונה על ידי‬ ‫ה־‪ FDA‬האמריקני לאחר סיום מחקר פאזה ‪ III‬בהתוויה של טיפול‬ ‫מונע בלבד (‪ ,)prophylaxis of HAE attacks‬ולאחרונה הוגש לרישום‬ ‫בישראל‪.‬‬ ‫ •פלסמה ‪ -‬בהתקף אנגיואדמה קשה‪ ,‬כגון כאבי בטן או בצקת‬ ‫של הלוע‪ ,‬כאשר אין בנמצא תרכיז של ‪ ,C1-INH‬אפשר לתת עירוי‬ ‫עם פלסמה (רצוי טרייה)‪ .‬יעילותו של הטיפול לעצירת התקף בעת‬ ‫התרחשותו אינה גבוהה‪ ,‬והיא פחותה משמעותית מתרכיזי ‪.C1INH‬‬ ‫תופעות לוואי‪ :‬סכנה להחמרת ההתקף עקב נוכחותם של קינינים‬ ‫בפלסמה‪ ,‬העלולים לספק "דלק" לבצקת‪ ,‬ותגובות אלרגיות‪.‬‬ ‫ •הורמונים אנדרוגניים ‪( -‬בישראל‪ )Danazol* :‬תכשירים אלה‬ ‫הם אנדרוגנים מתונים (‪ ,)attenuated‬אשר בדומה לטסטוסטרון‬

‫‪13‬‬

‫קווים מנחים ‪ -‬אנגיואדמה‬ ‫מגבירים את ייצור ‪ C1-INH‬בכבד‪ .‬הם יעילים פחות בעת התקף‪,‬‬ ‫וחשיבותם היא בעיקר כטיפול מונע או כטיפול קצר טווח ‪ -‬כהכנה‬ ‫לקראת פעולות העלולות לגרום לבצקת (כגון טיפולי שיניים)‪.‬‬ ‫תופעות לוואי‪ :‬עלייה במשקל‪ ,‬שינויים בקול‪ ,‬שיעור־יתר‪ ,‬הפרעות‬ ‫בסדירות המחזור‪ .‬אין לטפל באנדרוגנים בילדים לפני סיום גיל‬ ‫ההתבגרות (טאנר ‪ )5‬ובנשים בהיריון‪ .‬בספרות דווח על עלייה‬ ‫ברמות הכולסטרול ושומני הדם‪ ,‬ועל שיעור גבוה מהמקובל של‬ ‫שאתות טביות וממאירות בכבד‪ .‬מומלץ לבצע בדיקות תפקודי‬ ‫כבד לפני התחלת הטיפול ובמהלכו‪ ,‬וכן סקירה על־שמע של הכבד‬ ‫ופרופיל שומני דם מדי שנתיים (מדי שנה למטופלים יותר מ־‪10‬‬ ‫שנים ברציפות‪ ,‬וכל ‪ 6‬חודשים למקבלים מינון מעל ‪ 200‬מ"ג ליום)‪.‬‬ ‫* (אנדרוגנים אחרים‪Methyltestosteron, Oxandrolone, :‬‬ ‫‪ Fluoxymesteron‬ו־‪ Oxymetholone‬אינם משווקים בישראל)‬ ‫ •מעכבי פיברינוליזה ‪( -‬בישראל‪Hexacapron-Tranexamic :‬‬ ‫‪ .)*Acid‬מעכב אנזימים במערכת הפיברינוליזה‪ .‬משערים שבא"ת הם‬ ‫פועלים על ידי מניעת יצירת פלסמין‪ ,‬אשר מגביר יצירת ברדיקינין‬ ‫מקינינוגנים (‪ )HMWK‬בפלסמה‪ .‬הקסאקפרון מוגש כתכשיר פומי‬ ‫או פראנטרלי (‪ .)IV, IM‬תופעות לוואי‪ :‬כאבים וכיווץ שרירים‪ ,‬עלייה‬ ‫באנזימי שריר (‪ ,)CPK, Aldolase‬תמס שריר (ראבדומיוליזיס)‪,‬‬ ‫חולשה‪ ,‬סחרחורת‪ ,‬כאבי בטן‪ ,‬בחילות ושלשולים‪ .‬דווח על שאתות של‬ ‫הרשתית והכבד לאחר טיפול ממושך‪ ,‬ולכן מומלץ לבדוק את קרקעית‬ ‫העין ולבצע בדיקת תפקודי כבד מדי שנה‪ .‬למרות שסיבוכים פקקתיים־‬ ‫תסחיפיים הם נדירים‪ ,‬מומלץ לנקוט זהירות מיוחדת בקרישיות יתר‪,‬‬ ‫כגון‪ :‬נשים הנוטלות גלולות למניעת היריון‪ ,‬פקקת ורידים עמוקה בעבר‪,‬‬ ‫תסחיפים לריאות או מחלת לב טרשתית פעילה‪.‬‬ ‫* (מעכבי פיברינוליזה אחרים‪Epsilon-aminocaproic acid, :‬‬ ‫‪ Stanozolol‬אינם משווקים בישראל)‬ ‫ •חוסם ברדיקינין ‪Icatibant, Jerini-Shire Germany/USA) -‬‬ ‫‪ - )- Firazyr‬תרופה חדשה הפועלת על ידי עיכוב ייחודי של קולטנים‬ ‫לברדיקינין בדופן כלי הדם‪ .BK beta2-Receptor Antagonist :‬ניתן‬ ‫בהזרקה תת־עורית (בדרך כלל לדופן הבטן) ומוגש במזרק מוכן‪.‬‬ ‫במחקרים מבוקרים הוכח שאיקטיבנט מקצר באופן משמעותי את‬ ‫הזמן לנסיגה של התסמינים ואת משך ההתקף‪ .‬משך פעולתו קצר‬ ‫יחסית ‪ 24-12 -‬שעות‪ .‬תופעות לוואי‪ :‬כאב מקומי בזמן ההזרקה‪.‬‬ ‫התכשיר אושר לטיפול בקהילה האירופית והוגש לאישור ה־‪.FDA‬‬ ‫אין מידע על בטיחות התכשיר בהיריון ובילדים‪.‬‬ ‫ •תרופות הנמצאות בשלבי פיתוח ומחקר קליני‬ ‫‪Rhucin (rC1INH, Pharming BV, Netherlands) - C1INH‬‬ ‫רקומביננטי המיוצר בהנדסה גנטית ומופק מחלב של ארנבות‬ ‫טרנסגניות שהוטמע בהן גן אנושי המקדד ליצירת ‪ .INH-C1‬שלבי‬ ‫הניסוי הקליניים (‪ )Phase II/III‬בהתקפים חדים הסתיימו לאחרונה‪,‬‬ ‫וכעת נבדקת יעילותו כטיפול מונע‪.‬‬ ‫‪ - )Ecallantide (DX88, Dyax USA‬מעכב ייחודי של האנזים‬ ‫קאליקריין (‪ .)Kallikrein‬מיוצר בהנדסה גנטית בשיטת ‪Phage‬‬ ‫‪ .Display‬עדיין בשלבים אחרונים של ניסויים קליניים (‪.)Phase II/III‬‬

‫‪ .10‬הגישה לטיפול באנגיואדמה תורשתית‬ ‫(אלגוריתם טיפולי)‬ ‫הטיפול בא"ת מתחלק לשלושה מצבים שכיחים‪ :‬טיפול בהתקף‬ ‫חד‪ ,‬טיפול על פי הצורך וטיפול מונע‪ .‬להלן המלצותינו לגבי שלושת‬ ‫מצבים אלה (ראה איור מס' ‪:)2‬‬

‫‪14‬‬

‫הרפואה‪ | update‬אלרגיה ואימונולגיה | אוקטובר ‪2009‬‬

‫טיפול בזמן התקף ‪Acute treatment‬‬

‫ •טיפול תומך ‪ -‬כולל מתן נוזלים (בעיקר אם חלה ירידה בלחץ‬ ‫הדם וקיימים התקפים בטניים קשים)‪ ,‬משככי כאבים ותרופות נגד‬ ‫הקאות‪ .‬חולה בהתקף קל‪/‬בינוני יישאר להשגחה למשך שעות מספר‬ ‫עד חלוף התסמינים הקשים‪ .‬במקרה של סכנה לדרכי הנשימה‬ ‫(בצקת של הענבל או מיתרי הקול) יש לאשפז את החולה ולשקול‬ ‫פיום הקנה (טרכיאוסטומיה) עד חלוף הבצקת‪.‬‬ ‫ •תרכיזי ‪ - C1INH‬טיפול הבחירה בהתקפי אנגיואדמה בינוניים‬ ‫וחמורים‪ .‬על אף שטיפול זה עדיין אינו נפוץ בישראל‪ ,‬הניסיון שנרכש‬ ‫בארצות שבהן הטיפול נגיש ומקובל מוכיח שהוא מקצר במחצית את‬ ‫הזמן הנדרש לנסיגת התסמינים הקשים‪ ,‬ובשליש את משך ההתקף‬ ‫כולו‪ .‬לאחר מתן תרכיז (ניתן בעירוי לווריד תוך כ־‪ 10‬דקות) יש‬ ‫להמתין עד שעתיים לנסיגת התסמינים‪ ,‬ובמידה שאין שיפור ‪ -‬מומלץ‬ ‫לתת מנה נוספת‪ .‬המנה המקובלת למבוגר בהתקף‪1500-1000 :‬‬ ‫יח'‪ ,‬לילד‪ 1000-500 :‬יח'‪ ,‬בהתאם לחומרת ההתקף‪.‬‬ ‫ •)‪ - Firazyr (Icatibant‬אושר בשנה האחרונה באירופה‬ ‫ובארצות אחרות לטיפול בהתקף חד של א"ת‪ .‬מניסיוננו ומהמחקרים‬ ‫שפורסמו‪ ,‬התכשיר פועל במהירות וביעילות‪ ,‬מסוגל להפחית את‬ ‫הסבל ומונע את התפתחות ההתקף‪ ,‬אך טווח הפעולה שלו קצר‪.‬‬ ‫התכשיר מוגש לטיפול במזרק מוכן המקל את מתן הטיפול‪ .‬בעתיד‬ ‫ייתכן שיתאפשר טיפול עצמי על ידי החולה בביתו‪.‬‬ ‫אם אין אפשרות לתת תרכיז ‪ C1INH‬או ‪ ,Icatibant‬מקובל לטפל‬ ‫ב־‪ ,)Tranexamic acid Hexacapron‬על אף שיעילותו פחותה באופן‬ ‫משמעותי והתגובה לטיפול אטית (כמספר שעות)‪ .‬תכשיר זה ניתן‬ ‫בדרך פארנטרלית (לווריד או לשריר) או פומית‪ ,‬במינון של ‪1.5-1‬‬ ‫גרם מדי ‪ 4‬שעות (עד ‪ 6-4‬גרם ביממה)‪.‬‬ ‫ •פלסמה (‪ - )FFP‬כאמור‪ ,‬זהו טיפול שנוי במחלוקת‪ ,‬מאחר שהוא‬ ‫עלול לגרום להחמרת ההתקף עקב נוכחות קינינוגנים בפלסמה‪ .‬הטיפול‬ ‫יינתן רק אם אין כל דרך אחרת לטיפול בהתקף חריף (‪ 2-1‬מנות ‪.)FFP‬‬ ‫טיפול לפי הצורך ‪On-demand treatment‬‬

‫טיפול זה ניתן לפני פעולות העלולות לגרום להופעה של התקף‪,‬‬ ‫כגון ניתוחים‪ ,‬טיפולי שיניים ממושכים (בעיקר טיפול במכשירים‬ ‫המפעילים מתח ולחץ על רקמות הפה)‪ ,‬לידות מסובכות וכיו"ב‪.‬‬ ‫מומלץ לתת תרכיז ‪ C1INH‬בעירוי ‪ 1,000-500‬יחידות ‪ 24‬שעות לפני‬ ‫הפעולה‪ ,‬או סמוך לביצועה‪ .‬אם התרכיזים אינם זמינים‪ ,‬מומלץ לתת‬ ‫‪ Danazol - 600‬מ"ג ליממה‪ ,‬או ‪ Hexacapron - 4-2‬גרם (מחולק‬ ‫ל־‪ )4‬במשך ‪ 5‬ימים לפני הפעולה ויומיים אחריה‪.‬‬ ‫טיפול מניעתי ‪Prophylactic treatment‬‬

‫התקפי א"ת אינם צפויים‪ ,‬ותדירותם שונה מחולה אחד לשני‪ .‬במקרים‬ ‫שבהם תכיפות ההתקפים גבוהה או שהם מתרחשים באיברים בהם‬ ‫קיים סיכון לחיים‪ ,‬יש לשקול מתן טיפול מונע (‪.)prophylactic‬‬ ‫ •‪ Danazol‬במינון אחזקה של ‪ 400-200‬מ"ג ליממה‪ .‬טיפול זה‬ ‫היה מקובל במשך שנים רבות‪ ,‬אך הוא כרוך בתופעות לוואי והתברר‬ ‫שבעקבות זאת מטופלים רבים מפסיקים את מתן התרופה‪ .‬כאמור‪,‬‬ ‫טיפול באנדרוגנים אינו מומלץ לילדים ונשים‪ ,‬ובפרט לנשים בהיריון‪.‬‬ ‫ •‪ - Hexacapron‬מתן תכשיר פיברינוליטי באופן קבוע‪ ,‬במינון‬ ‫אחזקה של ‪ 2-0.5‬גרם ליממה‪ .‬יש לזכור שיעילותו בהפחתת התקפים‬ ‫קטנה בהשוואה לדאנזול‪.‬‬ ‫ •טיפול מונע בתרכיזי ‪ - C1INH‬במרכזים המתמחים בא"ת‬ ‫באירופה החלו בשנים האחרונות לבצע טיפול מונע קבוע (‪Replacement‬‬

‫הרפואה‪ | update‬אלרגיה ואימונולגיה | אוקטובר ‪2009‬‬

‫קווים מנחים ‪ -‬אנגיואדמה‬ ‫‪ .)therapy‬טיפול זה מפחית את תכיפות ההתקפים‪ ,‬משפר את איכות‬ ‫החיים של המטופלים ומונע התקפים גרוניים מסכני חיים‪ .‬המלצתנו‬ ‫היא לשקול טיפול מונע בתרכיזי ‪ C1INH‬במקרים הבאים‪:‬‬ ‫» »התקפים תכופים (יותר מהתקף קשה אחד בחודש)‪.‬‬ ‫» »התקפים חוזרים נשנים ומסכני חיים (בעיקר באזור הפנים‪ ,‬הפה‬ ‫והלוע)‪.‬‬ ‫» »תלות בתכשירים נרקוטיים‪.‬‬ ‫» »הוראת נגד‪ ,‬ריבוי תופעות לוואי‪ ,‬או חוסר היענות לטיפול קבוע‬ ‫בדאנזול‪.‬‬ ‫» »היעדרות קבועה מעבודה או לימודים יותר מ־‪ 5‬ימים בחודש‬ ‫בעקבות התקפי המחלה‪.‬‬ ‫» »אנו ממליצים כי הטיפול המונע יינתן בדרך כלל במסגרת‬ ‫מרפאה‪/‬בית חולים‪ ,‬אך במידה שהחולה נמצא מתאים וקיבל‬ ‫הדרכה מיוחדת על ידי צוות מרכז המתמחה בא"ת‪ ,‬יינתן אישור‬ ‫לטיפול בבית (על ידי החולה עצמו‪ ,Self-administration ,‬או על‬ ‫ידי בני משפחתו)‪.‬‬

‫‪ .11‬מצבים מיוחדים‬ ‫ילדים ומתבגרים‬ ‫ביטויי המחלה הראשונים אינם מופיעים בדרך כלל לפני גיל שנתיים‪,‬‬ ‫ונדיר שיופיעו סמוך ללידה‪ .‬מדידת רמת ‪ C4‬ו־‪C1INH (Antigenic and‬‬ ‫‪ )functional‬אינן אמינות בתינוקות‪ ,‬והרמות נמוכות מאד בדם הטבורי‪.‬‬ ‫במקרה של חשד (לדוגמה ‪ -‬תינוק חדש במשפחה) יש לחזור על‬ ‫הבדיקות לאחר גיל שנה‪ .‬ברוב הילדים ההתקף הראשון מאובחן לפני גיל‬ ‫‪( 12‬בעיקר כאבי בטן)‪ .‬הטיפול מומלץ לילדים הוא הקסאקפרון (‪1.5-‬‬ ‫‪ 1‬גרם ליממה או ‪ 40-20‬מ"ג לק"ג ליום)‪ ,‬ובמידה שיש תופעות לוואי‬ ‫מומלץ לטפל בתרכיזי ‪ C1INH‬לפי הצורך‪ ,‬או כטיפול מונע קבוע‪ .‬אין‬ ‫די מידע על שימוש בתכשירים לטיפול מונע אצל ילדים‪ ,‬אך טיפול קבוע‬ ‫באנדרוגנים (דאנזול) אינו מומלץ לפני סיום ההתבגרות‪ ,‬ויש לשקול את‬ ‫הטיפול בהם רק במקרים חריגים ובהתייעצות עם אנדוקרינולוג‪.‬‬

‫היריון ולידה‬ ‫המחלה מחמירה אצל כשליש מהנשים בהיריון‪ ,‬ואצל השאר מהלך‬ ‫המחלה משתפר או נשאר ללא שינוי‪ .‬הטיפול המומלץ בהריון הוא‬ ‫מתן תרכיזי ‪ C1INH‬בעת התקפים או כטיפול מונע (ראה להלן)‪.‬‬ ‫אנדרוגנים אסורים בהיריון‪ ,‬אך ניתן לטפל בהקסאקפרון מאחר‬ ‫שלמרות הסיכון הפוטנציאלי‪ ,‬לא דווח על עלייה בארועים פקקתיים־‬ ‫תסחיפיים‪ .‬ניתן להשתמש במשככי כאבים בהתקפי בטן‪ .‬מחקרים‬ ‫שפורסמו לאחרונה מעידים על כך שבזכות מעקב וטיפול נכון רוב‬ ‫ההריונות בא"ת מסתיימים ללא סיבוכים ובלידת ילד בריא‪.‬‬

‫הכנה לפעולות וניתוחים‬ ‫אלגוריתם הטיפול בא"ת כולל הנחיות להכנה לקראת טיפולי שיניים‬ ‫ופעולות ניתוחיות‪ ,‬ומבוסס על התרופות הקיימות (ראה איור מס'‬ ‫‪ .)2‬יש להבדיל בין פעולות "קטנות" ו"גדולות"‪ ,‬בעיקר מבחינת משך‬ ‫הפעולה והאפשרות של הפעלת לחץ ומתח על הרקמות (כגון טיפול‬ ‫שיניים כירורגי או הרדמה הכוללת ִצנרור הקנה)‪.‬‬

‫‪ .12‬מרכזים לטיפול באנגיואדמה‬ ‫א"ת היא מחלה קשה ומתמשכת המטילה נטל כבד מאד על המטופל‬ ‫ומשפחתו‪ .‬להתקפים הקשים והבלתי־צפויים של המחלה יש השלכות‬

‫‪16‬‬

‫משמעותית על איכות חייהם של החולים ועל תפקודם בעבודה‬ ‫ובמסגרת המשפחה‪ .‬ברבות השנים הוקמו מרכזים המתמחים בא"ת‬ ‫במדינות שונות (גרמניה‪ ,‬איטליה‪ ,‬הונגריה‪ ,‬אנגליה)‪ ,‬שבהם מתרכז‬ ‫הטיפול המקצועי והמחקרי במחלה על כל היבטיה‪ .‬מרכז מומחים‬ ‫בישראל צריך לכלול צוות של מומחים באלרגיה‪/‬אימונולוגיה‪ ,‬אחיות‬ ‫בעלות ניסיון ומעבדה המבצעת באופן שגרתי בדיקות לאבחנת א"ת‪.‬‬ ‫המרכז ייתן שירות רפואי אמבולטורי ואשפוזי‪ ,‬מחקר על אודות‬ ‫המחלה‪ ,‬וכן ייעוץ גנטי ותמיכה רחבה בחולים ובבני משפחתם‪ .‬בכלל‬ ‫זה יסופק לחולים ולבני משפחתם מידע שיאפשר למטופל להבין‬ ‫את המחלה ואת הטיפול בה‪ ,‬את הגורמים המעוררים התקפים‬ ‫ופכן תרונות להתמודדות ולשיפור איכות החיים‪ .‬במסגרת המעקב‬ ‫ניתן להתאים טיפול תרופתי למצבים מיוחדים‪ ,‬כגון‪ :‬הכנה לפעולות‬ ‫ניתוחיות טיפול בילדים‪ ,‬היריון‪ ,‬מחזור חודשי‪ ,‬וכן תיאום עם גורמי‬ ‫הרווחה וקופות החולים‪ .‬אנו מעריכים שבדומה למחלת ההמופיליה‪,‬‬ ‫יהיה ניתן לאפשר לחולים בישראל טיפול ביתי (מתן עצמי של תרכיז‬ ‫‪ C1INH‬או ‪ ,)Icatibant‬וזאת במגמה להפחית את התלות במערכת‬ ‫הרפואית ולהקל את ההתמודדות היומיומית עם המחלה‪.‬‬

‫‪ .13‬מודעות ציבורית‬ ‫מאחר שא"ת היא מחלה נדירה‪ ,‬מקרים רבים אינם מאובחנים בזמן ואינם‬ ‫זוכים לטיפול ראוי (הדחייה באבחנה מגיעה בממוצע ל־‪ 21‬שנה!)‪ .‬מומלץ‬ ‫לנקוט פעולות להגברת המודעות למחלה בקרב רופאים‪ ,‬אחיות וצוותי‬ ‫חירום (מוקדי חירום של הקופות‪ ,‬חדרי מיון ‪ -‬מלר"דים בבתי החולים)‪.‬‬ ‫בדומה לארצות רבות‪ ,‬החלה השנה לפעול גם בישראל עמותת חולי‬ ‫אנגיואדמה‪ :‬עמותת "א‪-‬ד‪-‬מ‪-‬ה" (‪ ,)hae.israel@gmail.com‬המספקת‬ ‫מידע על המחלה‪ ,‬עומדת לצד החולים בשמירה על זכויותיהם‪ ,‬מספקת‬ ‫תמיכה נפשית ומוראלית ומסייעת להשיג תרופות חדשות‪.‬‬

‫‪ .14‬סיכום‬ ‫א"ת היא מחלה תורשתית נדירה הגורמת לאירועים חוזרים ונשנים של‬ ‫בצקות באיברי גוף שונים‪ .‬עקב נדירותה והמיעוט היחסי של החולים‪,‬‬ ‫היא נחשבת ל"מחלה יתומה"‪ .‬שכיחות המחלה בישראל אינה ידועה‪,‬‬ ‫מאחר שלא קיים מאגר נתונים מרכזי‪ ,‬אך אנו מעריכים שמספר‬ ‫החולים מגיע לכמה מאות‪ .‬אבחון מוקדם ומודעות לקיום המחלה‪,‬‬ ‫תרופות חדשות ומעקב רפואי וסעודי על ידי צוות מנוסה במרכז‬ ‫מקצועי‪ ,‬נותנים תקווה לעתיד‪.‬‬

‫הרפואה‪ | update‬אלרגיה ואימונולגיה | אוקטובר ‪2009‬‬

‫קווים מנחים ‪ -‬אנגיואדמה‬

‫איור ‪ :1‬אלגוריתם לאבחון אנגיואדמה תורשתית‬ ‫ •התקפי בצקת (ללא אורטיקריה)‬ ‫ •התקפי כאבי בטן חוזרים ונשנים‬

‫ •בצקת חוזרת של הלשון או הלוע‬ ‫ •סיפור משפחתי של אנגיואדמה‬

‫בצע בדיקת מעבדה ל‪:‬‬

‫)‪1. C4 (serum‬‬ ‫)‪2. C1esterase Inhibitor (antigenic C1INH, serum‬‬ ‫‪1. Low C4‬‬ ‫‪2. Normal or Elevated Antigenic C1INH‬‬

‫‪1. Low C4‬‬ ‫‪2. Low Antigenic C1INH‬‬

‫בדוק רמה בנסיוב בזמן התקף‪:‬‬ ‫‪1. C4‬‬ ‫‪2. Antigenic C1INH‬‬

‫בצע בדיקת מעבדה ל‪:‬‬

‫ערכים גבוליים או‬ ‫האבחנה בספק‬

‫)‪Functional C1INH (plasma‬‬ ‫‪Normal Functional C1INH‬‬

‫‪Low Functional C1INH (<50%)m‬‬

‫ •תסמינים ראשונים בגיל צעיר‬ ‫ •ספור משפחתי של אנגיואדמה‬ ‫תורשתית‬

‫‪1. Normal C4‬‬ ‫‪2. Normal Antigenic C1INH‬‬

‫ •תסמינים ראשונים בגיל מבוגר (‪)<40‬‬ ‫ •אין סיפור משפחתי‬ ‫ •מחלה המטולוגית (לימפומה‪MGUS( ,‬‬ ‫או אוטואימונית‬ ‫ •רמת ‪ C1q‬ירודה‬

‫‪Hereditary Angioedema, HAE Type I or II‬‬

‫שקול סוגים אחרים של אנגיואדמה‪:‬‬ ‫‪ .1‬מתרופות‪.NSAID, ACEI etc :‬‬ ‫‪Hormone-related AE (Type II)I.2‬‬ ‫‪Mechanical, physical .3‬‬ ‫‪Idiopathic .4‬‬

‫‪Acquired Angioedema, AAE‬‬

‫איור ‪ :2‬אלגוריתם לטיפול באנגיואדמה תורשתית‬ ‫טיפול בהתקף חריף‬ ‫בצקת ‪ -‬הגורמת לעיוות צורה‪,‬‬ ‫לחץ‪ ,‬כאב‪ ,‬הפרעה לתפקוד‬ ‫כאב בטן קשה ‪ -‬מתמשך‪ ,‬מפריע‬ ‫לתפקוד תקין‪ ,‬מלווה בחילות‪,‬‬ ‫הקאות‪ ,‬שלשול‪.‬‬ ‫בצקת לשון‪ /‬לוע‪ /‬ענבל‪-‬‬ ‫צרידות‪ ,‬אבדן קול‪ ,‬מחנק‪ ,‬מצוקה‬ ‫נשימתית‪ ,‬הפרעה לבליעה‪ ,‬כיחלון‬ ‫‪1. IV C1INH Concentrate‬‬ ‫‪500-1500 Units (1-3 vials‬‬ ‫‪(<50kg= 500 U,>50=1000 U,‬‬ ‫)‪>100kg=1500 U‬‬ ‫‪or:‬‬ ‫‪2. SC Firazyr (Icatibant) 30mg‬‬

‫או‬ ‫אם ‪ C1INH‬או ‪Icatibant‬‬

‫אינם זמינים‪:‬‬

‫)‪1. IV Fresh Plasma (2 Units‬‬ ‫‪2. IM or IV Hexacapron 15mg/‬‬ ‫)‪Kg every 4h (up to 6 gram/day‬‬ ‫‪3. Consider admission to ICU‬‬

‫‪18‬‬

‫טיפול לפי צורך‬ ‫פעולה "גדולה"‬ ‫ •עקירת שן‪ ,‬ניתוח חניכיים‬ ‫ •ניתוח בהרדמה כללית‬ ‫ •לידה קיסרית‬ ‫ •אנדוסקופיה פיברואופטית‬ ‫‪IV C1INH Concentrate‬‬ ‫)‪500-1500 U (1-3 vials‬‬ ‫‪(<50kg= 500 U,>50=1000‬‬ ‫)‪U, >100kg=1500 U‬‬

‫או‬ ‫‪1. PO Danazol‬‬

‫‪600mg/day‬‬

‫‪or‬‬ ‫‪2. PO Hexacapron‬‬ ‫‪2-4 gr/day‬‬ ‫‪3-5 days before and‬‬ ‫‪2 days after procedure‬‬

‫פעולה "קטנה"‬ ‫ •סתימת שן‪ ,‬ניקוי‬ ‫אבנית‬ ‫ •הסרת נגע מהעור‬ ‫ •ביופסיה‬ ‫‪PO Danazol‬‬ ‫‪600mg/d‬‬ ‫‪or:‬‬ ‫‪PO Hexacapron‬‬ ‫‪2-4 gr/d‬‬ ‫‪3-5 days before‬‬ ‫‪and 2 days after‬‬ ‫‪procedure‬‬

‫טיפול מונע‬ ‫התוויה‪:‬‬ ‫ •התקפים תכופים וקשים (>‪1‬בחודש)‬ ‫ •התקפים חוזרים‪ :‬פנים‪ ,‬לשון‪ ,‬לוע‬ ‫ •שימוש תכוף בתכשירים נרקוטיים‬ ‫ •התקפים המביאים לאבדן ימי‬ ‫עבודה או לימודים (‪ <5‬בחודש)‬ ‫‪1. PO Danazol 200-400mg/day‬‬ ‫‪or‬‬ ‫‪2. PO Hexacapron 0.5-2.0gr/day‬‬

‫או‬ ‫התקפים תכופים או הוראת–נגד‬ ‫לטיפול בדנאזול או הקסאקפרון‬ ‫(נשים‪ ,‬הריון‪ ,‬ילדים‪ ,‬קרישיות יתר)‪:‬‬ ‫‪IV C1INH Concentrate‬‬ ‫‪ Units 500-1000‬כל ‪ 5-10‬ימים‬ ‫(<‪50kg= 500 U,>50=1000 U,‬‬ ‫‪)>100kg=1500 U‬‬

2009 ‫ | אלרגיה ואימונולגיה | אוקטובר‬update‫הרפואה‬

‫ אנגיואדמה‬- ‫קווים מנחים‬

‫ ספרות‬.15 ‫טיפולים‬

‫ ביטוים קליניים‬,‫ מנגנון‬,‫היסטוריה‬

11. Levi M, Choi G, Picavet C, Hack CE. Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol 2006; 117(4):904-8.

• Quincke H. Uber akutes umschriebenes Hautodem. Monatsh. Prakt Dermatol.1882: I: 129-31.

12. Cicardi M, Zingale LC, Zanichelli A, Deliliers DL, Caccia S. The use of plasma-derived C1 inhibitor in the treatment of hereditary angioedema. Expert Opin Pharmacother 2007;8(18):3173-81

• Donaldson VH, Evans RR. A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C' 1-esterase. Am J Med 1963; 35: 3744.

13. Cicardi M, Zingale L, Zanichelli A, Deliliers DL. Established and new treatments for hereditary angioedema: An update. Mol Immunol 2007; 44:3858-61.

• Nussberger J, Cugno M, Amstutz C, Cicardi M, et al. Plasma bradykinin in angio-oedema. Lancet 1998; 351: 1693-766.

14. Longhurst HJ, Carr S, Khair K. C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option. Clin Exp Immunol 2007;147:11-7.

• Han ED, MacFarlane RC, Mulligan AN, Scafidi J, Davis AE III. Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 2002; 109: 1057-63.

15. Bork K. Frank J, Grundt B, Schlattmann P, Nussberger J, Kreuz W. Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antaonist (Icatibant). J Allergy Clinical Immunol 2007; 119 (6): 1497-503.

16. Schneider L, Lumry W, Vegh A, Williams AH, Shmalbach T. Critical role of kallikrein in hereditary angioedema pathogenesis: A clinical trial of ecallantide, a novel kallikrein inhibitor. J Allergy Clin Immunol 2007; 120: 416-22.

17. Choi G, Soeters MR, Farkas H, et al. Recombinant human C1-inhibitor in the treatment of acute angioedema attacks. Transfusion 2007; 47 (6):1028-32.

18. Zuraw BL. Hereditary angiodema: a current state-of-the-art review, IV: short- and longterm treatment of hereditary angioedema: out with the old and in with the new? Ann Allergy Asthma Immunol 2008 Jan; 100(1 Suppl 2):S13-8.

19. Bork K. Pasteurized C1 inhibitor concentrate in hereditary angioedema: pharmacology, safety, efficacy and future directions. Expert Rev Clin Immunol 2008; 4(1):13-20.

20. Prematta MJ, Prematta T, Craig TJ. Treatment of hereditary angioedema with plasmaderived C1 inhibitor. Ther Clin Risk Manag 2008; 4(5): 975-82.

21. Kreutz W, Martinez-Saguer I, Aygoren-Pursun E et al. C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol propylaxis. Transfusion May 2009 (Epub ahead of print)

• Osler E. Hereditary angio-neurotic edema. Am J Med Sci 1888; 95: 362-7.

• Fremeaux-Bacchi V. Guinnepain MT, Cacoub P et al. Prevalence of monoclonal gammopathy in patients presenting with acquired angioedema type 2. Am J Med 2002; 113: 194-99.

• Cugno M, Nussberger J, Cicardi M, Agostoni A. Bradykinin and the pathophysiology of angioedema. Int Immunopharmacol 2003; 3: 311-7.

• C1 Inhibitor Gene Mutation Database (HAEdb) (http://hae.enzim.hu) • Bork K, Hardt J, Scheickentanz KH, Ressel N. Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Arch Int Med 2003; 163: 1229-35.

• Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 2006; 119 (3) 267-74 • Bork K, Wulff K, Hardt J et al. Hereditary angioedema caused by missense mutations in the factor XII gene: Clinical features trigger factors and therapy. J Allergy Clin Immunol 2009; 124: 129-34

‫ניירות עמדה מוסכמים‬ 1. Bowen T, Cicardi M, Bork K, et al. Canadian 2003 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. J Allergy Clin Immunol 2004; 114 (3): 629-37.

2. Gompels MM, Lock RJ, Abinun M et al. C1 Inhibitor deficiency: consensus document.

Clin Exp Immunol 2005; 139: 379-94 3. Bowen T, Cicardi M, Bork K, et al. Hereditary angioedema: a current state-of-theart review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol 2008; 100 (1 Suppl 2): S30-40.

‫סקירות‬ 4. Bracho FA. Hereditary angioedema. Curr Opin Hematol 2005; 12:493-98.

5. Farkas H, Varga L, Széplaki G, et al. Management of hereditary angioedema in pediatric patients. Pediatrics 2007; 120(3):713-22.

6. Cicardi M, Zingale L, Zanichelli A, Deliliers DL. Established and new treatments for hereditary angioedema: An update. Mol Immunol 2007;44: 3858-61.

7. Zuraw BL. Clinical Practice: Hereditary Angioedema. New Engl J Med 2008; 359 (10): 1027-36 8. Frank MM. Hereditary angioedema. J Allergy Clin Immunol 2008; 121: S398-401.

9. Reshef A, Leibovich I, Goren A. Hereditary Angioedema: New hopes for an orphan disease. Isr Med Assoc J. 2008; 10: 850-55.

10. Bernstein JA. Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies. Ann Allergy Asthma Immunol 2008; 100(1 Suppl 2 S41-6.).

20

‫הרפואה‪ | update‬אלרגיות ואימונולגיה | אוקטובר ‪2009‬‬

‫תוכנית הכינוס השנתי ‪2009‬‬

‫‪Clinical features and Management of Non-allergic Angioedema‬‬ ‫‪M. Magerl, Klinik für Dermatologie, Allergologie und Venerologie, University Hospital Charité, Berlin,‬‬ ‫‪Germany.‬‬

‫‪12:00–12:20‬‬

‫‪Prodromal signs and symptoms of hereditary angioedema.‬‬ ‫‪Avner Reshef. The Allergy&Immunology and Angioedema Center, Sheba Medical Center, Tel-Hashomer,‬‬ ‫‪Israel.‬‬

‫‪12:20–12:30‬‬

‫‪Xolair – Past, Present and Future.‬‬ ‫‪Menahem Rottem. Allergy asthma and Immunology Emek Medical Service, Afula.‬‬

‫‪12:30–12:40‬‬

‫‪Xolair – our experience in children.‬‬ ‫‪Mona kidon. The Allergy&Immunology and Angioedema Center, Sheba Medical Center, Tel-Hashomer,‬‬ ‫‪Israel.‬‬

‫‪12:40–12:50‬‬

‫‪Systemic lupus erythematosus and cardiovascular diseses‬‬ ‫‪Johan Frostegård. Department of Medicine, Karolinska University Hospital, Huddinge, Stockholm,‬‬ ‫‪Sweden.‬‬

‫‪12:55–13:15‬‬

‫כנס שנתי של אחיות אלרגיה‬

‫במסגרת הכנס השנתי של האיגוד לאלרגיה ואימונולוגיה ‪2009‬‬ ‫יום שישי ‪,30.10.09‬‬

‫באולם ההרצאות‪ ,‬בבית מלון כנען‪ ,‬צפת‬ ‫‪09:00-08:30‬‬

‫התכנסות ורישום‬

‫‪09:15-09:00‬‬

‫ברכות‪:‬‬ ‫פרופ' א‪.‬טובי‪ ,‬יו"ר האיגוד הישראלי לאלרגיה ואימונולוגיה קלינית‬ ‫דר' מנחם רותם יו"ר היוצא של האיגוד‬

‫‪09:45-09:15‬‬

‫"החיסון בארס דבורים"‬ ‫רעיה גונה‪ ,‬אחות ראשית‪ ,‬שרה גולדמן אחות מרפאות פנימיות ואלרגיה‪" ,‬הדסה"‪ ,‬ירושלים‬

‫‪10:15-09:45‬‬

‫"תגובות מסכנות‪ -‬חיים לעקיצות דבורים וצרעות"‬ ‫דר' אבנר רשף‪ ,‬מנהל היחידה לאלרגיה‪" ,‬שיבא"‪ ,‬תל השומר‬

‫‪10:45-10:15‬‬

‫הפסקת קפה‬

‫‪11:15-10:45‬‬

‫"חיסון זריז ‪"Rush Immunotherapy -‬‬ ‫רחל זומר‪ ,‬אחות אחראית‪ ,‬מרפאה לאלרגיה‪ ,‬בית חולים "מאיר"‪ ,‬כפר סבא‬

‫‪11:45-11:15‬‬

‫"איך למנוע תגובות אלרגיות קשות ומסוכנות"‬ ‫מיכל דויטש‪ ,‬אחות אחראית‪ ,‬מרפאה לאלרגיה‪ ,‬מרכז רפואי "שיבא"‪ ,‬תל השומר‬

‫‪12:15-11:45‬‬

‫"גישה עכשווית להלם אנאפילקטי"‬ ‫דר' שלמה בר סלע‪ ,‬מנהל מרפאה לאלרגיה‪ ,‬קופת חולים מאוחדת‪ ,‬י‪-‬ם‬

‫‪13:15-12:15‬‬

‫הצגת מקרים ודיון‪:‬‬ ‫חנה נויהאוס ‪ -‬אחות אחראית‪ ,‬מרפאה לאלרגיה‪ ,‬מרכז רפואי‪ " ,‬רבין" פ"ת‬ ‫דליה גיל ‪ -‬אחות אחראית‪,‬מרפאה לאלרגיה‪,‬קופת חולים כללית‪ ,‬עפולה‬ ‫חביבה אילות ‪ -‬אחות אחראית‪ ,‬מרפאה לאלרגיה‪ ",‬מכון רוקח"‪ ,‬י‪-‬ם‬ ‫דורית זילברצוויג ‪ -‬אחות אחראית‪ ,‬מרפאה לאלרגיה‪ ,‬בית חולים‪" ,‬אסף הרופא"‬

‫תודות לחברות שתרמו לכינוס‪:‬‬ ‫‪Schering-Plough, Teva, Novartis, GlaxoSmithKline,‬‬ ‫‪Astra Zeneca, MSD, Sanofi Aventis,‬‬

‫‪TRUPHARM, MEDISON, MEDILINE, GAMIDA, MEGAPHARM, PHARMABEST‬‬

‫‪22‬‬

2009 ‫תוכנית הכינוס השנתי‬

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

18:05–18:20

A tolerogenic peptide that induces suppressor of cytokine signaling (SOCS)-1 restores the aberrant control of IFN-gamma signaling in lupus-affected (NZBxNZW)F1 mice.

Zev M. Sthoeger. Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel and the Department of Internal Medicine B, Allergy, AIDS and Clinical Immunology, Kaplan Hospital, Rehovot, Israel.

18:20–19:00

Annual meeting IAACI (members only).

FRIDAY 30 OCTOBER 2009 ‫ באוקטובר‬30 ‫יום שישי‬ 08:30–10:15

First Session: Immunodeficiency, and Tumor immunology.

Co-Chairs: M. Rottem, Z. Sthoeger

08:30–08:50

WHIM Syndrome: An Autosomal Dominant Immune Deficiency Caused by Hyperfunction of CXCR4 Harry L. Malech. Laboratory of Host Defenses and Genetic Immunotherapy Section, NIAID, NIH, Bethesda, Maryland. USA.

08:50–09:00

Hypomorphic mutation of the Artemis gene in an Arab-Israeli family causing immunodeficiency and predisposition to lymphoma Ben Zion Garty. Kipper Institute of Allergy and Immunology and Department of Pediatrics B, Schneider Children’s Medical Center of Israel, Petah Tiqwa, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

09:00–09:10

Transient elevation of cancer marker CA-125 in the initial stages of HIV-1 infection: a defensive role?

Gamal Hassoun. Institute of Allergy, Immunology &AIDS, Rambam Medical Center and Rappaport Faculty of Medicine –Technion, Haifa.

09:10–09:25

Structured treatment interruption: does it play a role in the management of acute/primary HIV infection?

Israel Yust. Sourasky Medical Center, Tel Aviv, Israel.

09:25–09:50

Novel mechanisms in tumor immunity: role of Vitamin A Shimon Pollack. Department of Immunology, Rappaport Faculty of Medicine-Technion; Institute of Allergy & Clinical Immunology, Rambam Medical Center, Haifa.

09:50–10:15

SCID-X1: Growth Failure, Malabsorption and Infections in Older Children with Persistent Immune Deficiency Despite Haploidentical Transplant in Infancy Harry L. Malech. Laboratory of Host Defenses, and Genetic mmunotherapy Section, NIAID, NIH, Bethesda, Maryland. USA.

10:15–10:45

Coffee break and Exhibition.

10:45–13:15

Second Session: From Infections and autoimmunity to Asthma and Hereditary angioedema.

Co-Chairs: M. Shalit, S. Pollack

10:45–11:10

Infections and Autoimmunity Yehuda Shoenfeld. The Center for Autoimmune Diseases and Department of Internal Medicine B, Sheba Medical Center, Tel-Hashomer; Laura Schwarz-Kip Chair for Research of Autoimmune Diseases, TelAviv University, Israel.

11:10–11:30

Pediatric Psoriasis: What's New? Amy S. Paller. Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.

11:30–11:40

Type I hypersensitivity to Aspergillus fumigatus in severe Asthmatic patients.

Bernstein Manuel. Allergy and Immunology unit, Sourasky Medical Center; Sackler School of Medicine, Tel aviv, Israel.

11:40–11:50

Particulate matter-induced inflammation in the airways of asthmatic children.

Elizabeth Fireman. Institute of Pulmonary and Allergic Diseases, National Laboratory Service for ILD, Department of Pulmonary Medicine Sourasky Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel‑Aviv, Israel.

11:50–12:00

Sub populations of regulatory and TH17 lymphocytes in hypertrophic adenoids.

Kobi Sade. Allergy and Immunology unit, Sourasky Medical Center, Tel aviv; Israel.

23

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

2009 ‫תוכנית הכינוס השנתי‬

Israel Association of Allergy and Clinical Immunology (IAACI)

Annual Scientific Meeting 29–31 October 2009, Safed THURSDAY 29 OCTOBER 2009 ‫ באוקטובר‬29 ‫יום חמישי‬ 15:00–16:40

First Session: Allergy Co-Chairs: E. Toub‫ו‬, S. Bar-Sella.

15:00–15:10

Opening remarks E. Toubi, IAACI Executive Committee Chair

15:10–15:40

Update on Atopic Dermatitis Amy S. Paller. Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.

15:40–15:50

The protective role of Tregs and Mast Cells in Chronic Allergic Dermatitis.

Alon Hershko. Laboratory of Molecular Immunogenetics and the Molecular Immunology and Inflammation Branch, NIAMS, NIH, USA.

15:50–16:00

Elevated serum total IgE -a potential marker for severe chronic urticaria.

Kessel Aharon. Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Technion Faculty of Medicine, Haifa, Israel.

16:00–16:10

Presentation of Eosinophilic Esophagitis as Failure to Thrive in Young Children.

Ilan Dalal. Pediatric Allergy and Immunology Unit, E. Wolfson Medical Center,Holon, Israel Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

16:10–16:20

Rush venom immunotherapy: safety, efficacy and cost among bee venom allergic patients Arnon Goldberg. Allergy and Clinical Immunology Unit, Meir Hospital, Kfar Saba, Israel, affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

16:20–16:30

Anaphylactic reactions to patent blue; a preventable catastrophe?

Shlomo Bar-Sela. Allergy Clinic, Kupat Holim Meuhedet, Jerusalem and Department of Occupational and Environmental Medicine, School of Public Health, Hebrew University-Hadassah Medical School Jerusalem, Israel.

16:30–17:00

Coffee break and Exhibition

17:00–18:50

Second Session: Clinical Immunology and Autoimmuinty Co-Chairs: Y. Shoenfeld, I. Dalal.

17:00–17:30

Immune mechanisms in atherosclerosis and cardiovascular disease: novel diagnostic and therapeutic concepts.

Johan Frostegård. Department of Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden.

17:30–17:45

Vitamin D: an instrumental factor in the Anti-Phospholipids Syndrome.

Nancy Agmon-Levin. The Center for Autoimmune Diseases and Department of Internal medicin B, Sheba Medical Center, Tel Hahosmer, Israel.

17:45–17:55

Parotitis as the presenting symptom of necrotizing granulomatosis: case report and meta-analysis.

Martine Szyper-Kravitz. The Center for Autoimmune Diseases and Department of Internal Medicine B, Sheba Medical Center, Tel-Hashomer; Israel.

17:55–18:05

Infectious Antibodies in Systemic Lupus Erythematosus patients.

Yackov Berkun. The Center for Autoimmune Diseases Safra Children Hospital, Sheba Medical Center, Tel-Hashomer; Sackler Faculty of Medicine, Tel-Aviv University, Israel.

24

‫תקצירים‬ of 27, the patient underwent HIV-1 ELISA test which was negative.

Nevertheless, positive Ag/Ab combo tests, high HIV-1 RNA levels (6 x 106 copies/ml with a positive proviral DNA assay) with relatively high CD4 cell counts (450 cells/µl), established the diagnosis of acute HIV-1 infection. HAART (highly active antiretroviral therapy) with zidovudine/lamivudine and efavirenz was initiated with good immunological (CD4 – 858 cells/µl) and virological (VL<50 copies/ ml) responses within 6 weeks of treatment.

Conclusions: In agammaglobulinemic patients, routine serological tests for HIV-1 are not suitable. Instead, HIV-1 virological (Ag/viral RNA) assays should be done. Furthermore, it appears that despite of the humeral immune system malfunction, the response to treatment is good, comparable to that of patients with intact B cells.

STRUCTURED TREATMENT INTERRUPTION: DOES IT PLAY A ROLE IN THE MANAGEMENT OF ACUTE/PRIMARY HIV INFECTION? Israel Yust1, Dan Turner1, Boaz Avidor1, Michael Burke2 Aviv Sourasky Medical Center, Tel Aviv, Israel 2 Kaplan Medical Center, Rehovot, Israel 1 Tel

Background: The long-term virologic, immunologic and clinical benefits of antiretroviral treatment (ART) of acute/primary HIV infection (A/PHIV) are unknown, and currently such treatment is optional. Despite potential disadvantages, ART is more likely to produce undetectable viral load (VL) and cell-associated infectivity in A/PHIV than in chronic HIV infection. Structured treatment interruption (STI) studies on patients with A/PHIV using a small number of interruptions yielded equivocal results.

Objectives: To determine whether STI has a role in the management of A/PHIV. Methods: A 30 year old MSM presented on 7/10/01 with fever and a maculo-papular rash of 4 days’ duration. Investigations revealed subsequent HIV seroconversion, HLA B27 and B57 negativity and CCR5/CCR5 homozygous genotype (186 bp fragment). He received AZT/3TC and Efavirenz, which he continued taking for 16 months until 24/2/02. The VL fell from 70,000 copies/ml to <50 copies/ml (undetectable) and CD4 count rose from 693/mm3 (30%) to 1056/mm3 (50%). He then received multiple STI with gradually increasing interruption intervals until 16/6/06, whence therapy was stopped. Clinical and laboratory parameters were monitored over the next 3 years.

Results: The VL was undetectable throughout the course, and recent (11/5/09) CD4 count was 1056/mm3 (48%) with CD4/CD8 of 1.78.

Conclusions: This patient demonstrates the possibility that multiple STI over a prolonged period may permit cessation of therapy, without affecting biologic parameters, suggesting a potential beneficial role for STI in A/PHIV. Mechanisms may include activation of T-cytotoxic and T-regulatory cells, and eradication of the reservoir of latently infected memory CD4+ T-cells. Further studies are warranted to elucidate the therapeutic potential of STI.

25

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

4 Department

of Medical Genetics, Rabin Medical Center, Beilinson Campus, Petah Tiqwa 5 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 6 Hopital Necker Infants Malades, Paris, France

Background: The diagnosis of partial immunodeficiency is a clinical challenge because the laboratory findings are variable and non-specific.

Objective: To describe an Arab-Israeli family with partial immunodeficiency and a predisposition to lymphoma caused by a mutation in the Artemis gene.

Patients and Results: Four children belonging to 3 branches of a large Arab-Israeli family with multiple consanguinities presented with recurrent infections. The family history revealed the death of two other children, one from lymphoma and one after bone marrow transplantation from an unknown immunodeficiency.

Laboratory study of the cellular profile yielded the following findings: helper T cells - low; CD8+ cells - normal; B cells normal (2 patients) or reduced (2 patients); NK cells-normal.

Response to mitogenes was reduced (2 patients) or borderline (2 patients). A search for a possible mutation led to chromosome 10, and further investigation revealed an insertion of 8 nucleotides in exon 14 of the Artemis gene. One girl underwent stem-cell transplantation from her HLA-matched father and recovered, and one girl died of complications after transplantation. Her 6-yearold brother was a candidate for transplantation, but he acquired Hodgkin’s lymphoma for which he is currently being treated. The fourth patient, an 8-year-old boy, is being treated conventionally because the parents refused transplantation.

Discussion and Conclusions: Severe combined immunodeficiency (SCID), caused by a mutation in the Artemis gene, is common among the Navajo and Apache American Indian tribes, but rare in other ethnic groups. Some sporadic cases associated with less severe immunodeficiency have been reported.

We describe the first known patients in Israel with combined immunodeficiency due to an Artemis gene mutation. The mutation caused partial immunodeficiency and a predisposition to lymphoma.

Adrenal suppression and Cushing's syndrome due to the interaction between Ritonavir and inhaled Fluticasone Mahlev-Guri Keren, Elbirt Daniel, Gradstein Serge, Zung Amnon, Asher Ilan, Werner Ben, Radain-Sade Sara, Burke Michael and Sthoeger Zev Clinical Immunology, Allergy and AIDS Center and Pediatrics, Kaplan Medical Center, Affiliated with Hadassah-Hebrew University Medical School Jerusalem, Rehovot, Israel

Objective: To present 3 cases of HIV patients with adrenal suppression and Cushing's syndrome due to the interaction between inhaled fluticasone and ritonavir.

Methods: Evaluation of the clinical appearance, diagnosis and management of 3 HIV patients, treated with a ritonavir containing HAART (Highly Active Antiretroviral Therapy), who presented with

‫תקצירים‬ adrenal suppression and Cushing's syndrome following the addition of inhaled fluticasone.

Results: We present here 3 HIV female patients, ages 12, 65, and 55. All three patients were treated with Combivir® (zidovudine + lamivudine) and Kaletra® (ritonavir boosted lopaniavir). There was no use of Clarythromycin or Ketoconazole. Due to asthma exacerbations, inhaled fluticasone (at regular recommended doses) was added to the treatment for a mean time of 12 weeks (3-24 weeks). Thereafter, the patients presented with facial swelling ("moon face"), increased weight and fatigue. The initial clinical diagnosis was HAART induced lipodystrophy. However, laboratory workup revealed low morning cortisol blood levels and low 24 hours urinary free cortisol levels with abnormal (flat) Synacten tests, establishing the diagnosis of Cushing's syndrome with adrenal insufficiency. Following graduate discontinuation of inhaled fluticasone, all clinical and laboratory abnormalities were resolved. In one patient, fluticasone was replaced by another inhaled corticosteroid (Budesonide), with the continuation of ritonavir without any clinical or laboratory endocrinological adverse events.

Conclusions: The diagnosis of Cushing's syndrome in HIV patients on HAART is a challenging diagnosis, and should be suspected in all patients treated with ritonavir and inhaled fluticasone. Following such diagnosis, gradual discontinuation of fluticasone required close monitoring for adrenal insufficiency. The combination of ritonavir and fluticasone should be avoided, and other kinds of inhaled corticosteroids (e.g. Budesonide) should be used.

HIV-1 in a patient with Bruton X-linked Agammaglobulinemia (XLA) – diagnosis, treatment and course Elbirt Daniel, Gradstein Serge, Sthoeger Dalia, Mahlev-Guri Keren, Asher Ilan, Werner Ben, Radain-Sade Sara, Burke Michael and Sthoeger Zev Clinical Immunology, Allergy and AIDS Center and Pediatrics Departments, Kaplan Medical Center, Affiliated with Hadassah-Hebrew University Medical School Jerusalem, Rehovot, Israel

rationale:Diagnosis of HIV-1 is based on the detection of specific anti HIV-1 antibodies by ELISA and Western Blot analysis. Thus, HIV-1 diagnosis in agammaglobulinemic patients is problematic and misleading.

Methods: We describe the diagnosis and course of HIV-1 in a patient with Bruton X-linked Agammaglobulinemia (XLA).

Results: A homosexual male had repeated hospitalizations for recurrent infections (pneumonia, sinusitis, gastroenteritis) since the age of 4. Laboratory investigations revealed low immunoglobulin levels (IgG 200, IgM 40 and IgA 6 mg/dL), low number of peripheral B cells (CD19 – 2%), normal number of polymorphonuclear, T and NK cells. Complement levels were normal. DNA analysis established the diagnosis of XLA. The patient was treated monthly with IV immunoglobulins. Due to unprotected anal sex, the patient was tested several times for HIV-1 by ELISA and found to be negative.

Following an acute febrile illness with lymphadenopathy, at the age

26

‫תקצירים‬ polymorphism was found to associate with autoimmune thyroid diseases (AITD), however studies exploring levels of Vitamin-D in patients with AITD are scarce and yielded conflicting results.

Therefore, we aimed to evaluate the levels of vitamin-D in AITD patients compared to non autoimmune thyroid disease and healthy subjects.

Methods: Serum vitamin-D (25OH) levels were measured in 50 patients with AITDs, 42 patients with non-autoimmune thyroid diseases and 98 healthy subjects. Vitamin-D deficiency was designated at levels lower than 10ng/ml. The patients were evaluated for anti-thyroid antibodies and thyroid functions and demographic parameters.

Results: The prevalence of vitamin-D deficiency was significantly higher in patients with AITD compared with healthy individuals (72% Vs 30.6%; p=0.0005), and in patients with Hashimoto's thyroiditis compared with patients with non-autoimmune thyroid disease (79% Vs 52%; p=0.04). Vitamin-D deficiency significantly correlated with the presence of anti thyroid antibodies among patients with thyroid disease (p=0.01). A trend towards an association between euo-thyroid status and vitamin-D levels above 10ng/ml was also observed (p=0.06).

Conclusion: Significantly low levels of Vitamin-D were documented in patients with AITD, and were related to the presence of anti thyroid antibodies and disturbed thyroid functions. Vitamin-D might play a role in the pathogenesis of autoimmune thyroid diseases and supplementation should be considered.

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

‫חסר חיסוני ואיידס‬ TRANSIENT ELEVATION OF CANCER MARKER CA-125 IN THE INITIAL STAGES OF HIV-1 INFECTION: A DEFENSIVE ROLE? G.Hassoun, E.Shahar, E.Kedem, S.Pollack Institute of Allergy, Immunology &AIDS, Rambam Medical Center and Rappaport Faculty of Medicine –Technion, Haifa

Background: Primary HIV -1 infection (PHI) is a transient symptomatic illness presenting usually with fatigue, fever and lymphadenopathy accompanied by URI symptoms. There are very few reports of unusual presentations of PHI. Patient & Results: We report on an Israeli Arab woman, 26 years old, who was healthy until her marriage. Two months after, she suffered URI symptoms, fatigue, cervical lymphadenopathy, and later was hospitalized because of pleural effusion and massive ascites. At admission, liver function tests were normal.

Cytologic evaluation of ascitic fluid revealed only inflammatory cells. Lymph node biopsy showed reactive hyperplasia. Peripheral blood lymphocyte immunophenotyping was consistent with viral infection (CD4/CD8=0.16). Serum testing revealed polyclonal hypergammaglobulinemia and 6 fold increase of CA-125 (218 u/ ml). Levels of CEA, CA15-3, and CA19-9 were normal. Patient improved and has been discharged without definite diagnosis and was followed in the outpatient clinic. Pleural effusion and ascites resolved gradually within a few weeks and CA-125 levels returned to normal. One and a half years later her husband, a drug abuser, was admitted to the hospital with convulsions. Brain CT revealed pattern of Toxoplasmosis. Laboratory work-up revealed HIV-1 positivity in addition to carrier state of HBV. His wife (our patient) was called back to the clinic and tested for HIV-1 and HBV which were found positive. Anti HCV was negative.CD4 level was 150cells/ml Conclusions: Initial presentation of HIV-1 infection with pleural effusion and ascites is very unusual. Also, elevated levels of CA-125 are completely uncommon. Interestingly, CA-125 can bind to the dendritic cell receptor DC-SIGN, which, in turn, acts as an HIV-1 attachment receptor that facilitates viral infection of T lymphocytes.

Thus, increased levels of CA-125 in the initial stages of HIV-1 infection may act as a defensive mechanism, limiting HIV-1 spread.

Hypomorphic mutation of the Artemis gene in an Arab-Israeli family causing immunodeficiency and predisposition to lymphoma Garty Ben Zion1,2,5, Stein Jerry3, Marcus Nufar1,2,5, Magal Norit4, Shohat Mordechai4,5, de-Villartay Jean-Pierre6, Lagovsky Irena1,5 1 Kipper Institute of Allergy and Immunology, 2 Department of Pediatrics B, and 3 Department of Oncology, Bone Marrow Transplant Unit, Schneider Children’s Medical Center of Israel, Petah Tiqwa

27

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

sparing and control the patient's gastrointestinal symptoms, trials of azathioprine, hydroxychloroquine, Methotrexate, or mycophenolate mofetil were given unsuccessfully. An attempt to treat with of rituximab (i.e. two courses of 500mg/week for four weeks, given ten months apart) did not subside the gastrointestinal episodes as well. Currently the patient is treated with prednisone (30mg) and azathioprine (150mg) daily, and is hospitalized approximately every 2 months for severe gastrointestinal symptoms.

Conclusion: This case illustrates a rare combination of recurrent angioedema in a patient with Sjogren’s syndrome. Unlike several reports of beneficial effect of rituximab, this treatment did not help to control the patient's severe gastrointestinal symptoms.

Further understanding of the pathophysiology of Sjogren and its possible link to angioedema is critical to the institution of appropriate therapy.

Antibody clustering helps refine lupus prognosis Kessel A1, Rosner I.2, Halasz K1, Grushko G1, Shoenfeld Y3, Paran D4, Toubi E1.

1 Division of Clinical Immunology, Bnai Zion Medical Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.

2 Rheumatology Unit, Bnai Zion Medical Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.

3 Department of Medicine B and the Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel-Hashomer, Incumbent of the Laura Schwarz Kipp Chair for Research of Autoimmune Diseases, Tel-Aviv, Israel.

4 Rheumatology Department, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv, Israel.

Objective: Our aim was to investigate a possible association between patterns of anti-dsDNA antibody isotypes (IgG, IgM, and IgA), rheumatoid factor (RF) isotypes (IgG, IgM, IgA), and IgG anti-C reactive protein (CRP) and systemic lupus erythematosus (SLE) disease activity (SLEDAI). METHODS: Our study group included 98 patients, 86 women and 12 men, with a mean SLEDAI score of 7.9±4.1. We divided the patients into 4 groups by the serum anti-dsDNA antibody isotype intensity level.

Results: We found that patients in group 1 (IgG>IgM, 42 patients) had a statistically significantly higher SLEDAI score than group 2 (IgG<IgM, 13 patients) (10.57±4.62 versus 5.6±4, P=0.0012), group 3 (IgG=IgM, 8 patients) (10.57±4.62 versus 6.2±1.98, P=0.04), and group 4 (none, 35 patients) (10.57±4.62 versus 6±1.5, P=0.0001).

SLE patients with IgG RF or IgM RF isotype present had a significantly higher SLEDAI score compared with those without IgG RF or IgM RF (10.57±4.8 versus 7.6±4.1, P=0.03, 10.6±5 versus 7.6±3.9, P=0.046). The presence of IgA RF isotype was not associated with a higher SLEDAI score. IgG anti-CRP did not correlate differentially with SLEDAI scores.

Conclusions: A combination of high-titer IgG anti-dsDNA with a positive RF of IgM isotype may serve as a marker for more active SLE. Semin Arthritis Rheum. 2009 Aug; 39(1):66-70

‫תקצירים‬

Parotitis as the presenting symptom of necrotizing granulomatosis: case report and meta-analysis Martine Szyper-Kravitz1, Ilan Green1,2, Yehuda Shoenfeld1 1 Center for Autoimmune Diseases and Department of Internal Medicine B, Sheba Medical Center, Tel-Hashomer 2 Family Medicine Department, IDF.

Background: Necrotizing granulomatosis (NG) (historically termed Wegener's granulomatosis) is a systemic disease presenting with upper respiratory, pulmonary and renal involvement. Involvement of the salivary glands and specifically of the parotid gland is rare.

Objective: To describe a patient who developed parotitis as the presenting sign of NG, and review the literature on additional cases of NG with salivary gland involvement.

Methods: A MEDLINE search for adult patients reported in the literature. Search terms included "Wegener's granulomatosis" and "parotitis", "parotid gland", "salivary glands", "submandibular gland" or "sublingual gland". The data extracted included: age, sex, symptoms at presentation, additional organ involvement, and outcome.

Results: The MEDLINE search resulted in 39 additional cases of salivary gland involvement in NG. The parotid gland was the most common salivary gland involved (75%), followed by the submandibular (35%) and the sublingual gland (2.5%). In most of the cases salivary gland involvement was accompanied by upper respiratory (72%), lower respiratory (61%), and renal involvement (48%). A high frequency of hearing loss (44%), and facial nerve palsy (17%) was found. Data on patient survival was available for 31 patients, with 5 deaths (16%).

Conclusions: In our analysis of NG patients with salivary gland involvement, the majority of patients had the characteristic involvement of the upper and lower respiratory tract, but a significant lower incidence of renal involvement was found.

This finding and its possible implications on the disease phenotype, severity and prognosis is discussed, together with the possible role of parotid gland infection with S. aureus on NG development.

Thyroid diseases and vitamin-D deficiency Nancy Agmon-Levin*, Shaye Kivity*, Michael Zisapel, Katalin Danko, Zoltan Szekanecz and Yehuda Shoenfeld.

The Center for Autoimmune Diseases, Sheba Medical Center, Tel–Hashomer, Israel

Background: The role of vitamin-D as an immune-modulator has been emphasized in recent years, and its deficiency was observed in several autoimmune diseases such as multiple sclerosis, and systemic lupus erythematous. Vitamin-D mediates its effect though binding to Vitamin-D receptor (VDR) and activation of VDR-responsive genes. VDR-gene

28

‫תקצירים‬

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

associated autoantibodies and the following infection-associated antibodies: Toxoplama gondii, cytomegalovirus (CMV), antiEpstein-Barr virus (EBV) nuclear antigen, EBV viral capsid antigen, EBV early antigen, anti-treponema pallidum antibodies.

Anti-saccharomyces cerevisiae IgG & IgA. Anti-HB core Ag, AntiHCV and Anti-H.pylori antibodies were assessed by ELISA. Results: Significantly lower levels of antibodies against several infectious agents were detected in the T1DM patients. These included Helicobacter pylori (P=0.01), cytomegalovirus (P=0.001), Epstein-Barr virus (P=0.02) and Toxoplasma (P=0.001). T1DM patients had significantly higher levels of IgG-anti-gliadin antibodies (P=0.001) and IgG-anti- tissue transglutaminase antibodies (P=0.03), and a borderline association with anticentromere antibodies (P=0.06).

Conclusions: The lower level of antibodies against infectious agents in T1DM patients may be related to their younger ages, but may also point to a protective role of those infections in T1DM development in susceptible individuals. Our results confirm the association betweenT1DMand celiac disease. A possible association with anti-centromere antibody needs further studies.

were determined by radial immunodifusion performed in 1% agarose gels containing monospecific goat antibodies to human components.

Results: Sera from patients with PBC were characterized by significantly higher levels of all pro-inflammatory cytokines: IL-1β (433.3 ± 13.2 in PBC vs. 316.6 ± 14.7 in controls, P<0.001), IL-6 (701 ± 17.4 in PBC vs.158 ± 22.5, P<0.001), TNFα (3.38 ± 0.6 in PBC and undetectable in controls, P=0.001), and sIL-2R (1527.1 ± 106 in PBC vs. 566.4 ± 28.7, P<0.001) when compared to controls. Similarly, all complement components were also significantly higher in PBC than in control sera.

Conclusions: This is the first report on PBC patients who manifest higher levels of sera sIL-2R and complement components, suggesting they may reflect the perpetuated immune activation. Complementarily and as expected, we confirm that all major pro-inflammatory cytokine levels are enhanced in PBC. We hypothesize that further analyses may demonstrate a correlation between these markers and disease stage or inflammatory activity, thus proving as new useful tools in PBC management - for defining histological staging, disease activity, and therapeutic response of PBC patients.

SERUM sIL-2R, INFLAMMATORY CYTOKINES and COMPLEMENT COMPONENTS IN Primary biliary cirrhosis (PBC)

Recurrent angioedema associated with Sjögren’s syndrome, unresponsive to treatment with Rituximab - a case report

V. Barak1,M.Schlesinger2, M.Blank3 , N.Agmon-Levin3 , I.Kalickman1 , C.Selmi4, 5 ,M.E.Gershwin4, and Y.Shoenfeld3 1 Immunology Lab. for Tumor Diagnosis, Hadassah-Hebrew Univ. Medical Center, Jerusalem 2 The Clinical Immunology Unit, Barzilai Medical Center, Ashkelon; 3 Department of Medicine 'B', the Center for Autoimmune Diseases, Sheba Medical Center, Tel- Hashomer; Sackler Faculty of Medicine, Incumbent of the Laura Schwarz- Kip Chair for Research of Autoimmune Diseases, Tel-Aviv University, Israel.

4 Division of Rheumatology, Allergy, and Clinical Immunology, Univ. of California, Davis, USA 5 San Paolo Hospital School of Medicine, Univ.of Milan, Italy;

Background and aims: Primary biliary cirrhosis (PBC) is a chronic cholestatic autoimmune liver disease characterized by selective destruction of the intrahepatic bile ducts and highly specific serum anti-mitochondrial autoantibodies (AMA). Several studies have attempted to determine the cytokine pattern characterizing PBC; yet no definitive data have been gathered.

The present study was designed to evaluate serum proinflammatory cytokines (IL-1β, IL-6, TNFα) soluble IL-2 Receptor (sIL-2R, e.g. soluble CD25), and complement components (C1q, C3, factor B, properdin) in patients with PBC. methods: 84 patients with PBC and 41 controls were evaluated for serum levels of cytokines and complement.

Serum inflammatory cytokines (IL-1β, IL-6, TNFα) and sIL2R (interpreted as a general immune activation marker) were measured by solid phase ELISAs. High sensitive immunoassay kits were utilized for the determination of low levels of human cytokines (IL-1β, IL-6 and TNFα). Complement levels

29

Shaye Kivity 1, 2, 3, Nancy Agmon-Levin2, 4 Pnina Langevitz1,5 1 Rheumatology unit, Sheba Medical Center, Tel-Hashomer, Israel 2 The Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel 3 Department of Medicine 'A & C', Sheba Medical Center, Tel-Hashomer, Israel 4 Department of Medicine 'B', Sheba Medical Center, Tel-Hashomer, Israel 5 Department of Medicine 'F', Sheba Medical Center, Tel-Hashomer, Israel

Background: Sjögren's syndrome is rarely associated with angioedema, yet several cases have been described. Treatment with rituximab was found useful in some cases of severe refractory angioedema in patients with Sjögren's syndrome.

Case description: A 24 year old woman suffered from recurrent episodes of angioedema without urticaria, which initially presented at the age of 18 years with two episodes of severe laryngeal-edema, requiring resuscitation. Daily administration of corticosteroids managed to prevent those life threatening attacks. However, episodes of gastrointestinal symptoms (e.g. epigastric pain, vomiting and diarrhea) appeared every several months, and required hospitalization and treatment with high doses of intravenous methyl-prednisone. Immunological studies revealed normal levels and function of C1-esteraseinhibitor and normal C4 levels. In addition she was diagnosed with Sjogren’s syndrome, manifested by dry mouth and eyes, arthritis, the presence of anti-Ro and anti-La antibodies, and a positive lip biopsy. On evaluation, no evidence of malignancy was observed. In an attempt to achieve steroid

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

Infectious Antibodies in Systemic Lupus Erythematosus patients Yackov Berkun1,5*, Gisele Zandman-Goddard-Goddard2,5*, Ori Barzilai3,5, Mona Boaz4,5,Yaniv Sherer3,5, Juan-Manuel Anaya6, Miri Blank3,5, Aubrey Cox7 Bruno Larida7, Yehuda Shoenfeld3,5 1 Safra Children Hospital, Sheba Medical Center, Tel-Hashomer 2 Department of Medicine C, Wolfson Medical Center, Israel 3 Department of Medicine B and Center of Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 4 Epidemiology Unit, Wolfson Medical center 5 Sackler Faculty of Medicine, Tel-Aviv University, Israel 6 Center for Autoimmune Diseases Research, Corporación para Investigaciones Biológicas, Rosario University Medellin, Colombia 7 Bio-Rad Laboratories, California, USA.

Purpose: Infections can act as environmental triggers inducing or promoting systemic lupus erythematosus (SLE) in genetically predisposed individuals. New technologies, developed recently, enable simultaneous assessment of multiple antibodies (Abs). Abs to specific infectious agents may shed light into the mechanisms of induction of SLE. The aim of this study was to investigate the prevalence of seropositivity and the titers of Abs to bacterial, viral and parasitic agents in SLE patients compared to non autoimmune controls.

Methods: Sera from 260 individuals (120 SLE patients and 140 controls) were tested by the BioPlex 2200 Multiplexed Immunoassay method (BioRad) for the prevalence and titers of Abs to 8 infectious agents (EBV: early antigen IgG, nuclear antigen IgG, viral capsid antigen IgG and IgM, heterophile IgM; CMV IgG and IgM; Toxoplasma gondii IgG and IgM; Rubella IgG and IgM; Treponema Pallidum TPr15G, TPr17G, TPr47G; Herpes Simplex Virus type 1 and 2 IgG; Hepatitis C Virus and Hepatitis B core antibodies).

Results: CMV IgM and EBV early antigen IgG (but not other EBV antigens) were significantly more prevalent in SLE patients than controls. Conversely, positive titers of Hepatitis B core and Rubella IgG Abs were less prevalent in the SLE patients than controls. Other differences in titer positivity prevalence were not detected between patients and controls. The titers of the CMV IgM, Toxoplasma IgG, EBV early antigen and viral capsid antigen IgG Abs were significantly higher in SLE patients compared to controls.

Conclusions: Our data suggest the importance of previous exposure to infectious agents in the induction and the prevention of SLE.

Autoantibody Screen in Inflammatory Myopathies High Prevalence of Antibodies to Gliadin Hedi Orbach1, Nimrod Amitai2, Ori Barzilai2,3, Mona Boaz2,4, ,Maya Ram2,3, Gisele Zandman-Goddard2.5, Yehuda Shoenfeldb3,6 1 Department of Medicine 2 Wolfson Medical Center, Holon, Israel. bSackler Faculty of Medicine, Tel-Aviv University, Israel.

3 Center of Autoimmune Diseases & Dept. of Medicine B, Sheba Medical Center,

‫תקצירים‬ Tel Hashomer, Israel.

4 Epidemiology Unit, Wolfson Medical Center.

5 Department of Medicine C, Wolfson Medical Center, Holon, Israel. fIncumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases

Background and Aim: Inflammatory myopathies (IM) are associated with autoimmune diseases. Our aim was to evaluate the titers of autoantibodies specific to various autoimmune diseases in patients with IM compared to controls.

Methods: Sera from 99 IM patients and 100 healthy controls were tested for autoantibodies for vasculitis (Myeloperoxidase, PR3 and glomerular basement membrane) and autoimmune gastrointestinal diseases (IgA and IgG anti gliadin, anti tissue transglutaminase and Sacharomyces Serviciae) utilizing the BioPlex 2200 Multiplexed Immunoassay method (Biorad).

Results: Anti gliadin IgA levels were significantly elevated in IM patients compared to controls (0.37 ± 0.44 vs. 0.24 ± 0.15, p = 0.017). Anti tissue transglutaminase IgA was marginally increased in IM patients vs. controls: 0.36 ± 1.12 vs. 0.2 ± 0.0 (p=0.08).

Conclusions: Antibodies to gliadin and tissue transglutaminase characteristic for celiac disease were elevated in patients with IM compared to controls. This may indicate a higher prevalence of gluten sensitivity or celiac disease in IM.

Anti-infectious Antibodies and Autoimmune-associated Autoantibodies in Patients with Type I Diabetes Mellitus and their Close Family Members Ilan Krause1,2,3, Juan Manuel Anaya4, Abigail Fraser5, Ori Barzilai1, Maya Ram1, Ver´onica Abad6, Alvaro Arango,gJorge Garc´ıa8, and Yehuda Shoenfelda3,i 1 Center of Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Israel; 2 Department of Medicine E, Rabin Medical Center, Petah-Tiqva, Israel 3 Sackler Faculty of Medicine, Tel Aviv University, Israel 4 Corporaci´on para Investigaciones Biol ´ogicas-Universidad del Rosario, Colombia 5 MRC Centre for Causal Analysis in Translational Epidemiology, Department of Social; Medicine, University of Bristol, Bristol, UK 6 Hospital Pablo Tob´on Uribe, Medellin, Colombia; gCl´ınica Universitaria Bolivariana, Medellin, Colombia 7 Antioque ˜na de Diabetes, Medellin, Colombia; iDepartment of Medicine B, Sheba Medical Center, Tel Hashomer, Israel

Background and aim: Type 1 diabetes mellitus (T1DM) is an autoimmune disease with complex interactions between genetic and environmental factors such as infectious agents.

In the following article we examine the association between serological evidence of past-infection with various infectious agents and autoimmune-associated autoantibodies in patients with T1DM. Methods: 57 Colombian T1DM patients (24 male and 33 female) and 123 of their first degree family members (FM) were studied.

A group of 140 healthy subjects served as controls. We compared antibody levels to various infectious agents and of autoimmuneassociated autoantibodies between groups. Samples were tested via the Bio-Rad BioPlex 2200, for the presence of autoimmune-

30

‫תקצירים‬

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

phosphatydilserine, prothrombin) were common among PBC patients. When clinical features were compared, the presence of anti-prothrombin IgM was associated with a worse prognosis as represented by a higher Mayo score.

Conclusions: We demonstrate an increased prevalence of ANA and thrombophilia-associated autoantibodies in PBC sera and an association between the latter autoantibodies and PBC stage.

The role of thrombophilia associated antibodies will warrant further studies, based in particular on the incidence of portal hypertension at early stages of PBC.

EBV nuclear antigen (90.2% vs. 77.8%, p<0.01). IgG antibodies against the EBV early antigen was noted EA (25.6% vs. 23.3%).

This parameter did not reach statistical significance.

Conclusions: Our results imply that certain infections may generate an immunological environment that disfavors future appearance of certain autoimmune conditions such as celiac disease.

Infections may have a protective role in the etiopathogenesis of Celiac disease

Howard Amital1,2 , Chava Azoulai1,2, Ori Barzilai1, Maya Ramm1, Gabriele Valentini3, Marco Matucci-Cerinic3, Yehuda Shoenfeld1 1 Department of Internal Medicine B, Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel, 2 Department of Medicine 'D', Meir Medical Center, Kfar-Saba affiliated to TelAviv University Sackler Faculty of Medicine, Israel 3 Department of Biomedicine, Division of Rheumatology, University of Florence, Florence, Italy

Leeor Plot1, Howard Amital1, Ori Barzilai2, Maya Ram2, Bizzaro Nicola3 and Yehuda Shoenfeld2,4 1 Department of Medicine 'D', Meir Medical Center, Kfar-Saba affiliated to TelAviv University Sackler Faculty of Medicine, Israel 2 Department of Internal Medicine B, Center for Autoimmune Diseases, affiliated to Tel-Aviv University Sackler Faculty of Medicine, Sheba Medical Center, TelHashomer, Israel 3 Laboratorio di Patologia Clinica, Ospedale Civile, 30027 S. Donà di Piave (VE), Italy 4 Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Tel-Aviv University, Israel.

Background and aim: Infectious agents have been implicated in the pathogenesis of many autoimmune diseases via various pathogenic mechanisms, such as molecular mimicry, resulting in modulation of the host's immune tolerance. In the following article we examine the association between serological evidence of past-infection with various infectious agents and co-existence of celiac disease.

Patients and methods: Sera originating from 297 healthy subjects and 90 patients diagnosed with CD were analyzed for the presence of antibodies specific for Toxopalsma gondii, Rubella virus, Cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Treponema pallidum using the Bio-Rad BioPlex 2200 system® (Hercules, CA, USA), a fully automated immunoassay analyzer. Both groups were of European origin.

Results: Higher prevalence of positive serologies were found in the control group as compared to the CD group regarding T.gondii (25.9% vs. 23.3%, p-value -), Rubella virus (94.9% vs.

87.8%, p<0.05) and CMV (67.7% vs. 54.4%, p<0.01).

A higher prevalence of antibodies against most of the T.pallidum antibodies were observed in the CD group as compared to the control group (SYPHG 1.2% vs. 0.3%, TRP15 1.2% vs. 0.3%, TRP47 1.2% vs. 0.7%), but due to the small number of positive samples these rates did not reach statistical significance.

As regarding to positive serologies for EBV, a higher prevalence IgM antibodies was found in the CD group as compared to the control group (6.8% vs. 3%, p = 0.06) approaching statistical significance. A lower exposure rate of antibodies against EBV capsid antigen was detected in the control group as compared to the CD group (EBVCA 88.9% vs. 78.9%, p<0.01) and against the

31

Infectious aspects of the pathogenesis of systemic sclerosis

Background and aim: Infections are often believed to play a role in the etiopathogenesis of autoimmune disorders; such is the case in systemic sclerosis (SSc). In order to evaluate the potential role infections may have on the pathogenesis of SSc we assessed serological reactivity against various infectious agents in patients with SSc and compared them to healthy controls.

Methods: Serological samples obtained from 80 patients with SSc were compared to 296 compatible healthy controls. Both groups were of European origin. All samples were tested for the presence of antibodies directed against hepatitis B virus, hepatitis C virus, helicobacter, toxoplasmosis, rubella, CMV, EBV, and Treponema pallidum. We applied Bio-Rad (Hercules San Francisco, USA) commercial and experimental kits to assess most antigens and ELISA assays to complete the panel.

Results: Patients with SSc were shown to have elevated IgM against CMV, 27% vs. 18% in patients compared to healthy controls respectively (p<0.05, Mann-Whitney test). This trend was also demonstrated with antibodies of the IgM and IgG isotypes against Toxoplasmosis antibodies compared to healthy controls, 6.4% vs. 0% (p<0.05) and 55% vs. 32% (p<0.01) respectively.

Interestingly, we also detected higher rates of antibodies against the hepatitis B virus core protein (recombinant HBc antigen) using MONOLISA anti-HBc Plus commercial kit (Bio-Rad, Hercules San Francisco, USA); 23% SSc patients were found to be positive compared to 4% of the healthy controls (p<0.0001).

A significantly lower rate of antibodies the IgG isotype against the capsid antigen of the EBV was noted in SSc patients compared to healthy controls, 51% vs. 63% respectively (p<0.05).

Conclusion: These data indirectly imply that infections and particularly CMV, HBV and toxoplasmosis may play a role in the pathogenesis of SSc.

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

‫מחלות אוטואימוניות‬ The infectious origin of autoimmune diseases: a major factor in the mosaic - Sjogren at stake Yehuda Shoenfeld, MD, FRCP. Department of medicine B' and the Center for Autoimmune Diseases, Sheba Medical Center, Tel -Hashomer. Incumbent of the Laura Schwarz-kipp chair for research of autoimmune diseases, Sackler Faculty of Medicine, Tel-Aviv University, Israel.

The etiology of autoimmune diseases (AID) is multi-factorial where genetic, immunologic, hormonal and environmental factors play in concert in their induction. This combination of factors determining the date of emergence of an AID is most probably the environmental factor among which the infection agents are the most ubiquitous1. In the interplay between infectious agents and autoimmunity it was found that the same infectious agent (i.e. EBV) may be involved in inducing many autoimmune diseases, while the same autoimmune disease may be caused by various agents (i.e. EBV, CMV, Helicobacter pylori etc).

Recently, we have analyzed a large number of sera (>2500) from patients with AID such as SLE, APS, RA, Vasculitides, Sjogren's syndrome and others for the presence of a profile of anti-infectious agents antibodies including EBV, CMV, H. Pylori, rubella, trponema, HSV and Toxoplasmosis. In several diseases a higher prevalence and titers of anti-infectious antibodies were found compared with sex, age and ethnic matched healthy controls. For instance, in patients with Sjogren's syndrome, the prevalence and titers of antibodies against EBV- early antigen were significantly higher than in their control group (p = 0.0003).

Interestingly enough, in some diseases we found lower titers of anti-infectious agents, such as the lower prevalence and titers of rubella and CMV antibodies (IgM) detected in patients with Sjogren's syndrome, compared to their controls (p<0.02).

This may allude indirectly to the notion that some infectious agents may have a protective, rather than a pathogenic role, for a specific autoimmune disease.

Furthermore, a certain infectious agent may determine why an individual with the "proper" genetic background will develop one AID rather than others, as well as its clinical manifestations and severity.

In conclusion, the complicated interactions between infections and autoimmunity may be summarized in ten points2: • Infections can cause AID. • infections can trigger an underlying immune process to become overt AID. • Various agents (i.e. viruses, bacteria and parasites) may inflict autoimmunity.

‫תקצירים‬ • Infectious agents can alter the clinical manifestations of an AID. • Genetic susceptibility determines autoimmune response to certain agents.

• The "burden of infections" through life affects autoimmunity.

• Infections during childhood may inflict autoimmunity in adulthood.

• Vaccines, similarly to infectious agents may induce AID. • Infections can sometime protect from autoimmunity (i.e. the hygiene theory).

• A certain infectious agent can induce one AID and protect from another.

1

Shoenfeld Y, Blank M, Abu-Shakra M et al. The mosaic of autoimmunity: prediction, autoantibodies, and therapy in autoimmune diseases-2008. Isr Med Assoc J. 2008;10:13-9.

2 Kivity S, Agmon-Levin N, Shoenfeld Y. Infections and autoimmunity - friend or foe? Trends immunol, 2009.

Serum autoantibodies in primary biliary cirrhosis: a large-scale analysis Nancy Agmon-Levin 1,2, Yinon Shapira 1, Carlo Selmi 3, Ori Barzilai 1, Maya Ram 1, Martine Szyper-Kravitz 1,2, Sara Sella1, Bat-sheva Porat Katz 4, Pierre Youinou 5 , Yves Renaudineau 5, Bruno Larida 6, Pietro Invernizzi 3, M. Eric Gershwin 7, and Yehuda Shoenfeld 1, 2, 8 1 Center for Autoimmune Diseases Sheba Medical Center, Israel 2 Department of Medicine 'B', Sheba Medical Center, Israel 3 Department of Internal Medicine, IRCCS Istituto Clinico Humanitas, University of Milan, Italy 4 Faculty of Agricultural, Food and Environmental Quality Sciences The Hebrew University of Jerusalem 5 Laboratoire d’immunologie, Brest University Medical School Hospital, Brest, France 5 Department of Internal Medicine, IRCCS Istituto Clinico Humanitas, University of Milan, Italy 6 Bio-Rad Laboratories, California, USA 7 Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA-USA 8 Sackler Faculty of Medicine, Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune Diseases, Tel-Aviv University, Israel

Background and Aim: In primary biliary cirrhosis (PBC) serum markers, other than anti-mitochondrial antibodies (AMA), are promising in terms of disease severity and comorbidities, as well represented by the presence of anti-nuclear antibodies (ANA). The aim of the present study was thus to evaluate the prevalence and clinical significance of a large profile of serum autoantibodies in PBC sera.

Methods: We utilized 69 sera from European patients with PBC (including 20 AMA-negative) and 297 sera from geographically and sex-matched healthy controls. All sera were tested for the presence of ANA and autoantibodies associated with thrombophilia, vasculitis, and gastrointestinal disease using the Bio-Rad BioPlex 2200 system® (Hercules, CA, USA), a fully automated immunoassay analyzer.

Results: Autoantibodies other than AMA were detected in 53/69 (76%) PBC sera vs. 105/297 (35%) among controls.

The prevalence of ANA (targeting dsDNA, Sm, chromatin, ribosomal-P, RNP, SmRNP, SSA, SSB, and centromere) and thrombophilia-associated autoantibodies (i.e. anti-β2GPI,

32

‫תקצירים‬ patients at various stages of the disease. This is the first study to present IL-18BP levels in sera of SLE patients as well as the calculated, biologically active, free IL-18 concentrations that are most probably more relevant to the pathology of SLE. Sera from 48 unselective SLE patients (total of 195 samples) were obtained longitudinally with a mean follow up period of 11.1±8.9 years and were compared to sera from 100 healthy volunteers. Circulating levels of IL-18, IL-18BP and free IL-18 in the SLE patients were significantly higher than the levels of healthy controls (5 fold, 6 fold and 3 fold for IL-18, IL-18BP and free IL-18, respectively) and correlated with disease activity as scored by SLEDAI-2K. Furthermore, these levels during active disease (SLEADI 2K≥6) were higher compared to the levels measured in the sera of the same patients during remission or during mild disease (SLEDAI2K 0-5). The high levels of IL-18 and IL-18BP in sera of active SLE patients suggest their possible role in the pathogenesis and course of the disease. However, despite the elevated levels of IL-18BP during active disease, free IL-18 remained more than 2 fold higher than the levels in healthy controls suggesting a potential benefit of administration of exogenous IL-18BP as a novel therapeutic approach for active SLE.

TLR4 MEDIATED CYTOKINES PRODUCTION BY MONOCYTES OF CHILDREN WITH MILK ALLERGY Levy Yael 1,2, Nahum Amit1, Lagovsky Irena3, Vanichkin Alex3, Garty Ben-Zion1,2 1 Schneider Children's Medical Center of Israel, Petach Tikva, Israel, 2 Sackler Faculty of Medicine,Tel Aviv University,Tel Aviv,Israel, 3 Felsenstein Medical Research Center, Beilinson Campus,Petach Tikva.Israel.

Background: The prevalence of milk allergy including fatal anaphylactic reactions has increased. Variations in innate immunity responses may predispose to the development of allergic diseases. Our previous study did not find a difference in monocytes TLR4 membrane expression between milk allergic children and non allergic controls.

Objectives:To elucidate TLR4 mediated cytokines production by monocytes of children with milk allergy.

Methods: Peripheral blood mononuclear cells of infants and children with documented IgE mediated cow milk allergy and non allergic controls were separated and cultured for 24 hours either alone or with LPS 1µg/ml and β casein 80µg/ml .The monocytes(CD14+) were fixed and permeabilized, and then stained with phycoerythrin conjugated anti TNF-α, IL-6,IL-1 β and IL-12 monoclonal antibodies, or with the isotype control. The percentages of the cytokines positive monocytes were determined using FACS analyzer. The results are expressed as mean± SEM. Results: In reponse to LPS, TNF- α positive monocytes percentages were 58.14±4.94 in allergic children((n=16),compared to 54.2± 9.59 in non allergic controls(n=5, p value-NS).In response to β casein, the percentages were 36.56 ±3.05 and 26.6 ± 4.81 respectively (p value-NS).In response to LPS, IL-6 positive monocytes percentages were 57.33± 5 in allergic

33

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

children (n=14), and 63.8 ±8.22 in non allergic controls (n=5, p value-NS). In response to β casein the percentages were 44.89± 4.64 and 29.6 ±3.59 respectively (p value=0.007). For IL-1 β, the percentages were 14.38± 2.66 in allergic children (n=9) and 11.74± 3.09 in controls (n=5) in response to LPS, and 4.08± 1.08 and 2.51± 0.32 respectively in response to β casein (p value-NS).

No differences were found between the percentages of IL-12 positive monocytes of the two groups.

Conclusions: TLR4 mediated proinflamatory cytokines production is not impaired in children with milk allergy: TNF-α and IL-1 β production is similar to non allergic controls. However, IL-6 production is increased in response to β casein, which may point to the role of this cytokine in the pathogenesis of milk allergy.

SUB-POPULATIONS OF REGULATORY AND TH17 LYMPHOCYTES IN HYPERTROPHIC ADENOIDS Sade Kobi1, Langier Sheilach1, Fishman Gad2, Kivity Shmuel1 1 The Allergy and Immunology Department and The 2 Pediatric ENT Department, The Tel aviv, Sourasky Medical Center. Tel aviv.

Israel.

Background: Adenoid hypertrophy is an inflammatory disease with unclear pathogenesis. The identification of novel helper T cell subsets, i.e., Th17 cells and regulatory T cells (Treg cells), provided new insight into our understanding of the mechanisms involved in the development of various inflammatory diseases.

The present study evaluates the adenoid lymphocyte subsets using flow cytometry.

Methods: Twelve subjects undergoing adenoidectomy were recruited, and lymphocytes were isolated from their adenoids.

Detection of T cells sub-population by flow cytometry was performed using a fluoresceinated monoclonal antibody directed against CD4+ and CD8+ CD25+ FOXP3 IL17+ and other cell markers. The T cells subsets of Regulatory T cells (CD4+CD25+FOXP3+) and the inflammatory Th17 cells (CD4+ IL17+) were compared to the peripheral blood T cell subsets of healthy control subjects.

Results: The subsets percentage of CD4+, CD8+ CD25+ and Tregs lymphocytes from hypertrophic adenoids were similar to the peripheral blood lymphocytes subsets of normal healthy subjects (Tregs: 3.7%±1.8 vs. 3.52%±1.3; p=NS). However, we observed a statistically significant difference in percentage of Th17 lymphocytes between hypertrophic adenoids and normal healthy subjects (Th17: 4.55%±1.0 vs.1.4%±0.3, p<0.05).

Conclusion: The lymphocytes sub-population of hypertrophic adenoids demonstrated Th17 polarization, which suggests that Th17 cells may contribute to the pathogenesis of adenoid hypertrophy.

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

of etanercept, concentrations of TNFα in cell supernatants were decreased by 53% on average, with a range of 25%–87%.

Etanercept impaired the stimulated maturation of MDDCs by neutralizing the induced TNFα, produced by the same MDDCs after antigenic stimulation.

Conclusion: The reported data confirms that TNFα blockade may have a direct effect on DCs, with a wide spectrum of potential secondary effects downstream. The data also suggests the presence of TNFα-mediated autocrine signaling, serving to accelerate or catalyze the maturation process of MDDCs. Inflammation. 2009 Jun; 32(3): 146-50.

Circulating Endothelial Progenitor Cells, Th1/Th2/Th17 Related Cytokines and Endothelial Dysfunction in Resistant Hypertension Magen E, Feldman, Cohen Z, Ben Alon D, Minz E, Chernyavsky A, Linov L, Mishal J, Schlezinger M, Sthoeger Z. 1 Allergy and Clinical immunology Unit, Barzilai medical Center; Ben Gurion University of Negev, Ashkelon, Israel 2 Department of medicine B and Clinical Immunology Allergy and AIDS center, Kaplan Medical Center, Rehovot, Israel.

Background: A possible link between chronic vascular inflammation and arterial hypertension is now an object of intensive studies Objective: To compare Th1/Th2/Th17 cells related cytokines, circulating endothelial progenitor cells (EPC) and endothelial function in subjects with resistant arterial hypertension (RAH) and controlled arterial hypertension (CAH).

Methods: Blood pressure was measured by electronic sphygmomanometer. Endothelial progenitor cells (EPC) were identified as CD34+/CD133+/KDR+ cells by flow cytometry. Th1/ Th2/Th17 cells related cytokines were using the Human Th1/ Th2/TH17 Cytokines Multi-Analyte ELISArray Kit. Endotheliumdependent (FMD) vasodilatation of brachial artery was measured

by Doppler ultrasound scanning.

Results: RAH Group (n = 20) and CAH Group (n = 20) and 7 healthy individuals (Control group) were recruited. In RAH Group lower blood levels of EPC number (42,4±16,7 cells/ml) and EPC % (0,19±0,08%); were observed than in CAH group (93,1±88,7 cells/ml; p=0,017); (0,27±0,17; p=0,036) and Control Group (68,5±63,6 cells/ ml; p<0,001); (0,28±0,17 %; p= 0,003) respectively. Plasma TGFβ1 levels were significantly higher in RAH (1767± 364 pg/ml), than in CAH (1292 ± 349; p<0,001) and in Control group (1203 ± 419 pg/ml; p<0,001). In RAH Group statistically significant negative correlation was observed between SBP and EPC% (r = - 0.72, p<0.01). FMD in the RAH group was significantly lower (5,5±0,8%) than in CAH group (9,2±1,4; p<0,001) and in healthy controls (10,1±1,1%; p< 0,001).

Conclusion: RAH is characterized by reduced circulating EPC, substantial endothelial dysfunction and elevated plasma TGF-β1 levels.

‫תקצירים‬

NOVEL INSIGHTS INTO CANCER IMMUNITY INDUCED BY VITAMIN- A DERIVATIVES R. Golan , R. Katz , S. Pollack Dept. Immunology, Rappaport Faculty of Medicine- Technion, Institute of Allergy & Clinical Immunology, Rambam Medical Center, Haifa.

Background and aim: Macrophage Inhibitory factor (MIF) is a major factor associated with cancer cell proliferation and progression. Natural and synthetic derivatives of vitamin A (retinoids) possess anti-proliferative and pro- apoptotic properties. The aim of this study was to elucidate immunological mechanisms which may be involved in the effect of retinoids on cancer cells. Methods: Tissue array, FACS analysis, Western immunoblotting, cytokine array, quantitative ELISA, gene expression and RNA microarrays were used for measuring surface marker expression, intracellular protein content and phosphorylation, gene expression and cytokine secretion.

Results: Inhibitory effect of the retinoid ATRA on MIF and VEGF secretion and cell proliferation could be demonstrated only in colon cancer (Colo-205) and breast cancer (MCF-7) cells. ATRA could also down regulate both protein and gene expression of CD44, a major component of the MIF receptor complex. This was associated with decreased tyrosine phosphorylation of Lyn-kinase and increased intracellular expression of the proapoptotic proteins p53 and Bax. In vitro ATRA treatment of breast cancer patients PBMCs was associated with decreased MIF secretion and elevated secretion of TGF-beta in 15% of patients.

Conclusions: ATRA treatment can inhibit MIF and VEGF secretion which is associated with down regulation of CD44 and reduced signal transduction by the CD44-coupled Lyn kinase.

This, in turn, is associated with enhanced TGF-beta secretion and decreased cancer cell proliferation. Thus, due to its antiproliferative effects in breast cancer cells, ATRA (or some other retinoid) may serve as a potential adjuvant treatment for breast cancer patients.

High Circulating Levels of Free Interleukin-18 in Patients with Active SLE in the Presence of Elevated Levels of Interleukin-18 Binding Protein Zev M Sthoeger, Daniel Elbirt, Galit Miller, Charles A Dinarello, Menachem Rubinstein, Daniela Novick Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel; Department of Medicine B, Allergy, AIDS and Clinical Immunology Kaplan Medical Center Rehovot, Israel and the Division of Infectious diseases, University of Colorado, Denver, Co, USA

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies particularly to nuclear antigens and by an abnormal production of proinflammatory cytokines. In the present study, we measured the levels of the proinflammatory cytokine IL-18 and its natural inhibitor, the IL-18 binding protein (IL-18BP), in sera of SLE

34

‫תקצירים‬

‫אימונולוגיה‬ A tolerogenic peptide that induces suppressor of cytokine signaling (SOCS)-1 restores the aberrant control of IFN-gamma signaling in lupus-affected (NZBxNZW)F1 mice.

Zev M. Sthoeger, Amir Sharabi, Keren Mahlab, Smadar Lapter, Heidy Zinger and Edna Mozes Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel and the Department of Internal Medicine B, Allergy, AIDS and Clinical Immunology, Kaplan Hospital, Rehovot, Israel

Interferon-γ (IFN-γ) plays a pathogenic role in systemic lupus erythematosus (SLE). Uncontrolled IFN-γ signaling may result from a deficiency in the negative regulator, namely, suppressor of cytokine signaling-1 (SOCS-1). We investigated the activation status of IFN-γ signaling pathway in SLE-afflicted (NewZealand-Black × New-Zealand-White) F1 mice, and determined its responsiveness when treating with a tolerogenic peptide, hCDR1, which ameliorates SLE. SOCS-1 was suppressed and pSTAT1 was enhanced in spleen-derived cells from SLE-affected mice, as compared with healthy controls. Treatment with hCDR1 reversed the expression of these two molecules in association with clinical amelioration. In vitro stimulation with IFN-γ resulted in elevated levels of SOCS-1 in cells from both vehicle and hCDR1-treated mice, but this effect reached significance only in cells of the latter group, which also exhibited reduced levels of pSTAT1. Thus, SOCS-1 is diminished in SLE-affected mice, and treatment with hCDR1 results in its up-regulation, thereby restoring control of IFN-γ signaling pathway.

The protective role of Tregs and Mast Cells in Chronic Allergic Dermatitis Alon Hershko, Nicolas Charles, Arian Laurence*, and Juan Rivera Laboratory of Molecular Immunogenetics and the *Molecular Immunology and Inflammation Branch, NIAMS, NIH.

Atopic dermatitis is an exceedingly common skin disease, which affects mainly children with an atopic familial background. We have set out to determine what immune cells contribute to the dampening of the inflammatory response in the skin using a murine model of atopic dermatitis, which is induced by repeated applications of oxazolone to the ear skin. By manipulating the activity of the IL-2 receptor on Tregs in vivo, we demonstrated that binding of IL-2 to its receptor upon the first exposure to the allergen determines long term tolerance. Following this critical time-point, mice become resistant to any intervention in the IL-2/CD25 pathway. Next, a possible regulatory role of mast cells (MC’s) was studied, in light of recent reports that these cells may serve as mediators of Treg function. MC expansion

35

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

in the inflammatory site (i.e. the skin) is independent of Treg’s.

However, their absence in Wsh/Wsh mice is associated with severe dermatitis at the chronic stage of disease. This defect was corrected by reconstitution of Wsh/Wsh mice with bone marrow derived MC’s. Surprisingly, disease suppression did not require engraftment in the inflammatory site but only repopulation of the spleen. Consequently, we observed that chronic dermatitis involved IgE-dependent expansion of MCs in the spleens of WT mice. Even though our data show that Treg function remains considerably intact in mice lacking MC’s, at late stages of disease the presence of MC’s is required to achieve optimal Treg expansion and T-effector suppression in the spleen. The regulatory cellular changes detected in the spleens of mice with chronic oxazolone dermatitis last for several weeks following recovery from skin disease. These changes are associated with significant protection from OVA induced asthma. We suggest that Tregs are first line of defense from allergic skin disease, and their function is induced upon the initial sensitization and critically depends on IL-2. Following several exposures to oxazolone, an increase in IgE enhances splenic MC expansion, which, in turn, boosts Treg numbers.

These changes are sustained and confer subsequent nonallergen specific protection.

Etanercept Impairs Maturation of Human Monocyte-Derived Dendritic Cells by Inhibiting the Autocrine TNFα-mediated Signaling Gleb Slobodin1, Aharon Kessel2, Regina Peri2, Natalia Zaigraikin1, Michael Rozenbaum3, Itzhak Rosner3, and Elias Toubi2 1 Department of Internal Medicine A, Bnai Zion Medical Center, 2 Department of Immunology, Bnai Zion Medical Center, 3 Department of Rheumatology, Bnai Zion Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

Background: The success of anti-tumor necrosis factor alpha (TNFα) therapies has led to increased interest as to the mechanisms and consequences of TNFα blockade. Aim: The aim of the study was to examine the effects of TNFα blockade by etanercept on lipopolysaccharide (LPS) or peptidoglycan (PG)induced maturation of human monocyte-derived dendritic cells (MDDCs).

Methods: MDDCs grown from peripheral blood of healthy donors were stimulated by LPS or PG with/without the presence of etanercept. Concentrations of TNFα in cell supernatants were assessed by ELISA, while the cells were stained with monoclonal antibodies to CD83, CD80, CD86, CD11c, CD40, HLA-DR, and annexin-V and acquired using a flow cytometer.

Results: Etanercept significantly decreased the stimulated cell surface expression of HLA-DR, CD80, CD86, CD40 and CD83 on MDDCs in all examined samples. Etanercept in the same dose, but denatured to loss of specificity for TNFα, failed to change any of the aforementioned markers. In the presence

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

to these allergens was started. With increasing allergenic doses, she developed allergic skin reactions at the injection site as well as similar reactions at distant sites on other limbs, without any systemic affects. After testing each allergen alone, the cause of this unique reaction was proven to be grass.

Conclusions: Local and systemic reactions to immunotherapy due to allergen or diluents (glycerin/aluminum) are common.

Remote skin allergies without systemic features have been rarely described. The mechanism is unclear. It may be due to activation of allergen-primed CD4+CD45+ memory T cells at the site of the initial allergic reaction.

Type I hypersensitivity to Aspergillus fumigatus in severe Asthmatic patients Bernstein, M., Fireman, L., Shamshines, L., Sade, K., Kivity, S. Allergy and Immunology unit, Tel-Aviv medical center, Sackler School of Medicine.

Background: Patients with severe asthma require all types of investigations. Allergic workup is not always performed.

Objective: To examine type I hypersensitivity to Aspergillus F. (A.F.) in subgroup of patients with severe asthma.

Methods: Patients with severe asthma (n=13) were referred to our clinic in the last year for evaluation. They had the following tests done: Pulmonary function test; induced sputum for cell count and fungal examination; HRCT; Total IgE, skin test (prick or intradermal or RAST to A.F.).

Results: A total of 13 patients were seen, (M=8 F=5), of these 7 had Bronchiectasis (central). Pulmonary function results (X±SD): FVC%= 72 (±27), FEV1%= 58 (±35) FEV1/FVC%= 88 (±37).

The eosinophils in induced sputum were (X±SD) 35% (±37) (with a range of 0.5%-76%). Hyphae were seen in seven patients.

Two patients received Itraconasol for a 4 months period, with major improvement in their symptoms as well as a decrease in eosinophils in induced sputum and resolution of the bronchiectasis.

Summary: 13 patients with severe and poorly controlled asthma were diagnosed as having Aspergillus F. related disease, 7 of them were found to have bronchiectasis.

In patients who received antifungal treatment, symptoms markedly improved.

Conclusion: Aspergillus F. related diseases are common and underdiagnosed in severe asthmatics. Allergic evaluation, as well induced sputum, should be mandatory in all severe asthmatic subjects.

‫תקצירים‬ Background: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in children younger than 1 year. Severe RSV bronchiolitis contributes substantially to the risk of recurrent wheezing and possibly asthma in early childhood. Fractional exhaled nitric oxide (FeNO) is a marker of eosinophilic airway inflammation, and can be used to assess asthmatic status.

Objectives: To measure FeNO levels in infants with acute RSV bronchiolitis, and compare the values with those for non-RSV wheezy babies and healthy controls.

Methods: The study population included infants who were referred to our emergency room for wheezing, coughing and respiratory distress compatible with acute bronchiolitis. RSV infection was confirmed by nasopharyngeal secretion antigen analysis.

Results: The 85 study children included 43 with RSV bronchiolitis (mean age 6.83±7.33 months), 20 wheezy babies negative for RSV (10.85±7.59 months), and 22 healthy agematched controls (6.88±9.07 months). Mean FeNO levels at first visit were 1.8±1.7 ppb, 4.86±7.49 ppb, 6.29±3.3 ppb, respectively (P=0.001 for RSV-positive infants vs. healthy controls). The FeNO levels at the 2-month and 4-month follow-ups of the children with RSV bronchiolitis were 7.8±5.7 ppb and 11.3±6.3 ppb, respectively (P=0.001).

Conclusions: FeNO levels were significantly reduced in infants during the acute event of RSV bronchiolitis, compared with healthy controls and increased significantly following the acute event.

EXHALED NITRIC OXIDE IN RSV BRONCHIOLITIS Tali Gadish*, Ruth Soferman**, Tamar Merimovitch**, Yakov Sivan** *Pediatric Department, **Pulmonology, Critical Care & Sleep Medicine, Dana Children’s Hospital, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University.

36

‫תקצירים‬ Conclusions: Introduction of APMS to our clinic improved handling of patients, simplified professional communication between the staff, and increased the safety of routine diagnosis and treatment.

PRODROMAL SIGNS AND SYMPTOMS OF HEREDITARY ANGIOEDEMA Avner Reshef, Iris Leibovich, Mona Kidon-Yankovich The Allergy& Immunology and Angioedema Center, Sheba Medical Center, TelHashomer, Israel

Background: Heralding signs and symptoms may precede acute attacks of Hereditary Angioedema (HAE) by minutes, hours and sometimes days. These "prodroms" have been reported in individual case reports and small series of patients, but there are no uniform criteria for its diagnosis. Furthermore, its frequency, significance and contribution to the diagnosis and management of HAE are presently unknown.

Objectives: To determine the prevalence of prodromal signs and symptoms in a cohort of HAE patients, as related to predefined organ system clusters.

Methods: The survey was comprised of a questionnaire covering several organ systems, mentioned in the literature and often reported by the patients. 40 patients (20 males, 20 females, mean age: 28.8, range: 1.5-64 years) were interviewed personally or by a telephone call.

Results: 33 patients (82.5%) reported on having at least one sign or symptom preceding the attacks. 21 patients (63.6%) had a prodrome in more than half of their HAE attacks, and 7 (21.2%) experienced it on every attack. The majority were: Cutaneous or Soft-tissue symptoms (78.8%), followed by Gastrointestinal (60.6%), Emotional/ psychological (30.3%), Cardiovascular (30.3%), Respiratory (18.2%), Neurological (12.1%), and Urinary (9.1%).

Conclusions: Prodroms of HAE attacks might be overlooked by caretakers and specialists. The present findings imply that they are more frequent than previously reported. Clinical prodroms should be better defined to determine its contribution to the detection and treatment of HAE.

THE EFFICACY OF RECOMBINANT C1INHIBITOR FOR ACUTE TREATMENT OF HEREDITARY ANGIOEDEMA Avner Reshef, Iris Leibovich' The Allergy& Immunology and Angioedema Center, Sheba Medical Center, Tel-Hashomer, Israel

Background: Hereditary angioedema (HAE) attacks cause severe organ dysfunction, pain and risk of death from asphyxiation. Until recently, human plasma-derived C1 inhibitor concentrates were the only replacement therapy available. A recombinant C1 inhibitor (rC1INH) produced in transgenic

37

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

rabbit milk is currently being investigated.

Objectives: To evaluate the efficacy, safety and immunogenicity of rC1INH during acute HAE attacks.

Methods: rC1INH (350-1050mg) was given intravenously to 8 HAE patients (age 16-54), on 20 separate occasions, within 4-5 hours of the onset of an acute attack. Visual analog-scale (VAS) of 0 to 100mm was employed to assess the intensity of each key symptom (i.e. edema, pain, nausea, discomfort). Symptom severity was recorded at predetermined time points, until symptoms fully resolved, or at least 48 hours post treatment.

Immunologic parameters included: C4, C1q, both antigenic and functional C1INH, plasma C1INH and rC1INH-specific antibodies, and anti-rabbit milk antibodies.

Results: Mean symptom score (MSS) for edema or pain upon admission was 78.19±15.2mm, increasing to 86.24±11.3 before treatment. Mean reduction of 50% from maximal MSS was obtained within <2 hours in 12 attacks. MSS was: 22.2±24.2, 17.4±25.1 and 5.7±11.7 at 4h, 8h and 24h, respectively. Plasma levels of C1INH were maintained up to 4 hours. No significant early or late adverse reactions were observed and no additional rescue medications needed. Repeated infusions were not associated with hypersensitivity reactions or tolerance, and no antibody formation was observed.

Conclusions: rC1INH was found effective and well tolerated in the treatment of acute HAE attacks.

Remote allergic reactions following immunotherapy: report of two cases Werner, B., Elbirt, D., Burke, M., Machlev-Guri, K., Abraham, Z., Sthoeger, Z. Clinical Immunology, Allergy and AIDS Center Kaplan Medical Center, Affiliated with Hadassah-Hebrew University Medical School Jerusalem, Rehovot, Israel

Background: Allergic reactions following immunotherapy are quite common. These reactions are usually either systemic or local at site of injection. Remote, non-systemic, skin reactions distant from the site of injection are extremely uncommon.

O b j e c t i ve s a n d M e t h o d s : To d e s c r i b e p a t i e n t s o n immunotherapy that developed remote, non-systemic, allergic skin reactions and make physicians aware of this unusual form of reaction.

Patient 1. A male aged 35 developed an anaphylactic reaction after a bee sting. Skin testing revealed marked reactivity to bee venom and immunotherapy was initiated. Two years later when the patient was on maintenance dose, he developed a red pruritic swelling on the brow – the same site of his initial sting. This remote reaction was unaccompanied by any other local (injection site) or systemic reaction. This phenomenon recurred during every injection and was alleviated partially by antihistamines. Interestingly, during maintenance treatment, he was stung again, but had no reaction.

Patient 2. A female aged 42 with allergic rhinitis demonstrated positive skin reactions to grass, weed, and olive. Immunotherapy

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

Background: Air-borne particles may be responsible for the high prevalence of asthma, especially in children. Population: 64 symptomatic children (aged 12.5± 3 yrs) referred for induced sputum (IS) for differential diagnosis. Methods: The children underwent pulmonary function tests by conventional methods, fractional nitric oxide testing by FeNO Ecomedics AG analyser (Durnten, Switzerland), and IS by 20' ultrasonic nebulizer inhalation of 3% saline. Three-hundred cells were differentially counted in cytospin Giemsa‑stained slides.

Analysis of IS particle size and shape was done by Eyetech Analyser (Yokneam, Israel). TNF-α was measured in the IS supernatant by an ELISA kit (R&D SYSTEMS). Results: The children were grouped into those with >3% eosinophils (Group I, n=39, age 12.4±3.37 yrs) or with <3% eosinophils (Group II, n=25, age 12.57±2.39 yrs). FEV1/FVC ratio and FeNO differed significantly between groups: 88.28±13.44% and 98.88±13.09 %(p<0.003), and 55.1±37.09 ppm and 15.92±9.39 ppm (p<0.000) in Group I and Group II, respectively. The difference in particulate matter size distribution (prtc <5 um) was significant between the groups: 4.26±1.56% in Group I and 3.36±2.0% in Group II (p<0.05). Eosinophils significantly(+) correlated to prtc size (34µm, 4-5µm, 5-10µm) (r= 0.276 p<0.028, r= 0.385 p<0.002, r= 0.412, p<0.001 respectively). Rougher prtc were seen in Group I than group II (as measured by convexity pattern) 0.89±0.0165 vs. 0.91±0.044 p<0.041). The TNF-α levels were higher in Group I than Group II (p not significant). Conclusions: Particulate matter in airways correlates to eosinophilic inflammation in asthmatic children. Air pollution may be crucial in the increasing prevalence of pediatric asthma.

Increased platelet volume and CRP levels in chronic urticaria patients with a positive autologous serum skin test Magen Eli1,3, Mishal Joseph1, Feldman VK1, Kidon Mona2, Menachem Schlesinger* 3, thoeger Zev* 4 1 Medicine B Department, Barzilai medical Center; Ben Gurion University of Negev, Ashkelon, Israel 2 Allergy and Clinical Immunology Unit, Sheba Medical Center, Tel Hashomer, Israel 3 Allergy and Clinical immunology Unit, Barzilai medical Center; Ben Gurion University of Negev, Ashkelon, Israel 4 Department of medicine B and Clinical Immunology Allergy and AIDS center, Kaplan Medical Center, Rehovot, Israel

Background: Activation of the coagulation cascade resulting in thrombin production is a prominent feature of exacerbations in chronic spontaneous urticaria (CU). Autologous serum skin test (ASST) causes wheal-and-flare reactions in 30-50% of CU cases.

Objective: The aim of the study was to evaluate the clinical and laboratory data in CU patients with positive and negative ASST. To understand the role of platelets in CU, we investigated the relation between CU clinical severity, platelet count and their mean platelet volume (MPV).

‫תקצירים‬ Methods: Clinical and laboratory data were prospectively collected from 373 patients with CU who attended our Allergy and Clinical immunology Clinic, during the period 2003–2007.

The laboratory data was compared with 100 healthy subjects.

Results: There were no significant differences in platelet counts between the groups. Nevertheless, the platelets in ASST positive CU were characterized by a higher mean platelet volume (MPV) (9.12±1.25 fl), than the platelets in ASST negative patients (7.95±1.08 fl; p=0.039) and control group (7.89±0.96 fl; p=0.002).

There was a significant positive correlation between CUSS and MVP in ASST positive patients. Higher levels of C-reactive protein (5.31±2.74 mg/l) were measured in the ASST positive compared to ASST negative CU group (2.53±1.27; p=0.029) and to the control group (2.46±1.59; p=0.014).

Conclusion: CU with positive ASST is characterized with higher clinical severity, MPV and CRP.

DEVELOPMENT OF ALLERGY PATIENT MANGEMENT SOFTWARE AND ITS APPLICATION TO ALLERGY/IMMUNOLOGY OUTPATIENT CLINIC Michal Deutch, Mona Kidon-Yankovich, Avner Goren, Alan Zeav Siedlecki and Avner Reshef The Allergy& Immunology and Angioedema Center, Sheba Medical Center, TelHashomer, Israel

Background: Computers have revolutionized the way healthcare systems are operated. They became a common working tool for both organizations and individual practitioners, aiding in both patient management, and in storing and retrieving data.

Dedicated medical software can be assimilated into routine work to improve our professional capabilities.

Objectives: We decided to construct a specific Allergy Patient Management Software (APMS), and apply it to our allergy/ immunology clinic. It was presumed that APMS would amplify our performance in four critical areas: patient management, diagnosis, treatment, and overall communication between physicians and nurses.

Methods: The Chameleon software (ELAD Co., Israel) was adapted to conform to our needs by local software engineers.

Specific requests for routines and algorithms were provided to our software development team, while simultaneously tested by the clinic's staff. APMS was designed in accordance with our established clinic routines to include the following: patient medical history, environmental data, family history, physical findings, and medications. Later, we modified the system to include diagnostic tests and allergen immunotherapy.

Results: APMS has been incorporated to our allergy/immunology clinic for 18 months. The system is relatively easy to learn and apply. In addition to simplifying the management during a visit, it can automatically issue prescriptions, test results, and letters to patients' personal physicians. We observed a significant improvement in the quality and safety of patient care.

38

‫תקצירים‬ drug hypersensitivity – 45 (10%) were mistreated. Medicine specialists made significantly less errors than surgeons (p<0.0005). Most patients had NSAID hypersensitivity. Of 59 patients admitted for an allergic reaction, 78% did not receive referral to an allergist and/or instructions to procure epinephrine when indicated.

Conclusion: Altogether, 90 patients admitted to the ED were treated incorrectly. Known drug hypersensitivity was overlooked in 45 patients. The specialties of the treating physicians were the only significant factors found to affect their management. Acute allergic reaction was mistreated in the remaining patients. We did not find risk factors for these errors.

Physicians working in the ED, and especially surgeons, should receive guidance concerning the correct management of patients with drug hypersensitivity. All physicians who work in the ED should be aware of the optimal management of patients with allergic reactions.

Presentation of Eosinophilic Esophagitis as Failure to Thrive in Young Children Ilan Dalal1,4, Tsili Zangen2, Ron Shaoul3, Arie Levine2,4 1 Pediatric Allergy and Immunology Unit, E. Wolfson Medical Center, Holon, Israel 2 Pediatric Gastroenterology Unit, E. Wolfson Medical Center, Holon, Israel 3 Pediatric Gastroenterology Unit, Bnei Zion Medical Center, Haifa, Israel 4 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Background: Eosinophilic esophagitis (EE) is an emerging disorder in children and adults, characterized by eosinophilic infiltration of the esophagus. In children it presents most commonly with dysphagia or gastroesophageal reflux symptoms, while the knowledge regarding the presenting symptoms in young children (< 8 years of age) is scarce.

Patients and methods: We reviewed our data regarding clinical presentations of EE due to a high proportion presenting with failure to thrive (FTT). The diagnosis was based on clinical symptoms, typical macroscopic features on esophagogastroduodenoscopy and the identification of > 15 eosinophils/HPF in esophageal biopsy specimens. Patients were questioned regarding a personal and familial history of atopic diseases. Food hypersensitivity was evaluated using RAST or skin prick tests (SPT) to a panel of common and other suspected food allergens.

Results: Eighteen patients (thirteen males), aged 11 months to 19 years were diagnosed with EE. Six Infants and toddlers with onset under 3 years of age all presented with low intake FTT. In addition, only 3/5 patients between ages 3-8 yrs had dysphagia or GERD symptoms. In contrast, all 7 patients > 8 years presented with “classical features” of EE. Peripheral eosinophilia (absolute count > 600) was found in 8/18 (44.4 %) patients. Nine out of 18 (50%) had a history of chronic recurrent respiratory diseases, including asthma and/or allergic rhinitis.

Food sensitivity was disclosed in 11/14 (78.6%) tested. 13/18

39

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

(72%) responded to removal of cow’s milk from their diet.

Conclusion: Our observation highlights the need for high index of suspicion for EE in young children presented with low intake FTT.

Elevated serum total IgE – a potential marker for severe chronic urticaria Kessel Aharon MD.1, Helou Wissam MD.1, Bamberger Ellen MD.1, Sabo Edmond MD.1, Nusem David MD.2, Panassof Josef MD.2, Toubi Elias MD.1 1 Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Technion Faculty of Medicine, Haifa, Israel.

2 Clalit Health Services- Lin Medical Center, Allergy, Haifa, Israel.

Background: Elevated IgE levels in patients with chronic urticaria have been noted in several previous studies, but the significance of these findings has not been appreciated.

Objective: To measure the IgE levels in such patients and to examine the relationship between these levels and urticarial severity, autologous serum test, anti-thyroid antibodies and duration.

Methods: Serum total IgE levels from 203 patients with chronic urticaria were measured and compared with non-atopic individuals. In addition, patients were assessed for urticarial severity, the presence of autologus serum test and anti-thyroid antibodies.

Results: Of the chronic urticaria patients, 47 (23.2%) were classified as mild, whereas 156 (76.8%) were classified as having moderate-to-severe chronic urticaria. Total IgE levels were elevated in 69/203 (34%) of patients, compared with 7/81 (8.6%) of healthy controls (p<0.001). A significant association between increased total IgE and chronic urticaria severity was found. Whereas 93% of patients with increased level of total IgE suffered from moderate-to-severe chronic urticaria, this was observed in only 69% of patients with normal IgE (p<0.0001).

Autologous serum test and anti-thyroid antibodies were positive in 59/163 (36%) and 28/189 (15%) of patients, respectively. A significant association between increased total IgE levels and the presence of autologous serum test, anti-thyroid antibodies and urticarial duration lasting more than 25 months (p<0.0001, p<0.0001 and p=0.021 respectively) was also detected.

Conclusions: Total serum IgE levels are frequently elevated in patients with chronic urticaria and these are associated with disease severity and duration.

Particulate matter-induced inflammation in the airways of asthmatic children Brenda Toledano1, Ruth Soferman2, Moshe Stark1, Mor Sabag1, Yakov Sivan2, Shmuel Kivity1, Elizabeth Fireman1 1 Institute of Pulmonary and Allergic Diseases, National Laboratory Service for ILD, Department of Pulmonary Medicine, 2 Department of Pediatric Pulmonology, Critical Care and Sleep Medicine, Dana Children's Hospital, Sourasky Medical Center, Sackler School of Medicine, TelAviv University, Tel‑Aviv, Israel

2009 ‫ | אלרגיות ואימונולגיה | אוקטובר‬update‫הרפואה‬

‫אלרגיה‬ Rush venom immunotherapy: safety, efficacy and cost among bee venom allergic patients Arnon Goldberg, Ayala Yogev, Ronit Confino-Cohen From the Allergy and Clinical Immunology Unit, Meir Hospital, Kfar Saba, Israel, affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Background: Rush venom immunotherapy (VIT) has been applied successfully in vespid venom allergic patients, but data regarding its efficacy in bee venom (BV) allergy are sparse.

Objective: To evaluate the efficacy, safety, and cost of rush VIT in BV allergic patients.

Methods: Conventional or rush VIT were offered to all patients who experienced a systemic reaction to insect sting. In a subgroup of patients, rush VIT was given to hyper-reactive patients after recurrent failures of conventional VIT. In BV allergic patients, honeybee sting-challenge was performed within one week after reaching the maintenance dose.

Results: 179 patients received 253 rush VIT courses. The maintenance dose was reached by 173 patients (96.6%).

Immunotherapy with BV was given to 132 patients (73.7%). The incidence of systemic reactions was 29.6%. They were more common in VIT with BV than with vespid venoms (31.1% and 16.3%, respectively, P=0.01). After excluding the hyper-reactive sub-group (n=20), this difference was not significant (23.7% and 16%, respectively, P=0.19). Despite the high incidence of systemic reactions (75%) to rush VIT among hyper-reactive patients, 85% achieved the maintenance dose. Sting-challenges resulted in systemic reactions in 4 out of 8 (50%) and in 2 out of 47 (4.3%) patients of the hyper-reactive sub-group and of the regular group, respectively. The cost of rush VIT was 41% of that of conventional VIT. Conclusions: Rush VIT with BV is safe and efficacious. It is significantly cheaper and enables most patients with previous failures of conventional VIT to reach the maintenance dose.

Allergen Immunotherapy – Induced Biphasic Systemic Reactions: Incidence, Characteristics and Outcome – A Prospective Study Ronit Confino-Cohen, MD, Arnon Goldberg, MD From the Allergy and Clinical Immunology Unit, Meir Medical Center, Kfar-Saba, Israel, affiliated with the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

Background: An anaphylactic reaction is one of the alarming adverse effects of allergen immunotherapy. Although systemic reaction can follow a biphasic course, its incidence, outcome and the risk factors for its development are unknown in

‫תקצירים‬ patients treated with immunotherapy.

Objective: We aimed to record the incidence, characteristics and outcome of immunotherapy-inflicted biphasic reactions.

Methods: All patients attending large, in-hospital allergy clinic for immunotherapy were followed prospectively. Recorded patient's data included: demographics, diagnosis, type and phase of immunotherapy and peak expiratory flow (PEF) before each administration of the injections. If an anaphylactic reaction occurred, medical treatment was recorded and the patient was requested to complete a three-day diary that included symptoms and periodic measurements of PEF. A biphasic reaction was defined as a late decrease in PEF of more than 20%, with or without accompanying symptoms.

Results: During 10,040 visits, 453 patients received 21,022 immunotherapy injections and 131 anaphylactic reactions occurred. Eleven of these (10%) were biphasic. Most uniphasic and all biphasic reactions occurred in patients who were being treated for allergic rhinitis. Low baseline PEF or concomitant asthma was more common in patients with biphasic reactions.

Other parameters were comparable between patients with uniphasic and biphasic reactions. All biphasic reactions were mild and resolved either spontaneously or with oral antihistamines.

Conclusions: Immunotherapy-induced biphasic reactions are uncommon. They tend to be mild in nature and might be more common in patients with low baseline PEF or concomitant asthma. Hence, long observation after the initial reaction is not required.

Management of drug hypersensitivity and allergic reactions in an emergency department in Israel Sharon Reisfelda, Arnon Goldbergb, Ronit Confino-Cohenb From the Department of Internal Medicine Aa and the Allergy and Clinical Immunology Unitb, Meir Medical Center, Kfar Saba, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Background: Although drug allergies and allergic reactions are potentially life-threatening, their management in the emergency department (ED) is not always satisfactory. Previous studies evaluated the management of allergic reactions in the ED, but none of these have specifically addressed patients with known drug allergy. We aimed to analyze the treatment offered to these patients presenting at the ED for any reason, and the management of allergic reactions in an Israeli ED. Methods: Records of patients discharged from the ED in 19 random dates between 2/2004 and 9/2005 were retrospectively reviewed. Data included: demographics, diagnosis, previous drug allergies, training of ED physician, time and day of the week, management and discharge recommendations.

Results: Of 3,996 admissions to the ED, 436 (11%) had known

40

‫מהספרות המקומית‬

2009 ‫ | אלרגיה ואימונולגיה | אוקטובר‬update‫הרפואה‬

2. Bachelet I, Levi-Schaffer F, Mekori YA. Mast cells: not only in allergy. Immunol Allergy Clin North Am 2006;26:407–25.

antibody-enhanced dengue virus infection of human mast cells and associated CCL5 release. J Leukoc Biol 2006;80: 1242–50.

3. Mekori YA, Metcalfe DD. Mast cells in innate immunity. Immunol Rev 2000;173:131–40.

23. Heib V, Becker M, Warger T, et al. Mast cells are crucial for early inflammation, migration of Langerhans cells and CTL responses following topical application of TLR7 ligand in mice. Blood 2007; 110:946–53.

4. Dawicki W, Marshall JS. New and emerging roles for mast cells in host defence.

Curr Opin Immunol 2007;19:31–8.

5. Stelekati E, Orinska Z, Bulfone-Paus S. Mast cells in allergy: innate instructors of adaptive responses. J Imbio 2007;212:505–19.

6. Marshall JS. Mast cell responses to pathogens. Nat Rev Immunol 2004;4:787–99.

7. Dermott JR, Bartram RE, Knight PA, Miller HR, Garrod DR, Grencis RK. Mast cells disrupt epithelial barrier function during enteric nematode infection. Proc Natl Acad Sci USA 2003;100: 7761–6.

8. Onah DN, Nawa Y. Mucosal mast cell derived chondroitin sulphate levels in and worm expulsion from FcRγ-knockout mice following oral challenge with Strongyloides venezuelensis. J Vet Sci 2004;5:221–6.

9. Henderson WR, Chi EY. The importance of leukotrienes in mast cell mediated Toxoplasma gondii cytotoxicity. J Infect Dis 1997;177: 1437–43.

10. Ben-Rashed M, Ingram GA, Pentreath VW. Mast cells, histamine and the pathogenesis of intestinal damage in experimental Trypanosoma brucei infections.

Ann Trop Med Parasitol 2003;97:803–9.

11. Birdi M, Vouldoukis I, Mossalayi MD, et al. Evidence for direct interaction between mast cells and Leishmania parasites. Parasite Immunol 1997;19:475–83.

12. Echtenacher B, Mannel DN, Hultner L. Critical protective role of mast cells in a model of acute septic peritonitis. Nature 1996; 381:75–7.

13. Malaviva R, Ikeda T, Ross E, Abraham SN. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha. Nature 1996;381:77–80.

14. Kulka M, Fukuishi N, Rottem M, Mekori YA, Metcalfe DD. Mast cells, which interact with Escherichia coli, up-regulate genes associated with innate immunity and become less responsive to FcεRImediated activation. J Leukoc Biol 2006;79:339–50.

15. Thankavel K, Madison B, Ikeda T, et al. Localization of a domain in the FimH adhesin of Escherichia coli type 1 fimbriae capable of receptor recognition and use of a domain-specific antibody to confer protection against experimental urinary tract infection. J Clin Invest 1997;100:1123–36.

24. Kulka M, Alexopoulou L, Flavell RA, Metcalfe DD. Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3. J Allergy Clin Immunol 2004;114: 174–82.

25. Orinska Z, Bulanova E, Budagian V, Metz M, Maurer M, Bulfone-Paus S. TLR3induced activation of mast cells modulates CD8+T-cell recruitment. Blood 2005;106:978–87.

26. Sayed BA, Brown MA. Mast cells as modulators of T-cell responses. Immunol Rev 2007;217:53–64.

27. Malaviya R, Twesten N, Ross E, Abraham SN. Mast cells process bacterial antigens through a phagocytic route for class I MHC presentation to T cells. J Immunol 1996;156:1490–6.

28. Warbrick EV, Taylor AM, Botchkarev VA, Coleman JW. Rat connective tissuetype mast cells express MHC class II: up-regulation by IFN-gamma. Cell Immunol 1995;163:222–8.

29. Jawdat DM, Rowden G, Marshall JS. Mast cells have a pivotal role in TNFindependent lymph node hypertrophy and the mobilization of langerhans cells in response to bacterial peptidoglycan. J Immunol 2006;177:1755–62.

30. Wang HW, Tedla N, Lloyd AR, Wakefield D, Neil PH. Mast cell activation and migration to lymph nodes during induction of an immune response in mice. J Clin Invest 1998;102:1617–26.

31. Metz M, Grimbaldeston MA, Nakae S, Piliponsky AM, Tsai M, Galli SJ. Mast cells in the promotion and limitation of chronic inflammation. Immunol Rev 2007;217:304–28.

32. Galli SJ, Nakae S, Tsai M. Mast cells in the development of adaptive immune responses. Nat Immunol 2005;6:135–42.

33. Demeure CE, Brahimi K, Hacini F, et al. Anopheles mosquito bites activate cutaneous mast cells leading to a local inflammatory response and lymph node hyperplasia. J Immunol 2005;174: 3932–40.

16. Xu X, Zhang D, Lyubynska N, et al. Mast cells protect mice from Mycoplasma pneumonia. Am J Respir Crit Care Med 2007;173:219–25.

34. Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M. Mast cells as "tunable" effector and immunoregulatory cells: recent advances. Annu Rev Immunol 2005;23: 749–86.

17. Malaviya R, Ikeda T, Abraham SN. Contribution of mast cells to bacterial clearance and their proliferation during experimental cystitis induced by type 1 fimbriated E. coli. Immunol Lett 2004; 91:103–11.

35. Weber S, Babina M, Feller G, Henz BM. Human leukaemic mast cells (HMCS1) and normal skin mast cells express beta 2-integrins: characterization of beta 2-integrins and ICAM-1 on HMCS-1 cells. Scand J Immunol 1997;45:471–81.

18. Genovese A, Borgia G, Bouvet JP, et al. Protein Fv produced during viral hepatitis is an endogenous immunoglobulin superantigen activating human heart mast cells.

Int Arch Allergy Immunol 2003;132:336–45.

36. Stahl JL, Cook EB, Graziano FM, Barney NP. Human conjunctival mast cells: expression of Fc epsilonRI, c-kit, ICAM-1, and IgE. Arch Ophthalmol 1999;117:493–7.

19. Abraham S, Shin J, Malaviya R. Type 1 fimbriated Escherichia colimast cell interactions in cystitis. J Infect Dis 2001;183(S1):51–5.

20. King CA, Marshall JS, Alshurafa H, Anderson R. Release of vasoactive cytokines by antibody-enhanced dengue virus infection of a human mast cell/basophil line.

J Virol 2000;74:7146–50.

21. King CA, Anderson R, Marshall JS. Dengue virus selectively induces human mast cell chemokine production. J Virol 2002; 76:8408–19.

22. Brown MA, King CA, Marshall JS, Anderson RP. A dominant role for Fcγ.RII in

41

37. Maurer M, Wedemeyer J, Metz M, et al. Mast cells promote homeostasis by limiting endothelin-1-induced toxicity. Nature 2004; 432:512–16.

38. Metz M, Piliponsky AM, Chen CC, et al. Mast cells enhance resistance to snake and honeybee venoms. Science 2006;313:526–30.

39. Rivera J. Snake bites and bee stings: the mast cell strikes back. Nature Med 2006;12:999–1000.

40. Bischoff SC. Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data. Nature Rev Allergy Immunol 2007;7:93– 104.

2009 ‫ | אלרגיה ואימונולגיה | אוקטובר‬update‫הרפואה‬

in the recognition phase of innate immune responses [23,24]. For example, studies have shown that viruses activate MCs through interaction with TLR3 (that recognize dsRNA), resulting in the secretion of interferon-alpha, which inhibits viral replication and recruits other immune cells such as natural killer cells and macrophages [24,25].

Mast cells and adaptive immunity There is a growing body of evidence that bidirectional interactions between MCs and T lymphocytes have a major role in adaptive immunity [26]. MCs are able to phagocyte bacteria, process its antigens, and present it to T lymphocytes in the context of major histocompatibility complex class I and II, thus serving as antigen-presenting cells [5,27,28]. During induction of an immune response, MCs migrate into lymph nodes where they further secrete chemokines and cytokines that induce lymph node hypertrophy and aggregation of additional lymphocytes [26,29]. TNFα induces T lymphocyte recruitment to the lymph node while interleukin-6 promotes these cells’ activation [4,30]. On the one hand, most of the cytokines secreted by MCs induce Th2 differentiation, thereby escalating the allergic immune response. On the other hand MCs can secrete IL-12 and INFγ that support Th1 response, suggesting in fact that MCs are able to regulate the equilibrium between Th1 and Th2 responses [5].

MCs regulate T lymphocytes' specific immune responses indirectly by modulation of dendritic cells [5,31,32]. They promote recruitment, maturation and migration of immature dendritic cells from the circulation to the lymph nodes, where they present antigens to T lymphocytes [23,29,33]. Moreover, MCs have a regulatory effect on B cells through expression of MHC class II, stored in exosomes that release through exocytosis [5,34]. MCs express a wide variety of surface receptors and adhesion molecules that can be implicated in the co-stimulation process during the adaptive immune responses and enable them to interact with other inflammatory cells. Examples of such receptors are intercellular adhesion molecule-1, β2-integrins and CD40 ligand [2,34-36].

Snake bites and bee stings For many years MCs were believed to contribute to the complications caused by snake bites and bee stings through the release of tissue-damaging molecules. These molecules promote an increase in vascular permeability, local inflammation, disturbance of the clotting and the fibrinolysis systems, and eventually might lead to shock and death. In 2004, Maurer and colleagues [37] published a study where they investigated the association between MCs and endothelin-1 [37]. ET-1 is an endogenous vasoconstrictor peptide that participates in the vascular changes occurring during sepsis.

It is also known to activate MCs by binding to the ET-1 receptors, TLR = toll-like receptor TNFα= tumor necrosis factor-alpha IL = interleukin INFγ = interferon-gamma MHC = major histocompatibility complex

‫מהספרות המקומית‬ leading to degranulation and release of mediators. Interestingly, the authors showed that MCs promote the degradation of ET-1, thereby increasing survival during acute bacterial peritonitis [37].

ET-1 has high homology (> 70%) to sarafotoxin, the most potent toxic components of the venom of the Israeli mole viper (Seraph Ein Gedi). This raised the question whether MCs have a protective role in envenomation. In 2006, Metz and Galli [38] challenged this question. They found that MC-deficient mice were more susceptible to hypothermia and death as a result of injection of either sarafotoxin or complete Israeli mole viper venom, compared to normal mice or MC-deficient mice engrafted with normal MCs. Moreover, they showed that the levels of sarafotoxins in the peritoneal cavity of these mice were significantly lower than in the control group, suggesting that MCs have a role in reducing the toxin levels. They generated two groups of mice that contained MCs that either expressed or lacked the ET-1 receptor and found that those lacking the receptor failed to clear sarafotoxins and died quickly, indicating that sarafotoxins activate MCs, at least in part, through binding to this receptor.

In their search for a potential mechanism by which MCs reduced the venom toxicity, they found that carboxypeptidase A, a protease found in MC granules, was responsible for degrading the venom.

Normal mice given an inhibitor of CPA, or MC-deficient mice engrafted with MCs expressing an inhibitory RNA that silenced CPA, died within an hour after injection of sarafotoxins or whole venom. Further studies showed that MCs had a protective role against other venoms that did not contain ET-like peptides such as the American pit vipers, the western diamondback rattlesnake, and the southern copperhead [38]. It was also reported that MCs provided protection against honeybee venom, although it is still unclear if CPA is the major anti-venom agent in this case [39]. Despite the fact that human MCs are different from mice MCs, it is reasonable to assume that they share similar protective roles [40].

Conclusions It was not too long ago that the role of MCs was restricted to allergic inflammation. However, in the last two decades MCs have emerged as one of the most important factors at both the innate and the adaptive arms of the immune system. There is no doubt that we are only at the beginning of the journey towards better understanding of MC biology and extensive research is definitely needed.

Correspondence: Dr. A. Mor Laboratory of Allergy and Clinical Immunology, Meir Medical Center, Kfar Saba 44281, Israel.

Phone: (972-9) 747-2198, Fax: (972-3) 747-1311 email: adam.mor@clalit.org.il

References 1. Metz M, Maurer M. Mast cells – key effector cells in immune responses. Trends Immunol 2007;28:234–41.

ET-1 = endothelin-1 CPA = carboxypeptidase A

42

2009 ‫ | אלרגיה ואימונולגיה | אוקטובר‬update‫הרפואה‬

‫מהספרות המקומית‬

The Role of Mast Cells in Non-Allergic Inflammation Adaya Weissler MD1, Yoseph A. Mekori MD1,2,3 and Adam Mor MD1,2 1

Department of Medicine B and 2Laboratory of Allergy and Clinical Immunology, Meir Medical Center, Kfar Saba, and 3Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel

Key words: mast cells, inflammation, infection, allergy

I

n 1878 Paul Ehrlich described a new type of granular cells that were mainly localized to the connective tissue compartment.

These cells were prevalent in chronically inflamed human tissues.

He named the cells “Mastzellen," meaning “well-fed cells” due to the high content of cytoplasmatic granules. These cells, better known today as mast cells, were initially considered to be part of the connective tissue. However, in the 1970s it was shown that their precursors were actually the hematopoietic stem cells. Mast cells circulate in the bloodstream and migrate into mucosal or connective tissues, where they undergo maturation into long-lived cells. These sites are the interface with the external environment (i.e., skin and mucosal surfaces), thus enabling MCs to respond rapidly to environmental stimuli, making them 'sentinels' of the immune system [1].

At first, MCs were studied in the context of allergic inflammation. For decades they were notable for their high affinity FCε receptor-I, which after binding to immunoglobulin E forms the cell’s antigen receptor. The interaction with antigen and the crosslinking of the FCεRI causes degranulation of cytoplasmatic granules and the release of histamine, which increases vascular permeability and induces bronchoconstriction. The pathological consequences can be local, as in allergic rhinitis, or systemic as in anaphylaxis.

The discovery that MC granules contain preformed agents other than histamine (i.e., heparin, proteases, chondroitin sulfates and antimicrobial peptides) and their ability to selectively produce and release cytokines, chemokines, growth factors and lipid mediators (i.e., prostaglandins and leukotrienes) has led many investigators to believe that MCs participate in various biological responses other than IgE-mediated allergic inflammation. This review will focus on some of the recent advances in understanding these cells heterogeneity, mainly their role in non-allergic inflammation [2].

Mast cells and innate immunity Both the innate and the adaptive arms of the immune system participate in host defense against infections. The unique localization of MCs to the host-environment interface, being a common site of pathogen invasion, and their ability to react to a large variety of physical, biological and chemical stimuli, raised the idea that these MC = mast cells FCεR = FCε receptor Ig = immunoglobulin

43

cells might play a role in innate immunity against infections [3,4].

MCs were initially associated with host defense against parasites since these pathogens cause IgE-associated responses. Studies have shown that intestinal parasitic infections were associated with MC hyperplasia and subsequently the release of proteases that results in expulsion of parasites by disrupting the intestinal epithelial barrier [1,5-7]. Moreover, studies of MCdeficient or IgEdeficient mice showed that these factors had a role in protection against intestinal worms [1,4,6,8]. The role of MCs in the defense against intracellular parasites was also shown in several infection models, including: malaria, Toxoplasma gondii, Trypanosoma brucei, Giardia lamblia and Leishmania [5,9-11].

In 1996, two groups published reports that have changed our understanding of MC biology [12,13]. They studied the ability of MC-deficient mice (lacking the MC growth factor receptor-c-kit) to fight Klebsiella peritonitis. Both groups found that normal mice overcame the bacterial infection, whereas MC-deficient mice died as a result of it. This was attributed to the rapid MC secretion of tumor necrosis factor-alpha following the inoculation of the bacteria, resulting in an augmented neutrophil response. Their findings were the first to clearly demonstrate that MCs have an important role in innate immunity, a role that is not related to parasitic infections. Shortly after, other researchers demonstrated MCs’ roles in host defense against additional bacteria such as Escherichia coli and Mycoplasma pneumoniae [14-17].

MCs can be activated by host-derived signals or directly by the pathogen. The former include activated products of the complement system and endogenous peptides, which are formed quickly and in large quantities in response to infection [1,6]. For example, it has recently been shown that MCs were activated by Fv protein, an endogenous protein released by the liver during viral hepatitis [2,4,18]. Interestingly, the interaction was mediated through the Fc receptor. An example of the latter is the interaction between CD48 on the MCs and the fimbrial antigen FimH expressed by several gramnegative bacteria [2,15,17,19]. It has also been shown that MCs were activated following interaction between dengue virus and the FcγRII, resulting in the release of specific mediators that were different from those released after interaction with bacterial products [20-22].

The toll-like receptor family comprises single membranespanning receptors that recognize conserved molecules expressed by different pathogens but not by the host. These molecules include factors such as bacterial peptidoglycan, lipopolysacharide, dsRNA and bacterial DNA. TLRs are considered among the key players that alert the immune system to the presence of pathogens. Since they are expressed on MCs, it was reasonable to believe that MCs participate

2009 ‫ | אלרגיה ואימונולגיה | אוקטובר‬update‫הרפואה‬

differences related to gender or to Jewish compared to Arab origin.

Milk allergy has been associated with other allergic manifestations, and about 30% of milk-allergic children have atopic dermatitis [11].

The presence of atopic dermatitis does not apparently affect the predictive accuracy of IgE concentrations in relation to the outcome of milk challenges [12]. In this study 51% of children suffered from atopic dermatitis, but there was no correlation to the milk-specific IgE concentration. However, we found a highly significant correlation of CMsIgE level with the presence of additional diagnoses of urticaria and asthma and to other food allergies.

In recent years several studies have examined the possibility of using serial or special serum CMsIgE levels for decreasing or even avoiding the need for the complex oral challenge tests, while keeping the predictive values intact [3,4,6,13]. However, there is no full agreement on the validity of this approach [5]. Our work adds to the current knowledge by showing the predictive value of milk-specific concentrations in children under the age of 1 year on the outcome of milk allergy after the age of 3 years. While our results and those of others show that milkspecific IgE concentrations are a useful predictor of challenge outcome in patients with milk allergy [12] as a group, challenge tests under specialist medical supervision are still necessary, because the sensitivity and specificity of milk-specific IgE do not yet allow unequivocal prediction in individual cases

Conclusions Milk-specific IgE concentration in the first year of life can serve as a predictor of the persistence of milk allergy in children. However, their predictive value is such that oral challenges, safely performed by an allergy specialist, remain the gold standard in the diagnosis of food allergy and food allergy resolution.

‫מהספרות המקומית‬

Correspondence: Dr. M. Rottem Head, Allergy Asthma and Immunology, HaEmek Medical Center, Afula 18101, Israel.

Phone: (972-4) 000-0000; Fax: (972-4) 641-5080 email: menachem@rottem.net

References 1. Skripak JM, Matsui EC, Mudd K, Wood RA. The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol 2007;120(5): 1172–7.

2. Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004; 113(5):805–19.

3. Perry TT, Matsui EC, Conover-Walker MK, Wood RA. The relationship of allergen-specific IgE levels and oral food challenge outcome. J Allergy Clin Immunol 2004;114(1):127–30.

4. García-Ara MC, Boyano-Martínez MT, Díaz-Pena JM, Martín-Muñoz MF, MartínEsteban M. Cow's milk-specific immunoglobulin E levels as predictors of clinical reactivity in the follow-up of the cow's milk allergy infants. Clin Exp Allergy 2004;34(6):866–70.

5. Miceli Sopo S, Radzik D, Calvani M. The predictive value of specific immunoglobulin E levels for the first diagnosis of cow's milk allergy. A critical analysis of pediatric literature. Pediatr Allergy Immunol 2007;18(7):575–82.

6. Celik-Bilgili S, Mehl A, Verstege A, et al. The predictive value of specific immunoglobulin E levels in serum for the outcome of oral food challenges. Clin Exp Allergy 2005;35:268–73.

7. Saarinen KM, Pelkonen AS, Mäkelä MJ, Savilahti E. Clinical course and prognosis of cow's milk allergy are dependent on milk-specific IgE status. J Allergy Clin Immunol 2005;116(4):869–75.

8. Høst A, Halken S, Jacobsen HP, Christensen AE, Herskind AM, Plesner K. Clinical course of cow's milk protein allergy/intolerance and atopic diseases in childhood.

Pediatr Allergy Immunol 2002;13(Suppl 15):23–8.

9. Skripak JM, Matsui EC, Mudd K, Wood RA. The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol 2007;120(5): 1172–7.

10. Tikkanen S, Kokkonen J, Juntti H, Niinimäki A. Status of children with cow’s milk allergy in infancy by 10 years of age. Acta Paediatr 2000;89:1174–80.

11. Casimir GJ, Duchateau J, Gossart B, Cuvelier P, Vandaele F, Vis HL. Atopic dermatitis: role of food and house dust mite allergens. Pediatrics 1993;92:252–6.

12. Vassilopoulou E, Konstantinou G, Kassimos D, et al. Reintroduction of cow's milk in milk-allergic children: safety and risk factors. Int Arch Allergy Immunol 2008;146(2):156–61.

13. Niggemann B, Celik-Bilgili S, Ziegert M, Reibel S, Sommerfeld C, Wahn U. Specific IgE levels do not indicate persistence or transience of food allergy in children with atopic dermatitis. J Invest Allergol Clin Immunol 2004;14(2):98–103.

44

2009 ‫ | אלרגיה ואימונולגיה | אוקטובר‬update‫הרפואה‬

‫מהספרות המקומית‬ or a positive oral food challenge. Oral tolerance was defined as an uneventful oral challenge in the clinic or successful home introduction. The primary outcome of interest was acquisition of oral tolerance. Patients who were not likely to have acquired tolerance, on the basis of either a history of recent reactions or elevated milk-specific IgE levels, typically did not undergo oral challenges but continued follow-up.

Diagnoses of other allergic such as atopic dermatitis, asthma and rhinitis were based on history and clinical evaluation.

Statistical analysis

Table 2. Milk allergy and other conditions Condition

No. (%)

Urticaria

76 (56)

Atopic dermatitis

69 (51)

Asthma

37 (27)

Gastrointestinal symptoms

31 (23)

Allergic rhinitis

17 (13)

Anaphylaxis

2 (1.5)

Table 3. Milk allergy and other allergic phenomena Condition

Sensitivity (%)

Specificity (%)

P

Odds ratio

Positive predictive value

Analysis was performed using SPSS version 14.

Other food 26.8 96.3 0.01 1.53 93.8% allergies Association between the groups of children with and Urticaria 76.8 48 0.02 1.47 89.5% without clinical milk allergy in relation to age and Asthma 30.4 92.6 0.02 1.5 75.4% in comparison to their IgE level and other clinical allergic conditions was performed by chi-square test.

Multivariate logistic regression was used to predict clinical sensi- at age 3 years and above (P = 0.001) compared to milk-specific IgE tivity in relation to age together with odds ratio, relative risk and concentration of less than 3 IU/ml. The positive predictive value 95% confidence intervals. was 82.6% (P = 0.001). The sensitivity of this level is 67.9% and the specificity 70.4%. Seven (5%) of the 135 children had IgE above 100 IU/ml before 1 year of age, which was, as expected, clinically Results significant in all and had not resolved by age 3.

We next examined the correlation of milk allergy to other Milk-specific IgE was determined in the serum of 1800 infants and children aged 0–18 years referred for the evaluation of pos- allergic phenomena [Table 2]. Persistent cow’s milk allergy above sible milk allergy by their primary physicians in the community. the age of 3 years significantly correlated to the presence of other The majority of children were first referred at less than 1 year of food allergies, urticaria and asthma, but not to atopic dermatitis age: Mean age at first evaluation was 10.5 months (range 5 weeks (P = 0.01, P = 0.02, P = 0.02, P = 0.48, respectively) [Table 3]. to 11 years). Of these, 135 infants and children had milk-specific The positive predictive values were 93.8%, 89.5%, and 75.4%, IgE greater than 1 kU/L; 89 (66%) were males, 105 (78%) were respectively.

Only two children had anaphylactic reaction to milk, and Jewish and 30 (22%) were Arab, similar to their distribution in the general population in the area. Of the 135 enrolled children, 83 therefore no statistical correlation could be drawn in relation to (62%) were over 3 years old and 52 (38%) were under 3 years old anaphylaxis in this study. when the study was terminated. The relation of elevated milk IgE, age and clinical milk allergy is presented in Table 1. As shown, Discussion 42% of children older than 3 years still had clinical milk allergy.

Of the 56 children with persistent clinical milk allergy over The prevalence of milk allergy in industrial countries is 1.9–5.2% the age of 3 years, 38 (68%) had had milk-specific IgE > 3 IU/ in children under the age of 3 years, and tends to resolve with ml in their first year of life. In 19 (70%) of 27 children who had age in most children [9]. The ability to predict the course of milk lost their clinical milk allergy before age 3, milk-specific IgE was allergy in a specific child is important for both the parents and the < 3 IU/ml at or before the age of 1 year. Thus, milk-specific IgE physician and determines the necessity of subjecting the child to concentration higher than 3 IU/ml in the first year of life carries a repeated tests and oral milk challenges. In this work we tried to risk ratio of 1.69 (95% confidence level 1.19–2.43) of milk allergy analyze whether milk-specific IgE can be helpful in such prediction, by examining if the persistence of milk allergy is related to Table 1. Milk allergy in relation to age in infants and children with the initial CMIgE in the first year of life. In addition, we examined milkspecific IgE > 1 IU/ml the relation of milk-specific IgE concentrations to other allergic Milk allergy Milk allergy phenomena. Food allergy was diagnosed by specific IgE and either Age (yrs) positive negative Total a clear convincing history or food challenges. >3 56 (42%) 27 (20%) 83 (62%) A poor prognosis for milk allergy has been related to genetic and <3 41 (30%) 11 (8%) 52 (38%) environmental factors such as male gender, non-Caucasian origin, Total 97 (72%) 38 (28%) 135 (100%) asthma and smoking at home [10]. In this study we did not find

45

2009 ‫ | אלרגיה ואימונולגיה | אוקטובר‬update‫הרפואה‬

‫מהספרות המקומית‬

The Predictive Value of Specific Immunoglobulin E on the Outcome of Milk Allergy Menachem Rottem MD1,2, Daniela Shostak BSc1 and Sylvia Foldi MD1 1

Allergy Asthma and Immunology Service, HaEmek Medical Center, Afula, and 2Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

Background: Cow's milk allergy is the most prevalent food hypersensitivity, affecting 2–3% of infants, but it tends to resolve with age.

Cow’s milk-specific immunoglobulin E in the serum is an important measure in the diagnosis and follow-up of infants and children with cow's milk allergy. Objectives: To examine the relation between CmsIgE and the probability of resolution of milk allergy.

Methods: CMsIgE was determined in the serum of 1800 infants and children referred for the evaluation of possible milk allergy. All children with CmsIgE of 1 kU/L or above were followed at the allergy clinic and, according to their condition, underwent milk challenge. The diagnosis of cow's milk allergy was made on the basis of a significant and specific history or a positive oral food challenge. Subsequently, oral tolerance was defined as an uneventful oral challenge.

Results: A total of 135 infants and children had milk-specific IgE greater than 1 kU/L. Forty-one percent of children still had clinical milk allergy after the age of 3 years. Sixty-eight percent of children older than 3 years with persistence of cow's milk allergy had milk-specific IgE > 3 IU/ ml before the age of 1 year. Furthermore, 70% of children who at 3 years old had resolved their cow's milk allergy had milk-specific IgE that was lower than 3 IU/ml before the age of 1 year. The positive predictive value of CmsIgE > 3 IU/ml to persistent cow's milk allergy at age 3 years was 82.6% (P = 0.001), with a sensitivity of 67.9% and specificity of 70.4%.

Conclusions: Milk-specific IgE concentration in the first year of life can serve as a predictor of the persistence of milk allergy.

Key words: milk allergy, immunoglobulin E, asthma, atopic dermatitis, food allergy Abstract:

C

ow's milk allergy is the most prevalent of all food allergies and affects 2–3% of infants worldwide. Immunoglobulin E-mediated cow's milk allergy tends in most cases to disappear with age [1,2].

The sooner tolerance is ascertained the earlier children can enjoy a CmsIgE = cow’s milk-specific immunoglobulin E

normal and unrestricted diet. This has substantial importance for the normal growth and development of infants and children and in alleviating the emotional burden of their families.

Oral food challenge is the gold standard for the diagnosis of clinical food allergy and is also crucial in determining whether the allergy has been resolved. Advising the parents of children with known food allergy when to perform a repeat challenge is a critical step in the follow-up of these children. Determination of food-specific IgE levels in the serum has proved helpful, but the exact cutoff levels are still a matter of debate. Yet, milk-specific IgE is one of the most important measures in the diagnosis and in the follow-up of infants and children with food allergy [3-7].

Children with a history of food allergy are also at greater risk of having other atopic diseases, including asthma and rhinitis [8].

The aim of the present study was to examine the relation between milk-specific IgE levels in the serum and the probability of resolution of milk allergy, as well as the effect of other allergic conditions on the development of such tolerance.

Subjects and Methods All tests performed for milk-specific IgE between the years 1994 and 2006 at the immunology laboratory of HaEmek Medical Center for children suspected of having cow's milk allergy were seen by the pediatric allergy unit staff. The serum samples were sent by the primary physicians in the community for infants and children they suspected might have milk allergy. The laboratory serves as the main immunology laboratory for the northern region of Israel. Milk-specific IgE was assessed by the Immulite enzymelinked immunosorbent assay system and included total milk IgE as well as specific IgE towards the different milk components including alpha-lactalbuin, beta-lactoglobulin, and casein. The detection level for milk-IgE was an IgE level higher than 0.35 kU/L. All children with cow’s milk-specific IgE of 1 kU/l or above were brought in, examined, followed at the allergy clinic and, depending on their condition, underwent a challenge test with milk.

The cutoff point chosen was 1 kU/L because clinical milk allergy is extremely low at lower levels [2,5] Data collected included gender, other allergies and atopic conditions, family history of atopy, age at onset of symptoms, age and symptoms with accidental exposures to milk, the reported outcomes when milk was introduced at home, and the outcomes of other food allergies.

The diagnosis of cow's milk allergy was made on the basis of a history of symptoms clearly associated with exposure to milk

46

‫מהספרות המקומית‬ spinal or predominant DIP patterns of PsA, as well as measures of enthesitis and dactylitis in PsA are still unavailable [40]. This lag between the appearance of new effective treatment modalities and the difficulties in assessment of some variants of PsA may lead to underestimation of the severity of PsA and inappropriately chosen treatment in some patients. It should be mentioned that the blind translation of RA therapies (both traditional DMARDs and biologics) for patients with PsA may be unwise, regarding the potential differences in the efficacy and toxicity of medicines in two different conditions. In addition, coordinated therapy, directed at both psoriatic skin lesions and affected joints, may be preferred in PsA patients. Finally, combination therapy of two or more non-biologic DMARDs or biologic and non-biologic DMARDs (methotrexate being the most frequently used) has repeatedly been shown to be superior to monotherapy in PsA. In summary, significant progress has been achieved in the diagnosis and treatment of PsA during the last decade. However, additional studies elucidating the mechanisms of PsA are needed to explain the variability of its forms and severity to provide an improved, individualized approach to any single patient with PsA. Correspondence: Dr. G. Slobodin Dept. of Internal Medicine A, Bnai Zion Medical Center, Haifa 31048, Israel Fax: (972-4) 835-9790 email: gslobodin@yahoo.com

References 1. Taurog DJ. The spondyloarthritides. In: Kasper DL, Braunwald E, Hauser S, Longo D, Jameson JL, eds. Harrison's Principles of Internal Medicine. 16th edn. New York: McGraw Hill, 2005: 1998-9.

2. Blumberg BS, Bunim JJ, Calkins E, Pirani CL, Zvaifler NJ. ARA nomenclature and classification of arthritis and rheumatism. Arthritis Rheum 1964; 26: 93-7.

3. Pasero G, Marson P. The antiquity of psoriatic arthritis. Clin Exp Rheumatol 2006; 24: 351-3.

4. Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 2005; 64(Suppl II): ii14-17.

5. Zeboulon N, Dougados M, Gossec L. Prevalence and characteristics of uveitis in spondylarthropathies: a systematic literature review. Ann Rheum Dis 2008; 67: 955-9.

6. Slobodin G, Naschitz JE, Zuckerman E, et al. Aortic involvement in rheumatic diseases. Clin Exp Rheumatol 2006; 24(2 Suppl 41): S41-7.

7. Eder L, Zisman D, Barzilai M, et al. Subclinical atherosclerosis in psoriatic arthritis: a case-control study. J Rheumatol 2008; 35: 877-82.

2009 ‫ | אלרגיה ואימונולגיה | אוקטובר‬update‫הרפואה‬

14. Jiaravuthisan MM. Sasseville D, Vender RB, Murphy F, Muhn CY. Psoriasis of the nail: anatomy, pathology, clinical presentation, and a review of the literature on therapy. J Am Acad Dermatol 2007; 57: 1-27.

15. Gladman DD, Anhorn KA, Schachter RK, Mervart H. HLA antigens in psoriatic arthritis. J Rheumatol 1986; 13: 586-92.

16. Scarpa R, Soscia E, Peluso R, et al. Nail and distal interphalangeal joint in psoriatic arthritis. J Rheumatol 2006; 33: 1315-19.

17. Tan al, Grainer AJ, Tanner SF, Emery P, McGonagle D. A high-resolution magnetic resonance imaging study of distal interphalangeal joint arthropathy in psoriatic arthritis and osteoarthritis: are they the same? Arthritis Rheum 2006; 54: 1328-33.

18. Resnick D, Niwayama A. Psoriatic arthritis. In: Resnick D, Niwayama A, eds. Diagnosis of Bone and Joint Disorders, 2nd edn. Philadelphia: WB Saunders, 1988: 1171-99.

19. Bogliolo L, Alpini C, Caporali R, Scire CA, Moratti R, Montecucco C. Antibodies to cyclic citrullinated peptide in psoriatic arthritis. J Rheumatol 2005; 32: 511-15.

20. Alenius GM, Berglin E, Dahlquist SR. Antibodies against cyclic citrullinated peptide (CCP) in psoriatic patients with or without joint inflammation. Ann Rheum Dis 2006; 65: 398-400.

21. Korendowych E, Owen P, Ravindran J, Carmichael C, McHugh N. The clinical and genetic asociations of anti-cyclic citrullinated peptide antibodies in psoriatic arthritis. Rhematology 2005; 44: 1056-60.

22. Helliwell PS, Taylor WJ. Classification and diagnostic criteria for psoriatic arthritis.

Ann Rheum Dis 2005; 64(Suppl II): ii3-8.

23. Chandran V, Schentag CT, Gladman DD. Sensitivity of the classification of psoriatic arthritis criteria in early psoriatic arthritis. Arthritis Rheum 2007; 57: 1560-3.

24. Kruithof E, Baeten D, De Rycke L, et al. Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, resembles spondyloarthropathy more than it does rheumatoid arthritis. Arthritis Res Ther 2005; 7: R569-80.

25. Veale DJ, Ritchlin C, FitzGerald O. Immunopathology of psoriasis and psoriatic arthritis. Ann Rheum Dis 2005; 64 (Suppl II): ii26-29.

26. Costello PJ, Winchester RJ, Curran SA, et al. Psoriatic arthritis joint fluids are characterized by CD8 and CD4 T cell clonal expansions that appear antigen driven.

J Immunol 2001; 166: 2878-86.

27. Daoussis D, Andonopoulos AP, Liossis SNC. Increased expresion of CD154 (CD40L) on stimulated T cells from patients with psoriatic arthritis. Rheumatology 2007; 46: 227-31.

28. Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 2007; 8: 950-7.

29. Toh ML, Miossec P. The role of T cells in rheumatoid arthritis: new subsets and new targets. Curr Opin Rheumatol 2007; 19: 284-8.

30. Partsch G, Wagner E, Leeb BF, Broll H, Dunkey A, Smolen JS. T cell derived cytokines in psoriatic arthritis synovial fluids. Ann Rheum Dis 1998; 57: 691-3.

31. Kane D, FitzGerald O. Tumor necrosis factor alpha in psoriasis and psoriatic arthritis: a clinical, genetic and histopathologic perspective. Curr Rheumatol Rep 2004; 6: 292-8.

32. Veale D, Yanni G, Rogers S, Barnes L, Bresnihan B, FitzGerald O. Reduced synovial membrane macrophage numbers, ELAM-1 expression, and lining layer hyperplasia in psoriatic arthritis as compared with rheumatoid arthritis. Arthritis Rheum 1993; 36: 893-900.

33. Canete JD, Santiago B, Cantaert T, et al. Ectopic lymphoid neogenesis in psoriatic arthritis. Ann Rheum Dis 2007; 66: 720-6.

8. Moll JMH, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 1973; 3: 55-78.

34. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis.

Nature 2007; 445: 866-73.

9. Kane D, Stafford L, Bresnihan B, FitzGerald O. A prospective, clinical and radiological study of early psoriatic arthritis: an early synovitis clinic experience.

Rheumatology 2003; 42: 1460-8.

35. Jongbloed SL, Lebre MC, Fraser AR, et al. Enumeartion and phenotypical analysis of distinct dendritic cell subsets in psoriatic arthritis and rheumatoid arthitis.

Arhtiritis Res Ther 2006; 8: R15.

10. Symmons DPM, Lunt M, Watkins G, et al. Developing classification criteria for peripheral joint psoriatic arthritis. Step 1. Establishing whether the rheumatologist's opinion on the diagnosis can be used as the "gold standard." J Rheumatol 2006; 33: 552-7.

36. Colucci S, Brunetti G, Cantatore FP, et al. Lymphocytes and synovial fluid fibroblasts support osteoclastogenesis through RANKL, TNF, and IL-7 in an in vitro model derived from human psoriatic arthritis. J Pathol 2007; 212: 47-55.

11. Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H, and the CASPAR study group. Classification criteria for psoriatic arthritis. Development of new criteria from a large international study. Arthritis Rheum 2006; 54: 2665-73.

37. Ritchlin CT, Haas-Smith SA, Li P, Hicks DG, Shwartz EM. Mechanisms of TNFalpha and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest 2003; 111: 821-31.

12. Gladman DD. Clinical, radiological, and functional assessment in psoriatic arthritis: is it different from other inflammatory joint diseases? Ann Rheum Dis 2006; 65(Suppl III): iii22-4.

38. Turkiewicz AM, Moreland LW. Psoriatic arthritis. Current concepts on pathogenesisoriented therapeutic options. Arthritis Rheum 2007;5 6: 1051-66.

13. McGonagle D, Lories RJU, Tan AL, Benjamin M. The concept of a "synovioentheseal complex" and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond. Arthritis Rheum 2007; 56: 2482-91.

DMARDs = disease-modifying anti-rheumatic drugs

47

39. Braun-Moscovici Y, Markovits D, Rozin A, Toledano K, Nahir AM, Balbir-Gurman A. Anti-tumor necrosis factor therapy: 6 year experience of a single center in northern Israel and possible impact of health policy on results. Isr Med Assoc J 2008; 10: 277-81.

40. Gladman DD, Mease PJ, Krueger G, et al. Outcome measures in psoriatic arthritis.

J Rheumatol 2005; 32: 11.

2009 ‫ | אלרגיה ואימונולגיה | אוקטובר‬update‫הרפואה‬

‫מהספרות המקומית‬

Table 1. Available data on the efficacy of disease-modifying and biologic medicines in psoriatic arthritis and psoriasis Treatment

Target

Peripheral PsA

Axial PsA or AS

Enthesitis

Dactylitis

Skin psoriasis

SSZ

?

Y

N

N

N

Y

MTX

Adenosine receptor?

Y

N

NA

NA

Y

LEF

Pyrimidine

Y

N

NA

N

Y

CS

Calcineurin

Y

NA

NA

NA

Y

AZA

Inosinic acid

Y

N

NA

NA

NA

Infliximab

TNFα

Y

Y

Y

Y

Y

Etanercept

TNFα

Y

Y

Y

NA

Y

Adalimumab

TNFα

Y

Y

NA

NA

Y

Alefacept

CD2

Y

NA

NA

NA

Y

Efalizumab

LFA-1

N

NA

NA

NA

Y

Abatacept

CD80/86

NA

NA

NA

NA

Y

Pamidronate

Osteoclasts

NA

Y

NA

NA

NA

AS = ankylosing spondylitis, SSZ = sulfasalazine, MTX = methotrexate, LEF = leflunomide, CS = cyclosporine, AZA = azathioprine.

Efficacy: Y = efficient, N = non-efficient, NA = data unavailable.

well. Both CD4 and CD8 T cells, with the latter predominating in the joint effusions in PsA, may show oligoclonal expansion, suggesting an antigen-driven response [26]. However, the T cell-activating antigens have not yet been identified. Of relevance, CD40L was recently reported to be over-expressed on stimulated T cells from patients with psoriatic arthritis compared to RA patients and healthy volunteers [27]. Th17 lymphocytes, a recently reported lineage of pro-inflammatory T helper cells essential in both psoriasis and RA, have not yet been investigated in PsA [28,29].

The general pattern of T cell-derived cytokines – including interleukins-2, 4 and 10, tumor necrosis factor-beta and interferon-gamma – in the synovial fluid in PsA has been found similar to that of RA but in lower concentrations [30]. Of other inflammatory cytokines, TNFα is abundant in PsA synovium, as well as in both psoriatic skin lesions and inflammatory arthropathies [31].

Macrophages, which usually serve as a main source of TNFα, may differ in the inflamed synovium of PsA from that in RA by their numbers and subtypes, with more CD163+ macrophages found in PsA [24,32]. B cells, present in the PsA synovium, participate in the building of lymphoid aggregates in the synovium, which may point to antigen-driven B cell development [33]. However, the precise organization and function of B cells in PsA are not clear.

Dendritic cells recently gained attention as a potential key player in psoriasis [34]. Plasmacytoid CD123+ DCs serve as a major interferon-α producer, while myeloid CD11c+ DCs produce a variety of cytokines and chemokines, being abundant in psoriatic skin lesions [reviewed in 34]. DCs, while recognized in the synovium and joint fluid in PsA [35], have not been sufficiently studied.

Disturbed bone remodeling, as expressed by both extensive bone erosions and exaggerated bone formation in the same patients, is another characteristic and poorly understood feature of PsA. The receptor activator of nuclear factor-kappa B ligand (RANKL), TNFα TNFα = tumor necrosis factor-alpha DC = dentritic cell

and IL-7 were recently suggested as critical molecules in the activation of osteoclasts and subsequent bone resorption in PsA [36]. A reduction in the number of osteoclast precursors in the peripheral blood after anti-TNF treatment in patients with PsA was also reported [37].

On the other hand, the mechanisms of increased bone formation and its potential relation to PsA osteitis have not yet been explored.

Progress and problems in PsA treatment Enhanced understanding of disease mechanisms led to the introduction in the last decade of new, highly specific and effective therapies in the arsenal of medicines for treating PsA [Table 1].

Experience with some of these therapies was gained from RA and ankylosing spondylitis and applied to PsA, while others were used initially in patients with psoriasis. This new generation of "biologics" differs from traditional drugs used in PsA, such as methotrexate, sulfasalasine, cyclosporine and other disease-modifying anti-rheumatic drugs, by their targeted action on a specific structure, leading to the neutralization of this structure (i.e., anti-TNF treatments) or interruption of immunological signal transduction and modulation of T lymphocyte function (i.e., alefacept) [38].

While the efficacy of biologics in PsA has been repeatedly demonstrated in clinical trials and confirmed by evidence-based studies [reviewed in 38,39], the precise impact of these therapies on the disease course is unknown, primarily because of the absence of accepted outcome measures in PsA [40]. The widely used ACR (American College of Rheumatology) and DAS (Disease Activity Score) criteria, primarily developed for RA, as well as the Psoriatic Arthritis Response Criteria (PsARC), are based mainly on the affected joints count, and as such may be acceptable in polyarticular PsA, which shares some clinical similarities with RA. The widely agreed-upon measures of improvement in oligoarticular, IL = interleukin

48

‫מהספרות המקומית‬ majority of patients with PsA. Pitting is the most common psoriatic nail lesion, while onycholysis, nail bed discoloration, subungual hyperkeratosis, transverse grooves or longitudinal ridging may be seen as well [14]. Of interest, nail changes were reported to occur in about 90% of patients with PsA (all patterns), compared with 45% of psoriatic patients without arthritis [15]. Recent MRI studies demonstrated that involvement of the distal phalanges in the inflammatory process accompanies both the distal interphalangeal joints and psoriatic nail lesions in patients with PsA, being a potential connective link between the two phenomena [16,17].

Laboratory parameters of inflammation (erythrocyte sedimentation rate and C-reactive protein) are frequently normal or minimally elevated in PsA, contributing little to the differential diagnosis in this setting. However, the fine interpretation of X-rays may help to differentiate between PsA and osteoarthritis in some patients. The lack of apposition of adjacent bony margins would be characteristic of PsA, while in osteoarthritis undulating osseous surfaces are usually closely applied. Pencil-in-cup appearance of the joints, irregular periosteal bone proliferation, or resorption of the distal tuft, if present, may be diagnostic for PsA [18].

A polyarticular pattern must be distinguished from that of rheumatoid arthritis. In this setting, PsA may be recognized by its tendency to asymmetry and involvement of the joints in the 'ray' pattern rather than the 'raw' pattern typical for rheumatoid arthritis. The presence of erythema over the inflamed joint is unusual in rheumatoid arthritis but may be seen frequently in PsA, probably reflecting exaggerated angiogenesis characteristic of psoriatic disease. Concomitant involvement of DIP joints, spine, or psoriatic nail lesions in PsA patients should not be sought. Positive serology (both rheumatoid factor and anti-cyclic citrullinated peptide antibodies) may sometimes be deceptive, occurring in PsA (mainly polyarticular) in up to 10–15% of patients [19,20]. Intriguingly, an association of a positive test for anti-CCP antibodies and HLA-DRB1-shared epitope in patients with PsA was reported [21]. Radiologically, both PsA and RA are characterized by osseous erosions; however, irregular excrescences of bony proliferation and the lack of juxtaarticular osteoporosis would strongly favor the diagnosis of PsA. Arthritis mutilans is the most destructive form of PsA, which may lead to extensive and irreversible joint damage with appearance of the "telescoping" phenomenon and shortening of the digits within a short time. All the aforementioned clinical and radiological features of PsA may contribute to the diagnosis, which necessitates an aggressive therapeutic approach.

Classification criteria At least six different criteria sets have been proposed since the first diagnostic criteria of Moll and Wright, which included three main points: the existence of an inflammatory arthritis, DIP = distal interphalangeal Anit-CCP = anti-cyclic citrullinated peptide RA = rheumatoid arthritis

49

2009 ‫ | אלרגיה ואימונולגיה | אוקטובר‬update‫הרפואה‬

the presence of psoriasis, and seronegativity [8,22]. The many patterns of PsA necessitated, however, more specific classification criteria to distinguish PsA from other members of the spondyloarthritides group – osteoarthritis, rheumatoid arthritis, or gout (the latter may be a frequent phenomenon in extensive skin psoriasis). A high prevalence of both psoriasis and the aforementioned rheumatic diseases further complicates the diagnosis, leading to a statistically plausible non-causal association of skin psoriasis and other arthropathies.

Recently, an international group of experts on PsA, the ClASsification of Psoriatic ARthritis (CASPAR) study group, compiled a new set of simple and highly specific classification criteria [11]. These criteria allow the classification of an inflammatory articular disease as PsA with at least three points from the following (two points for current psoriasis, every other criterion one point): • current psoriasis (2 points) or personal or family history of psoriasis • typical psoriatic nail dystrophy • dactylitis • negative test for rheumatoid factor • juxtaarticular new bone formation (excluding osteophytes) on plain radiographs of the hand or foot.

The CASPAR criteria, which were developed on the basis of data analysis of 588 patients with PsA and 534 patients with other arthropathies, have a specificity of almost 99% and sensitivity of 91.4%. In addition to their very high specificity, the CASPAR criteria are progressive by permitting the diagnosis of PsA in the absence of psoriasis (PsA sine psoriasis) as well as in RF -positive patients.

Relatively low sensitivity, particularly in the early stage of disease, has been thought to limit the usefulness of these criteria [11]. A recent study, however, reported an excellent sensitivity and performance of the CASPAR criteria in early psoriatic arthritis [23]. A detailed comparison of the historical and current diagnostic and classification criteria for PsA can be found in the literature [11,22].

Psa mechanisms Both cellular interactions and molecular pathways of inflammation in PsA have not been elucidated sufficiently. In general, synovial histopathology of PsA, whether oligo- or polyarticular, is closer to that of other spondyloarthritides than to RA. Particularly, the increased synovial vascularity, triggered by vascular growth factors, and massive neutrophil infiltration are characteristic for PsA [24,25]. Of interest, both increased angiogenesis and abundance of neutrophils are seen also in psoriatic skin lesions.

Intracellular citrullinated peptides, frequently recognized in RA synovium, are not seen in PsA [24]. The synovial infiltrate in PsA, besides neutrophils, is formed mainly by T lymphocytes, with the presence of cells of B-lineage, macrophages and dendritic cells as RF = rheumatoid factor

2009 ‫ | אלרגיה ואימונולגיה | אוקטובר‬update‫הרפואה‬

‫מהספרות המקומית‬

Psoriatic Arthropathy: Where Now? Gleb Slobodin MD1, Itzhak Rosner MD2, Michael Rozenbaum MD2, Nina Boulman MD2, Aharon Kessel MD3 and Elias Toubi MD3 Departments of 1Internal Medicine A, 2Rheumatology and 3Immunology, Bnai Zion Medical Center, and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

Key words: psoriatic arthropathy, spondyloarthritides, biologicals

P

soriatic arthropathy is a common inflammatory arthritis that characteristically occurs in individuals with psoriasis [1].

PsA was classified as a distinct entity for the first time in 1964 [2], but the antiquity of this disease can be dated back tens of centuries [3]. The many faces of PsA have historically complicated the timely diagnosis on the one hand, while its aggressive and destructive behavior has been recently recognized in up to 20% of affected persons on the other [4]. As such, PsA has attracted much attention lately, resulting in tremendous progress in the understanding, classification and treatment of the disease in recent years. This review will summarize the current experience in PsA in light of the recent developments in the field.

Epidemiology and significance Since PsA occurs in about 30% of patients with psoriasis, its prevalence will be higher in populations prone to skin psoriasis and vice versa. Consequently, if the estimated prevalence of psoriasis in Europe and the United States is between 2% and 3%, the prevalence of PsA in these countries may come close to that of rheumatoid arthritis. PsA usually affects young persons (typically in their third or fourth decade), resulting in early joint damage and disability in many patients. About 20% of PsA patients may suffer from severe destructive disease [4]. Extra-articular manifestations of PsA, such as uveitis and aortitis, may be a significant cause of morbidity [5,6].

On the other hand, PsA, like rheumatoid arthritis and other chronic inflammatory arthropathies, may be accompanied by accelerated atherosclerotic vascular disease and a potentially higher rate of heart attack and stroke [7].

Clinical spectrum and differential diagnosis Traditionally classified as belonging to the group of spondyloarthritides, PsA may manifest clinically in the whole gamut of patterns, which were first recognized by Moll and Wright in 1973 [8]. Since then many large series of patients with PsA were reported and new data were accumulated. We recognize today that PsA may be not PsA = psoriatic arthropathy

only an oligoarticular or polyarticular disease, or affect peripheral or axial joints, or spine, but it may also evolve from one pattern to another with time [9]. These patterns may also overlap, particularly in patients with longstanding disease. In most patients PsA coexists with skin psoriasis, which may be extensive, limited, or even hidden with the patient unaware of its existence. On the other hand, in as many as 7–30% of patients, arthritis may precede the appearance of psoriatic skin lesions and is called "PsA sine psoriasis" [4]. In these patients, where a key trigger for its emergence is absent, the correct diagnosis of PsA will depend solely on the recognition of specific features of the articular disease. Nevertheless, no single clinical, radiological or laboratory sign, pathognomonic for PsA, has been reported, thus setting expert physician opinion as the gold standard in the diagnosis of PsA [10,11].

Of the five main patterns of PsA, both oligoarticular and spinal variants may be difficult to distinguish from the other members of the spondyloarthritides group [12]. In clinical presentation and radiological features these patterns of PsA are similar to those of reactive arthritis, while a wide spectrum of skin rashes and lesions in the course of the latter may merely complicate the differential diagnosis.

Enthesopathy, which is a characteristic feature of the entire group of spondyloarthritides, may be particularly prominent in PsA, affecting more frequently plantar fascia or Achilles tendons. Bone marrow edema adjacent to the entheseal insertion sites is characteristic of PsA and is thought to be a manifestation of underlying osteitis. The involvement of the entheses at the very earliest stage of PsA has been demonstrated by magnetic resonance imaging and led recently to an enthesis-based biomechanical hypothesis of disease pathogenesis [13].

Dactylitis, an inflammation affecting both the joints and tendons of the whole digit may be seen in 16–48% of patients with PsA, and is usually less common in other spondyloarthritides. PsA is also typified by the relative asymmetry of sacroiliac/spinal involvement and more extensive paramarginal syndesmosmophytes and/ or periosteal reaction compared to ankylosing spondylitis or spondyloarthritides related to inflammatory bowel disease.

The evidence of features of spondyloarthritides (inflammatory enthesopathy, dactylitis, spinal involvement, periosteal proliferation) in all patterns of PsA is of primary importance and may serve as a clue to the correct diagnosis in many patients.

A distal pattern affecting the distal interphalangeal joints must be differentiated from osteoarthritis, particularly inflammatory erosive osteoarthritis. The joint involvement in these two disorders may be very similar both clinically and radiologically. A clue to the correct diagnosis lies in the concomitant psoriatic nail involvement in the

50