Successful Treatment of Acquired Angioedema Using B-lymphocyte Depletion Therapy

1. Successful Treatment of Acquired Angioedema Using B-lymphocyte Depletion Therapy Chang Na, MD, David Podell, MD, Christopher Randolph, David Dreyfus, Denise Kearney. Yale Primary Care Program, Waterbury, CT1,2, Allergy, Asthma & Immunology, Waterbury, CT3,4,5 <?xml version="1.0"?><Settings><answerBulletFormat>Numeric</answerBulletFormat><answerNowAutoInsert>No</answerNowAutoInsert><answerNowStyle>Explosion</answerNowStyle><answerNowText>Answer Now</answerNowText><chartColors>Use PowerPoint Color Scheme</chartColors><chartType>Horizontal</chartType><correctAnswerIndicator>Checkmark</correctAnswerIndicator><countdownAutoInsert>No</countdownAutoInsert><countdownSeconds>10</countdownSeconds><countdownSound>TicToc.wav</countdownSound><countdownStyle>Box</countdownStyle><gridAutoInsert>No</gridAutoInsert><gridFillStyle>Answered</gridFillStyle><gridFillColor>255,255,0</gridFillColor><gridOpacity>50%</gridOpacity><gridTextStyle>Keypad #</gridTextStyle><inputSource>Response Devices</inputSource><multipleResponseDivisor># of Responses</multipleResponseDivisor><participantsLeaderBoard>5</participantsLeaderBoard><percentageDecimalPlaces>0</percentageDecimalPlaces><responseCounterAutoInsert>No</responseCounterAutoInsert><responseCounterStyle>Oval</responseCounterStyle><responseCounterDisplayValue># of Votes Received</responseCounterDisplayValue><insertObjectUsingColor>Red</insertObjectUsingColor><showResults>Yes</showResults><teamColors>Use PowerPoint Color Scheme</teamColors><teamIdentificationType>None</teamIdentificationType><teamScoringType>Voting pads only</teamScoringType><teamScoringDecimalPlaces>1</teamScoringDecimalPlaces><teamIdentificationItem></teamIdentificationItem><teamsLeaderBoard>5</teamsLeaderBoard><teamName1></teamName1><teamName2></teamName2><teamName3></teamName3><teamName4></teamName4><teamName5></teamName5><teamName6></teamName6><teamName7></teamName7><teamName8></teamName8><teamName9></teamName9><teamName10></teamName10><showControlBar>All Slides</showControlBar><defaultCorrectPointValue>0</defaultCorrectPointValue><defaultIncorrectPointValue>0</defaultIncorrectPointValue><chartColor1>187,224,227</chartColor1><chartColor2>51,51,153</chartColor2><chartColor3>0,153,153</chartColor3><chartColor4>153,204,0</chartColor4><chartColor5>128,128,128</chartColor5><chartColor6>0,0,0</chartColor6><chartColor7>0,102,204</chartColor7><chartColor8>204,204,255</chartColor8><chartColor9>255,0,0</chartColor9><chartColor10>255,255,0</chartColor10><teamColor1>187,224,227</teamColor1><teamColor2>51,51,153</teamColor2><teamColor3>0,153,153</teamColor3><teamColor4>153,204,0</teamColor4><teamColor5>128,128,128</teamColor5><teamColor6>0,0,0</teamColor6><teamColor7>0,102,204</teamColor7><teamColor8>204,204,255</teamColor8><teamColor9>255,0,0</teamColor9><teamColor10>255,255,0</teamColor10><displayAnswerImagesDuringVote>Yes</displayAnswerImagesDuringVote><displayAnswerImagesWithResponses>Yes</displayAnswerImagesWithResponses><displayAnswerTextDuringVote>Yes</displayAnswerTextDuringVote><displayAnswerTextWithResponses>Yes</displayAnswerTextWithResponses><questionSlideID></questionSlideID><controlBarState>Expanded</controlBarState><isGridColorKnownColor>True</isGridColorKnownColor><gridColorName>Yellow</gridColorName></Settings> <?xml version="1.0"?><AllResponses /> <?xml version="1.0"?><AllQuestions /> <?xml version="1.0"?><AllAnswers /> Discussion Continued Discussion Case Description Continued  Learning Objectives • Acquired C1-INH deficiency is a rare condition which results in recurrent angioedema. • The condition is characterized by reduced C1-INH level or function, hyperactivation of the classical complement pathway, and bradykinin mediated recurrent angioedema. • Acquired C1-INH deficiency had been reported in association with lymphoproliferative disease (LPD) and autoimmune disorders. • The discovery of an auto-antibody IgG against C1-INH in patients with angioedema demonstrates that an auto-antibody mechanism may cause acquired C1-INH deficiency. • B lymphocytes appear to play a key part in the mechanism of action of acquired angioedema in a variety of autoimmune syndromes. • Identify clinical manifestations of acquired C1 inhibitor (C1-INH) deficiency • Learn about the immunobiology underlying acquired C1-INH deficiency • Make treatment decisions based on mechanism of disease and the latest literature data • Patient B: A 37 year old woman with Crohn’s disease and allergic asthma, presented with angioedema associated with wheezing and urticaria. • Laboratory tests showed elevated IgE levels and positive aeroallergen skin testing. A hematologic evaluation showed no evidence of lymphoma. • Rituximab has been effective as adjunctive treatment of LPD, in particular B-cell lymphomas. Even though there was no associated LPD in our patients, they were successfully treated with B-lymphocyte depletion for acquired angioedema. • Rituximab appears to work by eliminating the clonal B lymphocyte population expressing a clonal Immunoglobulin G binding to C1 INH. • Anti-TNF agents such as adalizumab deplete B lymphocytes via effects on follicular dendritic cells and disruption of germinal center formation and maintenance. • B-lymphocyte depletion with humanized monoclonal antibodies such as rituximab or adalizumab appears to be an effective, long lasting therapy for acquired angioedema associated with a variety of autoimmune syndromes. • Patient C: A 41 year old woman with myasthenia gravis and anti-phospholipids syndrome, presented with angioedema and associated bowel and laryngeal edema requiring intubation. • Laboratory tests showed low C1q, C2, C3, C4 and anti-C1q antibody. Case Description • Patient A: A 38 year old woman presented with seropositive deforming erosive rheumatoid arthritis (RA) and angioedema associated with acquired C1-INH deficiency. • Laboratory tests showed decreased C1q, C3, C4, and Ch50, worsening anemia, and elevated ESR. • She had a normal CT chest/abdomen/pelvis, normal SPEP, and flow cytometry that showed decreased CD4 and CD8 T cells but otherwise normal lymphoid phenotype. Thickened ascending colon Clinical Course Learning Points • After failure of other therapy including etanercept and corticosteroids (A), xolair (B), and kallekrein antagonist and corticosteroids (C), all three patients responded with complete remission of symptoms after B-lymphocyte depletion therapy with rituximab (A, C) or adalizumab (B). • The patients have been symptom free for 5 years, 3 years and 6 months thus far. • C1-INH deficiency is a rare condition resulting in recurrent angioedema episodes. • A lymphoproliferative autoimmune mechanism may cause acquired C1-INH deficiency. • Our cases highlight that B-lymphocyte depletion may be an effective treatment for acquired C1-INH deficiency Advanced rheumatoid arthritis with fusion of the carpal bones (yellow arrow). Metacarpal phalangeal joint subluxation (blue arrow).