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 Table of Contents  
LETTER TO EDITOR
Year : 2019  |  Volume : 5  |  Issue : 1  |  Page : 54-57

Delayed-onset serum sickness due to rituximab in pemphigus vulgaris


Department of Dermatology, Maharashtra Medical Foundation Joshi Hospital, Pune, Maharashtra, India

Date of Web Publication22-Jul-2019

Correspondence Address:
Dr. Ajay Deshpande
3 Surya Tower C.T.S. No. 50-A, Erandwane, Pune - 411 004, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_5_19

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How to cite this article:
Deshpande A. Delayed-onset serum sickness due to rituximab in pemphigus vulgaris. Indian J Drugs Dermatol 2019;5:54-7

How to cite this URL:
Deshpande A. Delayed-onset serum sickness due to rituximab in pemphigus vulgaris. Indian J Drugs Dermatol [serial online] 2019 [cited 2019 Aug 18];5:54-7. Available from: http://www.ijdd.in/text.asp?2019/5/1/54/263102



Sir,

In autoimmune blistering disorders such as pemphigus vulgaris (PV), autoantibodies are produced by mature B-lymphocytes which are directed against cell adhesion molecules.[1] Rituximab is a novel therapeutic agent for severe and recalcitrant PV.[2],[3] It is now been approved by the US Food and Drug Administration (FDA) as the first-line drug for adult patients with moderate-to-severe form PV.[4] It is an anti-CD20 monoclonal antibody which is directed against mature B-lymphocytes that are responsible for antibody production. Toxicities related to rituximab include infusion reactions and delayed reactions. Delayed reactions include Type III hypersensitivity reaction known as serum sickness which can be seen 10–14 days after the first dose of rituximab. Rituximab-induced serum sickness (RISS) has been reported earlier in connective tissue diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, and hematological malignancies.[5] There are few reports of RISS in PV, but all the reported cases developed serum sickness after the first dose of rituximab.[6] The author hereby reports a case of serum sickness occurring after the sixth dose of rituximab in a patient with severe PV.

A 17-year-old male patient presented in the department of dermatology with vesiculobullous eruptions affecting the trunk, extremities, lips, oral [Figure 1], and genital mucosa of 3-week duration, which was diagnosed as PV on histopathology. He was put on tablet prednisolone 40 mg/day in divided doses. The patient was advised about the rituximab intravenous infusion following modified lymphoma protocol,[7] and accordingly, preliminary investigations were done including complete blood count (CBC), liver function test (LFT), renal function test (RFT), urine complete examination, viral markers for HIV, hepatitis B and C, electrocardiography, two-dimensional echocardiography, Mantoux test, X-ray chest, and abdominal ultrasonography. All investigations were within normal limits. In the intensive care unit setting and under strict observation, premedication with intravenous hydrocortisone, pheniramine maleate, and tablet paracetamol was done followed by infusion of 500 mg of rituximab in 500 ml of 5% dextrose solution over 4–6 h. The first infusion was uneventful. The follow-up was done on the 3rd day with routine CBC, LFT, RFT, and urine complete examination which was within normal limits. Similar infusions were given weekly for total six infusions, and tablet prednisolone was tapered gradually to 10 mg/day. All infusions were uneventful, and all the lesions healed completely [Figure 2]. At 10 days later the last (6th) infusion of rituximab, the patient developed a high-grade fever along with epigastric pain and vomiting. Two days later, he developed pain and swelling of both knee joints and redness of eyes. On examination, he had severe epigastric tenderness, diffuse nontender edema of bilateral knee joints [Figure 3], and bilateral conjunctival congestion [Figure 4]a and [Figure 4]b. There was no skin rash and lymphadenopathy. X-ray knee joints showed soft-tissue swelling probably due to effusion in the joint which was confirmed by magnetic resonance imaging study of both knee joints. Acute-phase reactants, C-reactive protein, and erythrocyte sedimentation rate were elevated. All other routine investigations including CBC, RFT, LFT, and urine complete examination were within normal limits. Abdominal ultrasonography was not significant. Human antichimeric antibodies (HACAs) were not tested. On the basis of clinical and biochemical evaluation, the diagnosis of serum sickness was confirmed. Further treatment was planned, and the dose of prednisolone was increased to 30 mg daily in three divided doses. Knee support was given with knee cap, and hydrocortisone eye drops were advocated 8 hourly after ophthalmological consultation. Resolution of fever was seen within 24 h followed by improvement in conjunctival congestion [Figure 5]a and [Figure 5]b. Knee joint arthralgia and swelling took 7 days to completely subside [Figure 6].
Figure 1: Erosions over both lips

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Figure 2: Complete resolution of lesions after six doses of rituximab

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Figure 3: Bilateral knee joint swelling

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Figure 4: (a and b) Conjunctival congestion

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Figure 5: (a and b) Conjunctival congestion resolved after increment in steroid dose

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Figure 6: Knee joint swelling reduced completely after increment of steroid dose

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Acute serum sickness was first described in 1905 by Von Pirquet as a complication of horse antiserum to diphtheria toxin.[8] The clinical syndrome is characterized by the development of fever, arthralgias, skin lesions, lymphadenopathy, gastrointestinal symptoms, and proteinuria, typically 8–13 days after injection of an antigen.[9] The disease is the result of tissue deposition of circulating antigen–antibody complexes, and laboratory evaluation usually demonstrates evidence of inflammation (elevated C-reactive protein levels), presence of immune complexes (elevated percentages on C1q binding assay), and activation of the classical pathway of complement (depressed C3 and C4 levels).[9] D”Arcy et al. first reported the case of serum sickness to rituximab in lymphoma.[9] RISS is due primarily to B-cell lysis leading to delivery of intracellular antigens to serum, which then precipitates by forming complexes with antibodies,[10] and secondarily to the presence of murine component in rituximab.[9] In serum sickness, the presence of foreign antigens (murine component in rituximab) elicits antibody response, HACA, and causes the production of an antigen–antibody complex that gets deposited in various tissues and initiates inflammatory response through complement cascade resulting in C3 and C4 hypocomplementenemia.[11]

In PV, HACA is known to cause treatment failure and adverse effects related to rituximab infusion.[12] The production of HACAs to the murine fragments of rituximab has previously been described in pemphigus and other autoimmune disease patients,[13],[14],[15],[16],[17] although a direct functional effect of these HACAs has not been reported. Few studies of rituximab in autoimmune disease patients have described a correlation between HACA and incomplete B-cell depletion in systemic lupus erythematosus,[13],[14] serum sickness-like reactions in Sjogren's syndrome and immune thrombocytopenic purpura,[15],[16] and partial clinical response in pemphigus.[17] In 2012, Lunardon and Payne for the first time demonstrated the pathologic role for rituximab HACA in blocking the binding of rituximab to B-cells.[12] The appearance of HACA coincided with the development of infusion reactions and a lack of therapeutic response.[12] Concomitant treatment with immunosuppressant or repeated maintenance therapy seems to be a useful strategy to prevent the production of HACA.[18]

In the author's case, all the clinical features, except for the absence of skin lesions, and laboratory findings present were suggestive of serum sickness. Joint effusion is also a feature of serum sickness.[19] Close differentials of similar clinical picture such as chikungunya infection were ruled out by performing their respective tests. Quick response to escalated dose of corticosteroid also favored the diagnosis of serum sickness. The only drug that could have attributed to serum sickness in this case was rituximab.

Two forms of infusion reactions have been identified, acute and delayed, both apparently related to the monoclonal components.[20] It has been reported that delayed serum sickness usually occurs 10–14 days following antigen exposure or within a few days of secondary antigen exposure in the acute setting.[21] However, in this case, the reaction developed after the 6th dose of rituximab which was not reported in the literature. As the patient was concomitantly taking systemic corticosteroid from day 1 of rituximab infusion, the antigen–antibody complexes could have been suppressed to such a level so as to prevent it from producing clinical manifestations, and as soon as the dose of corticosteroid was reduced, the balance shifted in favor of immune complexes to manifest clinically. And also, the formation of HACA could have been suppressed because of concomitant systemic corticosteroid therapy. This probably was the only explanation of late-onset serum sickness in this case.

The issue of drug-related antigenicity is not unique to rituximab.[22] Concomitant therapy of low-dose weekly methotrexate (MTX) significantly diminished the incidence of HACA in systemic lupus erythematosus.[18] In a cohort study of patients with Crohn's disease treated with serial infusions of infliximab, concomitant immunosuppressive therapy led to a lower incidence of HACA.[23] Similarly, concomitant systemic corticosteroid treatment would be exerting effects as that of other immunosuppressives such as MTX and azathioprine[23] on HACA, and this needs to be investigated.

The diagnosis of serum sickness is mainly clinical. Other causes such as malignancy and any other infection that can trigger serum sickness should be ruled out. In this case, investigations such as CBC, abdominal ultrasonography, and urine complete examination helped in ruling out malignancy and infectious cause. Furthermore, clinical presentation, the identified antigen (rituximab), and quick response to treatment helped in making the diagnosis of RISS.

Rituximab is an FDA-approved first-line drug in the management of moderate-to-severe life-threatening PV, and serum sickness is a known complication of rituximab in PV. Further studies reporting the side effects of rituximab are required to establish its safety, and also, there is a need of strict monitoring and vigilance to minimize the adverse effects.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Lunardon L, Payne AS. Rituximab for autoimmune blistering diseases: Recent studies, new insights. G Ital Dermatol Venereol 2012;147:269-76.  Back to cited text no. 1
    
2.
Cianchini G, Lupi F, Masini C, Corona R, Puddu P, De Pità O. Therapy with rituximab for autoimmune pemphigus: Results from a single-center observational study on 42 cases with long-term follow-up. J Am Acad Dermatol 2012;67:617-22.  Back to cited text no. 2
    
3.
Zakka LR, Shetty SS, Ahmed AR. Rituximab in the treatment of pemphigus vulgaris. Dermatol Ther (Heidelb) 2012;2:17.  Back to cited text no. 3
    
4.
Schmidt E. Rituximab as first-line treatment of pemphigus. Lancet 2017;389:1956-8.  Back to cited text no. 4
    
5.
Matsui T, Hidaka M, Kawakita T, Inoue Y, Sakai T, Harada N, et al. Serum sickness induced by rituximab infusion; report of two cases with hematological malignancies. Rinsho Ketsueki 2009;50:304-8.  Back to cited text no. 5
    
6.
Awal G, Kaur S, Kaur J, Sharma S. Rituximab-induced serum sickness in pemphigus vulgaris. J Egypt Women's Dermatol Soc 2018;15:54-6.  Back to cited text no. 6
    
7.
Mutalik SD, Rasal Y. Sustained remission of pemphigus vulgaris in Indian patients with a modified lymphoma rituximab protocol. J Dermatol Res 2018;3:135-8.  Back to cited text no. 7
    
8.
Bielory L, Gascon P, Lawley TJ, Young NS, Frank MM. Human serum sickness: A prospective analysis of 35 patients treated with equine anti-thymocyte globulin for bone marrow failure. Medicine (Baltimore) 1988;67:40-57.  Back to cited text no. 8
    
9.
D'Arcy CA, Mannik M. Serum sickness secondary to treatment with the murine-human chimeric antibody IDEC-C2B8 (rituximab). Arthritis Rheum 2001;44:1717-8.  Back to cited text no. 9
    
10.
Finger E, Scheinberg M. Development of serum sickness-like symptoms after rituximab infusion in two patients with severe hypergammaglobulinemia. J Clin Rheumatol 2007;13:94-5.  Back to cited text no. 10
    
11.
Vultaggio A, Castells MC. Hypersensitivity reactions to biologic agents. Immunol Allergy Clin North Am 2014;34:615-32, ix.  Back to cited text no. 11
    
12.
Lunardon L, Payne AS. Inhibitory human antichimeric antibodies to rituximab in a patient with pemphigus. J Allergy Clin Immunol 2012;130:800-3.  Back to cited text no. 12
    
13.
Albert D, Dunham J, Khan S, Stansberry J, Kolasinski S, Tsai D, et al. Variability in the biological response to anti-CD20 B cell depletion in systemic lupus erythaematosus. Ann Rheum Dis 2008;67:1724-31.  Back to cited text no. 13
    
14.
Looney RJ, Anolik JH, Campbell D, Felgar RE, Young F, Arend LJ, et al. Bcell depletion as a novel treatment for systemic lupus erythematosus: A phase I/II dose-escalation trial of rituximab. Arthritis Rheum 2004;50:2580-9.  Back to cited text no. 14
    
15.
Goto S, Goto H, Tanoshima R, Kato H, Takahashi H, Sekiguchi O, et al. Serum sickness with an elevated level of human anti-chimeric antibody following treatment with rituximab in a child with chronic immune thrombocytopenic purpura. Int J Hematol 2009;89:305-9.  Back to cited text no. 15
    
16.
Pijpe J, van Imhoff GW, Spijkervet FK, Roodenburg JL, Wolbink GJ, Mansour K, et al. Rituximab treatment in patients with primary sjögren's syndrome: An open-label phase II study. Arthritis Rheum 2005;52:2740-50.  Back to cited text no. 16
    
17.
Schmidt E, Hennig K, Mengede C, Zillikens D, Kromminga A. Immunogenicity of rituximab in patients with severe pemphigus. Clin Immunol 2009;132:334-41.  Back to cited text no. 17
    
18.
Saito K, Nawata M, Iwata S, Tokunaga M, Tanaka Y. Extremely high titer of anti-human chimeric antibody following re-treatment with rituximab in a patient with active systemic lupus erythematosus. Rheumatology (Oxford) 2005;44:1462-4.  Back to cited text no. 18
    
19.
Boots RH, Swift HF. The arthritis of serum sickness. J Am Med Assoc 1923;80:12-5.  Back to cited text no. 19
    
20.
Vendramin C, Thomas M, Westwood JP, McGuckin S, Scully M. Rituximab-induced acute and delayed serum sickness in thrombotic thrombocytopenic purpura: The role of anti-rituximab antibodies. Br J Haematol 2019;184:858-61.  Back to cited text no. 20
    
21.
Kumar A, Khamkar K, Gopal H. Serum sickness and severe angioedema following rituximab therapy in RA. Int J Rheum Dis 2012;15:e6-7.  Back to cited text no. 21
    
22.
Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: A randomized controlled trial. Gastroenterology 2003;124:917-24.  Back to cited text no. 22
    
23.
Jani M, Barton A, Warren RB, Griffiths CE, Chinoy H. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford) 2014;53:213-22.  Back to cited text no. 23
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]



 

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