Rituximab Induced Serum Sickness: A Systematic Review

Paras Karmacharya¹, Dilli Poudel¹, Ranjan Pathak¹, Anthony Donato², Sushil Ghimire¹, Smith Giri³, Madan Aryal¹ and Clifton O. Bingham III⁴, ¹Internal Medicine, Reading Health System, WEST READING, PA, ²Internal medicine, Reading Health System, WEST READING, PA, ³Internal medicine, University of Tennessee Health Science Center, Memphis, TN, ⁴Rheumatology, Johns Hopkins University, Baltimore, MD

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: immunology, infusions, rheumatoid arthritis (RA) and rituximab

Session Information

Date: Sunday, November 8, 2015

Title: Systemic Lupus Erythematosus - Clinical Aspects and Treatment Poster Session I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Rituximab (anti-CD20 monoclonal antibody) has been frequently used to treat various autoimmune diseases in which B-cells are participants, and for hematological malignancies in which CD20-bearing cells are increased. Infusion reactions including fever, chills and rigors, as well as allergic (Type IV) anaphylactoidspectrum reactions and less commonly serum sickness (or Type III) hypersensitivity reaction have been reported with its administration. It is important to recognize this as re-exposure can result in recurrent and more severe manifestations. We perform a systematic review and meta-analysis to characterize RISS in autoimmune diseases and hematological malignancies.

Methods: A comprehensive search of MEDLINE, EMBASE, ACR and EULAR databases was performed for relevant articles of patients with RISS from inception to September 2014 (Figure 1). Statistical analysis of demographic and clinical features was performed using Microsoft EXCEL 2007 and SPSS version 20.0.

Results: In the 33 patients (from 25 reports) with RISS, the mean age of presentation was 39.1±17.5 years with a female preponderance (n=23, 76.67%). The majority of cases were associated with an underlying autoimmune condition (n=28, 84.85%), most commonly immune thrombocytopenic purpura (n=10) and Sjögren’ssyndrome (n=7 and lymphomas in 5/33 cases (15.15%) (Table 1). Symptoms of RISS began 6.63±3.83 days following infusion with most episodes occurring during the first cycle. Classic triad of serum sickness (fever, rash and arthralgia) was reported in 16 (48.5%) cases. Time from drug exposure to symptom onset was significantly greater with the first doses of rituximab compared to the second dose (mean time 10.00 vs. 4.05 days, P=0.002), and time to resolution was significantly greater for rheumatologic vs. hematological indications (mean time 2.50 vs 1.00 days, P=0.035). Corticosteroids were the most commonly used treatment (n=21), with all cases reporting a complete resolution of symptoms in 2.15±1.34 days.

Conclusion: It is important to recognize and diagnose RISS clinically as it may mimic exacerbation of various rheumatologic conditions such as RA. Although elevated RF, immunoglobulins and HACA levels may play a role in the pathogenesis, these are not predictable markers, as the serologic and Ig levels are features of the underlying disease. RISS is often a benign condition with prompt and complete resolution with corticosteroids. That some patients have experienced recurrent RISS with re-exposure indicates that providers should carefully weigh risks and benefits of continuing or reintroducing rituximab.

SN	Author, Year	Study Design	Condition	Age/Sex	Dosing Protocol (amount x doses)	Dose Causing SS (cycle number, dosing number in the cycle)	Onset of SS from Last Dose	H/O Immediate Transfusion Reaction	Antibody Profile	Treatment for SS	Remarks
Autoimmune Diseases
1	D’Arcy et al.,2001	Case Study	Autoimmune Polyneuropathy	45/M	NA	1,NA	10	No	NA	IV MP pulse	–
2	Herishanu et al.,2002	Case Study	Refractory ITP	48/F	Mentioned as weekly dose	2,NA	6	No	ANA negative	IV MP 500mg x 2d	–
3	Hellerstedt et al.,2003	Case Study	SLE	23/F	NA	1,2	1	No	NA	IV Steroid bolus	–
4	Catuogno et al.,2005	Case Study	Cryoglobulinemia	60/F	375 mg/m2 x 4	1,1	7	No	RF positive (RA test, Fii latex, Waaler-Rose)	IV Betamethasone 4mg	–
5	Pijpe et al.,2005	Open-Label Phase II study	Sjӧgren’s Syndrome	41/F	375 mg/m2 x 4	1,2	5-7	No	RF (125 KIU/L); anti-SSA positive; anti-SSB positive; HACA positive	IV MP 1000mg	–
6	Pijpe et al.,2005	Open-Label Phase II study	Sjӧgren’s Syndrome	39/F	375 mg/m2 x 4	1,2	5-7	No	RF (16 KIU/L); anti-SSA positive; anti-SSB positive; HACA positive with 1.32% activity	IV MP 1000mg	–
7	Pijpe et al.,2005	Open-Label Phase II study	Sjӧgren’s Syndrome	27/F	375 mg/m2 x 4	1,2	5-7	No	RF (569 KIU/L); anti-SSA positive; HACA positive with <1% activity	NA	–
8	Wang et al.,2005	Prospective	Chronic ITP	14/F	375 mg/m2 x 4	1,2	7-14	No	NA	NA	–
9	Wang et al.,2005	Prospective	Chronic ITP	12/F	375 mg/m2 x 4	1,3	7-14	No	NA	NA	–
10	Wang et al.,2005	Prospective	Chronic ITP	12/F	375 mg/m2 x 4	1,1	NA	Yes	NA	NA	–
11	Bennett et al.,2006	Prospective	Chronic ITP	12/M	375 mg/m2 x 4	1,2	After second dose	No	NA	NA	–
12	Bennett et al.,2006	Prospective	Chronic ITP	11/F	375 mg/m2 x 4	1,2	After second dose	No	NA	NA	–
13	Schutgens et al.,2006	Case Study	Sjӧgren’s Syndrome	46/F	375 mg/m2 x 4	1,NA	2	No	NA	oral Prednisone 20 mg/d	MALT of right parotid gland
14	Devauchelle et al.,2007	Prospective	Sjӧgren’s Syndrome	NA	375 mg/m2 x 4	1,2	NA	No	NA	NA	–
15	Finger et al.,2007	Case Study	Polyclonal Hypergammaglobulinemia	45/F	NA	1,1	7	No	NA	IV HCT 125 QID x 3 days	Associated Sjӧgren’s Syndrome
16	Finger et al.,2007	Case Study	Polyclonal Hypergammaglobulinemia	38/F	1000 mg x 2	2,2	1	No	NA	IV HCT 125 QID x 3 days	–
17	Seror et al.,2007	Retrospective	Sjӧgren’s Syndrome	43/F	375 mg/m2 x 4	1,2	3	No	RF (499 IU/L); anti-SSA positive; anti-SSB positive; HACA (significant level)	None	Salivary Lymphoma (MALT)
18	Dass et al.,2008	Randomised, double-blind, placebo-controlled pilot study	Sjӧgren’s Syndrome	NA	1000 mg x 2	1,1	7	No	anti-SSA positive; anti-SSB (78% positive in treatment group)	IV steroid	–
19	Godeau et al.,2008	Prospective multicenter phase 2 study	Chronic ITP	NA	375 mg/m2 x 4	1,NA	NA	No	NA	NA	–
20	Medeot et al.,2008	Prospective Study	Relapsed or refractory ITP	NA	375 mg/m2 x 4	1,2	Soon after	No	NA	Steroid	–
21	Mehsen et al.,2008		MCTD	30/F	NA	1,1	13	No	NA	oral anti-Histaminics	–
22	Goto et al.,2009	Case Study	Chronic ITP	8/M	375 mg/m2 x 4	2,2	10	No	ANA (<40x); RF (0.30); anti-DNA (1 IU/ml); HACA (244 ng/ml)	Oral PDS 1.8 mg/kg/day x 1 mo;	–
23	Sène et al.,2009	Case Series	Cryoglobulinemia	47/M	1000 mg x 2	2,1	7	No	NA	NA	Hep C positive
24	Sène et al.,2009	Case Series	Cryoglobulinemia	53/F	1000 mg x 2	2,1	9	No	NA	NA	Hep C positive
25	Guenno et al.,2011	Case Study	Chronic ITP	31/F	375 mg/m2 x 4	1,1	13	No	RF negative	IV MP 120 mg x 1d then oral Steroid x 7d	–
26	Kumar et al.,2012	Case Study	RA	60/F	1000 mg x 2	2,1	6	Yes	RF (44.4 U/ml); anti-CCP (114 U/ml); ANA (negative)	IV MP 80mg x once; Levocetrizine	–
27	Sandhu et al.,2012	Case Study	Post kidney transplant rejection	52/M	NA	1,NA	14	No	ANA negative; RF negative; anti-CCP (0.5 Units/ml); anti-SSA (8 U/ml); anti-SSB (9 U/ml); anti-DNA (4 U/ml)	IV MP 500mg/d x 3d	Acute cellular and humoral rejection
28	Ungprasert et al.,2013	Case Study	Sjӧgren’s Syndrome and SLE	50/F	NA	2,1	7	No	NA	IV MP x 2d then oral Prednisone x 7d	–
Hematologic Diseases
29	Portlock et al., 2005	Prospective Phase 2 study	Lymphoma	51/F	375 mg/m2 x 4	2,1	7	No	HACA positive	Prednisone	Follicular lymphoma, previously treated
30	Portlock et al., 2005	Prospective Phase 2 study	Lymphoma	70/M	376 mg/m2 x 4	1,2	5	No	HACA negative	Prednisone	Follicular lymphoma, previously untreated
31	Todd et al., 2006	Case Study	Lymphoma	68/M	375 mg/m2 x 4	1,1	13	No	ANA normal; RF normal: anti-CCP normal; HACA negative	IA MP 80mg then oral Prednisone 20 mg/d tapered over 4 wks	Mantle cell, stage 2a
32	Disperati et al., 2007	Case Study	Lymphoma	52/F	180mg/m² x 4	5,1	2	Yes; during prior two cycles	RF negative; ANA negative	IV MP, IV Diphenhydramine and IV Mepiridine	Stage IV follicular
33	DeMonaco et al., 2007	Case Study	Lymphoma	47/F	375 mg/m2 x 4	4,2	7	No	HAMA negative	Steroid x 10d	Follicular, grade 3 of 3

Disclosure: P. Karmacharya, None; D. Poudel, None; R. Pathak, None; A. Donato, None; S. Ghimire, None; S. Giri, None; M. Aryal, None; C. O. Bingham III, None.

To cite this abstract in AMA style:

Karmacharya P, Poudel D, Pathak R, Donato A, Ghimire S, Giri S, Aryal M, Bingham CO III. Rituximab Induced Serum Sickness: A Systematic Review [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/rituximab-induced-serum-sickness-a-systematic-review/. Accessed .

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