Scandinavian Journal of Rheumatology

ISSN: 0300-9742 (Print) 1502-7732 (Online) Journal homepage: http://www.tandfonline.com/loi/irhe20

Systemic lupus erythematosus exacerbation following cessation of belimumab treatment V Furer, D Zisman, E Pokroy-Shapira, Y Molad, O Elkayam & D Paran To cite this article: V Furer, D Zisman, E Pokroy-Shapira, Y Molad, O Elkayam & D Paran (2015): Systemic lupus erythematosus exacerbation following cessation of belimumab treatment, Scandinavian Journal of Rheumatology, DOI: 10.3109/03009742.2015.1074277 To link to this article: http://dx.doi.org/10.3109/03009742.2015.1074277

Published online: 29 Oct 2015.

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Date: 11 January 2016, At: 18:01

Scand J Rheumatol 2015;1–4

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Systemic lupus erythematosus exacerbation following cessation of belimumab treatment V Furer1, D Zisman2, E Pokroy-Shapira3, Y Molad3,4, O Elkayam1,4, D Paran1,4 Department of Rheumatology, Tel Aviv Sourasky Medical Centre, Tel Aviv, 2Rheumatology Unit, Carmel Medical Centre, Rappoport Faculty of Medicine, Technion, Haifa, 3Rheumatology Unit, Rabin Medical Centre, Beilinson Hospital, Petach Tikva, and 4Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Objectives: Belimumab has recently been approved for the treatment of systemic lupus erythematosus (SLE) refractory to standard therapy. Following one case of an SLE flare after cessation of belimumab, we hypothesized that this might lead to a rebound phenomenon and possible exacerbation of SLE. Method: Members of the Israeli Society of Rheumatology were contacted by e-mail and asked to report cases of an SLE flare following cessation of belimumab treatment. Results: Three cases of SLE patients who experienced a severe SLE flare following cessation of belimumab therapy were reported. In all cases, belimumab was given as treatment for active mucocutaneous manifestations and/or polyarthritis with improvement in all three patients, one of whom achieved disease remission. In all three cases, patients experienced a severe flare in previously uninvolved major organ systems, including one case of class IV lupus nephritis accompanied by a new-onset severe headache with elevated cerebrospinal fluid (CSF) protein and white matter lesions on brain magnetic resonance imaging (MRI), one case of severe pneumonitis and haemolytic anaemia, and one case of a systemic flare, fatigue, arthritis, and severe abdominal pain. Conclusions: Belimumab therapy has been shown to be beneficial in the management of active SLE, mostly in patients with mucocutaneous and musculoskeletal manifestations. We suggest a possible rebound effect following cessation of belimumab that could be due to an increase in B-cell activating factor (BAFF) levels and lead to a disease flare. Future assessment of BAFF levels in patients stopping belimumab therapy and clinical correlation may support this hypothesis. Further studies are needed to confirm this observation.

Belimumab represents a novel treatment of systemic lupus erythematosus (SLE) that inactivates the B-cell activating factor (BAFF), an important B-cell regulator (1). We present three cases of adult SLE patients from Israel who experienced a severe SLE flare in previously uninvolved major organ systems following cessation of belimumab therapy, resulting in significant morbidity. We further propose various biological mechanisms to explain this clinical observation.

Method Members of the Israeli Society of Rheumatology were contacted by e-mail and asked to report cases of an SLE flare following cessation of belimumab treatment. Three cases of SLE patients who experienced a severe SLE flare following cessation of belimumab therapy were reported. Victoria Furer, Department of Rheumatology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. E-mail: [email protected] Accepted 15 July 2015

Case series Case 1 A 25-year-old woman was diagnosed with SLE at the age of 16 based on malar rash, photosensitivity, oral ulcers, arthritis, leucopenia, positive antinuclear antibodies (ANAs), anti-double-stranded DNA (anti-dsDNA) antibodies, and hypocomplementaemia. She had been treated with hydroxychloroquine (HCQ), azathioprine followed by methotrexate (MTX), and glucocorticoids (GCs). She had experienced an SLE flare at the age of 22 manifested by a photosensitive rash, arthritis, an increase in antidsDNA antibody titres, and hypocomplementaemia. She was treated with belimumab with a favourable clinical response. After 2 years, the treatment was discontinued due to a diffuse, urticarial skin eruption. A skin biopsy confirmed an allergic drug reaction that was attributed to belimumab. Her disease was controlled with HCQ and intermittent GC courses. Eight months after belimumab discontinuation, she suffered a severe flare with prolonged fever, rash, headache, leucopenia, thrombocytopenia, and new-onset, biopsy-proven class IV lupus nephritis. Brain magnetic resonance imaging (MRI) disclosed bilateral

© 2015 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation DOI: 10.3109/03009742.2015.1074277

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diffuse white matter hyperintense lesions. Cerebrospinal fluid (CSF) analysis disclosed sterile fluid with an elevated protein level without cells. She was treated with high-dose GCs and mycophenolate mofetil, resulting in clinical improvement but with persistence of an active urinary sediment, elevated anti-dsDNA antibodies, and hypocomplementaemia.

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Case 2 A 22-year-old woman was diagnosed with SLE based on oral ulcers, scleritis, arthritis, lymphopenia, positive ANA, positive anti-dsDNA antibodies, a positive Coombs test, low complement C4, positive anti-Ro, anti-La, and anticardiolipin antibodies. She had been treated for 6 years with HCQ and non-steroidal antiinflammatory drugs (NSAIDs). At the age of 28, she experienced an SLE flare manifested by arthritis, leucopenia, increased anti-dsDNA, and hypocomplementaemia. She was started on belimumab with improvement of arthritis. After 4 months of continued belimumab therapy, she developed a skin rash, hoarseness, and shortness of breath. Belimumab treatment was stopped due to a suspected allergic reaction to the drug. The patient was considered in remission based on resolution of arthritis, normalization of white blood count and complement levels, and a marked decrease in dsDNA levels. Two months after belimumab cessation, she developed an SLE flare manifested by low-grade fever, fatigue, arthritis, and severe abdominal pain. Gastroscopy, abdominal ultrasound, and computed tomography angiography of the abdomen and pelvis were unremarkable. Laboratory work-up was notable for a positive ANA, elevated anti-dsDNA antibodies, and mildly decreased C3. An extensive infectious diseases work-up was negative. The patient was treated with pulse methylprednisolone 250 mg for 3 days with a good response. Colonoscopy and terminal ileum biopsy, performed upon steroid treatment initiation, were unrevealing.

Case 3 A 56-year-old woman was diagnosed with SLE at the age of 54 based on acute SLE rash, discoid LE rash, polyarthritis, leucopenia, positive ANA, hypocomplementaemia, positive anti-Ro, anti-La, anti-Sm, antiRNP, and antiphospholipid antibodies. The patient was managed with HCQ 400 mg/day, prednisone 10–15 mg/ day, and azathioprine 100 mg/day with poor compliance. One year after her initial presentation, she was started on belimumab therapy with significant clinical improvement. Of note, mildly abnormal liver function tests and splenomegaly were noted before initiation of belimumab and were attributed to fatty liver and SLE, respectively. Because of continued liver enzyme abnormalities, a liver biopsy was performed, showing histological findings

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V Furer et al

compatible with autoimmune hepatitis or primary biliary cirrhosis. Further evaluation confirmed cirrhosis, leading to cessation of belimumab treatment. She was treated with high-dose prednisone and azathioprine for her liver disease with improvement in her liver function tests. Despite this treatment, she developed prolonged fever and significant weight loss, followed within a year by severe lupus pneumonitis and refractory Coombs-positive haemolytic anaemia, which required treatment with intravenous (IV) pulse methylprednisolone (1 g/day for 3 days) and IV cyclophosphamide (700 mg/m2 once a month for 10 months), followed by azathioprine with an adequate clinical response. A summary of the cases is presented in Table 1.

Discussion We present a case series of three patients with mild to moderate SLE who developed a severe flare following the discontinuation of belimumab. Belimumab administration resulted in improvement in all cases. Within several months up to a year after belimumab cessation, a severe disease flare involving previously unaffected major organs was observed in all patients. Patient no. 1 developed class IV lupus nephritis along with central nervous system (CNS) disease. Patient no. 2 developed a systemic flare with fever, fatigue, arthritis, and severe abdominal pain. Patient no. 3 developed severe pneumonitis and haemolytic anaemia. All required intensive therapy with high-dose systemic steroids and immunosuppression to control the disease. While disease fluctuations and flare may be a part of the natural history of SLE, a close relationship between belimumab therapy discontinuation and subsequent severe lupus flare cannot be excluded. There is compelling evidence of BAFF contribution to SLE pathogenesis. Elevated circulating BAFF levels have been observed in up to 50% of SLE patients (2). A significant correlation between circulating BAFF levels and clinical disease activity has been confirmed (3). SLE patients with elevated BAFF levels appear to be at greater risk for cumulative organ damage (4). We further discuss four potential mechanisms responsible for SLE flare following discontinuation of belimumab treatment.

Rebound of BAFF following B-cell depletion A rebound of BAFF levels induced by B-cell depletion seems to be the most plausible biological explanation for SLE exacerbation following cessation of antiBAFF therapy. Soluble BAFF levels correlate inversely with peripheral B-cell numbers and the expression of BAFF receptors (5). Whereas no data on BAFF levels following belimumab cessation are available, there is a well-documented rebound of BAFF levels following rituximab therapy in patients with rheumatoid arthritis (6) and SLE (7).

2 57 3

6 28 2

SLE, Systemic lupus erythematosus; HCQ, hydroxychloroquine; AZA, azathioprine; MTX, methotrexate; GC, glucocorticoids; APS, antiphospholipid syndrome; LN, lupus nephritis; CNS, central nervous system; AIH, autoimmune hepatitis.

Fever, lupus pneumonitis, Coombs-positive haemolytic anaemia 12 9 months HCQ, AZA, GC

HCQ

4 months

Infusion-related reaction with dyspnoea, clinical remission AIH

2

Prolonged fever rash, leucopenia, thrombocytopenia class IV, LN, CNS disease Fever, fatigue polyarthritis, severe abdominal pain 8 Drug eruption 2 years HCQ, AZA, MTX, GC

Treatment history Past SLE manifestations

3

Mucocutaneous polyarthritis, leucopenia Mucocutaneous polyarthritis, scleritis, lymphopenia Mucocutaneous polyarthritis, stroke due to APS 9 25 1

Reason for cessation

Time to flare after belimumab cessation (months) Duration of belimumab treatment Disease duration (years) Age (years) Case no.

Table 1. Clinical course prior and following belimumab treatment.

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SLE manifestations at flare after belimumab cessation

SLE exacerbation after belimumab

Autoreactive B cells are normally eliminated by B-cell receptor-induced apoptosis during negative selection in the periphery. However, this could be inhibited by the increased availability of BAFF, which by binding to the BAFF receptor induces upregulation of anti-apoptotic proteins (8). SLE patients treated with rituximab demonstrated that BAFF levels were significantly higher during relapse, as compared with disease remission (9). At the time of post-rituximab relapse, BAFF levels were significantly greater than at disease flare prior to rituximab treatment and were inversely correlated with B-cell numbers (9). High BAFF levels after rituximab therapy and peripheral B-cell repopulation were found to distinguish relapse from ongoing clinical remission (7). These findings suggest a significant role for BAFF in driving disease flare after B-cell repopulation following rituximab treatment. Thus, a similar mechanism involving rebound of BAFF levels may occur following cessation of belimumab therapy.

Persistence of memory B cells Pathogenic memory B cells may be relatively resistant to therapeutic BAFF neutralization. These cells may give rise to a progeny secreting the entire undesirable autoantibody repertoire (10). Nevertheless, this mechanism alone would probably not explain a rare clinical phenomenon, not reported in large clinical trials.

Potentiation of anti-BAFF autoantibodies Price et al recently reported the presence of immunoglobulin (Ig)G anti-BAFF autoantibodies in the sera of a small SLE cohort detected by protein microarray analysis (11). While these autoantibodies can neutralize BAFF activity in vitro, their ability to neutralize BAFF activity in vivo remains to be investigated. A positive correlation was shown between the presence of anti-BAFF antibodies and features associated with SLE severity, including interferon (IFN)-α signature, elevated titres of anti-dsDNA antibodies, and elevated levels of proinflammatory chemokines (11). Sarantopoulos and Su further suggested that antiBAFF antibodies may paradoxically stimulate soluble BAFF production by stimulation of monocytes through BAFF–IgG immune complex-related positive feedback and/or inhibition of the BAFF natural regulator (12). Presuming that anti-BAFF antibodies contribute to SLE pathogenesis, we could speculate that, in a subset of SLE patients with elevated anti-BAFF antibody levels at baseline, cessation of belimumab may lead to significantly increased levels of soluble BAFF, thus contributing to disease flare following treatment cessation.

Upregulation of BAFF receptors on peripheral B cells Pontarini et al recently presented a novel observation of the effect of belimumab on BAFF receptor expression on

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peripheral B cells in patients with primary Sjogren’s syndrome (13). Whereas treatment with belimumab only transiently reduced serum BAFF levels, it resulted in a pronounced upregulation of BAFF receptors that were initially reduced prior to the therapy. Thus, if validated in patients with SLE, the increased expression of BAFF receptors in a setting of stable BAFF levels might possibly explain an SLE flare following belimumab cessation. In summary, the presented cases emphasize open questions regarding the application of anti-BAFF therapy and its impact on the course of SLE. We report a clinically significant disease flare in three patients with SLE following cessation of belimumab treatment and would like to raise awareness and prompt further prospective study of a possible rebound effect leading to disease flare. Assessment of BAFF levels after stopping belimumab therapy and clinical correlation may support this hypothesis. Gradual tapering of belimumab therapy might attenuate the rebound of BAFF levels, possibly preventing a clinically significant disease flare after treatment discontinuation. Further studies are needed to confirm this observation.

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References 1. Cancro MP, D’Cruz DP, Khamashta MA. The role of B lymphocyte stimulator (BLyS) in systemic lupus erythematosus. J Clin Invest 2009;119:1066–73. 2. Stohl W, Metyas S, Tan SM, Cheema GS, Oamar B, Xu D, et al. B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum 2003;48:3475–86. 3. Petri M, Stohl W, Chatham W, McCune WJ, Chevrier M, Ryel J, et al. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum 2008;58:2453–9. 4. McCarthy EM, Lee RZ, Ni Gabhann J, Smith S, Cunnane G, Doran MF, et al. Elevated B lymphocyte stimulator levels are

www.scandjrheumatol.dk

11.

12. 13.

associated with increased damage in an Irish systemic lupus erythematosus cohort. Rheumatology (Oxford) 2013;52: 1279–84. Kreuzaler M, Rauch M, Salzer U, Birmelin J, Rizzi M, Grimbacher B, et al. Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors. J Immunol 2012;188:497–503. Cambridge G, Stohl W, Leandro MJ, Migone TS, Hilbert DM, Edwards JC. Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: relationships with B cell depletion, circulating antibodies, and clinical relapse. Arthritis Rheum 2006;54:723–32. Cambridge G, Isenberg DA, Edwards JC, Leandro MJ, Migone TS, Teodorescu M, et al. B cell depletion therapy in systemic lupus erythematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response. Ann Rheum Dis 2008;67:1011–16. Lesley R, Xu Y, Kalled SL, Hess DM, Schwab SR, Shu HB, et al. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 2004;20: 441–53. Carter LM, Isenberg DA, Ehrenstein MR. Elevated serum BAFF levels are associated with rising anti-double-stranded DNA antibody levels and disease flare following B cell depletion therapy in systemic lupus erythematosus. Arthritis Rheum 2013;65:2672–9. Jacobi AM, Huang W, Wang T, Freimuth W, Sanz I, Furie R, et al. Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, doubleblind, placebo-controlled, dose-ranging study. Arthritis Rheum 2010;62:201–10. Price JV, Haddon DJ, Kemmer D, Delepine G, Mandelbaum G, Jarrell JA, et al. Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus. J Clin Invest 2013;123:5135–45. Sarantopoulos S, Su MA. BAFF-ling autoantibodies. J Clin Invest 2013;123:5006–8. Pontarini E, Fabris M, Quartuccio L, Cappeletti M, Calcaterra F, Roberto A, et al. Treatment with belimumab restores B cell subsets and their expression of B cell activating factor receptor in patients with primary Sjogren’s syndrome. Rheumatology (Oxford) 2015;54:1429–34.

Systemic lupus erythematosus exacerbation following cessation of belimumab treatment.

Belimumab has recently been approved for the treatment of systemic lupus erythematosus (SLE) refractory to standard therapy. Following one case of an ...
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