International Journal of Rheumatic Diseases 2014

REVIEW ARTICLE

Current role of rituximab in systemic lupus erythematosus Chi Chiu MOK Department of Medicine, Tuen Mun Hospital, Hong Kong, China

Abstract Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by periods of flares and remission, resulting in organ damage over time caused by persistent disease activity and treatment-related complications. Conventional therapies are not ideal in terms of efficacy and safety. Novel biological therapies are being developed to enhance therapeutic efficacy, minimize disease exacerbation and reduce toxicities. As dysregulation of B cells is the hallmark of SLE, B-cell targeted therapies are the focus of recent clinical research. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been used with success in recalcitrant lupus manifestations. However, randomized controlled trials have failed to reveal its benefit in renal and non-renal SLE when combined with conventional immunosuppressive protocols. Although heterogeneity of SLE manifestations, pitfalls in study design and the limitations of the assessment tools for various clinical end points may have contributed to the discouraging results, rituximab remains an option in patients who are refractory or intolerant to conventional therapies. Recently, a regimen consisting of rituximab and mycophenolate mofetil without oral corticosteroids was reported to be effective in lupus nephritis. While the efficacy of this regimen has to be confirmed, future controlled trials should focus on the efficacy of rituximab in refractory lupus manifestations and its synergistic effect with other immunosuppressive agents such as cyclophosphamide. In short-term randomized controlled trials, a non-significant increase in serious adverse events was observed in SLE patients treated with rituximab. Long-term safety data of rituximab in SLE, in particular the incidence of hypogammaglobulinemia and serious/opportunistic infections, have to be continuously surveyed. Key words: anti-CD20, biologics, lupus, novel, therapeutics, therapy.

INTRODUCTION Systemic lupus erythematosus (SLE) is a multi-systemic autoimmune disease that predominantly affects women of the reproductive age. The pathogenesis of SLE remains obscure but multiple genetic, environmental and hormonal factors are likely to be involved in the disease predisposition and initiation of disease onset.1 Systemic lupus erythematosus is characterized by a myriad of aberrations in the immune system, which include defects in the clearance of apoptotic materials containing nuclear autoantigens and nucleosomes and Correspondence: Dr Chi Chiu Mok, Chief of Rheumatology, Department of Medicine, Tuen Mun Hospital, Tsing Chung Koon Road, New Territories, Hong Kong, SAR, China. Email: [email protected]

immune complexes by macrophages and the complement system,2 increase in the maturation of myeloid dendritic cells that drive the development of the T cells into a pro-inflammatory Th17 phenotype,3 as well as suppressed functions of the regulatory T (Tregs) and B cells (Bregs). The end results of this immune dysregulation are hyperactivity of the helper T cells and the activation of B cells,4 leading to the over-production of autoantibodies that mediate tissue injury by the immune complex formation and subsequent activation of the complement cascade, or direct antibody-mediated cytotoxicity.

B cell defects in SLE The characteristic B cell abnormality in SLE is loss in cellular tolerance, leading to the production of a variety

© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd

C.C. Mok

of autoantibodies that direct against nuclear complexes, DNA and components of the nucleosome.4 These B cell defects may be intrinsic and manifest as diminished B cell activation threshold or increased cellular survival. Toll-like receptors (TLR7 and TLR9) on the surface of B cells and dendritic cells may be activated by endogenous DNA and RNA that is contained within the immune complexes, leading to cellular activation and production of inflammatory cytokines and the type I interferons.5 In addition, B cells in SLE may mediate autoimmune responses by a number of antibody-independent mechanisms such as auto-antigen presentation to T cells that contribute to their activation and polarization, as well as cytokine and chemokine production that reduces regulatory T cell activity and enhances recruitment of dendritic cells.6–8 Qualitative and quantitative defects of B cells have been well described in patients with SLE. These include altered B cell receptor (BCR)-mediated and downstream intracellular signaling because of defects in the regulation of proteins and calcium influx,9,10 increased expression of the co-stimulatory molecule11 and aberrant signaling through the innate immune receptors.12 In patients with SLE, the proportion of peripheral preimmune B cells (pre-na€ıve B cells, na€ıve B cells and transitional B cells),13 antigen-experienced postswitched memory B cells14 and plasmablasts/plasma cells is expanded.15 The BCR repertoire in these SLE B cells is characterized by abnormal selection, exaggerated somatic hypermutation and receptor editing, which is related to auto-reactivity and lower threshold of cellular activation.16 Finally, there is recent evidence to suggest that regulatory B cells are functionally impaired in patients with SLE.17

A large number of novel therapeutic agents have been tested in SLE but disappointingly only a few are promising so far. Optimization of study design and treatment protocol, including background immunosuppressive regimens, recruitment of appropriate SLE subsets and the utilization of appropriate outcome criteria, are essential in the design of future treatment trials in patients with SLE.20

B cell targeted therapy for SLE Because B cells play a central role in the pathophysiology of SLE, elimination of memory and/or autoreactive B cell clones, restoration of immune tolerance to selfantigens, enhancement of the regulatory activity on B cells and reconstitution of a normal B cell repertoire are logical approaches to target an ultimate cure of the disease. Novel therapeutic agents are developed to target at the growth/survival factors, surface molecules and receptors of B cells, leading to their apoptosis, depletion or anergy (Table 1). The mechanisms of action of various novel B cell-modulating agents that are in the pipeline are illustrated in Figure 1. This review article mainly focuses on the clinical information of rituximab, which has been marketed for more than a decade, in the treatment of SLE.

RITUXIMAB Rituximab is a chimeric monoclonal antibody that specifically directs against the CD20 molecule on the surface of B cells. Mature B cells and B cell precursors from pre-B cell to memory B cell stage are depleted by this compound, with the sparing of stem cell pro-B cells and terminally differentiated plasma cells that do not

Current SLE therapies and unmet needs The mainstay of SLE treatment are the non-steroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine and the immunosuppressive agents such as glucocorticoids, azathioprine (AZA), cyclophosphamide (CYC) and mycophenolate mofetil (MMF).18 Despite the major improvement in survival in SLE in the past few decades, further improvement in disease prognosis is hindered by the development of organ damage as a result of treatment refractoriness and adverse effects to the conventional immunosuppressive agents, in particular the glucocorticoids.19 Thus, the unmet need in the therapeutics of SLE is to develop newer agents or treatment regimens that are more efficacious but associated with fewer toxic side effects.

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Table 1 Targets for B cell modulation in SLE A. Growth/survival factors Belimumab Atacicept Blisibimod Tabalumab B. Surface molecules Rituximab (chimeric anti-CD20) Ocrelizumab (fully humanized anti-CD20) Epratuzumab (fully humanized anti-CD22) C. Immunoglobulin receptori Abetimus sodium D. Proteasomes Bortezomib

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from patients with systemic lupus erythematosus. Arthritis Rheum 62, 2412–23. Bijl M, Horst G, Limburg PC, Kallenberg CG (2001) Expression of costimulatory molecules on peripheral blood lymphocytes of patients with systemic lupus erythematosus. Ann Rheum Dis 60, 523–6. Celhar T, Magalh~aes R, Fairhurst AM (2012) TLR7 and TLR9 in SLE: when sensing self goes wrong. Immunol Res 53, 58–77. Lee J, Kuchen S, Fischer R et al. (2009) Identification and characterization of a human CD5 + pre-naive B cell population. J Immunol 182, 4116–26. Odendahl M, Jacobi A, Hansen A et al. (2000) Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 165, 5970–9. Odendahl M, Keitzer R, Wahn U et al. (2003) Perturbations of peripheral B lymphocyte homoeostasis in children with systemic lupus erythematosus. Ann Rheum Dis 62, 851–8. D€ orner T, Foster SJ, Farner NL, Lipsky PE (1998) Immunoglobulin kappa chain receptor editing in systemic lupus erythematosus. J Clin Invest 102, 688–94. Blair PA, Nore~ na LY, Flores-Borja F et al. (2010) CD19(+) CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity 32, 129–40. Mok CC (2010) Update on emerging drug therapies for systemic lupus erythematosus. Expert Opin Emerg Drugs 15, 53–70. Mok CC (2011) Epidemiology and survival of systemic lupus erythematosus in Hong Kong Chinese. Lupus 20, 767–71. Mok CC (2014) Emerging biological therapies for systemic lupus erythematosus. Expert Opin Emerg Drugs 19, 303–322. March 3. [Epub ahead of print] Pescovitz MD (2006) Rituximab, an anti-cd20 monoclonal antibody: history and mechanism of action. Am J Transplant 6, 859–66. Leandro MJ, Cooper N, Cambridge G et al. (2007) Bone marrow B-lineage cells in patients with rheumatoid arthritis following rituximab therapy. Rheumatology (Oxford) 46, 29–36. Gottenberg JE, Ravaud P, Bardin T et al. (2010) AutoImmunity and Rituximab registry and French Society of Rheumatology. Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum 62, 2625–32. Sfikakis PP, Boletis JN, Lionaki S et al. (2005) Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial. Arthritis Rheum 52, 501–13. Gunnarsson I, Sundelin B, J onsd ottir T et al. (2007) Histopathologic and clinical outcome of rituximab treatment in

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patients with cyclophosphamide-resistant proliferative lupus nephritis. Arthritis Rheum 56, 1263–72. Leandro MJ, Cambridge G, Edwards JC et al. (2005) B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology (Oxford) 44, 1542–5. Marks SD, Patey S, Brogan PA et al. (2005) B lymphocyte depletion therapy in children with refractory systemic lupus erythematosus. Arthritis Rheum 52, 3168–74. Gottenberg JE, Guillevin L, Lambotte O et al. (2005) Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann Rheum Dis 64, 913–20. Li EK, Tam LS, Zhu TY et al. (2009) Is combination rituximab with cyclophosphamide better than rituximab alone in the treatment of lupus nephritis? Rheumatology (Oxford) 48, 892–8. Melander C, Sallee M, Trolliet P et al. (2009) Rituximab in severe lupus nephritis: early B-cell depletion affects long-term renal outcome. Clin J Am Soc Nephrol 4, 579–87. Boletis JN, Marinaki S, Skalioti C et al. (2009) Rituximab and mycophenolate mofetil for relapsing proliferative lupus nephritis: a long-term prospective study. Nephrol Dial Transplant 24, 2157–60. Roccatello D, Sciascia S, Rossi D et al. (2011) Intensive short-term treatment with rituximab, cyclophosphamide and methylprednisolone pulses induces remission in severe cases of SLE with nephritis and avoids further immunosuppressive maintenance therapy. Nephrol Dial Transplant 26, 3987–92. Catapano F, Chaudhry AN, Jones RB et al. (2010) Longterm efficacy and safety of rituximab in refractory and relapsing systemic lupus erythematosus. Nephrol Dial Transplant 25, 3586–92. Fernandez-Nebro A, de la Fuente JL, Carre~ no L et al. (2012) Multicenter longitudinal study of B-lymphocyte depletion in refractory systemic lupus erythematosus: the LESIMAB study. Lupus 21, 1063–76. Ramos-Casals M, Soto MJ, Cuadrado MJ, Khamashta MA (2009) Rituximab in systemic lupus erythematosus: a systematic review of off-label use in 188 cases. Lupus 18, 767–76. Weidenbusch M, R€ ommele C, Schr€ ottle A, Anders HJ (2013) Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis. Nephrol Dial Transplant 28, 106–11. Dıaz-Lagares C, Croca S, Sangle S et al. (2012) Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: pooled data from European cohorts. Autoimmun Rev 11, 357–64. Terrier B, Amoura Z, Ravaud P et al. (2010) Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum 62, 2458–66.

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B cell precursor

Pro-B cells

Pre-B cells

Immature B cells

Transitional B cells

Mature B cells

Acvated B cells

Memory B cells

Plasma cells

CD19 CD20 CD22 CD24 CD27 CD38

Figure 2 Development of B cells and their surface markers.

index was noted in all patients. A reduction in the number of CD3, CD4 and CD20 cells in the renal interstitium was also seen in half of the patients.

Rituximab for refractory SLE manifestations Subsequently, a number of authors have reported efficacy of rituximab in adult and pediatric patients with refractory SLE manifestations, including renal disease.26–28 More recent open-labeled studies have also confirmed efficacy of rituximab in refractory, relapsing or new-onset lupus manifestations, including nephritis and neuropsychiatric disease.29–33 However, in one study, two-thirds of patients treated with rituximab relapsed after a median of 11 months, with and without return of circulating B cells.33 Re-treatment with rituximab, nevertheless, was effective. A more recent multicenter study revealed a clinical response (complete or partial) to rituximab at 6 months in 63% of 116 patients who presented with severe refractory manifestations.34 On further observation at 20 months, SLE flares occurred in 38% of patients. These data suggested that relapse of SLE after initial response to rituximab was fairly common, but amenable to retreatment with the drug.

Data from systematic reviews and registries Ramos-Casals et al.35 conducted a systematic review of the clinical efficacy of rituximab in 188 patients with refractory SLE reported in the literature between 2002 and 2007. Clinical response was reported in 91% of the rituximab-treated patients. The commonest indication of rituximab was lupus nephritis, followed by articular, mucocutaneous and hematological disease. In all patients, rituximab was used in conjunction with glucocorticoids and 22% of patients were treated

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with a protocol consisting of intravenous pulse methylprednisolone and cyclophosphamide. The weekly regimen (375 mg/m2 9 4 doses) was used in 39% of cases and the fortnightly regimen (1000 mg for two doses) was used in 22% of the reports. Another systematic review summarized 26 published reports (n = 300) regarding the efficacy of rituximab in refractory lupus nephritis.36 The weekly regimen (375 mg/m2 9 4 doses) and the fortnightly regimen (1000 mg for two doses) was used in 49% and 37% of the patients, respectively. After 60 weeks, complete or partial renal response was met in 87% of patients with class III, 76% of patients with class IV and 67% patients with class V lupus nephritis, respectively. In a European registry study, rituximab was administered concomitantly with glucocorticoids (99%) and CYC (35%) or MMF (34%) in 164 patients with lupus nephritis.37 At 1 year, complete and partial clinical response was observed in 30% and 37% of the patients, respectively. A higher response rate (complete or partial) was found in patients with class III or mixed types of lupus nephritis compared to class IV or pure class V lupus nephritis. These collective data suggested that rituximab was effective in two-thirds of patients with refractory lupus nephritis. Finally, a French registry38 reported that among 136 SLE patients treated with rituximab (375 mg/m2 for four doses in 36% and 1000 mg for two doses in 60%), an overall response rate of 71% by improvement in the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI score was observed. Efficacy was similar between patients receiving rituximab monotherapy and those receiving concomitant immunosuppressive agents. Articular, cutaneous, renal and hematologic improvements were noted in 72%, 70%,

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74% and 88% of the patients, respectively. Among responders, 41% experienced a disease flare after a mean of 18.6 months, which responded to re-treatment with rituximab in the majority of cases (91%).

prolonged clinical response and sero-conversion of the autoantibodies.44

Factors associated with less optimal response to rituximab

The optimal dosage regimen of rituximab, frequency of re-treatment and combination with other immunosuppressive agents, such as CYC and MMF, in the treatment of SLE is still unknown. Recently, a rituximab regimen without long-term oral corticosteroids in SLE has been proposed.45 Condon et al. followed 50 patients with lupus nephritis treated with two doses of rituximab (1000 mg 14 days apart) with intravenous methylprednisolone (500 mg on days 1 and 15) together with maintenance treatment of MMF (1 g/day titrating to a maximum dose of 3 g/day to a 12-h trough mycophenolic acid level of 1.2–2.4 mg/L). At 1 year, complete response and partial response was achieved in 52% and 34% of the patients, respectively. Patients with classes III, IV and V lupus nephritis had similar clinical responses. Adverse events were infrequent, with hospital admission in 18% of patients and infection occurring in 10% of patients. The efficacy of this regimen has to be confirmed and compared with conventional regimens in future controlled trials.

In a study of 39 SLE patients treated with one course of rituximab (1000 mg for two doses) and corticosteroids,39 50% of patients relapsed after 6–18 months. The time to relapse, B cell depletion and repopulation was highly variable. Persistence of B cells after rituximab is associated with a greater likelihood of having a suboptimal clinical response, whereas a quicker repopulation of memory B cells and plasmablasts was associated with an earlier relapse of SLE. Other factors that have been reported to affect the efficacy of rituximab in SLE include the FcgammaRIIIa genotype,40 higher absolute CD19+ B cell counts at baseline,41 failure of early B cell depletion in the first month of treatment,30 the African race and patients with an expanded autoantibody profile (Ro/nRNP/Sm) and raised B lymphocyte stimulator (BLyS) levels at baseline.42 In addition, up to a third of SLE patients develop neutralizing antibodies to rituximab,41,43 which may reduce its B cell depletion efficacy. An extended follow-up of 41 months in 15 SLE patients treated with rituximab revealed that delayed reconstitution of peripheral blood CD27+ memory B cells occurred in a subset of patients and was associated with

Rituximab without oral corticosteroids for lupus nephritis

Randomized controlled trials of rituximab in SLE Two randomized controlled trials (RCTs) were conducted to study the efficacy of rituximab in non-renal and renal SLE (Table 2). The EXPLORER study46 is a

Table 2 Randomized controlled trials of rituximab in SLE No. and ethnicity

Study duration and comparator

Inclusion

EXPLORER (phase III)46

257 (42% Asians, Hispanics or Africans)

52 weeks RTX (1 g 9 2) versus PBO in addition to steroid and background therapies

≥ 1 BILAG A (except severe or organthreatening disease) or ≥ 2 BILAG B score

LUNAR (phase III)47

144 (69% Asians, Hispanics or Africans)

RTX (1 g 9 2) versus PBO in addition to high-dose steroid and MMF (3 g/day)

Biopsy-confirmed active class III/IV lupus nephritis with urine P/Cr ratio > 1.0

Main results Major clinical response at week 52 (RTX vs. PBO: 12% vs. 16%); partial clinical response (RTX vs. PBO: 17% vs. 13%) (differences NS) Complete renal response at week 52 (RTX vs. PBO: 26% vs. 31%); partial renal response (RTX vs. PBO: 31% vs. 15%) (differences NS)

Adverse events AEs, SAEs and infusion reactions similar between RTX and PBO

AEs, SAEs, rates of infusion reaction and infection similar between RTX and PBO; neutropenia, leukopenia and hypotension more common with RTX

AE, adverse events; BILAG, British Isles Lupus Assessment Group; MMF, mycophenolate mofetil; NS, not significant; PBO, placebo;; P/Cr, protein to creatinine ratio; RTX, rituximab; SAE, serious adverse events; SLE, systemic lupus erythematosus.

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multicentered placebo-controlled trial of rituximab in 257 SLE patients with moderate to severe extra-renal disease (defined as ≥ 1 domain with a British Isles Lupus Assessment Group index [BILAG] A or ≥ 2 domains with BILAG B) despite treatment with AZA, MMF or methotrexate. Participants were randomized to either rituximab (1000 mg for two doses 14 days apart) or placebo for two courses administered at baseline and week 26. At week 52, clinical responses (major and partial), area under the curve (AUC) of disease activity over time and analysis of the BILAG index results did not reveal significant differences between the rituxumab and placebo groups of patients. A subgroup analysis showed that rituximab-treated African and Hispanic patients had better clinical improvement. In those patients who responded to treatment, the incidence of disease flares was not significantly different between the two groups. However, rituximab treatment was associated with a lower rate of annualized BILAG A flares, and a trend toward a longer time to these flares. The frequency of adverse events (AEs) and serious adverse events (SAEs) were also similar between the two treatment arms. Using a similar protocol, a double-blind, placebocontrolled multicenter study (LUNAR) was performed in patients with active proliferative lupus nephritis.47 Patients with histologically class III or IV lupus nephritis and urine protein to creatinine (UP/Cr) ratio > 1.0 were randomized to receive rituximab (1000 mg) or placebo infusion on days 1, 15, 168 (week 24) and 182 (week 26), on top of corticosteroid and MMF (> 2 g/day). Seventy-two patients were recruited in each treatment arm and two-thirds of patients had class IV lupus nephritis. At week 52, no statistically significant differences in the primary and secondary outcomes were observed between the two groups of patients, although there were numerically more responders in the rituximab group (57% vs. 46% in the placebo group). Moreover, improvement in anti-dsDNA and complement levels was more marked in rituximab-treated patients. Like the EXPLORER study, Africans showed a trend of better response to rituximab compared to the Caucasians. A recent comparative study of three different regimens for active lupus nephritis, namely rituximab (1000 mg 9 2 doses) (n = 17), MMF (2–2.5 g/day) (n = 17) and intravenous pulse CYC (500 mg every fortnight 9 6 doses) (n = 20) in addition to highdose glucocorticoids (shifted to AZA, cyclosporin A or MMF at month 4), showed that rituximab was at least as effective as the other two agents in terms of

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renal response at 3 and 12 months.48 However, this study is not powered to detect a difference among the regimens. The clinical response at 3 months may be contributed to by high-dose corticosteroids per se and the efficacy at 12 months may be contributed to by the consolidation/maintenance therapy with different agents, which is selected at the discretion of physicians.

Adverse effects of rituximab in SLE In the EXPLOERER study,46 the rates of SAEs and AEs were similar between the rituximab and placebo groups of patients. Infusion reactions (starting from the third infusion) and neutropenia were numerically more common in rituximab users. The rates of serious infections were not significantly higher in rituximab-treated patients. In the LUNAR study,47 although the rates of SAEs and AEs were similar between the rituximab and placebo groups, neutropenia, leukopenia, hypotension, infusion-related reactions, herpes zoster and opportunistic infections occurred at higher frequencies in patients treated with rituximab. Data from the French rituximab registry38 revealed that 13% of SLE patients developed infusion-related reactions to the drug – serious in 12% and delayed onset in 29% of patients. Serum sickness-like reactions occurred in 4% of patients. Serious infections occurred in 9% of patients (6.6/100 patient-years of follow-up), which was not apparently associated with low immunoglobulin G (IgG) or gamma globulin level. Data from rheumatoid arthritis (RA) registries reported that repeated administration of rituximab in RA patients (n = 3194) for 9.5 years was associated with hypogammaglobulinemia (22.4% of patients developed low IgM, 3.5% had low IgG levels and 1.1% had low IgA for ≥ 4 months).49 Serious infection was more frequent in patients with low IgG than those who did not developed low IgG. These patients were older, had longer disease, lower B cell counts and IgG levels, and had received more non-biologic DMARDs at baseline. As patients with SLE are generally more immunocompromized than RA because of multiple immunosuppressive therapies, rituximab-induced hypogammaglobulinemia may be a serious concern. Baseline immunoglobulin level should be checked in all SLE patients and monitored serially during prolonged rituximab treatment. Discontinuation of rituximab should be considered when IgG levels drop progressively to below normal range or when recurrent infections develop. The incidence of

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hypogammaglobulinemia and long-term risk of serious infections in patients with SLE has to be captured in rituximab registries. Progressive multifocal leukoencephalopathy (PML) is a rare, progressive and typically fatal demyelinating disease of the central nervous system caused by the JC virus.50 After the US Food and Drug Administration (FDA) MedWatch reported two fatal cases of PML in SLE patients treated with rituximab in 2006,51 a literature search revealed 50 other cases of PML in rheumatic diseases,52 of which SLE was overrepresented (64% of all). In 41% of these SLE patients, minimal or no immunosuppressive therapy was given 6 months prior to onset of PML. These observations raised the alert that PML in SLE might be unrelated to the degree of immunosuppression, suggesting a role of host factors in the predisposition to this virus. Physicians should be aware of the fact that PML occurs at a higher frequency in patients with SLE and should suspect this infection in any SLE patient who presents with new-onset neurological symptoms, particularly those worsened with immunosuppressive therapies.

RITUXIMAB IN SLE: THE OUTLOOK Rituximab induces a general B cell depletion, including memory B cells.22 Repopulation of B cells after rituximab therapy is characterized by an increase in the number of peripheral na€ıve and transitional B cells.22 Rituximab reduces anti-dsDNA levels in SLE patients and a quicker repopulation of the memory B cells is associated with disease flares.39,44 Because of these effects of rituximab on B cells, rituximab has a higher theoretical potential of restoring B cell homeostasis in SLE during repopulation compared to other B cell modulating agents such as belimumab and epratuzumab. On the other hand, depletion of B cells is associated with an increase in serum level of BLyS which drives the repopulation of B cells. As a return of memory B cells may be associated with disease flares, designing a treatment regimen that involves the use of inhibitors such as belimumab to block the upsurge of BLyS after rituximab administration may be an approach to further enhance the efficacy of B cell depletion therapy in SLE. Despite the favorable mechanisms of rituximab, RCTs have failed to show a benefit of this agent in renal and non-renal SLE.46,47 While the negative results remain to be explained, improvement of study design is necessary in future clinical trials of biological agents in patients with SLE.

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Study design and protocol Systemic lupus erythematosus is a clinically and immunologically heterogeneous disease. When manifestations with different pathogenic mechanisms are grouped together for evaluation, the efficacy of a novel treatment modality may not be truly reflected. Recruitment of a targeted subgroup of SLE patients may be more revealing but the sample size required is much bigger. In the LUNAR study,47 the sample size and duration of follow-up may not be optimal to detect a difference in treatment effect between rituximab and placebo groups of patients. Although a more favorable response was observed in Blacks, the study was not powered to evaluate further this subgroup. As lupus nephritis may take a longer time period to achieve a clinical response, the superiority of rituximab to placebo may not be apparent in 52 weeks. On the other hand, patients recruited in the two rituximab RCTs46,47 did not have refractory renal disease. Patients were assigned per protocol to receive heavy concomitant immunosuppressive treatment (such as moderate to high-dose corticosteroids), which by itself might have been effective for the manifestations, leading to a higher than expected placebo response rates. This may have contributed to a false negative result because a much bigger sample size is required to show a difference in efficacy between rituximab and placebo. Minimization of background immunosuppressive therapies before study entry should be considered in future clinical trials of novel therapeutic agents in SLE. While most positive reports of rituximab in severe/ refractory SLE involved a combination of rituximab (375 mg/m2 for 4 weekly doses) with CYC instead of MMF, it remains to be seen if the lower efficacy of the regimen in the rituximab controlled studies is related to the lower rituximab dosage used (1000 mg for two doses in total) and with the combination of MMF. Synergism between rituximab and CYC has to be explored in future trials involving more serious/refractory lupus manifestations.

Assessment tools for efficacy end points There are no ideal tools for the assessment of efficacy end points in SLE trials. A key problem of a global score of SLE disease activity such as the SLEDAI53 and its modifications, SLEDAI-200054 and SELENA-SLEDAI55 is that the change of activity in individual systems cannot be reflected by the total score. Moreover, partial improvement or deterioration to treatment cannot be captured. The BILAG scoring system56 captures

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improvement and deterioration of disease activity in different organ systems, mainly based on the need to change therapies. However, it is tedious to complete and the decision to change therapy by physicians may not necessarily reflect the presence of disease activity. Adequate training for investigators is needed for BILAG scoring. The physician’s global assessment (PGA)57 is simple to score and sensitive to change in the overall status of patients but is subjective, semi-quantitative and subject to inter-assessor variability. Because of the limitations of individual disease activity indices, a composite index is designed to define primary treatment efficacy end point. For instance, in the belimumab trials,58,59 a composite clinical response index, known as the SRI, was used to define the primary outcome. This SRI incorporates the strengths of different activity indices by quantifying the improvement in disease activity (SELENA-SLEDAI), and ensuring no worsening in the overall status of the patients (PGA) and in previously unaffected organ systems (BILAG). However, in actual clinical practice, the SRI is fairly tedious and may not be practical. Moreover, the cut-off of improvement by ≥ 4 points in SLEDAI may still be insensitive to capture improvement in certain systems, meaning that patients who do not meet the SRI criteria for a response may not necessarily be non-responders from the clinical point of view. Recently, a SLEDAI-2K Responder Index 50 was developed to capture partial improvement in disease activity in different domains of the index.60 This responder index has been validated to be sensitive in identifying clinical response in longitudinal studies of SLE61 and may prove useful in future clinical trials of novel therapeutic agents in SLE.

CURRENT ROLE OF RITUXIMAB IN SLE Although RCTs do not show benefits of rituximab in renal and non-renal SLE when combined with conventional protocols, taking into account the encouraging results of rituximab in open observational trials and registries,24–38 this agent remains a treatment option for SLE manifestations that do not respond adequately to conventional regimens or patients who are contraindicated for/intolerant to conventional modalities. These manifestations include renal, neuropsychiatric, hematological and musculoskeletal (arthritis) disease. The weekly regimen (375 mg/m2 for four doses) of rituximab is more commonly adopted in open-label studies. RCTs addressing the efficacy of rituximab in refractory lupus manifestations are needed in the future. Whether

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rituximab should be combined with CYC or MMF also requires further evaluation.

CONCLUSION The variability of clinical response among SLE patients to rituximab may reflect the clinical and immunological heterogeneity of the disease. Improvement in study design with the inclusion of a more homogeneous patient population and a stringent control of background immunosuppressive therapies is needed in future clinical trials of biologics in SLE. The efficacy of rituximab in more serious or refractory SLE manifestations has to be tested in future controlled trials and the long-term safety and cost-effectiveness of rituximab in SLE has to be explored. Despite the caveats of recent RCTs, rituximab remains a treatment option in SLE patients who are refractory or intolerant to conventional regimens.

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International Journal of Rheumatic Diseases 2014

Current role of rituximab in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by periods of flares and remission, resulting in organ damage over t...
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