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Evolving Views of B-Cell Targeted Therapies in Rheumatoid Arthritis - Activity

Key Points

  • Two-way interactions between B and T cells may be a key to understanding RA: B cells signal and activate T cells through antigen presentation and other ligand interactions; in addition, T cells signal and activate B cells through cytokines and cell-surface ligands
  • The first B-cell–targeting therapy for RA, rituximab, depletes CD20+ B cells and is active against DMARD and TNFα antagonist-resistant RA
  • Emerging B-cell–targeted therapies deplete CD20+ or CD22+ B cells, or target B-cell regulatory factors such as BLyS, APRIL, or their common receptor TACI

New insights into the immune dysfunction underlying rheumatoid arthritis (RA) have uncovered specific molecular targets for therapy such as cytokines (eg, TNFα, IL-1), cell types (eg, B cells, T cells), or unique signaling pathways. (1,2) While the trigger that initiates the autoimmune response in RA is unknown, elements of the immune system that sustain RA are current targets for therapy. At one time, CD4+ T cells were thought to play the dominant role in the development of RA, on the basis of predominance of T cells in the synovium of RA patients and the role of T cells in inflammation. (1) Although T cells are important in the initiation and perpetuation of RA, recent clinical studies with B-cell–targeted therapy have shown that B cells are also important effector cells in the pathogenesis of RA. (2-4)

Two-way interactions between B and T cells may be a key to understanding RA: B cells signal and activate T cells through antigen presentation and through other ligand interactions, and T cells signal and activate B cells through cytokines and cell-surface ligands. These interactions are postulated to create a positivefeedback loop leading to autoimmunity and chronic inflammation. (3) T-cell activation and the resultant synovial inflammation appear to be at least partially B-cell-dependent, the likely result of B- and T-cell interactions. B-cell production of proinflammatory cytokines such as TNFα and IL-6 is thought to play a role in RA pathology. Finally, the autoimmune response is exacerbated by autoantibody production by plasma cells and B cells. (2)

Targets for therapy include mechanisms for B-cell survival and maturation as well as cell-surface ligands (Figure 1). (2-4) Two such B-cell-specific cell-surface markers are CD20 and CD22. These are targets for therapeutic monoclonal antibodies (mAbs), the effect of which is to deplete B cells at specific stages in their development. Other therapeutic targets include factors that regulate B-cell maturation and amplification. (2) A proliferation-inducing ligand (APRIL) and soluble factors, including B-cell stimulator protein (BLyS, also known as B-cell-activating factor or BAFF), are part of the TNF family and are involved in synovial inflammation. BLyS and APRIL share receptors that are primarily expressed on B cells and plasma cells; BLyS and APRIL are elevated in RA patients. (5,6) Two common receptors for BLyS and APRIL are the B-cell maturation antigen (BCMA) and TACI (transmembrane activator and CAML [calcium-modulating cyclophilin ligand] interactor). (2)

Therapeutic Target: B-Cell Depletion

The idea that B-cell depletion is effective at reducing clinical disease through disruption of B-cell-dependent processes is supported by clinical trials. (2-4) The most-studied B-cell–targeted therapy to date is rituximab, (7,8) an anti-CD20 mAb currently approved for use in RA patients who respond inadequately to TNFα antagonists. (9) Rituximab is an important clinical option given that up to 40% of patients may not have an adequate response to TNFα antagonists. (10)

Figure 1. Therapeutic Targets for B-Cell Therapy

Figure 1. Therapeutic Targets for B-Cell Therapy (2, 5, 6)

Rituximab affects BLyS and APRIL in different ways, reflecting the fact that BLyS and APRIL are part of different B-cell regulatory feedback loops. B-cell depletion following treatment with rituximab were reported to increase levels of BLyS, while elevated levels of baseline APRIL were not affected by rituximab administration. (5) This finding highlights the complexity of B-cell–related processes in RA, suggesting that effective B-cell–targeted therapy may require multiple targets.

In the earliest clinical trials, rituximab resulted in B-cell depletion without serious adverse events in the short term. (1,11-13) A rapid and at least partial decrease in synovial B cells was noted in most subjects within 4 weeks following B-cell depletion with rituximab. (13) B-cell depletion was sustained, lasting up to 2 years or more, and resulted in major clinical improvement of RA symptoms at 6 months posttreatment. (1) Early imaging studies showed decreased synovitis and erosions in two patients, one with an ACR50 response and the other with an ACR70 response, (12) suggesting that the impact of B-cell depletion was disease– modifying, not only anti-inflammatory. Studies are needed to fully understand the long-term consequences of B-cell depletion on plasma cell populations and the immune response (eg, the effects on protective immunoglobulin [Ig] levels); studies are also necessary to identify or clarify safety issues, such as the risk of infection.

Phase 2 studies showed that rituximab significantly reduced RA disease activity. Rituximab alone, or combined with either methotrexate or cyclophosphamide, significantly improved the signs and symptoms of RA, as determined by ACR criteria, at weeks 24 and 48. (1,14) All patients had long-term, active RA with a previous inadequate response to methotrexate. The phase 2b Dose–Ranging Assessment International Clinical Evaluation of Rituximab in RA (DANCER) trial examined patients with an inadequate response to methotrexate as well as patients who had a lack or loss of response to other DMARDs or TNFα antagonists. Rituximab combined with methotrexate significantly improved the proportion of patients who achieved a week-24 ACR20, ACR50, or ACR70, and significantly improved the Disease Activity Score (DAS) in this patient population. (15) The ACR20 response was independent of the peri-infusional use of oral or intravenous glucocorticoids, although premedicating with intravenous glucocorticoids prior to the first rituximab infusion attenuated but did not eliminate the risk of infusion reactions.

The phase 3 Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) trial evaluated a single course of rituximab and methotrexate compared with methotrexate alone in patients who failed prior TNFα antagonist therapy. The use of rituximab significantly improved ACR20, ACR50, and ACR70 response. Clinically meaningful decreases in fatigue and disability and improved quality of life were also noted. (16) In a limited assessment of radiographs from a subset of trial subjects, there was significantly less radiographic progression with rituximab at week 56, indicating that rituximab inhibited joint damage. Moreover, progression of week-24 erosion scores and overall Genant–modified Sharp scores were significantly lower (by one-half) in the rituximab group. (17) Some patients continued to show significant clinical improvement through week 56, although in other patients the response tapered off. This cohort continues to be monitored. (18)

An early pilot study of repeat administration of rituximab in patients with refractory RA resulted in an average duration of benefit of 15 months after each cycle of rituximab. (19) Long-term follow-up from these studies showed that a single course of rituximab with background methotrexate provided meaningful improvement in physical function for up to 2 years in some patients, as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). (20) More recent retreatment data from phase 2 and phase 3 multicenter trials suggest that the average time until retreatment (triggered by a recurrence of symptoms) is approximately 9 months. (21)

Repeat rituximab administration has been relatively well tolerated over time, although a reduction in Ig levels (eg, IgM, IgG, IgA) has been noted, with a possible trend toward more serious infections in patients whose Ig levels fall below the normal range. (22,23) Clinical trials to date have not demonstrated an overall increased risk of serious infection in RA patients treated with rituximab. (24,25) The clinical impact of reduced Ig levels is unclear, and long-term surveillance of rituximab–treated patients with reduced Ig levels is ongoing. In the absence of studies to determine if rituximab affects vaccine efficacy, immunizations should be administered before starting rituximab, to preserve vaccine efficacy. (26)

The most common major adverse event with rituximab seen in clinical trials is an infusion reaction (transient hypotension or hypertension, cough, pruritus, and rash), which occurred in about one-third of patients, most often during or within the first 24 hours after the first infusion.

About 10% of patients may experience an infusion reaction after the second infusion. Most infusion reactions are mild to moderate; however, use of medications such as IV glucocorticoids, antihistamines, and acetaminophen to attenuate a potential infusion reaction may be required. Severe reactions may require interruption of the infusion and subsequent reduction of the infusion rate. (9,26,27) Additional phase 3 trials are studying rituximab in the treatment of methotrexate-naive patients, rituximab combined with other DMARDs, or rituximab in the treatment of patients with early RA who are DMARD-naive.

Emerging B-Cell–Targeted Therapies

Ocrelizumab and ofatumumab are second-generation, humanized, anti-CD20 antibodies. Humanized antibodies are designed to be less immunogenic, although the clinical significance of this is unknown. In a phase 1/2 study of moderate-to-severe RA, rheumatoid factor–positive (RF+) patients with an inadequate methotrexate response were treated with ocrelizumab plus methotrexate. Ocrelizumab and methotrexate resulted in B-cell depletion and clinical improvements in some patients; as with rituximab, infusion-related reactions were the most common adverse event. (28) Phase 3 trials are proceeding to assess the effect of ocrelizumab in RA patients who are refractory to TNFα antagonists, or ocrelizumab in combination with methotrexate in methotrexate-naive patients or patients with a prior inadequate response to methotrexate. Early results from a phase 2 trial of patients with refractory RA show that ofatumumab was associated with a significant ACR20 response and few serious infusion-related reactions. (29) Ocrelizumab and ofatumumab target different epitopes on the CD20 molecule.

TRU-015 is a truncated antibody-like molecule (smaller than a multichain antibody) with the functional, antigenbinding domains of an anti-CD20 antibody. (30,31) TRU-015 binds and depletes CD20+ B cells. In a dose-finding phase 2 trial comparing TRU-015 with placebo, TRU-015 was associated with significant improvements in DAS28 and HAQ-DI, and was not associated with significant toxicity. (30,31) Another mAb, epratuzumab, is a humanized anti-CD22 mAb currently under study for systemic lupus erythematosus and Sjögren’s syndrome; epratuzumab may have future application in RA. (32)

Atacicept (TACI-Ig) is a recombinant fusion protein that blocks both BLyS and APRIL. (33,34) A phase 1 study showed that atacicept was well tolerated in healthy subjects. (33) In another phase 1 study, atacicept was active in moderate-tosevere active RA when measured by biologic markers (eg, IgM, IgA, IgG, RF, anti-CCP, numbers of B-cells). (34) A phase 2 dose-finding study is underway in patients with RA who responded poorly to treatment with TNFα antagonists.

Belimumab, (2) a fully human IgG1ι mAb directed against BLyS, (35-39) decreased the signs and symptoms of RA with a reportedly favorable safety profile. (36) In moderate-to-severe RA, belimumab combined with standard of care significantly improved ACR20, reduced RF, and depleted CD20+ B cells (37); however, more profound improvement (ACR50, ACR70) relative to placebo was not seen.

The results seen with the different B-cell–directed therapies confirm a role for B cells in RA. However, variable responses have been seen to date following the use of compounds with different mechanisms of action. This would indicate probable heterogeneity of the B-cell population in RA pathogenesis. Additional research is needed to understand these different responses and their possible associations with other longer-term risks.

Consensus Statements

Two recent consensus statements have focused on the treatment of rheumatic diseases using B-cell–targeting biologic agents: a 2007 consensus statement on the use of biologic agents, including rituximab, for use in rheumatic diseases, (9) and a 2007 consensus statement on the use of rituximab in the routine care of patients with RA. (27) These statements have summarized the literature to date regarding rituximab in clinical practice. The latter consensus notes that rituximab has been tested in clinical trials that enrolled patients with at least moderate disease activity (eg, DAS ≥3.2 or the Simplified Disease Activity Index, SDAI >11), which may not be reflective of patients seen in clinical practice.

One important topic that is covered in the consensus statements is the timing of rituximab following prior TNFα antagonist treatments. In clinical trials, therapy with rituximab was typically started at least 4 weeks after discontinuing etanercept, or 8 weeks after discontinuing adalimumab or infliximab. (27)

Clinical trial experience is important in guiding patient screening prior to starting a course of any new therapy. Exclusion criteria from clinical studies of rituximab included evidence of major systemic involvement due to RA, other major illnesses, a history of recurrent, significant infections, and underlying hypogammaglobulinemia. (15,40) On the basis of these exclusions, before beginning treatment with rituximab, screening for hepatitis B and C, as well as tuberculosis, is suggested to monitor for potential reactivation of latent infections during and after treatment. Hepatitis B reactivation has been seen with the use of rituximab in the treatment of hematologic malignancies. (41) Rituximab therapy during pregnancy and lactation is not advised because of a lack of safety data in these patients. (9,26,27)

The currently approved course of rituximab includes two infusions of rituximab 1000 mg, on days 1 and 15 (2 weeks apart), as well as premedication with an intravenous glucocorticoid. (27,39) However, the DANCER study found that both the 1000 mg dose and a 500 mg dose, each given as two infusions 2 weeks apart, resulted in a significant number of patients achieving an ACR20 response, in a population of methotrexate-inadequate responders. (15) Although rituximab is currently licensed for use in combination with methotrexate (usually 10–25 mg methotrexate per week), rituximab monotherapy has also resulted in clinical improvement in RA compared with placebo. (14) As seen in studies of other biologic therapies, the clinical benefit observed with combination methotrexate and rituximab therapy was greater than with rituximab alone. (8,9)

In clinical studies, responses to treatment with rituximab were usually apparent by 16 weeks after the first infusion. A transient improvement through approximately 8 weeks following the rituximab infusion may appear as a result of premedication with a glucocorticoid at the time of the infusion. (27) The consensus statements suggest that the minimal response criterion should be improvement in the DAS28 score of ≥1.2 or the equivalent.

Repeated treatment with rituximab has been studied and is an option in patients with an inadequate response or a loss of response (eg, DAS28 >3.2) to rituximab after at least 24 weeks. The optimal schedule for repeated rituximab treatment is under investigation. Clinical data thus far suggest that responses to repeated rituximab treatment are usually similar to the initial response. (18,27,42) As noted above, the effect of long-term B-cell depletion resulting from repeated treatment with rituximab, including possible Ig depletion, is still under investigation.

Important Issues for Research

Rituximab is the first available and best studied B-cell– directed therapy for RA to date. The clinical use of rituximab has raised many questions that will require further research involving this agent and others that target B cells (Table 1). Subsequent use of other biologic therapies following treatment with rituximab is one important area encountered in clinical practice, although there is a dearth of information to guide decision making. The use of TNFα antagonists after a course of rituximab reportedly has benefit in some patients, but the potential risk of serious infections in this setting requires further study. (43) Furthermore, there are as yet no data concerning subsequent treatment with therapies such as abatacept that target other cell populations following treatment with rituximab. In addition, the minimal effective dose and optimal intervals between rituximab infusions raise questions for further study. (9) It is important to evaluate the safety and effectiveness of biologic DMARDs in general in combination with other nonbiologic DMARDs other than methotrexate as methotrexate is not well tolerated by many patients. (27) The optimal time and patient populations in whom B-cell–directed therapy is most appropriate are also under investigation, with studies of rituximab treatment in patients with early RA in progress. (44)

Safety issues that need to be addressed regarding rituximab and all biologic therapies include safety during pregnancy and lactation, and use in patients with congestive heart failure and other comorbidities. Studies to further understand the effect of long-term B-cell depletion, including the effects on immune response and infection risk, are underway. (9,27)

The identification of biomarkers or predictors of response to B-cell–targeted therapies would aid clinical decision making in identifying the therapy most likely to provide patient benefit. Biomarkers may also aid in decisions surrounding the time to retreat with these agents. Finally, research that clarifies the mechanism of action of B-cell– targeting therapies may also lead to a better understanding of the pathophysiology of RA and other autoimmune diseases, which may in turn lead to better patient care and management of these conditions.

Table 1. B-Cell–Targeted Therapy: Questions for Research
Combined, or used in sequence with TNFα antagonists
The effect of B-cell–targeted therapy in early RA
Long-term effects of B-cell depletion
Safety of repeated administration
Optimal dosing and dosing intervals
Infection risk with long-term B-cell–targeted therapy
Infection risk with other biologic therapy following B-cell–targeted therapy
Use of biomarkers and predictors of response
Better understanding of the mechanism of action
Use during pregnancy and lactation

Summary

B-cell–targeted therapies, along with other biologic targets, are important in the treatment of RA, (2-4,7,8) given that up to 40% of patients do not respond to TNFα antagonists.10 Clinical trials with B-cell depletion using rituximab show efficacy in patients with long-standing RA, in both methotrexate– and TNFα antagonist–resistant disease. In patients with an initial response, repeated rituximab infusions are often effective and generally safe. Ongoing research will continue to explore the effects of new B-cell–targeted therapies and further clarify the optimal use of currently available treatment.

References

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