Abstract: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease for which therapeutic advances in immunosuppressive and support therapy have significantly improved survival over the last 5 decades. Unfortunately, SLE still carries substantially increased rates of mortality and end stage renal disease which are even more elevated in younger patients. No new drugs have been approved for SLE in over 50 years. Hence, a lot of hope and excitement has been generated by the development of biological agents designed to eliminate B cells either through direct killing (anti-B cell antibodies such as rituximab) or attrition by inhibition of survival (anti-BLyS/BAFF agents such as belimumab). Indeed a strong rationale for targeting B cells in SLE is supported by the major pathogenic roles they play in SLE through both autoantibody production and multiple antibody-independent functions. These hopes, however, have been darted by the failure of two different phase III randomized placebo-controlled trials of rituximab. Yet, clinicians continue to use rituximab off-label with the belief that it provides significant benefit and can rescue patients with disease that is refractory to current modalities. Moreover, recent positive results of two large controlled trials of belimumab have restored confidence that B cell targeting may after all be of benefit in SLE. In this review we discuss the background and rationale for the use of anti-B cell agents in SLE, review the available results, and provide models that could help reconcile the opposing results observed in different studies. These models could also help frame the design and evaluation of current and future B cell therapies.
“What’s Past Is Prologue.”
The Tempest, William Shakespeare
B cell therapies have been at the forefront of experimental treatments for SLE for the last decade. Despite great initial promise and hope, the field has fallen into disarray due to the failure of controlled phase III trials of rituximab (Sanz and Lee, 2010). A recent editorial commentary published in Arthritis and Rheumatism by prominent lupus experts illustrates the ongoing controversy in the field of B cell depletion (BCD) for treating SLE (Merrill and Buyon, 2010). That publication discussed the continued use of off-label rituximab in clinical practice based on clinical need and the perception of benefit despite the failure of controlled clinical trials that many experts in the field appear to consider as the final word on the matter. The said editorial suggested that clinicians are clinging to the notion that killing B cells in SLE will work even though the specific approach via rituximab is dead. To paraphrase Mark Twain, we believe that the news of the death of rituximab (or similar approaches to BCD) in SLE has been greatly exaggerated. Here, we will discuss the evidence derived from the clinical trials and observational studies available and raise important questions that should be addressed before the approach of B cell depletion is prematurely buried.
Is the Rationale for Killing B Cells in SLE Still Alive?
In the last year, two well-designed, albeit of moderate size and relatively short follow-up period, phase III randomized placebo-controlled trials of rituximab for the treatment of moderately active non-renal SLE (EXPLORER) or class III/IV lupus nephritis (LUNAR) have failed to demonstrate superiority of this B cell depleting agent over placebo plus conventional immunosuppressive therapy (Furie et al., 2010a; Merrill et al., 2010). The negative results have been quite disappointing to both SLE patients and their physicians alike, setting back the expectation for the effectiveness of this modality in a disease that, despite significant improvements over the last decades, still carries significantly increased adjusted mortality rates and for which no new treatments have been approved in more than 50 years.
The results were also perplexing since B cells are considered central to the pathogenesis of SLE, at a minimum, through the production of autoantibodies that target a vast array of self antigens and induce inflammation and tissue damage. In addition, B cells are also adept at exerting multiple pathogenic functions including the disruption of T cell tolerance, the activation of autoreactive memory T cells, the induction of pathogenic effector T helper 1 (Th1) and T helper 17 (Th17) cells, the attraction and activation of dendritic cells, the inhibition of regulatory T cells, and the activation/recruitment of follicular B-helper T cells (TFH) (Chan et al., 1999; Manjarrez-Orduno et al., 2009; Townsend et al., 2010). Of note, these important functions are independent of antibody secretion, the classical effector function of the B cell lineage which is carried out by differentiated antibody secreting cells (ASC; plasmablasts and plasma cells). Instead, these antibody-independent pathogenic B cell functions are mediated through antigen-presentation and co-stimulation and production of proinflammatory cytokines. Accordingly, one would expect that the elimination of B cells should provide therapeutic benefit in SLE at least to the extent that the intervention achieves profound and sustained elimination of pathogenic B cells and/or pathogenic autoantibodies. However, given that most ASC do not express the molecular target of rituximab (CD20), the effect of this drug on autoantibody levels is limited, selective, and slow since multiple autoantibodies are generated by long-lived plasma cells that may survive for many years in the absence of precursor B cells. In keeping with this notion, rituximab treatment does not impact the generation of antibodies against RNA-binding proteins (RBP; Smith/RNP, Ro, and La), which are thought to be produced by long-lived plasma cells and induce the production of type 1 interferon, a cytokine widely considered to be central to the pathogenesis of SLE (Cambridge et al., 2006; Eloranta et al., 2009; Tew et al., 2010).
Are B Cells Still an Appropriate Therapeutic Target for the Treatment of SLE?
While the limited effect of rituximab on the production of many autoantibodies was well known going into the phase III studies, the failure of this drug in SLE is also quite unexpected given its ability to decrease anti-DNA antibodies, the multiple B cell pathogenic functions, and the positive results of early trials and multiple observational studies and clinical experience. Additional support for this approach is provided by the demonstrated benefit of this drug in several other autoimmune diseases including rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and antineutrophil cytoplasmic antibody (ANCA)-mediated vasculitis (Edwards et al., 2004; Hauser et al., 2008; Pescovitz et al., 2009; Stone et al., 2010; Townsend et al., 2010). Of note, despite the presence of disease-associated autoantibodies, these are autoimmune diseases traditionally considered to be mediated by T cells yet responded well to B cell depletion. Perhaps more importantly, early indication of clinical efficacy in SLE has been recently provided by other anti-B cell therapies, in particular anti-BLyS/BAFF and anti-CD22 antibodies (belimumab and epratuzumab, respectively) (Chatham et al., 2010; Dall’Era and Wofsy, 2010; Kalunian et al., 2010; Navarra et al., 2010; van Vollenhoven et al., 2010). These studies provide strong support for the notion that B cell targeting may indeed represent a viable approach to the treatment of SLE. Of particular significance, two large phase III studies (BLISS-52 and BLISS-76) of moderately active (non-nephritis) SLE patients treated with belimumab met their primary efficacy endpoint of clinical superiority as compared to placebo plus standard of care when both groups, totaling 1,684 patients, were analyzed after 52 weeks of continuous treatment. On the basis of these findings, belimumab has been granted a priority review designation by the U.S. Food and Drug Administration (FDA). In addition, preliminary results of a 12-week phase IIb study of epratuzumab, an antibody targeting the B cell inhibitory receptor CD22, also seem to point to favorable clinical results (Kalunian et al., 2010). Of note, these two anti-B cell therapies induce a much lesser and slower degree of B cell depletion than rituximab (Dorner et al., 2006).
How Can We Reconcile Apparently Contradictory Results of B Cell Targeting Therapies?
In contrast to the negative results of controlled trials, multiple observational studies of rituximab and randomized placebo-controlled trial studies of other B cell targeting agents appear to indicate clinical benefit (Bauerle et al., 2010; Diaz-Lagares et al., 2010; Furie et al., 2010a; Furie et al., 2010b; Jonsdottir et al., 2010; Kalunian et al., 2010; Kur-Zalewska et al., 2010; Marenco et al., 2010; Tony and GRAID, 2010; Torgashina et al., 2010; Vital et al., 2010). Multiple, non-exclusive factors could help reconcile these discrepancies. First, as it has been extensively discussed in multiple forums, EXPLORER and LUNAR as well as other lupus clinical studies in general suffer from inadequate clinical outcome instruments and the length of follow-up (mostly in the nephritis study for which the outcome measurements are more unequivocal) may have been too short to demonstrate separation between the different treatments. These two factors are likely to raise the bar for any new intervention to demonstrate superiority over conventional therapies known to provide significant short-term benefit. Of special relevance to this argument, superiority in BLISS-52/76 was only observed when the clinical outcome was measured with a newly developed combined responder index. It is also important to mention that while the relative differences in responders and non-responders in the and EXPLORER trials were not substantially different from those in BLISS-52/76, the larger numbers of patients enrolled in the anti-BLyS studies may have been a major contributor to establishing statistical differences. In addition, careful scrutiny of EXPLORER and LUNAR results can bring up important considerations. Thus, despite relative low patient numbers, pre-specified subset analysis in EXPLORER showed significantly better results for B cell depletion in African-American and Hispanic patients. A trend for benefit in African-Americans with lupus nephritis has also been recently reported in a subset analysis of the LUNAR study despite low numbers of patients (20 in each group) and short follow-up (52 weeks) (Furie et al., 2010a; Merrill et al., 2010). As in the EXPLORER, B cell depleting treatment was associated with significant improvement in serological manifestations of disease activity (Furie et al., 2010b; Tew et al., 2010).
Also important is to realize that rather than a failure to induce response, EXPLORER indicated lack of superiority in maintaining the initial benefit observed with both rituximab and significant doses of corticosteroids added to stable immunosuppressive therapy (Merrill et al., 2010). While this fact may be of little consolation in terms of the final outcome, it may nonetheless help us think about study design and interpretation of results in the context of testable hypothesis and mechanistic models. Indeed, as we have proposed elsewhere, it seems reasonable to postulate that the final therapeutic impact of B cell targeting agents will depend on the balance they achieve between complete depletion of pathogenic B cells obtained in early phases after treatment and the relative abundance of protective regulatory B cells over pathogenic ones achieved during the expansive reconstitution phase that typically starts 4-6 months after treatments and may continue for several years at least in good responders (Figure 1) (Anolik et al., 2007; Anolik et al., 2006; Calero et al., 2010; Haas et al., 2010; Matsushita et al., 2008; Sanz and Lee, 2010). A corollary of this model is that remission induction would depend on the depth of initial (presumably universal) depletion while the maintenance of remission would depend on the relative dominance of regulatory B cells at later time points (Haas et al., 2010; Matsushita et al., 2008). Accordingly, it is important to consider that both EXPLORER and LUNAR included a second cycle of rituximab treatment at six months which could have halted the emergence of regulatory B cells thereby negating or at least delaying the beneficial effect of the intervention beyond the relatively short extension of the study. Understanding whether this was indeed the case would be important and could be done, at least in part, through the identification of long-term responders. As shown in our initial studies, these responders may remain disease free without additional immunosuppressive therapies for prolonged periods of time and display for several years a specific peripheral blood signature characterized by large numbers of B cells dominated by transitional and naïve B cells. Of great interest, different authors have shown that these cells may possess regulatory properties through the production of IL-10, and that their IL-10 production capability may be decreased in active autoimmune disease and restored by rituximab-induced B cell depletion (Blair et al., 2010; Duddy et al., 2007; Evans et al., 2007; Mauri et al., 2003).
Unfortunately, information regarding B cell subset homeostasis in rituximab treated patients is limited to global phenotypic markers that cannot differentiate between these possibilities. As for the depth of initial depletion, the available information also appears to be insufficient to judge this presumably critical biological effect of the intervention. Thus, clinical laboratories and all controlled clinical trials have only measured gross elimination of B cells from the peripheral blood with “complete” B cell depletion adjudicated if <5 CD19+ cells/ml are detected by conventional flow cytometry. This is clearly insufficient. We initially reported in an early phase I-II study that good responders to rituximab achieve deeper depletion than non-responders as assessed by high sensitivity flow cytometry capable of measuring as few as 0.01 B cells/ml of blood (Looney et al., 2004). This observation has been clearly documented by Emery and colleagues both in rheumatoid arthritis and more recently in SLE (Dass et al., 2008; Vital et al., 2010). Thus, in an open study of rituximab in SLE only 17/41 patients treated achieved complete depletion when the more stringent definition was used. All 17 had favorable clinical responses compared to only 18/24 who did not achieve maximal depletion (p=0.03). Interestingly, retreatment of 14 relapsing patients resulted in an increase in the rate of complete B cell depletion and clinical benefit in 13 patients.
These mechanistic considerations are also important to understand other B cell targeting therapies. Thus, BLyS inhibition induces only gradual and selective B cell depletion with attrition occurring preferentially in transitional and naïve B cell compartments as well as in a CD27-, isotype switched memory population with effector surface phenotype but not in conventional CD27+ memory cells or antibody-secreting cells (Jacobi et al., 2010). The favored mechanism of benefit for this intervention is the restoration of tolerance at the critical transitional B cell checkpoint, which has been shown at least in animal models to be BLyS-dependent (Cancro, 2006; Lesley et al., 2004; Mackay et al., 2003; Wardemann et al., 2003). Under this model, long-term BLyS blockade would interrupt the recruitment of new autoreactive naïve B cells into the post-antigenic compartment without significantly impacting pre-existing autoreactive memory. If this model is correct, it would have profound implications for our understanding of the relative pathogenic roles of long-lived autoimmune memory cells (presumably not affected by anti-BLyS therapy despite its clinical benefit) as compared to newly recruited/activated naïve B cells. The flip side of anti-BLyS therapy could be the prolonged decline observed in transitional and naïve cells of regulatory potential (Blair et al., 2010; Duddy et al., 2007; Jacobi, 2008). As for rituximab, detailed studies of B cell immuno-phenotype and function in responders and non-responders will be critical to understand this new therapy, optimize it, and apply it in the appropriate patient subsets and settings.
Which Patients Represent the Best Target for B Cell Depletion Therapies?
The collective considerations discussed above suggest that, as recently pointed out by other investigators (Favas and Isenberg, 2009), it seems premature to abandon B cell targeting in SLE, including universal B cell depletion if it is done in a way that favors repopulation with a dominance of protective B cells or possibly after restoration of B cell tolerance after restoration, a possibility hinted by our observations in long-term responders to rituximab. How can we then define which patient subsets are most likely to respond favorably? In part, as discussed above, this critical question may be answered by understanding the peculiarities of long-term responders treated either in controlled or open studies. Available evidence points to African-Americans and Hispanics as possible responsive populations (Furie et al., 2010a; Merrill et al., 2010). There is also evidence to suggest that patients with anti-RBP antibodies might be preferentially responsive to rituximab at least in part due to their ability to induce the production of type 1 interferon (IFN), a cytokine central to the pathogenesis of SLE that exerts significant influence on B cell activation and differentiation and on B cell hematopoiesis and bone marrow output (Cambridge et al., 2006; Looney et al., 2010; Looney et al., 2004). Therefore, it seems intuitive that patients with high levels of IFN might be less responsive and, consequently, the decreasing levels of this cytokine might make patients more responsive to B cell depletion by maximizing depletion of pre-existing cells and increasing the output of newly generated bone marrow B cells. In addition to new biological agents currently undergoing clinical testing, one could envision simpler and perhaps safer conditioning regimens including the commonly used high-dose pulses of methylprednisolone, an intervention known to abolish the SLE IFN signature if only transiently (Guiducci et al., 2010).
Also informative and immediately important, would be to understand the apparent benefit of BCD observed in multiple open studies often with an emphasis on refractory patients (Bauerle et al., 2010; Diaz-Lagares et al., 2010; Faria and Isenberg, 2010; Jonsdottir et al., 2010; Kur-Zalewska et al., 2010; Marenco et al., 2010; Ng et al., 2005; Ramos-Casals et al., 2010a; Ramos-Casals et al., 2010b; Terrier et al., 2010; Torgashina et al., 2010; Vital et al., 2010). This situation is well encapsulated by a series of 188 adult SLE cases recently reviewed by Ramos-Casals et al. (2009). Clinical complications included nephritis (55%), articular involvement (54%), mucosal and cutaneous involvement (47%), hematological features (28%), serositis (17%), central nervous system disease (15%), and cardiopulmonary manifestations (7%). Previous therapy included cyclophosphamide in 56% of cases. In all cases, rituximab was administered together with corticosteroids and 58 patients received intravenous methylprednisolone as induction therapy. In 97 patients, treatment with rituximab was administered concomitantly with intravenous cyclophosphamide (750 mg with the first and fourth doses). In 41 (22%) patients, induction therapy included rituximab, cyclophosphamide, and intravenous methylprednisolone. The majority of these studies defined clinical response as the disappearance of the symptoms, motivating the use of biological therapy or the emphasis on significant improvement in one or more of the systemic SLE manifestations. Using these criteria, 171 (91%) had a clinical response. Patients treated with the original lymphoma regimen (4 weekly doses of 375 mg/m2) obtained a higher rate of therapeutic response compared with the more current regimen used for rheumatoid arthritis (RA regimen) of 2 doses of 1,000 mg two weeks apart (94 % vs. 83%, p=0.048). After a mean follow-up of 17 months (at least 6 months in 90% of patients), 46 (27%) relapsed. Of these 46 patients, 24 were retreated with rituximab, with a clinical response in 16 (80%) of the 20 patients for whom information was available.
The same authors analyzed 106 biopsy-proven lupus nephritis patients included in seven observational studies published since 2005 (Ramos-Casals et al., 2010a). Previous immunosuppressive therapies included cyclophosphamide (61%), azathioprine (48%), mycophenolate mofetil (43%), methotrexate (21%), and cyclosporine A (7%). Rituximab was administered for refractory lupus nephritis (49%) patients, nephritis flare (35%), and as the first-line therapy for newly diagnosed patients (16%). RA doses were used in 56% of the patients and weekly “lymphoma” doses were administered in 44%. Twenty-seven (25%) patients received intravenous pulses of methylprednisolone. All patients continued maintenance therapy with corticosteroids, with 22 (21%) having also received cyclophosphamide, 22 (21%) mycophenolate, 17 (16%) azathioprine, and 12 (11%) methotrexate. A favorable therapeutic response was achieved in 69% of patients (35 partial, 33 complete). The highest rates of response were obtained in patients with type III nephritis (80%). Interestingly, and in contrast to recent reports in ANCA-associated vasculitis, patients in this series who did not respond to rituximab were more likely to have previously received cyclophosphamide (Jones et al., 2010).
Other serious manifestations of SLE, such as severe central nervous system (CNS) involvement, have also been reported to respond to B cell depletion in admittedly small, open studies. Thus, Tokunaga et al. (2007) studied 10 CNS lupus patients with highly active CNS disease resistant to conventional treatment including cyclosporine A, cyclophosphamide, mizoribine, and azathioprine. In addition, five patients had received plasma exchange due to lack of response. Six patients were treated with 375 mg per m2 body surface once a week for 2 weeks, one patient received a single administration of the same dose, two patients received 500 mg rituximab once a week for 4 weeks, and another patient was treated with two doses of 1,000 mg over 4 weeks. Treatment with rituximab resulted in rapid substantial improvement, particularly in cases with acute confusional state. Cognitive impairment resulting from psychosis and seizures, MRI and SPECT abnormalities, as well as global Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores also improved.
Collectively, the reasons for the benefit perceived for rituximab in clinical practice and in particular for refractory disease remain poorly understood but are likely to include the use in many cases of rituximab in combination with cyclophosphamide which remains and deserves to be tested in controlled clinical trials. Also poorly understood is the relative benefit that might be afforded by the use of the original regimen of 4 doses of 375 mg/m2 administered over 1 month versus the trial regimen of two doses of 1,000 mg administered over 2 weeks as these regimens would result in different total doses and pharmacokinetics and could possibly induce more profound tissue depletion with the former protocol. Finally, it is possible that regulatory B cells might simply play a lesser compensatory role in refractory cases than in less advanced cases and, consequently, the benefit of depleting pathogenic B cells would not be diminished by the elimination of these protective B cells (Figure 1).
Whatever the basis for the benefit of BCD, or lack thereof, may be in SLE, there is little doubt that this is a very heterogeneous disease whose manifestations, outcome, and response to therapy may be profoundly influenced by ethnic and genetic factors. It is also clear from emerging results in the field (Sanz and Lee, 2010) that SLE patients display substantial heterogeneity in terms of B cell homeostasis whose functional consequences and implications for therapy remain to be understood. Accordingly, it is apparent that new treatments and the successful application of current ones will heavily rest on a proper understanding of these variables. Such knowledge should allow for customized application of different biological agents targeting specific pathways or B cell subsets in the appropriate patient populations thereby not only maximizing the benefit of the treatment but also gaining important insights on the best biological readouts and biomarkers of response.
This work was supported by NIH grants U19 AI56390 (Rochester Autoimmunity Center of Excellence) (I.S.), R37 AI049660-07 AI049660 (I.S.), and N01-AI50029 (Rochester Center for Biodefense of Immunocompromised Populations) (I.S.).
(Corresponding author: Iñaki Sanz, M.D., Professor and Chief, Division of Clinical Immunology & Rheumatology, University of Rochester Medical Center, Rochester, New York 14642, USA.)
Dr. Sanz has served as a consultant for Genentech (B Cell Summit participation) and GlaxoSmithKline (less than $10,000 each). Dr. Sanz has an ongoing research collaboration with Biogen Idec which provides research funding in basic B cell biology.
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[Discovery Medicine; ISSN: 1539-6509; Discov Med 10(54):416-424, November 2010.]