Rheumatology Advance Access originally published online on March 3, 2007
Rheumatology 2007 46(4):563-564; doi:10.1093/rheumatology/kel424
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EDITORIALS |
No B cells—no active RA? Advances in B cell depletion in RA—repeated therapy under conditions of clinical practice
Charite Universitätsmedizin and Deutsches Rheumaforschungszentrum, Berlin, Germany.
Correspondence to: Prof. Dr Thomas Dörner. E-mail: thomas.doerner{at}charite.de
Early observations in 1999 by Jo Edwards’ group at University College London, UK [1] provided evidence that using a B-cell depleting antibody licensed for non-Hodgkin lymphoma was able to significantly reduce signs and symptoms of RA with an acceptable safety profile during a single treatment course of induced B-cell depletion and subsequently led to clinical development of this drug based on large randomized clinical trials (proof of concept/IIa, DANCER, REFLEX) and finally to approval in the US, Switzerland and the EU for this indication. This is the first cell-directed therapy for the treatment of RA arriving in the clinics after studies of T-cell directed therapy using anti-CD4 antibodies opened this area more than 10 yrs ago [2]. Importantly, it offers alternative treatment options to severe RA patients inadequately responding to TNF blockers.
The breath-taking pace of this clinical development with inducing a clinical response for several months in individual patients confronts the rheumatology community with a number of issues and questions that need to be addressed under ‘non-study’ conditions, such as
- what is the best retreatment schedule,
- what are the most frequently occurring side effects outside clinical trials,
- do certain subsets of patients preferentially benefit from this therapy as compared to a profile of non-responders.
Right at the time of international approval of anti-CD20 therapy with rituximab in RA after failing TNF blockers, the update report of the largest experiences of recurrent B-cell depletion of the UCL RA cohort provides us with additional information of 37 RA patients by the pioneers in the field, published in this issue of Rheumatology [3]. Patients with moderate to severe RA were chosen for this treatment after failing other DMARDs and TNF blockers. Most importantly, they had co-morbidities, such as secondary amyloidosis, psoriasis, a history of MALT lymphoma, etc. This heterogeneity reflects a realistic patient population under daily clinical practice. Most importantly, this study contributes to our understanding of long-term efficacy and safety of repeated B-cell depletion.
Retreatment
So far, retreatment data have not been published based on clinical trial data but we have learned from DANCER [4] and REFLEX [5] as compared with the early proof of concept phase IIa study [6] that patients with previous inadequate responses to TNF blockers achieve lower ACR responses than patients who have failed methotrexate only.
Despite clear evidence of an overall robust response to repeated cycles of B-cell depletion in RA, Popa et al. [3] report an average duration of response of 15 months and time to retreat of 20 months. These data set out the task for the future! How can we minimize the gap of about 5 months between flaring disease and re-treatment or is this the best way forward. In order to answer this question, we believe that combined evaluation of clinical data (i.e. DAS28 parameters) and identifying reliable biomarkers is needed for professional re-treatment.
In this study [3], simply measuring peripheral blood B cells did not correlate with the clinical course in the experiences of the UCL group. About 50% of cases showed a relapse before B cells returned, the remaining 50% showed relapse on average after 2.5 yrs. This is likely related to the fact that not recurrence of B cells per se is important but more dependent on early recurrences of memory B cells [7,8]. To which extent this applies to larger populations needs further analyses. Although re-occurring B cells apparently do not necessarily indicate relapse of RA, Popa et al. [3] nicely demonstrate in their Fig. 1 that relapse did not occur without peripheral B cell. This implicates two major, apparently interrelated aspects. First, the dogma ‘no B cells—no RA relapse’ was confirmed by re-treatment analyses. Secondly, there is an intimate role of B-cells in the pathogenesis of RA that cannot be substituted by other mechanisms of the immune system.
Consistent with that, one patient even had a response for up to 43 months after a single cycle of rituximab treatment indicating that the time of response varies and precludes regular retreatment as we practice with TNF blockers and other small molecule DMARDs. Subsequent cycles of Rituximab treatment in the current article was apparently based on clinical judgement and raised CRP levels. We believe that clinical judgement with DAS28 is currently the best way to define the requirement of retreatment after successful previous administration of this drug as recommended by an international consensus [9].
Another biomarker for a potential relapse identified earlier by this very same group [10] was an increase in one of the autoantibodies (IgG, IgM, IgA RF, anti-CCP antibodies). The possibility of antibody profiling over time has not been explored in re-treatment studies but would be of utmost interest for daily practice because of its feasibility.
Subsets of patients
Experiences of the efficacy of rituximab in RF– patients are still limited, given that in phase IIa only RF+ patients were considered and in DANCER RF+ patients were the primary study population. A total of 79% patients enroled in the REFLEX trial were RF+. Although RF– patients were included in an exploratory analysis, the available data are still limited and RF– patients in DANCER had a high placebo response with 52%. In the report by Popa et al. [3], five patients did not respond to B-cell depletion, four of them (80%) were RF–. Reconsideration of the RF– patients classified them into psoriasis arthropathy which may indicate exclusion of B-cell depletion as potential therapy. Consistently, patients with psoriasis lacked response to B-cell depletion independently of RF. This is an interesting distinction to what we learned by TNF blockade. If these clinical observations will be confirmed and robust, differential therapy with biologics becomes reality.
The presence of certain autoantibody profiles in RA and their potential relation to the efficacy of B-cell depletion has not been investigated thoroughly. Despite follow-ups of RF titre, very limited data are available for anti-CCP antibodies [10] after B-cell depletion in RA. Previous studies demonstrated that at least one autoantibody increases prior to a flare [10] and underscores the role of B cells and ‘humoral imprinting’ in RA.
Most frequently occurring side effects
A major strength of the report by Popa et al. [3] reflects safety aspects of re-treatment. Patients with RA represent usually a multimorbid cohort with early cardiovascular events and a higher rate of B-cell non-Hodgkin's lymphoma [11,12]. Therefore, development of new drugs for RA patients is very challenging to ensure improved risk/benefit ratios but otherwise taking into account the underlying genuine risks of RA, such as cardiovascular complications, enhanced risks for infections and cancer.
The three available randomized controlled trials comprising about 1035 patients did not indicate significant safety signal for any infection or other adverse event when treatment groups were compared with placebo. These patients usually had also very severe rheumatoid arthritis, a history of several previous DMARDs and longstanding disease (usually over 10 yrs). The study by Popa et al. [3] observed an increased rate of lower respiratory infections under daily practice conditions. Moreover, no relation to hypogamaglobulinaemia and infections was seen. This is of interest for wider use in severe RA if confirmed.
Patients with humoral immunodeficiency have a higher risk of airway infections. In this regard, IgM was reduced after B-cell depletion as expanded by the data of the study [3]. If this predisposes to the reported enhanced rates for lower respiratory infections, is uncertain. To some surprise, even in patients with five cycles of rituximab treatment, IgA and IgG levels do not decline as one may have expected. This confirms that retreatment is feasible in RA without unforeseen declines in protective immunity even in the very severe patients usually immunocompromised. Ig levels under repeated cycles of rituximab are of great interest with regard to potential (and expected) disturbances in protective Igs. Data of individual patients can vary even between different cycles of B cell depletion as demonstrated by Popa et al.
Although we do not have direct comparisons with methylprednisolone, which is able to inhibit Ig synthesis in plasma cells [13] with effects within a few days on IgG, B-cell depletion has apparently only an effect via turnover of plasma cells. As discussed before, the potential role of follow-up measurements of Ig levels needs to be explored (i) in terms of efficacy of repeated B-cell depletion as well as (ii) as surrogate marker for safety aspects. Consistent with the RCTs, there was no relation with certain infections seen.
Mechanism of action
After experiences with TNF blockers as the first biologics used on large scales in rheumatology, we learned that they usually led to rapid clinical improvements and require re-treatment after specific time intervals. Selective B-cell depletion has a different timing of repeated treatment and the mechanisms of repletion within 6–8 months in RA are quite remarkable. It is not clear whether some pre-B cells can also be depleted [14] potentially contributing to a longer period of peripheral B-cell depletion seen in individual patients. However, the underlying factors leading to prolonged B-cell depletion are interesting, not solely dependent on the presence of the anti-CD20 antibody [15] and significantly longer than the period of B-cell reconstitution after bone marrow transplantation.
Moreover, involvement of T–B interaction, T-cell activation, precursors of (auto)antibody producing cells, production of pro-inflammatory cytokines do not fully explain all the clinical observations after B-cell depletion. A striking feature is the time of clinical effectiveness which is delayed for 6–12 weeks after B-cell depletion which occurs within hours. Although some B cells may remain in tissues [16], it may not necessarily explain this time course in the clinics.
Conclusion
Overall, the first fully published study on repeated treatment cycles with rituximab in RA patients reports robust and comparable efficacy in subsequent treatments but also points our interest toward the needs for biomarkers (B-cell subsets, autoantibody profile, Ig levels etc.) that allow improved patient-tailored therapy. Although declines in Ig levels occur, they are not necessarily related to infections. Registries for this additional biologic [17] are needed to provide a large database for the safety profile for potentially less frequent adverse events.
Conflict of interest: T.D. and G.R.B. received speaker's honoraria, less than 10, 000 USD and served at advisory boards of Roche Ltd.
References
- Protheroe A, Edwards JCW, Simmons A, Maclennan K, Selby P. (1999) Remission of inflammatory arthropathy in association with anti-CD20 therapy for non-Hodgkin's lymphoma. Rheumatology 38:1150–2.
[Abstract/Free Full Text] - Horneff G, Burmester GR, Emmrich F, Kalden JR. (1991) Treatment of rheumatoid-arthritis with an anti-Cd4 monoclonal-antibody. Arthritis Rheum 34:129–40.[ISI][Medline]
- Popa C, Leandro MJ, Cambridge G, Edwards JCW. (2006) Repeated B lymphocyte depletion with rituximab in rheumatoid arthritis over 7 years. Rheumatology 46:711–715.
- Emery P, Szczepanski L, Szechinski J, et al. (2003) Sustained efficacy at 48 weeks after single treatment course of rituximab in patients with rheumatoid arthritis. Arthritis Rheum 48:S439.
- Cohen SB, Emery P, Greenwald MW, et al. (2006) Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54:2793–806.[CrossRef][ISI][Medline]
- Edwards JCW, Szczepanski L, Szechinski J, et al. (2004) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350:2572–81.
[Abstract/Free Full Text] - Roll P, Palanichamy A, Kneitz C, Dorner T, Tony HP. (2006) Regeneration of B cell subsets after transient B cell depletion using anti-CD20 antibodies in rheumatoid arthritis. Arthritis Rheum 54:2377–86.[CrossRef][ISI][Medline]
- Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JCW. (2006) Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 54:613–20.[CrossRef][ISI][Medline]
- Smolen JS, Keystone EC, Emery P, et al. ( Dec 20, 2006) Consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis [Epub ahead of print].
- Cambridge G, Leandro MJ, Edwards JCW, et al. (2003) Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum 48:2146–54.[CrossRef][ISI][Medline]
- Baecklund E, Ekbom A, Sparen P, Feltelius N, Klareskog L. (1997) Disease activity determines lymphoma risk in patients with rheumatoid arthritis. A nested case-control study. Arthritis Rheum 40:1696.
- Baecklund E, Sundstrom C, Ekbom A, et al. (2003) Lymphoma subtypes in patients with rheumatoid arthritis - Increased proportion of diffuse large B cell lymphoma. Arthritis Rheum 48:1543–50.[CrossRef][ISI][Medline]
- Butler WT, Couch RB, Rossen RD, Hersh EM. (1974) Methylprednisolone fails to inhibit primary and secondary antibody-responses but causes marked suppression of on-going antibody-formation in man. J Clin Invest 53:A14.
- Leandro MJ, Edwards JCW, Ehrenstein MR, Cambridge G, Isenberg DA. (2005) Follow up study of B-lymphocyte depletion in the treatment of patients with systemic lupus erythematosus. Rheumatology 44:I25.
- Silverman GJ. (2006) Therapeutic B cell depletion and regeneration in rheumatoid arthritis – Emerging patterns and paradigms. Arthritis Rheum 54:2356–67.[CrossRef][ISI][Medline]
- Gong Q, Ou QL, Ye SM, et al. (2005) Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J Immuno 174:817–26.
[Abstract/Free Full Text] - Scott DL and Kingsley GH. (2006) Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med 355:704–12.
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  J. C. W. Edwards, G. Cambridge, and M. J. Leandro Repeated B-cell depletion in clinical practice Rheumatology, September 1, 2007; 46(9): 1509 - 1509. [Full Text] [PDF]
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