Mj Leandro

Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion

Objectives: To obtain evidence for dose response and to extend evidence of safety and efficacy for B lymphocyte depletion in rheumatoid arthritis. Methods: Twenty two patients with rheumatoid arthritis received a total of 29 treatments with five different combinations of rituximab (RTX), cyclophosphamide (CP), and/or high dose prednisolone (PR) on an open basis as follows; cohort I: RTX 1400 mg/m2, CP 750×2+PR; cohort II: RTX 300–700 mg/m2, −CP±PR); cohort III: RTX 600–700 mg/m2, CP 750×2+PR; cohort IV: RTX 1200 mg/m2, CP 750×2−PR; cohort V: RTX 500 mg/m2, CP 750×2+PR. American College of Rheumatology (ACR) criteria of improvement at six months were chosen as the primary outcome measure. Disease activity scores and total duration of improvement and of B cytopenia were also recorded. Results: No major adverse events attributable to treatment were seen. ACR grades of improvement at six months were as follows: cohort I: ACR70×3, ACR50×2; cohort II: ACR20×1, ACR0×3; cohort III: ACR70×6, ACR50×2, ACR20×2; cohort IV: ACR70×2, ACR50×2, ACR20×1, ACR0×1; cohort V: ACR0×4. Conclusions: B lymphocyte depletion in rheumatoid arthritis has so far proved to be safe and associated with major improvement with protocols including RTX 600 mg/m2 or more and CP, but not with more limited protocols. These observations provide an initial basis for the design of formal trials of B cell depletion and other B cell directed treatments, including a phase II controlled trial now in progress.

A retrospective seven-year analysis of the use of B cell depletion therapy in systemic lupus erythematosus at University College London Hospital: the first fifty patients.

OBJECTIVE To describe the 6-month clinical outcome and the long-term safety profile of B cell depletion therapy (BCDT) in 50 patients with active systemic lupus erythematosus (SLE), who were nonresponsive or poorly responsive to conventional immunosuppression. METHODS All except 4 of 50 patients with active SLE received 1 gm of rituximab, 750 mg of cyclophosphamide, and 100-250 mg of methylprednisolone, administered on 2 occasions 2 weeks apart, to achieve B cell depletion. Clinical outcome was assessed using the British Isles Lupus Assessment Group (BILAG) activity index and serial serologic measurements of disease activity. Remission was defined as a change from a BILAG A or B score to a C or D score in every organ system. Partial remission was a change from a BILAG A or B score to a C or D score in at least 1 system, but with the persistence of 1 score of A or B in another system. No improvement was defined as a BILAG A or B score that remained unchanged after treatment. RESULTS Of the 45 patients available for followup at 6 months, 19 patients (42%) achieved remission, and 21 patients (47%) reached partial remission after 1 cycle of BCDT (mean followup 39.6 months). BCDT resulted in a decrease in median global BILAG scores from 12 to 5 (P < 0.0001) and median anti-double-stranded DNA antibody titers from 106 to 42 IU/ml (P < 0.0001), and an increase in the median C3 level from 0.81 to 0.95 mg/liter (P < 0.02) at 6 months. Five serious adverse events were observed. CONCLUSION BCDT is an effective treatment for patients with active SLE whose disease has failed to respond to standard immunosuppressive therapy. Although the safety profile of BCDT is favorable, ongoing monitoring is required.

B cell depletion therapy in systemic lupus erythematosus: long-term follow-up and predictors of response

Objectives: To describe the long-term clinical outcome and safety profile of B cell depletion therapy (BCDT) in patients with systemic lupus erythematosus (SLE). It was also determined whether baseline parameters can predict the likelihood of disease flare. Methods: 32 patients with refractory SLE were treated with BCDT using a combination protocol (rituximab and cyclo-phosphamide). Patients were assessed with the British Isles Lupus Assessment Group (BILAG) activity index, and baseline serology was measured. Flare was defined as a new BILAG ‘A’ or two new subsequent ‘B’s in any organ system. Results: Of the 32 patients, 12 have remained well after one cycle of BCDT (median follow-up 39 months). BCDT was followed by a decrease of median global BILAG scores from 13 to 5 at 6 months (p = 0.006). Baseline anti-extractable nuclear antigen (ENA) was the only identified independent predictor of flare post-BCDT (p = 0.034, odds ratio = 8, 95% CI 1.2 to 55) from multivariable analysis. Patients with low baseline serum C3 had a shorter time to flare post-BCDT (p = 0.008). Four serious adverse events were observed. Conclusion: Autoantibody profiling may help identify patients who will have a more sustained response. Although the long-term safety profile of BCDT is favourable, ongoing vigilance is recommended.

B cell depletion therapy in systemic lupus erythaematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response

Objective: To assess the relationships between serum B lymphocyte stimulator (BLyS) levels, autoantibody profile and clinical response in patients with systemic lupus erythaematosus (SLE) following rituximab-based B cell depletion therapy (BCDT). Methods: A total of 25 patients with active refractory SLE were followed for ⩾1 year following BCDT. Disease activity was assessed using the British Isles Lupus Assessment Group (BILAG) system, and serum levels of BLyS and autoantibodies to dsDNA and extractable nuclear antigens (ENA) measured by ELISA. Serum immunoglobulins and anti-dsDNA antibodies were assessed for expression of the 9G4 idiotope (indicating VH4–34 germline gene origin). Results: Following BCDT, all patients depleted in the peripheral blood and improved clinically for ⩾3 months. Pre-BCDT BLyS levels were quantifiable (median 1.9 ng/ml) in 18/25 patients and rose in most patients at 3 months post-BCDT (median 4.15 ng/ml). Nine patients, all with quantifiable pre-BCDT serum BLyS, experienced a disease flare within 1 year. This group of patients was more likely to harbour anti-Ro/SSA antibodies (odds ratio 1.76; p = 0.06) with higher serum levels (p = 0.0027; Mann–Whitney U test). Serum levels of anti-ribonucleoprotein (RNP)/Sm were also higher in this group (p<0.05). Expression of VH4–34 by serum immunoglobulins and anti-dsDNA antibodies had no predictive value for the length of clinical response. Conclusions: Patients with SLE with an expanded autoantibody profile and raised BLyS levels at baseline had shorter clinical responses to BCDT. This may reflect a greater propensity to, and degree of, epitope spreading in such patients and suggests that treatment regimens beyond BCDT may be necessary to induce long-lasting clinical remissions in these individuals.

Repeated B cell depletion in treatment of refractory systemic lupus erythematosus

Objectives: To report the clinical outcome and safety profile of repeated B cell depletion in seven patients with refractory systemic lupus erythematosus (SLE). Methods: Since June 2000, seven patients with refractory SLE had repeated cycles of B cell depletion (18 cycles in total, up to three cycles per patient) because of disease relapse. The clinical response (assessed by the British Isles Lupus Activity Guide (BILAG) activity index), duration of B cell depletion, and adverse events in these patients was reviewed. Results: Four patients (Nos 1, 2, 3, 6) had three cycles of treatment and three (Nos 4, 5, 7) had two cycles. Four of the seven patients (Nos 1, 3, 5, 6) improved. The mean global BILAG scores dropped from 15 to 6 at 5–7 months. The median duration of clinical response and B cell depletion was 13 months and 6 months, respectively. After the third cycle, 2/4 patients (Nos 1 and 2) improved. The median duration of clinical benefit was 12 months. Most patients tolerate re-treatment very well. Conclusion: Re-treatment with B cell depletion of patients with severe SLE is safe and may be effective for 6–12 months on average.

Rheumatic diseases and malignancy ? is there an association?

An association between rheumatic diseases and malignancy has been claimed in a variety of settings. This editorial reviews published data addressing the overall risk of malignancy, and of particular types of cancer, in the context of various autoimmune rheumatic diseases. For patients with Sjögrens syndrome, systemic sclerosis with pulmonary fibrosis, or with dermatomyositis/polymyositis there is a documented association with an increased risk of malignant disease. Patients with rheumatoid arthritis may also have an increased risk of cancer. It is still controversial whether systemic lupus erythematosus is associated with an increased risk of developing malignancy. More epidemiologic studies are needed to try and clarify many of these associations, in particular the potential risks associated with cytotoxic therapy.An association between rheumatic diseases and malignancy has been claimed in a variety of settings. This editorial reviews published data addressing the overall risk of malignancy, and of particular types of cancer, in the context of various autoimmune rheumatic diseases. For patients with Sjo¨grens syndrome, systemic sclerosis with pulmonary fibrosis, or with dermatomyositis/polymyositis there is a documented association with an increased risk of malignant disease. Patients with rheumatoid arthritis may also have an increased risk of cancer. It is still controversial whether systemic lupus erythematosus is associated with an increased risk of developing malignancy. More epidemiologic studies are needed to try and clarify many of these associations, in particular the potential risks associated with cytotoxic therapy.

B-cell subpopulations in humans and their differential susceptibility to depletionwith anti-CD20 monoclonal antibodies

In humans, different B-cell subpopulations can be distinguished in peripheral bloodand other tissues on the basis of differential expression of various surface markers.These different subsets correspond to different stages of maturation, activation anddifferentiation. B-cell depletion therapy based on rituximab, an anti-CD20 mAb, iswidely used in the treatment of various malignant and autoimmune diseases. Rituximabinduces a very significant depletion of B-cell subpopulations in the peripheral bloodusually for a period of 6 to 9 months after one cycle of therapy. Cells detectedcirculating during depletion are mainly CD20 negative plasmablasts. Data on depletionof CD20-expressing B cells in solid tissues are limited but show that depletion issignificant but not complete, with bone marrow and spleen being more easily depletedthan lymph nodes. Factors influencing depletion are thought to include not only thetotal drug dose administered and distribution into various tissues, but also B-cellintrinsic and microenvironment factors influencing recruitment of effector mechanismsand antigen and effector modulation. Available studies show that the degree ofdepletion varies between individuals, even if treated with the same dose, but that ittends to be consistent in the same individual. This suggests that individual factorsare important in determining the final extent of depletion.

B cell depletion in autoimmune disease

The CD20 cell marker appears early in the process of B cell development. In this review we focus on the results of attempts to utilize B cell depletion based on the use of a chimeric monoclonal antibody (MAb) specific for human CD20, rituximab, for the treatment of patients with autoimmune diseases. In 1997, rituximab was approved for the treatment of low-grade B cell non-Hodgkins lymphoma. Following these encouraging results, rituximab started to be used experimentally in other diseases presumed to be due to B cell pathology. The first autoimmune disease to be treated effectively was chronic idiopathic thrombocytopaenia. More recent success has been demonstrated in patients with rheumatoid arthritis and systemic lupus erythematosus.

Total serum immunoglobulin levels in patients with RA after multiple B-cell depletion cycles based on rituximab: relationship with B-cell kinetics

OBJECTIVE To investigate whether the incidence of secondary hypogammaglobulinaemia in patients with RA following rituximab was related to patterns of B-cell return and relapse. METHODS CD19(+) B-cell and serum immunoglobulin (sIg) determinations were done every 2 or 3 months in 137 consecutive patients treated with one or more courses of rituximab-based B-cell depletion therapy. The pattern of B-cell return, either concordant or discordant with relapse, was also recorded. RESULTS There were 119 responders. Before treatment, three patients had low IgM and four had low IgG. After the first cycle, low IgM or IgG was present in 9.2% (11/119) and 11.8% (14/119) of the patients, respectively, increasing to 38.8% (8/18) and 22.2% (4/18) after five cycles. The mean percent maximum sIg decrease/cycle was relatively constant. The CD19(+) B-cell count at repopulation was not correlated with immunoglobulin (Ig) levels after each cycle. Patients discordant for B-cell return and relapse developed significantly lower serum IgM and more low IgM episodes than concordant patients (P < 0.05). CONCLUSION Patients with lower baseline sIg levels tended to develop persistent IgM and IgG hypogammaglobulinaemia, resulting from an accumulation of incremental decreases after repeat cycles. This was not due to lower numbers of returning B cells in those developing low sIgs. The association of low IgM in patients with a discordant pattern of relapse suggests that underlying defects in B cells relating to survival and maturation into Ig-secreting cells, as well as attrition of IgG plasma cells may be contributing to low sIg levels in some patients.

Translational Mini-Review Series on B Cell-Directed Therapies: The pathogenic role of B cells in autoantibody-associated autoimmune diseases – lessons from B cell-depletion therapy

B cell depletion therapy with rituximab (BCDT) is a licensed treatment for rheumatoid arthritis and has shown promising results in the treatment of severe, refractory patients with other autoantibody‐associated autoimmune diseases (AAID). The exact role that B cells play in the pathogenesis of AAID and consequently the mechanisms by which BCDT is effective are not known. The two more widely discussed hypotheses are that BCDT is effective because it removes the precursors of plasma cells producing pathogenic autoantibody species, or because it depletes a critical mass of autoreactive B cell clones that present antigen to pathogenic autoreactive T cells. This review will focus on the effects of BCDT and whether the response of patients with AAID to BCDT could be due ultimately to its effects on autoantibodies. A better knowledge of the main role that B cells play in the pathogenesis of the different diseases and a better understanding of the most likely mechanism of relapse following an earlier response to BCDT would help to guide further developments of B cell targeting therapies and potentially increase the chance of designing a protocol that could induce a long‐term remission.