Jonathan C. W. Edwards

B-cell targeting in rheumatoid arthritis and other autoimmune diseases

B-cell-targeted therapy for autoimmune disease emerged from theoretical proposition to practical reality between 1997 and 1998, with the availability of the B-cell-depleting monoclonal antibody rituximab. Since then, a score of autoantibody-associated disorders have been treated, with most convincing evidence of efficacy seen in subjects with rheumatoid arthritis. Several classes of B-cell-targeted agent are now under investigation. From the outset, a major goal of B-cell targeting has been the re-establishment of some form of immunological tolerance. In some subjects, the observed improvement of disease for years following therapy fuels hope that this goal might ultimately be achievable.

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.

Do self‐perpetuating B lymphocytes drive human autoimmune disease?

Normal immunological memory is thought to be underpinned by T lymphocytes. However, in rheumatoid arthritis there are indications that T‐lymphocyte control has been subverted by self‐perpetuating B lymphocytes. Potential mechanisms in other autoimmune states are less clear, but a number of observations suggest that misappropriation of immunological memory by B lymphocytes may be a common feature of human autoantibody‐associated disease. Put simply, autoantibodies drive their own production. If so, the availability of safe B‐lymphocyte‐depleting agents provides a potential means for reversal of autoimmunity.

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.

Induction of tumor necrosis factor α production by adhered human monocytes: A key role for Fcγ receptor type IIIA in rheumatoid arthritis

OBJECTIVE: Small IgG rheumatoid factor immune complexes may provide the trigger for macrophage-derived tumor necrosis factor alpha (TNFalpha) production in rheumatoid arthritis. Immune complexes may bind to any of 3 IgG Fc receptors (FcgammaR). Therefore, the ability of monocyte-derived macrophages to produce TNFalpha was examined following ligation of each of the 3 human FcgammaR, using murine monoclonal antibodies (mAb) to each receptor as a model for small immune complexes. METHODS: Adhered human monocytes expressing all 3 FcgammaR were incubated with murine anti-FcgammaR mAb directed against FcgammaRI, FcgammaRII, or FcgammaRIII. Supernatants were collected at various time points and tested for the presence of TNFalpha and interleukin-1alpha (IL-1alpha) by enzyme-linked immunosorbent assay. RESULTS: The anti-FcgammaRIII mAb induced adhered human monocytes to release TNFalpha. However, F(ab)2 and Fab fragments of the anti-FcgammaRIII mAb failed to induce TNFalpha production. TNFalpha was undetectable following incubation with the anti-FcgammaRI or anti-FcgammaRII mAb. Furthermore, blocking FcgammaRI or FcgammaRII had no effect on the levels of TNFalpha released in response to the anti-FcgammaRIII mAb. Of the 3 anti-FcgammaR mAb, only anti-FcgammaRIII induced IL-1alpha production from adhered human monocytes, and this was inhibited by the presence of a neutralizing anti-TNFalpha mAb. CONCLUSION: This study suggests a dominant role for FcgammaRIIIA in the induction of both TNFalpha and IL-1alpha production by human macrophages in rheumatoid arthritis following receptor ligation by small immune complexes. The signaling of TNFalpha production may require the ligation of either 3 FcgammaRIIIA receptors or only 2 FcgammaRIIIA receptors, where one interaction must involve binding via an Fc domain. In addition, IL-1alpha production following FcgammaRIIIA ligation appears to be dependent on the presence of TNFalpha.

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.

Differential distribution of Fc gamma RIIIa in normal human tissues and co-localization with DAF and fibrillin-1: implications for immunological microenvironments.

FcγRIIIa is a cytokine‐inducible IgG Fc receptor implicated in the activation of macrophages by imm_une complexes. Differential expression of FcγRIIIa by macrophages in different tissues may therefore modulate local imm_une responsiveness. FcγRIIIa expression in normal human tissues was assessed semiquantitatively using microdensitometry. Synovial intimal, serosal, alveolar, salivary gland and placental macrophages, Kupffer cells, and macrophages in mechanically stressed dermis expressed high levels of FcγRIIIa. Less consistent expression was seen in skeletal muscle and lymphoid organs. No significant expression was observed in brain, thyroid, spine, intestine, myocardium, prostate, uterus, flexor forearm dermis, uterus, or kidney. Staining for FcγRIII was also observed on extracellular matrix, and co‐localized with both complement decay‐accelerating factor and fibrillin‐1. It is proposed that differential levels of both cellular and extracellular FcγRIIIa, by modulating the response to imm_une complexes, may contribute to relative tissue susceptibility to infection and autoimm_une disease.

Jekyll and Hyde: the transformation of HLA-B27

Abstract HLA-B27 can adopt a homodimeric form. In spondyloarthritis, such aberrant expression of B27 may override a tissue-specific inhibition of major histocompatibility complex (MHC) class I-dependent events, leading to inflammation and fibrosis.

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.

B Lymphocyte Depletion in Rheumatoid Arthritis:Targeting of CD20

BACKGROUND During the 1990s evidence emerged to suggest that B lymphocyte depletion in rheumatoid arthritis (RA) might be of major benefit. METHODS AND RESULTS In 1997 the B lympholytic monoclonal anti-CD20 antibody rituximab became available. Significant clinical efficacy has been demonstrated in RA, initially in open studies at University College London and recently in a multicentre randomised controlled trial. Forty RA patients at University College London have now received in total 75 treatment cycles with rituximab (up to 4 individually) alone or in combination with corticosteroid, cyclophosphamide and/or methotrexate. Ongoing immunodynamic studies of these patients have shed light on a number of questions about both the therapeutic potential of B cell targeting, and the pathogenesis of RA. CONCLUSIONS The effects of B lymphocyte depletion lend increasing support to the idea that both the inflammatory effector mechanism and the underlying immunoregulatory disturbance in RA are driven by autoantibody rather than T cells.