Rheumatoid Arthritis: Isenberg DA

Hyrich KL, Watson KD, Isenberg DA, Symmons DP, Anonymous00067. · No affiliation provided · Rheumatology (Oxford). · Pubmed #18596052 No free full text.

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Isenberg DA. · No affiliation provided · Arthritis Rheum. · Pubmed #15022304 links to  free full text

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Leandro MJ, Isenberg DA. · No affiliation provided · Scand J Rheumatol. · Pubmed #11578009 No free full text.

Abstract: 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 Sjögren's 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.

Ng KP, Isenberg DA. · Centre for Rheumatology Research, Division of Medicine, University College London, London, UK. · Drugs Aging. · Pubmed #18184026 No free full text.

Abstract: Sjögren's syndrome (SS) is a chronic autoimmune rheumatic disease characterized by keratoconjunctivitis sicca and xerostomia as a result of lymphocytic infiltration of the lacrimal and salivary glands. Extra-glandular manifestations occur in about one-third of patients with SS. The diagnosis of SS in the geriatric population is not straightforward and consideration needs to be given to exclusion of other conditions that may have similar presenting symptoms. The presence of autoantibodies, in particular anti-Ro and anti-La antibodies, may aid in the diagnosis of SS. Salivary gland biopsy findings represent one of the objective criteria included in the widely accepted American-European classification diagnostic criteria. However, SS-like histological changes can also be present in the healthy elderly, adding to the dilemma in diagnosing this condition in the geriatric population. Management of SS involves local treatment of dry eyes and mouth with replacement and stimulation therapies. Patients with more serious systemic involvement may require immunosuppressive therapy. Medications that are routinely used in the treatment of patients with SS often have limited use in the elderly population because patients in the latter group may have complex co-morbid conditions and be taking multiple medications. Recently, use of newer targeted therapies has been explored in SS. This article provides an update on recent developments in the diagnosis and management of SS, with emphasis on issues that may arise when treating elderly patients with this condition.

Goldblatt F, Isenberg DA. · Centre for Rheumatology, Department of Medicine, University College London Hospital, 250 Euston Road, London, UK. · Handb Exp Pharmacol. · Pubmed #18071946 No free full text.

Abstract: Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are both chronic autoimmune rheumatic diseases. In the last few years, evolution in the understanding of RA and SLE pathogenesis and underlying molecular mechanisms has resulted in development and availability of novel therapies. In particular, the recent acknowledgement of a more significant role for B cells in the pathogenesis of RA, in contrast to the view that it was predominantly a T cell disorder, provided rationale for trials of B cell depletion therapy with the chimeric anti-CD20 monoclonal antibody rituximab. The efficacy and favourable safety profile of rituximab have resulted in the recent approval by the European Medicines Agency for its usage in patients with RA unresponsive to conventional therapies. The salient features from the pivotal open and randomised controlled trials are reviewed in this chapter. Given the recognition of B cell dysfunction as central to SLE pathogenesis, the use of anti-CD20 antibody therapy for this patient group has also been established. Results of the open trials have been encouraging, particularly in patients not responding to usual therapies, and a randomised controlled trial is underway.

Isenberg DA. · University College Hospital, Centre for Rheumatology, The Middlesex Hospital, London, United Kingdom. · J Rheumatol Suppl. · Pubmed #16652442 No free full text.

Abstract: In addition to rheumatoid arthritis (RA), B cells are likely to play a significant role in the development of other autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE), myositis, and vasculitis. Small-vessel vasculitis subtypes may be immune complex-mediated (cryoglobulinemia) or antineutrophil cytoplasmic antibody (ANCA)-associated; ANCA may be involved in the pathogenesis of vasculitis. In SLE, both antibody-associated and antibody-independent processes are almost certainly involved. B cell activity and autoantibody production are increased, while patients often have reduced peripheral B cells and abnormal B cell profiles. B lymphocyte stimulator (BLyS) protein regulates B cell activation and differentiation. For these reasons, B cells and the molecules that activate them are potential therapeutic targets in these diseases. Recent clinical trial data from small studies of rituximab (RTX) in SLE suggest that treatment improved clinical variables and measures of disease activity in patients, including those with central nervous system SLE. With retreatment, patients whose B cells were successfully depleted continued to show improvement in clinical and laboratory variables. Preliminary data suggest that treatment with RTX may be effective in ANCA-associated vasculitis. In addition a recent study showed significant benefit with myositis. Although these studies contain small cohorts of patients, they demonstrate that B cell-modulating therapies show promise in treatment of a variety of autoimmune diseases.

Goldblatt F, Isenberg DA. · Centre for Rheumatology, The Middlesex Hospital, University College London, Arthur Stanley House, 40-50 Tottenham Street, London W1T 4NJ, UK. · Clin Exp Immunol. · Pubmed #15807842 links to  free full text

Abstract: Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease, which continues to cause significant morbidity in affected persons. In the past few years, a number of new exciting therapeutic options have become available. These reflect the application of knowledge obtained from advancements in understanding of disease pathogenesis and underlying molecular mechanisms. A number of these therapies are outlined in the following review, including the various biological modifiers, in particular, anti-tumour necrosis factor-alpha agents and interleukin-1 (IL-1) receptor antagonists, which have been developed in recognition of the role of pro-inflammatory cytokines in RA. Also notable, is the current interest centring on the development and trials with B cell depletion therapies, specifically rituximab, in patients with RA. This demonstrates acknowledgment for a more significant role for B cells in the aetiology of RA, in contrast to the long held view that RA was a predominantly T cell mediated disease. To evaluate this therapeutic option for RA, salient features from recent rituximab trials have been collated. Finally, a selection of other therapeutic alternatives, including anti-IL-6 receptor monoclonal antibody and tacrolimus, and newer anti-rheumatic therapies presently in development are summarized.

Potter KN, Mockridge CI, Rahman A, Buchan S, Hamblin T, Davidson B, Isenberg DA, Stevenson FK. · Molecular Immunology Group, Tenovus Laboratory, Southampton University Hospitals Trust, Southampton, UK. · Lupus. · Pubmed #12529053 No free full text.

Abstract: A variety of cell surface markers are being used to identify B cell subpopulations in peripheral blood. Currently at least eight subpopulations have been identified. Analyses of healthy individuals indicate that in general the various B cell subpopulations exist in relatively similar ratios in unrelated individuals. It has been demonstrated that B lymphocyte homeostasis is disturbed during infection and autoimmune disease. In this review we compare the distribution of B cell subpopulations in the peripheral blood of patients with systemic lupus erythematosus, rheumatoid arthritis and primary Sjogren's syndrome with each other, and with healthy individuals. The different autoimmune diseases have distinct changes in the B cell subpopulations. Understanding the nature of these B subpopulation signatures will potentially impact understanding the mechanisms of disease, diagnosis and therapy.

Mageed RA, Isenberg DA. · Department of Immunology and Molecular Pathology, Royal Free and University College London, The Windeyer Institute, London, UK. · Lupus. · Pubmed #12529050 No free full text.

Abstract: Tumour necrosis factor (TNFalpha) is a cytokine with a wide range of diverse and at times paradoxical effects. These include immunoregulatory, lymphoid organogenesis and pro-inflammatory effects. In recent years, TNFalpha has become a focus of interest more for its inflammatory effects in a number of chronic autoimmune diseases. This interest culminated in the successful treatment of patients with rheumatoid arthritis, Crohn's diseases and ankylosing spondylitis with blocking antibodies or soluble TNFalpha receptors. Paradoxically, however, TNFalpha also has immunomodulatory effects in some autoimmune conditions such as lupus in some mouse models of the disease and in diabetes in the none-obese diabetic mouse. The role TNFalpha plays in human systemic lupus erythematosus is, however, controversial. In this article we review some of the studies carried out to elucidate the effects of TNFalpha in lupus disease and likely mechanisms of action. Further, we discuss recent data on the likely effects of blocking TNFalpha on anti-DNA autoantibody production.

Ioannou Y, Isenberg DA. · University College London, UK. · Arthritis Rheum. · Pubmed #10902743 links to  free full text

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Hussain S, Isenberg DA. · Bloomsbury Rheumatology Unit, University College London. · Hosp Med. · Pubmed #10320838 No free full text.

Abstract: Involvement of the heart is a common finding in autoimmune rheumatic diseases. Although clinically silent changes are common, potentially life-threatening manifestations are well known but early recognition is important if appropriate therapy is to be instituted.

Choy EH, Isenberg DA, Garrood T, Farrow S, Ioannou Y, Bird H, Cheung N, Williams B, Hazleman B, Price R, Yoshizaki K, Nishimoto N, Kishimoto T, Panayi GS. · Guy's, King's, and St. Thomas' School of Medicine, King's College, London, UK. · Arthritis Rheum. · Pubmed #12483717 links to  free full text

Abstract: OBJECTIVE: To investigate the safety and efficacy of MRA, a recombinant human anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody of the IgG1 subclass that inhibits the function of IL-6, in patients with established rheumatoid arthritis (RA). METHODS: A randomized, double-blind, placebo-controlled, dose-escalation trial was conducted in 45 patients with active RA, as defined by the American College of Rheumatology (ACR) revised criteria. Patients were sequentially allocated to receive a single intravenous dose of either 0.1, 1, 5, or 10 mg/kg of MRA or placebo. The primary efficacy end point was meeting the ACR 20% response criteria at week 2 after treatment. RESULTS: Demographic features were similar between treatment groups. At week 2, a significant treatment difference was observed between the 5 mg/kg of MRA and placebo, with 5 patients (55.6%) in the MRA cohort and none in the placebo cohort achieving ACR 20% improvement. There was no statistically significant difference in the ACR 20% response between the other 3 MRA cohorts and placebo at week 2. The mean disease activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was 4.8 and 4.7 (P < 0.001 and P < 0.001 by analysis of variance), respectively. These mean scores were statistically significantly lower than those in the 0.1- and 1-mg/kg MRA and the placebo cohorts (6.4, 6.2, and 7.0, respectively). The erythrocyte sedimentation rate and C-reactive protein values fell significantly in the 5- and 10-mg/kg MRA cohorts and normalized 2 weeks after treatment. Seventeen patients (5, 4, 6, 2, and 0 patients in the placebo, 0.1-, 1-, 5-, and 10-mg/kg MRA cohorts, respectively) required corticosteroid or disease-modifying antirheumatic drug treatment because of active disease before study end. They were regarded as nonresponders from the time they received these treatments. Diarrhea was the most common adverse event, occurring in 8% of patients. Seven patients (15.6%) reported a severe adverse event (3, 1, 2, and 2 patients in the placebo, 0.1-, 1-, and 10-mg/kg MRA cohorts). There were no serious adverse events that were thought to be related to the study drug. CONCLUSION: This is the first randomized controlled trial showing that inhibition of IL-6 significantly improved the signs and symptoms of RA and normalized the acute-phase reactants. Further research with multiple dosing is necessary to define the most appropriate therapeutic regimen of MRA in RA.

Choy EH, Hazleman B, Smith M, Moss K, Lisi L, Scott DG, Patel J, Sopwith M, Isenberg DA. · Academic Department of Rheumatology, GKT School of Medicine, King's College London, King's College Hospital, London, UK. · Rheumatology (Oxford). · Pubmed #12364632 links to  free full text

Abstract: OBJECTIVE: Biological products that neutralize tumour necrosis factor alpha (TNF-alpha) are beneficial in rheumatoid arthritis (RA). We studied the effects of CDP870, a novel anti-TNF-alpha antibody fragment modified to obtain a prolonged plasma half-life ( approximately 14 days). METHODS: Thirty-six patients were randomized in a double-blind, ascending-dose group study to a single intravenous infusion of placebo (n = 12) or 1, 5 or 20 mg/kg CDP870 (each n = 8). The patients were predominantly female (30/36), had a mean age of 56 yr and a mean duration of RA of 13 years. They had received a mean of five DMARDs or experimental therapies (with 1 month washout before the study started) and had active disease. Continuation of NSAIDs and up to 7.5 mg prednisolone daily was allowed. Following the blinded dosing period, 32 patients received a single open-label infusion of either 5 or 20 mg/kg CDP870. RESULTS: In the blinded dosing period, 6/12 placebo patients withdrew from the study (for deteriorating RA < or =4 weeks after dosing). Two of 24 CDP870-treated patients withdrew, both in the 1 mg/kg group (for deteriorating RA or lost to follow up >4 weeks after dosing). The proportion of patients with ACR20 improvement for the per-protocol population with the last observation carried forward was 16.7, 50, 87.5 and 62.5% after 0, 1, 5 and 20 mg/kg CDP870 respectively (combined treatment effect, P = 0.012, primary analysis) at 4 weeks and 16.7, 25, 75 and 75% (P = 0.032) at 8 weeks. The proportion of patients with ACR50 improvement for the per-protocol population with the last observation carried forward was 0, 12.5, 12.5 and 50% after 0, 1, 5 and 20 mg/kg CDP870 respectively (combined treatment effect, P = 0.079) at 4 weeks and 0, 12.5, 12.5 and 50% (P = 0.079) at 8 weeks. Following the open-label dose of CDP870, similar beneficial effects were achieved. CONCLUSION: CDP870 is effective, was very well tolerated in this small study, and has an extended duration of action following one or more intravenous doses.

Choy EH, Rankin EC, Kassimos D, Vetterlein O, Garyfallos A, Ravirajan CT, Sopwith M, Eastell R, Kingsley GH, Isenberg DA, Panayi GS. · Department of Clinical and Molecular Rheumatology, The Guy's Hospital Medical and Dental School, London, United Kingdom. · J Rheumatol. · Pubmed #10555883 No free full text.

Abstract: OBJECTIVE: We investigated the effect of an engineered human anti-tumor necrosis factor-alpha antibody, CDP571, on immune functions as well as bone and cartilage turnover in patients with rheumatoid arthritis (RA) in a placebo controlled trial. We also assessed the effects of repeated treatment with CDP571 in an open label continuation study. METHOD: Thirty-six patients were treated with either placebo or 0.1, 1, or 10 mg/kg of CDP571 given as an intravenous infusion. The followup period was 8 weeks. Lymphocyte phenotype, soluble CD4 (sCD4), soluble interleukin 2 receptor (sIL-2R), IL-6, and stromelysin levels in the blood were measured before and after treatment; bone and cartilage markers (pyridinoline, deoxypyridinoline, N-terminal telopeptide) were similarly assessed in the urine. Patients who completed a placebo controlled trial of CDP571 were offered further treatment with CDP571. They received a maximum of 2 further doses of 1 mg/kg (7 patients) or 10 mg/kg (9 patients) in an open study. RESULTS: Plasma IL-6 level was statistically significantly reduced in the 1 and 10 mg/kg groups. In the 10 mg/kg group, there were also reductions in plasma stromelysin and urine bone markers, although there was no change in sCD4 and sIL-2R levels. Repeat doses of CDP571 were well tolerated and continued to suppress the acute phase response and disease activity. CONCLUSION: Treatment with 10 mg/kg of CDP571 reduced IL-6 and surrogate markers of bone turnover in RA, suggesting that CDP571 might prevent joint damage in RA. Since there was no effect on lymphocyte markers despite the marked reduction in inflammation, CDP571 appears to have no effect on ongoing CD4 T cell activation.

Voulgarelis M, Dafni UG, Isenberg DA, Moutsopoulos HM. · National University of Athens, Greece. · Arthritis Rheum. · Pubmed #10446879 links to  free full text

Abstract: OBJECTIVE: Several reports have noted an increased incidence of malignant lymphoma in patients with Sjögren's syndrome (SS). Each case series has consisted of a limited number of patients with malignant non-Hodgkin's lymphoma (MNHL). In this report, we describe the disease characteristics, the clinical course, and the evolution in 33 patients followed up in 9 European medical centers. METHODS: The pool of MNHL patients from participating centers in a European Concerted Action on SS were analyzed. We report on the disease characteristics, its evolution, prognosis, current treatment practices, and survival. RESULTS: The MNHLs in this study were primarily situated in the marginal zone (48.5%), with the manifestations mostly extranodal (78.8%) and most often identified in the salivary glands (54.6%). Lymphadenopathy (65.6%), skin vasculitis (33.3%), peripheral nerve involvement (24.2%), low-grade fever (25.0%), anemia (48.1%), and lymphopenia (78.6%) were observed significantly more frequently than in the general SS population. Patients with high-to-intermediate grade lymphoma had significantly worse survival (P = 0.041). The presence of B symptoms (fever, night sweats, and weight loss) and a large tumor diameter (>7 cm) were additional independent risk factors for death. CONCLUSION: The novel observations of this study were those related to the type of MNHL, the survival prognosis, and the very high frequency of skin vasculitis, peripheral nerve involvement, anemia, and lymphopenia. Some of the previously reported results on extranodal manifestations were confirmed.

Habib HM, Taher TE, Isenberg DA, Mageed RA. · Centre for Rheumatology, University College London School of Medicine, London, UK. · Scand J Rheumatol. · Pubmed #19110660 No free full text.

Abstract: OBJECTIVE: To determine the effect of inflammation through exposure to tumour necrosis factor (TNF)alpha on T lymphocytes in patients with systemic lupus erythematosus (SLE). METHODS: We studied the effect of TNFalpha on T-lymphocyte apoptosis in patients with SLE, rheumatoid arthritis (RA), and in healthy controls. Apoptosis of CD4 and CD8 T lymphocytes and naive and memory subpopulations was determined by flow cytometry using 7-amino-actinomycin D (7AAD) and propidium iodide (PI). In SLE, apoptosis was studied in patients with active and inactive disease and in patients on different medications. RESULTS: TNFalpha enhanced apoptosis of anti-CD3-activated T lymphocytes. The percentage of apoptotic cells was significantly higher in T lymphocytes from patients with SLE than RA patients and healthy controls. After 3 days of culture, 38% of CD4+ and 37% of CD8+ cells from SLE patients underwent apoptosis in the presence of TNFalpha compared with 25% CD4+ and 26% CD8+ T cells from the controls (p<0.001). In healthy controls, more memory than naive T lymphocytes underwent apoptosis. By contrast, in patients with SLE, more naive T cells underwent apoptosis with TNFalpha (p<0.01). Enhanced apoptosis of T cells in SLE was independent of disease activity or medication. Finally, inhibition experiments showed that apoptosis in the presence of TNFalpha was only partly blocked with anti-Fas ligand (FasL) antibody. CONCLUSIONS: This study demonstrates that T lymphocytes in patients with SLE are more prone to apoptosis in the presence of TNFalpha than T lymphocytes from healthy controls. Defects in TNFalpha signalling pathways rather than distribution of TNF receptors (TNFRs) probably explain the enhanced apoptosis in SLE.

Barry RJ, Sutcliffe N, Isenberg DA, Price E, Goldblatt F, Adler M, Canavan A, Hamburger J, Richards A, Regan M, Gadsby K, Rigby S, Jones A, Mathew R, Mulherin D, Stevenson A, Nightingale P, Rauz S, Bowman SJ. · Academic Unit of Ophthalmology, University of Birmingham, UK. · Rheumatology (Oxford). · Pubmed #18524804 No free full text.

Abstract: OBJECTIVE: To validate a tool for assessment of accumulated damage in patients with Primary SS (PSS). METHODS: Of the total 114 patients fulfilling American-European Consensus Group (AECG) criteria for PSS 104 were included in the study and assessed by rheumatologists at T (time) = 0 months and T = 12 months. On each occasion, damage and activity data, and autoantibody status were collected. SF-36 and Profile of Fatigue and Discomfort-Sicca Symptoms Inventory (PROFAD-SSI) questionnaires were completed. Cross-sectional analysis of this data was subject to a process of expert validation by 11 ophthalmologists, 14 oral medicine specialists and 8 rheumatologists. Items were removed from the index if >or= 50% of respondents recommended exclusion. Statistical validation was performed on remaining items. Spearman's rank analysis was used to investigate associations between damage scores and other disease status measures and Wilcoxon matched-pair analysis to assess sensitivity to change in the damage score. RESULTS: Based on the expert validation, a 29-item damage score was agreed incorporating ocular, oral and systemic domains. Total damage score correlated with disease duration at study entry (r = 0.436; P < 0.001), physical function as measured by SF-36 (r = 0.250, T = 0 months; r = 0.261 T = 12 months) and activity as measured by the Sjögren's Systemic Clinical Activity Index (r = 0.213, T = 0 months; r = 0.215, T =12 months). Ocular damage score correlated with the 'eye dry' domain of PROFAD-SSI (r = 0.228, T = 0 months; r = 0.365, T = 12 months). Other associations not present on both assessments were considered clinically insignificant. On Wilcoxon analysis, the index was sensitive to change over 12 months (z = -3.262; P < 0.01). CONCLUSION: This study begins validation of a tool for collection of longitudinal damage data in PSS. We recommend further trial in both the experimental and clinical environment.

Bowman SJ, Sutcliffe N, Isenberg DA, Goldblatt F, Adler M, Price E, Canavan A, Hamburger J, Richards A, Rauz S, Regan M, Gadsby K, Rigby S, Jones A, Mathew R, Mulherin D, Stevenson A, Nightingale P. · Rheumatology Department, University Hospital Birmingham NHS Foundation Trust, Selly Oak, Birmingham B29 6JD, UK. · Rheumatology (Oxford). · Pubmed #18032543 No free full text.

Abstract: OBJECTIVE: This article describes the development of the Sjögren's Systemic Clinical Activity Index (SCAI) for the measurement of systemic disease activity in patients with primary Sjögren's syndrome (PSS). METHODS: A pilot tool was developed based on expert consensus and previous published data. One hundred and four patients with PSS were evaluated in a cross-sectional analysis, of whom 65 were reviewed at 3-monthly intervals, using this index, over a 12-month period. Factor analysis was used to evaluate the proposed domain structure. External validation was assessed by comparison with relevant domains of the Profile of Fatigue and Discomfort (PROFAD), Medical Outcomes Study Short Form-36 (SF-36) and The World Health Organization Quality of Life-Bref (WHOQOL-BREF). Sensitivity to change was assessed by comparing SCAI-derived flares with physician-designated disease flare and intention-to-treat analysis. A reliability and repeatability workshop was also held. RESULTS: Factor analysis supported the proposed domain structure. There were strong correlations between the SCAI fatigue, musculoskeletal and Raynaud's components and the PROFAD fatigue, arthralgia and vascular domains. There was a significant correlation between change in therapy and SCAI-defined flares (P = 0.01). The mean kappa-test results both for reliability of the SCAI and for physician repeatability were 0.71. CONCLUSION: This initial evaluation supports the potential for the SCAI as a tool for systemic activity assessment in patients with PSS but additional work is required to assess sensitivity to change in clinical therapeutic trials.

Ioannou Y, Lambrianides A, Cambridge G, Leandro MJ, Edwards JC, Isenberg DA. · Centre for Rheumatology, Department of Medicine, University College London, 250 Euston Road, London NW1 2PG, UK. · Ann Rheum Dis. · Pubmed #17905784 No free full text.

Abstract: BACKGROUND: B cell depletion therapy (BCDT) has recently been used with success to treat patients with rheumatoid arthritis and systemic lupus erythematosus (SLE). As antiphospholipid antibodies have been implicated in the pathogenesis of the antiphospholipid syndrome (APS), we asked the question whether BCDT affects levels of IgG anticardiolipin antibodies (aCL) in our cohort of 32 SLE patients given this treatment. METHODS: We identified seven SLE patients who had undergone BCDT and had had at least two moderate positive aCL titres at least 12 weeks apart. Of these only one patient had APS. IgG aCL were measured at time 0 and 6-9 months post BCDT. RESULTS: At time 0, the mean IgG aCL level was 20.6 standardized IgG antiphospholipid units (GPLU) (range (SD) 10-32, (10.1), normal level <5). At 6-9 months post depletion the IgG aCL levels in six of the seven patients was undetectable and in the other patient the level reduced from 25 GPLU to 15 GPLU (p<0.005, two-tailed paired t test). At baseline, only one patient had a mildly positive anti-beta(2)-glycoprotein I (beta(2)GPI) antibody level at 30% (compared to an in-house standard), which fell to 5% post-BCDT. CONCLUSIONS: This small observational study in patients with SLE is the first to demonstrate that BCDT results in a significant reduction in levels of IgG aCL.

Green MR, Kennell AS, Larche MJ, Seifert MH, Isenberg DA, Salaman MR. · Imperial College School of Medicine, London, UK. · Arthritis Rheum. · Pubmed #17195234 links to  free full text

Abstract: OBJECTIVE: To determine whether there is a link between the frequency of natural killer T (NKT) cells and high levels of IgG in patients with systemic lupus erythematosus (SLE) and their relatives. METHODS: Blood samples were obtained from patients with SLE, their first-degree relatives, patients with rheumatoid arthritis (RA), and healthy control subjects. The frequency of NKT cells (defined as CD56+ T cells) was expressed as a percentage of total blood lymphocytes. Plasma levels of total IgG and IgM, and IgG antibodies to double-stranded DNA (dsDNA) were determined. RESULTS: The frequency of NKT cells was lower in patients with SLE than in control subjects. No such decrease was observed in the relatives of patients with SLE or in patients with RA. High levels of IgG were observed in both patients with SLE and their relatives, while low levels of IgM were observed in these same groups. In relatives of patients with SLE, an inverse correlation between the frequency of NKT cells and IgG levels was observed. Moreover, raised levels of IgG in patients with SLE and their relatives and high levels of IgG anti-dsDNA in patients were associated with low frequencies of NKT cells. CONCLUSION: These results suggest that NKT cells have an important role in the regulation of IgG production, although NKT cells with invariant T cell receptors may not necessarily be involved. NKT cells in the setting of SLE could lack the cytokine stimulus from NK or other cells that is needed to exert control on IgG production. Enhancement of NKT cell activity may provide a novel basis for therapy in SLE.

Lazarus MN, Robinson D, Mak V, Møller H, Isenberg DA. · Centre for Rheumatology, Department of Medicine, University College London, Arthur Stanley House, 40-50 Tottenham Street, London W1T 4NJ, UK. · Rheumatology (Oxford). · Pubmed #16490754 links to  free full text

Abstract: OBJECTIVE: To compare the incidence of subsequent cancers in a cohort of patients with primary Sjögren's syndrome (pSS) with that of the general population in the same region of England. METHODS: A retrospective analysis was carried out on 112 patients who had attended the out-patients department at University College Hospital, London, from 1979 onwards. Patients were followed up from diagnosis of pSS to diagnosis of first subsequent cancer, death, loss to follow-up or 31 December 2003 (the censoring date) to determine the person-years at risk for each individual. The expected numbers of subsequent cancers were calculated from sex-/age-/period-specific rates for the general population of southeast England, derived from registrations at the Thames Cancer Registry. Standardized incidence ratios (SIRs) were then calculated as the ratio of observed to expected numbers of cancers, along with 95% confidence intervals (CIs). Separate analyses were performed for all malignant cancers combined, lymphomas and non-lymphoid cancers. RESULTS: Among the 112 patients with pSS, 25 developed cancer (either before or after development of pSS), with lymphoma occurring in 11 cases. Nine patients had two cancers. There was a significantly elevated incidence of lymphomas in pSS patients compared with the general population (SIR 37.5, 95% CI 20.7-67.6). For non-lymphoid cancer, the observed increase in incidence was small and not statistically significant (SIR 1.5, 95% CI 0.9-2.6). CONCLUSION: This study confirms that there is an increased incidence of lymphoma in patients with pSS. An increase in the incidence of other cancers was not proven but the observation that some patients developed more than one cancer raises the possibility that there may be a subgroup of patients who are at greater risk of developing cancer.

Flores-Borja F, Kabouridis PS, Jury EC, Isenberg DA, Mageed RA. · William Harvey Institute, Queen Mary School of Medicine and Dentistry, London, UK. · Arthritis Rheum. · Pubmed #16320343 links to  free full text

Abstract: OBJECTIVE: B lymphocytes from patients with systemic lupus erythematosus (SLE) are hyperactive and produce anti-double-stranded DNA (anti-dsDNA) autoantibodies. The cause or causes of B cell defects in SLE are unknown. In this study, we determined the level and subcellular distribution of Lyn protein, a key negative regulator of B cell receptor signaling, and assessed whether altered Lyn expression is characteristic of B cells in the setting of SLE. METHODS: Negative selection was used to isolate B lymphocytes from blood. Lipid raft signaling domains were purified from B cells obtained from 62 patients with SLE, 15 patients with rheumatoid arthritis, and 31 healthy controls, by gradient ultracentrifugation. The total Lyn protein level was determined by Western blotting, confocal microscopy, and fluorescein-activated cell sorting (FACS). The distribution of Lyn into lipid raft and nonlipid raft domains was determined by Western blotting and confocal microscopy. Lyn content in B cell subpopulations was determined by FACS. In order to assess B lymphocyte activity, we used (3)H-thymidine incorporation and enzyme-linked immunosorbent assay to measure spontaneous proliferation and IgG and cytokine production by B cells. RESULTS: This study revealed that B lymphocytes from a majority of patients with SLE have a reduced level of Lyn and manifest altered translocation to lipid rafts. An investigation into the mechanisms of Lyn reduction suggested that increased ubiquitination is involved. This was evident from increased ubiquitination of Lyn and translocation of c-Cbl into lipid rafts. Studies of B cell responses showed that altered Lyn expression was associated with heightened spontaneous proliferation, anti-dsDNA autoantibodies, and increased interleukin-10 production. CONCLUSION: This study provides evidence for altered Lyn expression in B cells from a majority of patients with SLE. Altered Lyn expression in SLE may influence the B cell receptor signaling and B cell hyperactivity that are characteristic of the disease.

Lazarus MN, Isenberg DA. · Centre for Rheumatology, The Middlesex Hospital, University College London, Arthur Stanley House, 40-50 Tottenham Street, London W1T 4NJ, UK. · Ann Rheum Dis. · Pubmed #15958760 links to  free full text

Abstract: BACKGROUND: To investigate whether patients with primary Sjögren's syndrome (pSS) have an increased tendency to develop other autoimmune diseases. METHODS: A retrospective case note review was carried out on 114 patients in whom a diagnosis of pSS had been made in a department of rheumatology from 1979 onwards. The year of diagnosis of pSS was recorded, plus the diagnosis and year of diagnosis of any other identified autoimmune disease. RESULTS: Of the 114 patients with pSS, seven (6%) were male and 107 (94%) female. Mean age at diagnosis of pSS was 53 years (range 21 to 83). Patients were followed up for an average of 10.5 years (range 0 to 23). Thirty eight patients (33.3%) were diagnosed as having another autoimmune disease, while nine (7.9%) had two or more. Thirteen additional autoimmune diseases were identified. Twenty five diagnoses (51.0%) were made before the diagnosis of pSS, three (6.1%) within the same year, and 21 (42.9%) after the diagnosis. Hypothyroidism was the most common autoimmune disease (n = 16). CONCLUSIONS: Although pSS is a relatively benign condition, affected individuals have an increased tendency to develop additional autoimmune diseases. Patients with pSS should be monitored on a regular basis for such diseases.

Green MR, Kennell AS, Larche MJ, Seifert MH, Isenberg DA, Salaman MR. · Department of Immunology, Imperial College School of Medicine, London, UK. · Clin Exp Immunol. · Pubmed #15958083 links to  free full text

Abstract: Natural killer (NK) cell cytotoxic activity and cell frequency, expressed as a percentage of total lymphocytes, have been determined in peripheral blood mononuclear cells from first-degree relatives of patients with systemic lupus erythematosus (SLE), the patients themselves, a group of rheumatoid arthritis (RA) patients and controls. Low levels of killing activity relative to controls were found in some members of all groups with the extent of depression falling into two ranges. Moderate reductions were seen in female (3/31, 10%) and male (4/14, 29%) relatives of SLE patients, female (12/60, 20%) and male (3/4, 75%) SLE patients and female RA patients (6/17, 35%). A more profound depression of killing activity was confined to other female SLE patients (15/60, 25%). There were strong correlations in all groups between killing activity and percentage of NK cells, but analysis of the ratio of these parameters and studies with purified preparations of NK cells suggest that the reduced activity in SLE frequently involves a defect in the killing capacity of the individual cells in addition to the reduced levels of NK cells. Azathioprine (AZA), which was used in treatment of 12 SLE patients, was invariably associated with low values of killing activity. It appears to substantially reduce the percentage of NK and B cells in an action unconnected with the NK cell abnormalities associated with SLE. The finding of low killing activity in relatives and a correlation between their activity and that of their patients support the view that NK cell deficiency is a genetic determinant of SLE. NK cells in SLE may produce insufficient levels of cytokines required for the regulation of IgG production.

Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C. · Dept. of Medicine, Centre For Rheumatology, Windeyer Institute, University College London, London W1T 4JF, England, UK. · J Exp Med. · Pubmed #15280421 links to  free full text

Abstract: Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4(+)CD25(+)) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4(+)CD25(-) T cells. Treatment with antitumor necrosis factor alpha (TNFalpha; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to "conventional" T cells. Furthermore, anti-TNFalpha treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFalpha therapy may be a further mechanism by which this disease is ameliorated.