Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE-1, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study.

OBJECTIVES: Evaluate efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that binds and neutralises membrane and soluble B-cell activating factor (BAFF) versus placebo plus standard of care (SoC) in patients with systemic lupus erythematosus (SLE). METHODS: This phase III, 52-week study randomised 1164 patients with moderate-to-severe SLE (Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index ≥6 at baseline). Patients received SoC plus subcutaneous injections of tabalumab or placebo, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every two weeks (120 Q2W, n=387), 120 mg every four weeks (120 Q4W, n=389) or placebo Q2W (n=388). PRIMARY ENDPOINT: proportion of patients achieving SLE Responder Index 5 (SRI-5) response at week 52. RESULTS: Similar proportions of patients in each group achieved SRI-5 response at week 52 (120 Q2W: 31.8%; 120 Q4W: 35.2% and placebo: 29.3%). Key secondary endpoints were not met. In a sensitivity analysis not excluding patients who decreased antimalarials or immunosuppressants, SRI-5 response was achieved with 120 Q4W (37.0% vs 29.8% placebo; p=0.021), but not 120 Q2W (34.1%; p=0.171). Significant reductions in anti-dsDNA antibodies, increases in C3 and C4, and reductions in total B cells and immunoglobulins were observed with tabalumab. No differences were observed between treatment groups in percentage of deaths (120 Q2W: 0.8%; 120 Q4W: 0.5%; placebo: 0.5%), serious adverse events (AEs) (range 11.1-14.4%) or treatment-emergent AEs (range 81.1-82.3%). CONCLUSIONS: Tabalumab had biological activity-changes in anti-dsDNA, complement, B cells and immunoglobulins-consistent with BAFF pathway inhibition. Key clinical efficacy endpoints did not achieve statistical significance. Safety profiles were similar with tabalumab and placebo. TRIAL REGISTRATION NUMBER: NCT01196091.

Drug-induced lupus: Including anti-tumour necrosis factor and interferon induced.

Drug-induced lupus erythematosus is defined as a syndrome with clinical and serological features similar to systemic lupus erythematosus that is temporally related to continuous drug exposure and which resolves after discontinuation of this drug. More than 90 drugs, including biological modulators such as tumour necrosis factor-α inhibitors and interferons, have been identified as likely 'culprits'. While there are no standard diagnostic criteria for drug-induced lupus erythematosus, guidelines that can help to distinguish drug-induced lupus erythematosus from systemic lupus erythematosus have been proposed and several different patterns of drug-induced lupus erythematosus are emerging. Distinguishing drug-induced lupus erythematosus from systemic lupus erythematosus is important because the prognosis of drug-induced lupus erythematosus is usually good when the drug is withdrawn. This review discusses the differences between drug-induced lupus erythematosus and systemic lupus erythematosus, the mechanisms of action of drug-induced lupus erythematosus and drugs that are usually associated with drug-induced lupus erythematosus, with particular focus on the biological treatments.

Retrospective analysis of the outcome of patients with idiopathic inflammatory myopathy: a long-term follow-up study.

OBJECTIVES: Several factors have been implicated in the prognosis of idiopathic inflammatory myopathies, including age, gender, delay in diagnosis, neoplasia, creatine kinase levels and some autoantibodies. We have reviewed the main factors contributing to mortality in patients with idiopathic inflammatory myopathy (IIM) diagnosed between 1976 and 2007 who were followed for at least 5 years in the Rheumatology Unit at University College Hospital in London. METHODS: An observational retrospective study was carried out on patients with IIM diagnosed between 1976 and 2007. All the patients fullfilled at least three out of four of the Bohan and Peter criteria. The subjects were divided into the following groups: adult-onset polymyositis (APM); adult-onset dermatomyositis (ADM); juvenile dermatomyositis (JDM); Overlap syndromes with another autoimmune rheumatic disease. RESULTS: 90 patients were identified. The female to male ratio was 2.5:1 and the mean age at diagnosis was 38.5 years (SD 15.03). 47.8% of the patients had APM, 30% adult-onset ADM, 15.6% Overlap and 6.7% JDM. Among the extramuscular features, 18.9% had pulmonary involvement. In 70% the highest CK was >5 times the upper normal. Prednisolone was prescribed in 98.9%. 11.1% received rituximab. 34.4% had monophasic, 31.1% relapsing and remitting and 34.4% continuous progressive course of the disease. The median follow-up was 11.5 years (IQR 12.00). 14.4% of the patients died, 30.8% due to infection, 30.8% from a cardiovascular event and 23.1% due to neoplasia. The 1, 5 and 10-year survival was 100%, 97.8% and 91%, respectively. Male gender (Hazards Ratio (HR) 3.222; p=0.037), pulmonary involvement (HR 5.247; p=0.009), chronic progressive course (HR 3.711; p=0.030) and use of rituximab (HR 3.562; p=0.036) were the only risk factors to be statistically significantly associated (p<0.05) with death. CONCLUSIONS: We conclude that long-term survival in these patients is generally quite good with an estimated 10-year survival >90% in our cohort, which is even higher than previously reported.

Cancer complicating systemic lupus erythematosus--a dichotomy emerging from a nested case-control study.

OBJECTIVES: We determined whether any individual cancers are increased or decreased in a cohort of 595 patients with systemic lupus erythematosus (SLE) followed for up to 32 years at the University College London Hospitals Lupus Clinic, looking for any associated clinical or serological factors and the prognosis after cancer diagnosis. METHODS: We undertook a careful retrospective review of the medical records and identified all individuals diagnosed with cancer. For controls, we selected three other patients in the cohort who had not developed cancer, carefully matched for age, sex, ethnicity and disease duration, to determine if any obvious differences emerged in a nested case-control design. RESULTS: Thirty-three patients developed cancer after being diagnosed with SLE. There was a statistically insignificant small increase in overall cancer risk, standardized incidence ratios (SIRs) 1.05 (95% CI 0.52-1.58) and increased SIRs for cervical, prostate, anal and pancreatic cancers and reduction in breast cancer SIRs. Haematological and musculoskeletal manifestations, anticardiolipin and antithyroid globulin antibodies were found to be positively associated with cancer risk in multivariate analysis. There was no drug, dose or duration was associated with cancer risk. There was a reduction in survival with a cancer fatality rate of 84.2% (p < 0.0001). CONCLUSION: We found a very small but statistically insignificant increased cancer risk with reduction in survival. Whereas some cancers appear to be more common in SLE, notably prostate and cervical cancer, others, particularly breast cancer, are less frequent. Multiple clinical and serological factors are involved in the increased risk of malignancy in SLE. No drug dose or duration effect was identified.

Heart failure in a woman with SLE, anti-phospholipid syndrome and Fabry's disease.

We describe a female patient with systemic lupus erythematosus (SLE) also diagnosed with Fabry's disease and anti-phospholipid antibody syndrome (APS). SLE and Fabry's disease are both systemic diseases with variable clinical presentations. Recent studies have shown a relatively high incidence of late onset Fabry's disease in female heterozygous individuals, suggesting that this condition could be under-diagnosed. We discuss a possible association between SLE and Fabry's disease and consider the role of lipid abnormalities in the pathogenesis of SLE.

Concomitant diseases in a cohort of patients with idiopathic myositis during long-term follow-up.

This study aims to report the concomitant diseases observed and damage outcome in a cohort of patients with adult idiopathic inflammatory myositis (IIM) during long-term follow-up. All patients with IIM were identified from a single centre (follow-up between 1979 and 2006) and fulfilled at least three of the four Bohan and Peter criteria. Patients with inclusion body myositis, juvenile-onset myositis and overt overlap syndromes were excluded. Medical notes were retrospectively reviewed. Concomitant diseases identified were divided into 12 different organ systems (bone, cardiac, respiratory, gastrointestinal, renal, central nervous, malignancy, infection, endocrine, eyes, dermatological and haematological). Patient damage index was calculated using the Myositis Damage Index tool. Fifty-five patients (31 polymyositis, 24 dermatomyositis) were identified. The most prevalent organ system involved was lung with 40 events per 1,000 patient years follow-up. There was significant steroid-related complications with 17/18 patients with bone involvement having osteopenia/osteoporosis. Sjogren's syndrome (n = 3) was the most frequent concomitant auto-immune disease observed. Patients with a higher number of organ systems involved had a significantly higher damage index (r = 0.48, p = 0.001). White patients showed a significant trend to develop more than three other organ system involvement (p < 0.0001) and myositis-related lung disease (p < 0.0001) compared to other races. There is significant steroid-related morbidity in adult IIM patients under long-term follow-up. The prevalence of another concomitant auto-immune disease unlike patients with lupus or Sjogren's syndrome is low.

Enhanced propensity of T lymphocytes in patients with systemic lupus erythematosus to apoptosis in the presence of tumour necrosis factor alpha.

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.

Clinical outcome following B cell depletion therapy in eight patients with refractory idiopathic inflammatory myopathy.

OBJECTIVE: To assess the efficacy of B lymphocyte depletion therapy (BCDT) in patients with refractive idiopathic inflammatory myopathy (IIM). METHODS: Eight patients thought to have IIM were treated with BCDT utilising rituximab. Five were treated as part of an open label trial and three on the basis of perceived clinical need. Rituximab (1 gram) and methylprednisolone (100 mg) were given as intravenous infusions on days 0 and 14. The primary efficacy outcome at 6 months was 15% improvement in muscle strength and 30% reduction in CPK. RESULTS: Two patients with Jo-1 antibody positive dermatomyositis (DM) demonstrated a clinical response. Both achieved >30% improvement in CPK. In one, the CPK remained within the normal range for 10 months, the other had a normalised CPK and stabilisation of lung function tests for 36 months. Muscle strength by myometry, however, did not achieve the primary outcome, although, patient 1, demonstrated an improvement of 20% at 8 months (the patient had elective surgery of the hand during the study period). Jo-1 antibody levels fell modestly in both patients but remained detectable. Re-evaluation of three patients revealed that one had inclusion body myositis, one had sporadic muscular dystrophy and one subsequently developed nodular sclerosing lymphoma. All except one patient showed adequate B cell depletion with re-population occurring 3- >42 months after BCDT. One patient did not deplete and died of an unrelated cause. CONCLUSIONS: This study emphasizes the importance of identifying and selecting the appropriate sub-group of patients with IIM most likely to respond to BCDT.

B cell depletion therapy in systemic lupus erythematosus: 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 erythematosus (SLE) following rituximab-based B cell depletion therapy (BCDT). METHODS: A total of 25 patients with active refractory SLE were followed for >or=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 >or=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.

A comparison of autoimmune liver disease in juvenile and adult populations with systemic lupus erythematosus-a retrospective review of cases.

OBJECTIVE: To compare the prevalence and type of autoimmune liver disease in adult and juvenile patients with systemic lupus erythematosus (SLE) in a large UK cohort. METHODS: A retrospective analysis was performed of patients attending the adult and juvenile lupus clinics at University College Hospital and Great Ormond Street Hospital, respectively, between January 1978 and December 2004. Patients with autoimmune liver disease were identified by searching an existing database (adults) and by case note review (juveniles). Histological diagnosis and autoantibody profile was noted and the time that had elapsed in months between the two diagnoses calculated. RESULTS: Of 377 adult patients and 92 juvenile patients, 5 and 9 respectively, had histologically confirmed autoimmune liver disease. This corresponds to a statistically significant (P < 0.001) greater prevalence in juvenile onset patients of 9.8% compared with 1.3% in adult patients. The juvenile patients were all positive for smooth muscle antibody and had histological changes consistent with autoimmune hepatitis. The adult patients had a variable antibody profile and one patient had histological changes consistent with primary biliary cirrhosis. In all of the juvenile patients, but notably in none of the adult patients, the liver disease predated the diagnosis of SLE (P < 0.001). CONCLUSIONS: Our study confirms that autoimmune liver disease occurs infrequently in adult lupus patients but should be considered in a patient with persistent liver enzyme abnormalities. However, in our study there is a significantly higher prevalence in juvenile lupus patients. This association is previously unreported.

Incidence of cancer in a cohort of patients with primary Sjogren's syndrome.

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.

B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients.

OBJECTIVES: To assess the clinical and basic serological consequences of B-cell depletion with rituximab in the treatment of patients with systemic lupus erythematosus (SLE) who have failed conventional immunosuppression. METHODS: An open study of 24 patients with severe SLE followed for a minimum of 3 months is reported. In the majority of patients (19 out of 24), 6 months follow-up data are described. Disease activity in these patients was assessed every 1-2 months using the British Isles Lupus Assessment Group (BILAG) system and estimates of anti-double-stranded DNA antibodies and serum C3 levels. During the follow-up period, significant side-effects were sought and the reduction in oral prednisolone was recorded. It was our general practice to stop concomitant immunosuppression (e.g. azathioprine, mycophenolate) when B-cell depletion was given (in most cases in the form of two 1 g intravenous infusions of rituximab 2 weeks apart accompanied by two 750 mg intravenous cyclophosphamide infusions and two methylprednisolone infusions of 250 mg each). RESULTS: Twenty-two patients were female and two male. At the time of B-cell depletion, the mean age was 28.9 yr (range 17-49) and the mean disease duration was 7.9 yr (range 1-18). The global BILAG score (P < 0.00001), serum C3 (P < 0.0005) and double-stranded DNA binding (P < 0.002) all improved from the time of B-cell depletion to 6 months after this treatment. Only one patient failed to achieve B-lymphocyte depletion in the peripheral blood. The period of B-lymphocyte depletion ranged from 3 to 8 months except for one patient who remains depleted at more than 4 yr. Analysis of the regular BILAG assessments showed that improvements occurred in each of the eight organs or systems. The mean daily prednisolone dose fell from 13.8 mg (s.d. 11.3) to 10 mg (s.d. 3.1). CONCLUSION: In this open study of patients who had failed conventional immunosuppressive therapy, considerable utility in the use of B-cell depletion has been demonstrated. Our data provide strong support for the performance of a full double-blind control trial.

Natural killer cell activity in families of patients with systemic lupus erythematosus: demonstration of a killing defect in patients.

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.

Raised levels of interleukin 6 in systemic lupus erythematosus correlate with anaemia.

OBJECTIVES: Raised levels of the cytokines interleukin (IL) 6 and IL10 have been reported in patients with systemic lupus erythematosus (SLE). OBJECTIVE: To determine if levels of IL6 and IL10 correlate with organ/system-specific disease activity in SLE, using the British Isles Lupus Assessment Group (BILAG) Disease Activity Index. METHODS: Levels of IL6 and IL10 in serum samples from 171 patients with SLE and 50 normal controls were determined by enzyme linked immunosorbent assay (ELISA). Levels of cytokines in individual patients with SLE were compared with the presence or absence of active disease in eight organ/systems using the BILAG index. RESULTS: Levels of IL6 were significantly higher (p = 0.005) in patients with active compared with inactive haematological disease, as scored by the BILAG index. Further analysis showed that this association was dependent on an inverse correlation (p = 0.002, r = -0.26) between IL6 levels and haemoglobin levels in patients with SLE. In contrast, IL10 levels did not correlate with individual organ/system disease activity. CONCLUSIONS: Raised levels of IL6 in SLE may influence the development of anaemia in this disease. These findings are in agreement with an increasing number of studies, which support physiological links between IL6 and anaemia. Importantly, with the exception of the haematological system, our studies do not provide evidence of any individual organ/system which would respond to therapeutic manipulation of either IL6 or IL10 levels.

New therapies for systemic lupus erythematosus.

In the past 40 years, prognosis for patients with systemic lupus erythematosus (SLE) has improved, with 10-year survival now approximately 90%. This is due probably to a combination of earlier disease diagnosis and diagnosis of milder disease, due in part to availability of multiple serological tests for SLE, use of steroids and other immunosuppressive agents, and availability of renal dialysis and transplantation. Despite this, however, the potential for significant morbidity and mortality remains in the group of patients with partially responsive or treatment resistant disease. More recently, advancements in the understanding of molecular mechanisms involved in the pathogenesis of SLE have translated to the development of novel therapies, offering possible alternatives to this patient cohort. Discussion of these pharmacological options and ongoing research forms the basis of this review.

New therapies for rheumatoid arthritis.

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.

Novel therapies in lupus nephritis.

Renal disease continues to cause major morbidity and some mortality for around 30-40% of patients with systemic lupus erythematosus (SLE). Although the combinations of prednisolone and azathioprine or prednisolone and cyclophosphamide have been beneficial to many patients with SLE, they are not always effective and have significant side effects. It is very encouraging that new immunosuppressive drugs such as mycophenolate mofetil and more targeted therapies e.g., anti-CD20 are coming rapidly to larger scale clinical trials. The treatment of lupus nephritis is set to change quite rapidly in the next decade. In this review we highlight the likely major therapeutic advances.