ObjectivesThis phase II trial evaluated the efficacy and safety of an interleukin (IL) 6 monoclonal antibody for systemic lupus erythematosus (SLE).MethodsPatients with active disease were randomised to placebo or PF-04236921 10 mg, 50 mg or 200 mg, subcutaneously, every 8 weeks with stable background therapy. SLE Responder Index (SRI-4; primary end point) and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) were assessed at week 24. Post hoc analysis identified an enriched population based upon planned univariate analyses.Results183 patients received treatment (placebo, n=45; 10 mg, n=45; 50 mg, n=47; 200 mg, n=46). The 200 mg dose was discontinued due to safety findings and not included in the primary efficacy analysis. The SRI-4 response rates were not significant for any dose compared with placebo; however, the BICLA response rate was significant for 10 mg (p=0.026). The incidence of severe flares was significantly reduced with 10 mg (n=0) and 50 mg (n=2) combined versus placebo (n=8; p<0.01). In patients with greater baseline disease activity (enriched population), the SRI-4 (p=0.004) and BICLA (p=0.012) response rates were significantly different with 10 mg versus placebo. Four deaths (200 mg, n=3; 10 mg, n=1) occurred. The most frequently reported adverse events included headache, nausea and diarrhoea.ConclusionsPF-04236921 was not significantly different from placebo for the primary efficacy end point in patients with SLE. Evidence of an effect with 10 mg was seen in a post hoc analysis. Safety was acceptable for doses up to 50 mg as the 200 mg dose was discontinued due to safety findings.Trial registration numberNCT01405196; Pre-results.

Objectives Molecular medicine raised expectations for strategically targeted biologics in systemic lupus erythematosus (SLE), but clinical trials have been disappointing and difficult to interpret. Most studies add investigational agents to various, often effective, standard of care (SoC) immunosuppressants used at baseline, with unknown treatment interactions. Eliminating polypharmacy in trials of active lupus patients remains controversial. The BOLD study tested immunosuppressant withdrawal as a novel approach to interpretable SLE trials. Methods In 41 patients with active, non-organ threatening SLE flare (Group A), temporary steroids were given while background immunosuppressants were withdrawn. Time to loss of disease suppression (“flare”) and safety were evaluated; SoC was immediately resumed when symptoms recurred. Immunologic impacts of SoC treatments were studied at baseline by multiplex assay, ELISA, and mRNA array in Group A plus 62 additional patients donating a single sample (Group B). Results Patients with lower or higher baseline disease had median times-to-flare of 71 or 45 days, respectively; 98% (40/41) flared by six months. All flares were treated and resolved within six weeks. No serious adverse events occurred from flare or infection. Type I interferon, TH17, and BLyS pathways tracked together. Baseline immunosuppressants had distinct impacts on TH17 and BLyS, depending on interferon signature. Conclusion Trials in active, non-organ-threatening SLE can safely withdraw background treatments if patients who flare are designated non-responders and returned to SoC. Immunologic effects of SoC vary between interferon-defined subsets. These findings provide a strategy for minimizing or optimizing treatment combinations in lupus trials and clinical care.

The use of rhBMP-12/ACS has been shown to be feasible and safe in a concentration of 0.015 mg/mL when used in open rotator cuff repair. Higher dose concentrations of rhBMP-12 should be evaluated in the future to evaluate their safety and potential to increase rotator cuff healing after open surgical repair.

The vasculitides comprise various clinical and pathological entities which pose a therapeutic challenge in terms of disease control versus drug toxicity. Glucocorticoids are important in most regimens; duration of exposure and dosages can be minimised by the use of cytotoxic drugs and transplant immunosuppressives such as cyclosporin, tacrolimus and mycophenolate mofetil. Among alkylating agents, cyclophosphamide has proven to be highly effective; switching to less toxic antimetabolites, typically methotrexate, for maintenance after achieving disease control is an effective strategy. Plasmapheresis may be considered when pharmacological options are maximised. IVIG infusions are of proven benefit in Kawasaki disease and possible benefit in other vasculitides. Targeting infective aetiologies is the basis of therapies such as lamivudine and vidarabine for hepatitis B associated polyarteritis nodosa as well as ribavarin and IFN-alpha for hepatitis C associated cryoglobinaemic vasculitis. IFN-alpha also has immunomodulatory effect even in non-hepatitis C-associated vasculitis. Trimethoprim-sulphamethoxazole has been used in limited Wegener's granulomatosis. Thalidomide, colchicine and dapsone are miscellaneous agents that have been used in Behcet's disease and cutaneous vasculitis. Anti-lymphocytic monoclonal antibodies have been employed for induction therapy in Wegener's granulomatosis. The tumour necrosis factor inhibitor etanercept is just being explored as a therapeutic agent. Bone marrow and stem cell transplantation may find a role in refractory disease.

Systemic lupus erythematosus (SLE) flares elicit progressive organ damage, leading to disability and early mortality. This study evaluated clinical and immunologic factors associated with impending flare in the Biomarkers of Lupus Disease study. Autoantibodies and 32 soluble mediators were measured by multiplex assays, immune pathway activation by gene expression module scores, and immune cell subset frequencies and activation states by flow cytometry. After providing baseline samples, participants received transient steroids to suppress disease and were followed until flare. Flare occurred early (within 60 days of baseline) in 21 participants and late (90–165 days) in 13. At baseline, compared to the late flare group, the early flare group had differential gene expression in monocyte, T cell, interferon, and inflammation modules, as well as significantly higher frequencies of activated (aCD11b + ) neutrophils and monocytes, and activated (CD86 hi ) naïve B cells. Random forest models showed three subgroups of early flare patients, distinguished by greater baseline frequencies of aCD11b + monocytes, or CD86 hi naïve B cells, or both. Increases in these cell populations were the most accurate biomarkers for early flare in this study. These results suggest that SLE flares may arise from an overlapping spectrum of lymphoid and myeloid mechanisms in different patients.