Biologic predictors of clinical improvement in rituximab-treated refractory myositis Clinical rheumatology and osteoporosis

Background: To examine the longitudinal utility of a biomarker signature in conjunction with myositis autoantibodies (autoAbs) as predictors of disease improvement in refractory myositis patients treated with rituximab. Methods: In the RIM Trial, all subjects received rituximab on 2 consecutive weeks. Using start of treatment as baseline, serum samples (n∈=∈177) were analyzed at baseline and after rituximab with multiplexed sandwich immunoassays to quantify type-1 IFN-regulated and other pro-inflammatory chemokines and cytokines. Biomarker scores were generated for the following pathways: type-1 IFN-inducible (IFNCK), innate, Th1, Th2, Th17 and regulatory cytokines. Myositis autoAbs (anti-synthetase n∈=∈28, TIF-γ n∈=∈19, Mi-2 n∈=∈25, SRP n∈=∈21, MJ n∈=∈18, non-MAA n∈=∈24, unidentified autoantibody n∈=∈9, and no autoantibodies n∈=∈33) determined by immunoprecipitation at baseline, were correlated with outcome measures. Kruskal-Wallis rank sum tests were used for comparisons. Results: The mean (SD) values for muscle disease and physician global disease activity VAS scores (0-100 mm) were 46 (22) and 49 (19). IFNCK scores (median values) were higher at baseline in subjects with anti-synthetase (43), TIF1-γ (31) and Mi-2 (30) compared with other autoAb groups (p∈30) and autoAb group (Mi-2, non-MAA, and undefined autoantibody) demonstrated the greatest clinical improvement based on muscle VAS (muscle-interaction p∈=∈0.075). Conclusion: Biomarker signatures in conjunction with autoAbs help predict response to rituximab in refractory myositis. Biomarker and clinical responses are greatest at 16 weeks after rituximab

Serum anti-lipocalin 2 IgG is a novel biomarker in the diagnosis of systemic lupus erythematosus

Background: Previous work suggests that lipocalin 2 is involved in the pathogenesis of systemic lupus erythematosus (SLE) and that this novel antigen could serve as a high-quality renal biomarker of acute kidney injury in SLE. However, serum lipocalin 2 antibody levels remain unclear. We have therefore undertaken this study to assess the level of serum IgG antibody against lipocalin 2 in different disease states and to evaluate the diagnostic value of this potential biomarker in SLE. Methods: Serum levels of anti-lipocalin IgG antibodies were measured by ELISA in 103 SLE patients, 93 rheumatoid arthritis (RA) patients, 29 primary Sjogren's syndrome (pSS) patients, 13 systemic sclerosis (SSc) patients, and 91 healthy controls. Diagnostic properties of anti-lipocalin IgG were determined by receiver-operating characteristic (ROC) curve analysis. Results: The level of serum anti-lipocalin IgG in patients with SLE was significantly higher than in patients with RA, pSS, SSc, or healthy controls (p < 0.05), effectively distinguishing SLE from other conditions with high sensitivity and specificity (49.5% and 90.7%, respectively). In ROC curve analysis, the area under the curve (AUC) is 0.783, with a 95% confidence interval (CI) extending from 0.729 to 0.839. Anti-lipocalin antibodies were present in 48.1% of anti-Sm-negative SLE patients, and also occurred in SLE patients lacking anti-dsDNA (52%) or anti-nucleosome antibodies (46.3%) antibodies. Finally, SLE patients with positive anti-lipocalin IgG possessed higher levels of IgA and CRP than the negative group (p < 0.05), clearly demonstrating a positive correlation between anti-lipocalin IgG and these laboratory parameters. Conclusions: Anti-lipocalin 2 IgG is a promising biomarker for the diagnosis of SLE, particularly when obtained in conjunction with anti-Sm, anti-dsDNA, and anti-nucleosome antibody levels.RheumatologySCI(E)[email protected]; [email protected]

Efficacy and safety of Bimagrumab in sporadic inclusion body myositis : long-term extension of RESILIENT

ObjectiveTo assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM).MethodsParticipants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety.ResultsBetween November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had >= 1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [ n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively).ConclusionExtended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint.Classification of EvidenceThis study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, welltolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.Neurological Motor Disorder

Pathogenesis of Myositis

In this overview of pathogenic mechanisms contributing to the development of idiopathic inflammatory myopathy, we highlight the relative contributions of genetic risk, environmental triggering, adaptive immunity, innate immunity, and “nonimmune” signaling pathways that culminate in muscular as well as extra-muscular tissue pathology. Improved understanding of this complex network will enhance our ability to develop novel therapeutic targets