Trial of canakinumab, an IL-1β receptor antagonist, in patients with inclusion body myositis.

Objective: To assess whether canakinumab, a monoclonal antibody against IL-1β approved for autoinflammatory diseases, is effective as target-specific therapy in patients with sporadic inclusion body myositis (sIBM). Methods: Because in sIBM IL-1β colocalizes with amyloid precursor protein and upregulates amyloid aggregates enhancing degeneration, targeting IL-1β with canakinumab may arrest disease progression. On this basis, 5 ambulatory patients with sIBM participated in an institutional review board--approved open-labeled study with 150 mg canakinumab [4 bimonthly, then monthly subcutaneous injections] for a mean period of 15.8 months. Patients were assessed bimonthly with a manual dynamometer in 12 proximal and distal muscles and with grip force (GF) in both hands. Total muscle strength (TMS) was expressed in kilograms. Efficacy was defined as \u3e15% increased strength after 12 months. Results: Patient 1 stopped at month 5 because of 23% loss in TMS and 32.35% in GF; patient 2 showed 37.1% increase in TMS and 13% in GF by month 9; patient 3 exhibited 26.7% reduction in TMS and 10% in GF at month 33; patient 4 showed 6.5% reduction in TMS and 1.6% in GF after 15 months, denoting relative stability; and patient 5 showed 30.4% loss in TMS and 20.8% in GF after 18 months. In patients 2 and 4, in whom 3-year longitudinal data were available, no effect on disease progression was noted. Conclusions: In this long-term, open-label study, canakinumab showed small, but not clinically appreciable, stabilizing benefits in 2 of 5 patients with sIBM over 1 year, was ineffective in 2 others, and might have worsened one. No patient improved. Classification of evidence: This study provides Class IV evidence that canakinumab was ineffective for patients with sIBM

Presence of antiphospholipid antibodies is associated with increased implantation failure following in vitro fertilization technique and embryo transfer: A systematic review and meta-analysis

PURPOSE: A systematic review and meta-analysis was conducted comparing the presence of anti-phospholipid (anti-PL) antibodies between women of reproductive age, without diagnosis of antiphospholipid syndrome, who experienced at least two implantation failures following in vitro fertilization and embryo transfer (IVF-ET), and either women who had a successful implantation after IVF-ET or women with at least one successful spontaneous pregnancy or unselected healthy fertile women with no history of IVF-ET. METHODS: Systematic search of the literature and meta-analysis of the relevant studies studying presence of antiphospholipid antibodies in women experiencing at least two implantation failures in IVF-ET as compared to either women who had a successful implantation after IVF-ET or/and women with at least one successful spontaneous pregnancy or unselected healthy fertile women with no history of IVF-ET. Six hundred ninety-four published reports were retrieved; 17 of them fulfilled the inclusion criteria set. RESULTS: Presence of either any type of anti-phospholipid or anticardiolipin antibodies or lupus-anticoagulant in women experiencing at least two implantation failures in IVF-ET was associated with increased implantation failure compared to women who had a successful implantation after IVF-ET (relative risk, RR: 3.06, 5.06 and 5.81, respectively). Presence of either anticardiolipin or lupus-anticoagulant or anti-beta(2) glycoprotein-I or anti-phosphatidylserine antibodies in women experiencing at least two implantation failures in IVF-EΤ was associated with increased implantation failure compared to unselected healthy fertile women with no history of IVF-ET (RR:13.92, 6.37, 15.04 and 164.58, respectively). CONCLUSION: The prevalence of antiphospholipid antibodies, particularly that of anti-beta(2) glycoprotein-I and anti-phosphatidylserine antibodies, in women experiencing at least two implantation failures in IVF-ET without diagnosis of antiphospholipid syndrome is significantly greater than either in women who had a successful implantation after IVF-ET or women with at least one successful spontaneous pregnancy or unselected healthy fertile women with no history of IVF-ET. TRIAL REGISTRATION NUMBER: PROSPERO ID: CRD4201808145

Incidence and prevalence of major central nervous system involvement in Systemic Lupus Erythematosus: A 3-year prospective study of 370 patients

Background: The incidence and prevalence of CNS involvement in SLE remains unclear owing to conflicting results in the published studies. The aim of the study was to evaluate the incidence and prevalence of major definite CNS events in SLE patients. Methods: 370 SLE patients with no previous history of CNS involvement were prospectively evaluated in a tertiary hospital referral center for 3 years. Major CNS manifestations were codified according to ACR definitions, including chorea, aseptic meningitis, psychosis, seizures, myelopathy, demyelinating syndrome, acute confusional state and strokes. Minor CNS events were excluded. ECLAM and SLEDAI-SELENA Modification scores were used to evaluate disease activity and SLICC/ACR Damage Index was used to assess accumulated damage. Results: 16/370 (4.3%) patients presented with a total of 23 major CNS events. These included seizures (35%), strokes (26%), myelopathy (22%), optic neuritis (8.7%), aseptic meningitis (4.3%) and acute psychosis (4.3%). Incidence was 7.8/100 person years. Among hospitalizations for SLE, 13% were due to CNS manifestations. Epileptic seizures were associated with high disease activity, while myelopathy correlated with lower disease activity and NMO-IgG antibodies (P#0.05). Stroke incidence correlated with APS coexistence (P = 0.06). Overall, CNS involvement correlated with high ECLAM and SLEDAI scores (P,0.001). Conclusions: Clinically severe CNS involvement is rare in SLE patients, accounting for 7.8/100 person years. CNS involvement correlates with high disease activity and coexistence of specific features that define the respective CNS syndromes

Autoimmune thyroiditis in antinuclear antibody positive children without rheumatologic disease

<p>Abstract</p> <p>Background</p> <p>Children are commonly referred to a pediatric rheumatology center for the laboratory finding of an Anti-nuclear antibody (ANA) of undetermined significance. Previous studies regarding adult rheumatology patients have supported an association between ANA and anti-thyroid antibodies, with the prevalence of thyroid antibodies being significantly higher in patients referred to a rheumatology center for an ANA without evidence of connective tissue disease compared to the general population. The purpose of the present study was to determine the frequency of thyroid antibodies in children referred to a pediatric rheumatology center for a positive ANA without evidence of a connective tissue disease.</p> <p>Methods</p> <p>A retrospective chart review was performed on children who were referred to our pediatric rheumatology center between August 2003 and March 2007 for positive ANA with concurrent thyroid antibody and thyroid function tests performed who did not fulfill criteria for a specific connective tissue disease. Laboratory and clinical features were recorded and analyzed. Mean and standard deviation were used to describe continuous data. Chi-square or Fisher's exact tests were used to compare proportions between variables.</p> <p>Results</p> <p>One-hundred and four ANA-positive patients with concurrent thyroid studies were evaluated (88% female, 93% Caucasian, mean age 11.9 ± 4.0 years). Half of patients had an ANA titer ≥ 1:320. The ANA pattern was speckled in 60% of the patients. Thyroid antibodies were detected in 30% of the patients. Anti-Thyroglobulin (ATG) was detected in 29% and Anti-thyroid peroxidase (ATPO) in 21% of the patients; of these children, 14% had hypothyroidism. ANA pattern and titer were not associated with anti-thyroid antibody positivity.</p> <p>Conclusion</p> <p>Thyroid antibodies associated with chronic lymphocytic thyroiditis, ATG and ATPO, were detected significantly higher in ANA-positive children without a rheumatologic condition (30%) as compared to the general pediatric population (1.3 - 3.4%). ANA titer and pattern did not help predict the presence or absence of thyroid antibodies. Given the high frequency of thyroid antibodies and increased risk of developing hypothyroidism over time, routine evaluation of ATG and ATPO with thyroid function tests in ANA-positive children is recommended.</p

Nailfold Videocapillaroscopic Features and Other Clinical Risk Factors for Digital Ulcers in Systemic Sclerosis: A Multicenter, Prospective Cohort Study

OBJECTIVE: To identify nailfold videocapillaroscopic and other clinical risk factors for new digital ulcers (DUs) in a 6-month period in patients with systemic sclerosis (SSc), the videoCAPillaroscopy (CAP) study. METHODS: Overall 623 patients with SSc from 59 centers (14 countries) were stratified into two groups: "DU History" and "No-DU History". At enrollment, patients underwent detailed nailfold videocapillaroscopic evaluation and an assessment of demographics, DU status, and clinical and SSc characteristics. Risk factors for developing new DUs were assessed using univariable and multivariable logistic regression analyses. RESULTS: Of the "DU History" group (n = 468), 79.5% were female, the mean age was 54.0 ± 13.7 years, 59.8% had limited cutaneous SSc, and 22% developed a new DU during follow-up. The strongest risk factors for new DUs identified by multivariable logistic regression (MLR) in the "DU History" group included: mean number of capillaries/mm in the middle finger of the dominant hand, number of DUs (0, 1, 2, ≥3), and presence of critical digital ischemia. The receiver operating characteristic area under the curve (ROC-AUC) (95% confidence interval [CI]) of the final MLR model was 0.738 (0.681-0.795). Internal validation through bootstrap generated a ROC-AUC (95% CI) of 0.633 (0.510-0.756). CONCLUSION: This international, prospective study including detailed nailfold videocapillaroscopic evaluation and extensive clinical characterization of patients with SSc identified the mean number of capillaries/mm in the middle finger of the dominant hand, number of DUs and presence of critical digital ischemia at enrollment as risk factors for the development of new DUs. This article is protected by copyright. All rights reserved

Novel Assays of Thrombogenic Pathogenicity in the Antiphospholipid Syndrome Based on the Detection of Molecular Oxidative Modification of the Major Autoantigen β2-Glycoprotein I

Objective. Beta-2-glycoprotein I (beta(2)GPI) constitutes the major autoantigen in the antiphospholipid syndrome (APS), a common acquired cause of arterial and venous thrombosis. We recently described the novel observation that beta(2)GPI may exist in healthy individuals in a free thiol (biochemically reduced) form. The present study was undertaken to quantify the levels of total, reduced, and posttranslationally modified oxidized beta(2)GPI in APS patients compared to various control groups.Methods. In a retrospective multicenter analysis, the proportion of beta(2)GPI with free thiols in serum from healthy volunteers was quantified. Assays for measurement of reduced as well as total circulating beta(2)GPI were developed and tested in the following groups: APS (with thrombosis) (n = 139), autoimmune disease with or without persistent antiphospholipid antibodies (aPL) but without APS (n = 188), vascular thrombosis without APS or aPL (n = 38), and healthy volunteers (n = 91).Results. Total beta(2)GPI was significantly elevated in patients with APS (median 216.2 mu g/ml [interquartile range 173.3-263.8]) as compared to healthy subjects (median 178.4 mu g/ml [interquartile range 149.4-227.5] [P < 0.0002]) or control patients with autoimmune disease or vascular thrombosis (both P < 0.0001). The proportion of total beta(2)GPI in an oxidized form (i.e., lacking free thiols) was significantly greater in the APS group than in each of the 3 control groups (all P < 0.0001).Conclusion. This large retrospective multicenter study shows that posttranslational modification of beta(2)GPI via thiol-exchange reactions is a highly specific phenomenon in the setting of APS thrombosis. Quantification of posttranslational modifications of beta(2)GPI in conjunction with standard laboratory tests for APS may offer the potential to more accurately predict the risk of occurrence of a thrombotic event in the setting of APS