Endotheliitis in Coronavirus Disease 2019-Positive Patients After Extremity Amputation for Acute Thrombotic Events.

BACKGROUND: Both arterial and venous thrombotic events of the extremities occur in coronavirus disease 2019 (COVID-19) infection, but the etiology of these events remains unclear. This study sought to evaluate pathology specimens of COVID-19-positive patients postamputation, who were found to have Rutherford 3 acute limb ischemia requiring amputation. METHODS: A retrospective review was performed of all vascular surgery emergency room and inpatient consultations in patients who presented to the Mount Sinai Health System from March 26, 2020, to May 10, 2020. Pathology specimens were examined using hematoxylin and eosin stain. The specimens were assessed for the following: inflammatory cells associated with endothelium/apoptotic bodies, mononuclear cells, small vessel congestion, and lymphocytic endotheliitis. Of the specimens evaluated, 2 patients with a known history of peripheral vascular disease were excluded. RESULTS: Inflammatory cells associated with endothelium/apoptotic bodies were seen in all 4 patients and in 4 of 5 specimens. Mononuclear cells were found in 2 of 4 patients. Small vessel congestion was seen in all patients. Lymphocytic endotheliitis was seen in 1 of 4 patients. CONCLUSIONS: This study shows endotheliitis in amputation specimens of four patients with COVID-19 disease and Rutherford Class 3 acute limb ischemia. The findings in these patients is more likely an infectious angiitis because of COVID-19.

Validation of Sonography findings of synovitis and tenosynovitis of hands and wrists in patients with systemic sclerosis.

Objectives: Validating musculoskeletal ultrasound features of the joints and tendons of the hands in a large scleroderma cohort. Methods: A total of 81 scleroderma patients participated in this prospective, cross-sectional study. Grayscale and power Doppler musculoskeletal ultrasound images of 13 joints and 5 tendons of the wrist and hand were obtained. Clinical assessment included modified Rodnan skin thickness score, joint count, and Scleroderma Health Assessment Questionnaire. Face validity, content validity, construct validity, and feasibility were assessed. Results: Mean age was 53.8 years (range 22-80), 76.5% were females, and disease duration ranged from 0.25 to 29 years. Mean length of the examination was 36 min. Scleroderma Health Assessment Questionnaire-Disability Index correlated with musculoskeletal ultrasound erosions (r = 0.5, p = 0.0003). Skin score correlated with tendinitis grayscale (r = 0.26, p = 0.02). Intra-reader correlation coefficient for musculoskeletal ultrasound was 0.96 for the joints and could not be calculated for tendons because there were too few positive findings. When tendon changes existed, percent of agreement was 77.7%-83.3%. Conclusion: Musculoskeletal ultrasound of 13 joints and 5 tendons of the hands and wrist has face and content validity. Construct validity was shown for the tendons and erosion scores. Feasibility and reliability were partially validated.

Comparative Immunogenicity of TNF Inhibitors: Impact on Clinical Efficacy and Tolerability in the Management of Autoimmune Diseases. A Systematic Review and Meta-Analysis.

BACKGROUND: Tumor necrosis factor (TNF) inhibitors are a mainstay in the treatment of rheumatoid arthritis (RA), as well as in the management of spondyloarthritis (SpA) and inflammatory bowel diseases (IBD). Unfortunately, a portion of patients taking these drugs require escalating doses within the approved label to achieve response, while others lose response altogether. This may be due to the development of antibodies against TNFi agents. OBJECTIVES: Our objective was to examine the immunogenicity of TNF inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab) in RA, SpA, and IBD, and to examine the potential effect of anti-drug antibodies (ADABs) on the loss of clinical response through a systematic literature review and meta-analysis. METHODS: We conducted a comprehensive literature search using three databases (PubMed, Web of Science, and the Cochrane library) to identify studies examining the immunogenicity of TNF inhibitors in autoimmune diseases between 1966 and 31 December 2013. Inclusion criteria required that studies be in English, be randomized controlled trials, observational studies, or case reports involving more than five patients, and that the patients be aged 18 years or older. Studies were excluded if they were strictly genetic with no clinical correlate, if the patients had concomitant cancer within 5 years of the study, or if the patients had a renal disease requiring dialysis. Double extraction was followed by a third extraction if needed. Consensus was reached by discussion when disagreements occurred. Random-effect models were generated for the meta-analysis of 68 studies to estimate the odds ratio (OR) of the ADAB effects on TNF inhibitor response. Regression analysis was used to compare among the drugs and diseases. RESULTS: A total of 68 studies (14,651 patients) matched the inclusion/exclusion criteria. Overall, the cumulative incidence of ADABs was 12.7 % [95 % confidence interval (CI) 9.5-16.7]. Of the patients using infliximab, 25.3 % (95 % CI 19.5-32.3) developed ADABs compared with 14.1 % (95 % CI 8.6-22.3) using adalimumab, 6.9 % (95 % CI 3.4-13.5) for certolizumab, 3.8 % (95 % CI 2.1-6.6) for golimumab, and 1.2 % (95 % CI 0.4-3.8) for etanercept. ADABs reduced the odds of clinical response by 67 % overall, although most of the data were derived from articles involving infliximab (nine) and adalimumab (eight). The summary effect for infliximab yielded an estimated OR (with ADABs vs. without) of 0.42 (95 % CI 0.30-0.58); the summary effect for adalimumab yielded an estimated OR (as above) of 0.13 (95 % CI 0.08-0.22); and the OR (as above) for golimumab was 0.42 (95 % CI 0.22-0.81). All figures were statistically significant. ADABS decreased response by 27 % in RA and 18 % in SpA, both of which were statistically significant. However, the effect of ADABS on response was not statistically significant for IBD when we only included the studies that reported the duration of exposure in the regression analysis. The use of concomitant immunosuppressives (methotrexate, 6-mercaptopurine, azathioprine, and others) reduced the odds of ADAB formation in all patients by 74 %. The OR for risk with immunosuppressives versus without was 0.26 (95 % CI 0.21-0.32). CONCLUSION: ADABs developed in 13 % of patients. All five TNF inhibitors were associated with ADABs, but to varying degrees depending on the specific TNF inhibitor and the disease. ADABs are associated with reduced clinical response and an increased incidence of infusion reactions and injection site reactions. Concomitant use of immunosuppressives can reduce ADAB formation.

Improved transplant-free survival in patients with systemic sclerosis-associated pulmonary hypertension and interstitial lung disease.

OBJECTIVE: Survival in patients with systemic sclerosis (SSc)-associated pulmonary hypertension (PH) and interstitial lung disease (ILD) is poor. Evidence supporting the efficacy of aggressive pulmonary arterial hypertension (PAH)-targeted therapy in this population is limited. The aim of this study was to investigate transplant-free survival in patients with isolated SSc-related PAH or SSc-related PH-ILD who were treated with aggressive PAH-targeted therapy. METHODS: SSc patients with right-sided heart catheterization (RHC)-diagnosed precapillary PH (mean pulmonary artery pressure ≥25 mm Hg, pulmonary capillary wedge pressure ≤15 mm Hg, and pulmonary vascular resistance ≥240 dynes × second/cm(5) ) were included. Patients were classified as having ILD based on review of high-resolution computed tomography (CT) chest imaging and spirometry. The Kaplan-Meier method was applied and Cox proportional hazards models were constructed to analyze survival and identify predictive variables. RESULTS: Of 99 patients with SSc-related precapillary PH, 28% had SSc-related PAH and 72% had SSc-related PH-ILD. The 1- and 2-year survival estimates were, respectively, 72% and 59% in the SSc-related PH-ILD group versus 82% and 66% in the SSc-related PAH group (P = 0.5). Within 6 months of the diagnostic RHC, 24% of all patients were started on prostanoid therapy; an additional 24% were started on prostanoid therapy after 6 months. In the multivariate model, male sex (hazard ratio [HR] 0.7, P = 0.01) and prostanoid therapy initiation within 6 months of the RHC (HR 1.4, P = 0.01) were the only factors significantly associated with transplant-free survival, after accounting for the presence of ILD and severity of PH. CONCLUSION: In this study, survival of patients with SSc-related PH-ILD was modestly improved relative to historical series. While these findings may not be generalizable, improved survival may be due partly to aggressive PAH-targeted therapy.