Belimumab treatment of adult idiopathic inflammatory myopathy.

OBJECTIVE: To evaluate belimumab addition to the standard of care in patents with refractory idiopathic inflammatory myopathy (IIM). METHODS: We conducted a 40-week multicentre, randomized, double-blind, placebo-controlled trial with 1:1 IV belimumab 10 mg/kg or placebo randomization and a 24-week open-label extension. Clinical responses were measured by the definition of improvement (DOI) and total improvement score (TIS). Flow cytometry analyses were performed on available samples before randomization, at 24 and 60-64 weeks. Descriptive statistics, t-test, Fisher's exact test and analysis of variance tests were used. RESULTS: A total of 17 patients were randomized, 15 received five or more doses of belimumab or placebo and were included in the intention-to-treat analysis. More belimumab patients vs placebo attained a TIS ≥40 [55.5% vs 33.3%; P = non-significant (NS)] and achieved the DOI (33.3% vs 16.7%; P = NS) at weeks 40 and 64; the mean TIS was similar among groups. Two patients achieved major responses (TIS = 72.5) after week 40 in the belimumab arm and none in the placebo arm. No improvement in the placebo arm after switching to the open-label phase was observed. There was no steroid-sparing effect. No new safety signals were detected. Although total B cells were not reduced, belimumab induced naïve B cell depletion while enhancing the number and frequency memory B cells. CONCLUSION: The study did not meet the primary endpoint and no statistically significant differences were observed in clinical responses between arms. More patients achieved sustained TIS ≥40 and reached the DOI. Most patients who received belimumab for >40 weeks had clinical improvement. Phenotypic changes in B cell populations were not associated with clinical responses. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (https://clinicaltrials.gov/), NCT02347891.

Postdischarge thromboembolic outcomes and mortality of hospitalized patients with COVID-19: the CORE-19 registry.

Thromboembolic events, including venous thromboembolism (VTE) and arterial thromboembolism (ATE), and mortality from subclinical thrombotic events occur frequently in coronavirus disease 2019 (COVID-19) inpatients. Whether the risk extends postdischarge has been controversial. Our prospective registry included consecutive patients with COVID-19 hospitalized within our multihospital system from 1 March to 31 May 2020. We captured demographics, comorbidities, laboratory parameters, medications, postdischarge thromboprophylaxis, and 90-day outcomes. Data from electronic health records, health informatics exchange, radiology database, and telephonic follow-up were merged. Primary outcome was a composite of adjudicated VTE, ATE, and all-cause mortality (ACM). Principal safety outcome was major bleeding (MB). Among 4906 patients (53.7% male), mean age was 61.7 years. Comorbidities included hypertension (38.6%), diabetes (25.1%), obesity (18.9%), and cancer history (13.1%). Postdischarge thromboprophylaxis was prescribed in 13.2%. VTE rate was 1.55%; ATE, 1.71%; ΑCM, 4.83%; and MB, 1.73%. Composite primary outcome rate was 7.13% and significantly associated with advanced age (odds ratio [OR], 3.66; 95% CI, 2.84-4.71), prior VTE (OR, 2.99; 95% CI, 2.00-4.47), intensive care unit (ICU) stay (OR, 2.22; 95% CI, 1.78-2.93), chronic kidney disease (CKD; OR, 2.10; 95% CI, 1.47-3.0), peripheral arterial disease (OR, 2.04; 95% CI, 1.10-3.80), carotid occlusive disease (OR, 2.02; 95% CI, 1.30-3.14), IMPROVE-DD VTE score ≥4 (OR, 1.51; 95% CI, 1.06-2.14), and coronary artery disease (OR, 1.50; 95% CI, 1.04-2.17). Postdischarge anticoagulation was significantly associated with reduction in primary outcome (OR, 0.54; 95% CI, 0.47-0.81). Postdischarge VTE, ATE, and ACM occurred frequently after COVID-19 hospitalization. Advanced age, cardiovascular risk factors, CKD, IMPROVE-DD VTE score ≥4, and ICU stay increased risk. Postdischarge anticoagulation reduced risk by 46%.

Follow-up results of myositis patients treated with H. P. Acthar gel.

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by proximal muscle weakness. H. P. Acthar gel [repository corticotropin injection (RCI)] is a formulation of adrenocorticotropic hormone and has been approved by Food and Drug Administration for use in IIM; however, literature is limited. In this study, we report longitudinal follow-up of myositis patients treated with RCI. METHODS: Patients with refractory IIM who were enrolled in the prospective, open-label RCI trial were included in this study. The post-trial follow-up period was 6 months with assessments every 2 months, which included myositis core set measures including extra-muscular global, muscle and patient global disease activities, HAQ, and manual muscle testing. RESULTS: Two patients were lost to follow-up after finalization of the trial, and the remaining eight patients were enrolled in the follow-up study. One patient remained on RCI after the trial. In the follow-up period, four of eight patients had flare at on average 4.1 months after the RCI trial. Among the patients who flared, three required an increase in prednisone. One patient was restarted on RCI at 5.5 months, but had minimal improvement after 3 months. Four patients who remained stable continued to satisfy criteria for the definition of improvement through the 6-month follow-up. However, none showed any further improvement in the primary or secondary efficacy outcomes after the initial RCI trial. CONCLUSION: To our knowledge, this is the first study reporting the follow-up results of patients treated with standard dose and duration of Acthar. We believe that our study will provide the basis for the development of future randomized RCI trials in IIM.

Efficacy and safety of adrenocorticotropic hormone gel in refractory dermatomyositis and polymyositis.

AIM: To evaluate the efficacy, safety, tolerability and steroid-sparing effect of repository corticotropin injection (RCI), in an open-label clinical trial, in refractory adult polymyositis (PM) and dermatomyositis (DM). METHODS: Adults with refractory PM and DM were enrolled by two centres. Inclusion criteria included refractory disease defined as failing glucocorticoid and/or ≥1 immunosuppressive agent, as well as active disease defined as significant muscle weakness and >2 additional abnormal core set measures (CSMs) or a cutaneous 10 cm Visual Analogue Scale score of ≥3 cm and at least three other abnormal CSMs. All patients received RCI of 80 units subcutaneously twice weekly for 24 weeks. The primary end point for the trial was the International Myositis Assessment and Clinical Studies definition of improvement. Secondary end points included safety, tolerability, steroid-sparing as well as the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism myositis response criteria (EULAR) RESULTS: Ten of the 11 enrolled subjects (6 DM, 4 PM) completed the study. Seven of 10 met the primary end point of efficacy at a median of 8 weeks. There was a significant decrease in prednisone dose from baseline to conclusion (18.5 (15.7) vs 2.3 (3.2); P<0.01). Most individual CSMs improved at week 24 compared with the baseline, with the muscle strength improving by >10% and the physician global by >40%. RCI was considered safe and tolerable. No patient developed significant weight gain or an increase of haemoglobin A1c or cushingoid features. CONCLUSION: Treatment with RCI was effective in 70% of patients, safe and tolerable, and led to a steroid dose reduction in patients with adult myositis refractory to glucocorticoid and traditional immunosuppressive drugs. TRIAL REGISTRATION NUMBER: NCT01906372; Results.

The differential role of SSa/SSb and Ro52 antibodies in defining clinical phenotypes in idiopathic inflammatory myopathies.

OBJECTIVE: In idiopathic inflammatory myopathies, anti-SSa/SSb and anti-Ro52 are associated with interstitial lung disease (ILD), yet few studies have compared their prognostic utility. Our study analyzes clinical phenotypes associated with anti-SSa/SSb and anti-Ro52 positivity in IIM and their association with ILD. METHODS: We performed a retrospective analysis of IIM patients >18-years-old, seen at Northwell Myositis Center 2007- 2018 who met 2017 EULAR/ACR criteria with available anti-SSa/SSb data. Patients who were anti-SSa/SSb(-) and anti-Ro52(+) were excluded from anti-SSa/SSb subgroup analysis but included in Ro52 subgroup analysis. Organ manifestations, pulmonary function tests (PFTs) and comorbidities were recorded. Statistical analyses included Chi-square, Fisher's Exact, Wilcoxon Rank Sum, McNemar's test. RESULTS: Of 94 patients included in the final analysis, 35% (33/94) were anti-SSa/SSb positive (+). Of 60 patients with anti-Ro52 data, 42% (25/60) were (+). ILD was more common in anti-SSa/SSb (+) versus anti-SSa/SSb negative patients and anti-Ro52(+) versus anti-Ro52 negative patients (58% vs 25%; p = 0.003 and 64% vs.26%; p = 0,004 respectively). Anti-SSa/SSb (+) was not associated with increased ILD severity based on PFTs. Anti-Ro52(+) group had lower DLCO than anti-Ro52(-) (47% vs 68%; p = 0.003). Anti-SSa/SSb positivity did not confer a difference in the frequency of other manifestations. Elevated rates of venous thromboembolism (VTE) (10%-12%) and osteoporosis (13-17%) were observed independent of anti-SSa/SSb or anti-Ro52 status. CONCLUSION: In IIM anti-SSa/SSb or anti-Ro52 positivity is associated with higher ILD rate. Both assays are useful to confer ILD risk, but anti-Ro52 is more predictive of severe ILD. High frequencies of osteoporosis and VTE were observed in all subgroups.

Factors associated with immune responses to SARS-CoV-2 vaccination in individuals with autoimmune diseases.

Patients with autoimmune diseases are at higher risk for severe infection due to their underlying disease and immunosuppressive treatments. In this real-world observational study of 463 patients with autoimmune diseases, we examined risk factors for poor B and T cell responses to SARS-CoV-2 vaccination. We show a high frequency of inadequate anti-spike IgG responses to vaccination and boosting in the autoimmune population but minimal suppression of T cell responses. Low IgG responses in B cell-depleted patients with multiple sclerosis (MS) were associated with higher CD8 T cell responses. By contrast, patients taking mycophenolate mofetil (MMF) exhibited concordant suppression of B and T cell responses. Treatments with highest risk for low anti-spike IgG response included B cell depletion within the last year, fingolimod, and combination treatment with MMF and belimumab. Our data show that the mRNA-1273 (Moderna) vaccine is the most effective vaccine in the autoimmune population. There was minimal induction of either disease flares or autoantibodies by vaccination and no significant effect of preexisting anti-type I IFN antibodies on either vaccine response or breakthrough infections. The low frequency of breakthrough infections and lack of SARS-CoV-2-related deaths suggest that T cell immunity contributes to protection in autoimmune disease.

Randomized Trial of Tocilizumab in the Treatment of Refractory Adult Polymyositis and Dermatomyositis.

OBJECTIVE: To assess the efficacy and tolerability of tocilizumab in a multicenter, randomized, double-blind, placebo-controlled trial in refractory adult patients with dermatomyositis (DM) and polymyositis (PM). METHODS: Thirty-six subjects with probable or definite DM/PM were enrolled in a 6-month phase 2B clinical trial and randomized 1:1 to receive tocilizumab (8 mg/kg intravenously) or placebo every 4 weeks for 24 weeks. Eligible subjects had either a DM rash, a myositis-associated autoantibody or an adjudicated PM diagnosis. Active disease was defined by at least three of six abnormal core set measures (CSMs), including a manual muscle testing (MMT)-8 score of less than 136/150. If the MMT-8 score was greater than 136, then a cutaneous score of 3 or more (10 cm visual analogue scale) was required along with three additional abnormal CSMs indicating disease activity. The primary endpoint compared the Total Improvement Score (TIS) between both arms from week 4 to 24. Secondary outcomes included time to meeting minimal TIS improvement, changes in CSMs, time to worsening, steroid-sparing effect, proportion of subjects meeting more stringent improvement criteria, and safety outcomes. RESULTS: There was no significant difference (P = 0.86) in the TIS over 24 weeks between tocilizumab and placebo arms. The secondary endpoints of time to improvement (minimal, moderate, or major), time to worsening, CSM changes, safety outcomes, and steroid-sparing effect were also not significantly different between arms. CONCLUSION: Tocilizumab was safe and well tolerated but did not meet the primary or secondary efficacy outcomes in refractory DM and PM in this 24-week phase 2B study.

Antisynthetase syndrome.

Autoantibodies to eight of the aminoacyl-transfer RNA synthetases-the most well-recognized of which is anti-histidyl (Jo-1)-have all been implicated in the pathogenesis of antisynthetase syndrome (AS). AS is characterized by varying degrees of interstitial lung disease, myositis, arthropathy, fever, Raynaud's phenomenon, and mechanic's hands, and the morbidity and mortality of the disease are usually linked to the pulmonary findings. The value of a lung biopsy in AS cannot be overemphasized, as it serves to describe the underlying etiology of the interstitial lung disease, guide therapy, and estimate prognosis. Muscle disease shares many clinical features of polymyositis, yet histologically, the inflammatory involvement resembles that of dermatomyositis. Because inflammatory arthritis mimics rheumatoid arthritis, AS should be considered in atypical cases. Corticosteroids are the mainstay of acute therapy, although treatment often requires immunosuppressant medications such as cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, or rituximab.

The Longitudinal Immune Response to Coronavirus Disease 2019: Chasing the Cytokine Storm.

The clinical progression of the severe acute respiratory syndrome coronavirus 2 infection, coronavirus 2019 (COVID-19), to critical illness is associated with an exaggerated immune response, leading to magnified inflammation termed the "cytokine storm." This response is thought to contribute to the pathogenicity of severe COVID-19. There is an initial weak interferon response and macrophage activation that results in delayed neutrophil recruitment leading to impeded viral clearance. This causes prolonged immune stimulation and the release of proinflammatory cytokines. Elevated inflammatory markers in COVID-19 (e.g., d-dimer, C-reactive protein, lactate dehydrogenase, ferritin, and interleukin-6) are reminiscent of the cytokine storm seen in severe hyperinflammatory macrophage disorders. The dysfunctional immune response in COVID-19 also includes lymphopenia, reduced T cells, reduced natural killer cell maturation, and unmitigated plasmablast proliferation causing aberrant IgG levels. The progression to severe disease is accompanied by endotheliopathy, immunothrombosis, and hypercoagulability. Thus, both parts of the immune system-innate and adaptive-play a significant role in the cytokine storm, multiorgan dysfunction, and coagulopathy. This review highlights the importance of understanding the immunologic mechanisms of COVID-19 as they inform the clinical presentation and advise potential therapeutic targets.

Comparative Survival Analysis of Immunomodulatory Therapy for Coronavirus Disease 2019 Cytokine Storm.

BACKGROUND: Cytokine storm is a marker of coronavirus disease 2019 (COVID-19) illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes. RESEARCH QUESTION: Do immunomodulatory therapies improve survival in patients with COVID-19 cytokine storm (CCS)? STUDY DESIGN AND METHODS: We conducted a retrospective analysis of electronic health records across the Northwell Health system. COVID-19 patients hospitalized between March 1, 2020, and April 24, 2020, were included. CCS was defined by inflammatory markers: ferritin, > 700 ng/mL; C-reactive protein (CRP), > 30 mg/dL; or lactate dehydrogenase (LDH), > 300 U/L. Patients were subdivided into six groups: no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-IL-6 antibody (tocilizumab), or anti-IL-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality. RESULTS: Five thousand seven hundred seventy-six patients met the inclusion criteria. The most common comorbidities were hypertension (44%-59%), diabetes (32%-46%), and cardiovascular disease (5%-14%). Patients most frequently met criteria with high LDH (76.2%) alone or in combination, followed by ferritin (63.2%) and CRP (8.4%). More than 80% of patients showed an elevated D-dimer. Patients treated with corticosteroids and tocilizumab combination showed lower mortality compared with patients receiving standard-of-care (SoC) treatment (hazard ratio [HR], 0.44; 95% CI, 0.35-0.55; P < .0001) and with patients treated with corticosteroids alone (HR, 0.66; 95% CI, 0.53-0.83; P = .004) or in combination with anakinra (HR, 0.64; 95% CI, 0.50-0.81; P = .003). Corticosteroids when administered alone (HR, 0.66; 95% CI, 0.57-0.76; P < .0001) or in combination with tocilizumab (HR, 0.43; 95% CI, 0.35-0.55; P < .0001) or anakinra (HR, 0.68; 95% CI, 0.57-0.81; P < .0001) improved hospital survival compared with SoC treatment. INTERPRETATION: The combination of corticosteroids with tocilizumab showed superior survival outcome when compared with SoC treatment as well as treatment with corticosteroids alone or in combination with anakinra. Furthermore, corticosteroid use either alone or in combination with tocilizumab or anakinra was associated with reduced hospital mortality for patients with CCS compared with patients receiving SoC treatment.

Secondary thrombotic microangiopathy in systemic lupus erythematosus and antiphospholipid syndrome, the role of complement and use of eculizumab: Case series and review of literature.

INTRODUCTION: Thrombotic microangiopathy (TMA) is a life-threatening, albeit infrequent, complication of systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS). Recommendations for the treatment of SLE- and APS-related secondary TMA are currently based solely on case reports and expert opinion. Unfortunately, interventions may not yield timely results or effectively halt the progression of TMA. Since complement activation plays a key role in the pathogenesis of secondary TMA due to SLE, APS, a therapy that targets the complement pathway is an attractive intervention. Eculizumab, a recombinant, fully humanized IgG2/IgG4 monoclonal antibody inhibits C5 activation and is FDA-approved for PNH and atypical HUS (aHUS). However, limited case reports are available on its use in treatment of secondary TMA. CASE PRESENTATION AND RESULTS: We present the largest case series to date that includes 9 patients with SLE and/or APS who were successfully treated with eculizumab for refractory secondary TMA. In this case series, we report significant responses in hematology values, renal function and other organs following treatment with eculizumab. At 4 weeks, 75% improvement in platelet counts was observed in 78% of patients. Two-thirds of patients demonstrated >75% improvement of haptoglobin and LDH at four weeks. At 4 weeks, eGFR improved by 25% in half of the patients, and 43% had reductions in proteinuria. Two of 3 patients that required hemodialysis were able to be taken off hemodialysis. CONCLUSION: Based on these observations, we suggest that eculizumab may be a potential treatment option for acutely ill patients with secondary TMA due to SLE and/or APS who have failed standard of care. A collective approach is needed to better elucidate the role and optimal timing of eculizumab use in the management of TMA complicating SLE and/or APS.

IgG4-Related Sclerosing Disease of the Breast in a Male Patient.

IgG4-related sclerosing disease of the breast is a rare entity with 10 reports in the literature. We report the first case in a male patient. A 48-year-old male presented with 4-week history of palpable right upper outer quadrant breast mass associated with skin puckering. He reported a family history of breast cancer in his aunt. Ultrasound and mammography showed a spiculated 2.5-cm mass associated with skin retraction with extension to the pectoralis muscle. Ultrasound-guided core biopsy was performed. The findings were interpreted as acute and chronic inflammatory process. The patient subsequently denied improvement of the mass, and an excisional biopsy was performed. Histologic examination showed fibrosis and dense lymphoplasmacytic inflammation in the breast mass and muscle biopsy. Focal obliterative phlebitis was noted. IgG4-positive plasma cells were increased with counts of over 50 per high-power field. The diagnosis was confirmed as sclerosing IgG4-related disease of breast.

Biphasic flow-volume loop in granulomatosis with polyangiitis related unilateral bronchus obstruction.

Spirometry flow-volume measurement is used routinely in the outpatient setting to rule out obstructive lung diseases. Biphasic flow-volume loop is a classic presentation of unilateral bronchial stenosis due to multiple etiologies and it should raise clinical suspicion. Granulomatosis with polyangiitis (GPA) is a systemic inflammatory condition with pulmonary manifestations that may be infiltrative (e.g., pneumonia), hemorrhagic, and may rarely cause bronchial stenosis. Herein, we present a case of GPA-related, bronchial obstruction that caused biphasic flow-volume loop along with a literature review.

Severe upper airway obstruction from cricoarytenoiditis as the sole presenting manifestation of a systemic lupus erythematosus flare.

Upper airway obstruction due to laryngeal involvement is a known complication of systemic lupus erythematosus (SLE). Laryngeal involvement typically accompanies inflammatory activity involving other sites and varies from mild mucosal inflammation to bilateral vocal cord immobility. Cricoarytenoid arthropathy is a rare cause of severe airway obstruction in patients with SLE and almost always occurs in the presence of other associated symptoms. Furthermore, in contrast to patients with rheumatoid arthritis, in whom chronic involvement of cricoarytenoid joints occurs more commonly and often requires surgical intervention, patients with SLE typically present with acute arthritis of cricoarytenoid joints and respond to corticosteroid therapy alone. We describe a patient with known SLE who presented with severe acute upper airway obstruction as the sole manifestation of active SLE after several years of quiescence. The laryngeal involvement progressed from mucosal inflammation to acute cricoarytenoiditis, despite the administration of high-dose corticosteroid therapy, necessitating emergent intubation and tracheostomy. This case illustrates the importance of considering SLE in the differential diagnosis of patients presenting with acute upper airway obstruction.

Potential applications of matrix metalloproteinase inhibitors in geriatric practice.

Matrix metalloproteinases are a family of enzymes that degrade different components of extracellular matrix. They play an important role in normal physiologic processes of maintaining tissue integrity and remodeling, as in wound healing, processes of development, and regeneration. However, excessive expression of MMP has been observed in many disease states, including rheumatoid arthritis and osteoarthritis, vascular remodeling in atherosclerosis and aortic aneurysm formation, neoplastic processes, macular degeneration and many others.

The effect of moderate-dose corticosteroids in preventing severe flares in patients with serologically active, but clinically stable, systemic lupus erythematosus: findings of a prospective, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Serial measurements of anti-double-stranded DNA (anti-dsDNA) and complement are routine in the management of systemic lupus erythematosus (SLE), but their utility as biomarkers in preemptive treatment to prevent flares remains a subject of controversy. We hypothesized that concomitant elevation of anti-dsDNA and C3a can predict SLE activity in patients with stable or inactive disease and that short-term treatment with corticosteroids can avert flares. METHODS: In this prospective, randomized, double-blind, placebo-controlled trial, 154 patients were evaluated monthly for up to 18 months, with measurements of C3a, C3, C4, CH50, and anti-dsDNA levels. Patients who remained clinically stable but showed serologic evidence of an SLE flare (elevation of both the anti-dsDNA level by 25% and the C3a level by 50% over the previous 1-2 monthly visits) were randomized to receive either prednisone or placebo therapy at a dosage of 30 mg/day for 2 weeks, 20 mg/day for 1 week, and 10 mg/day for 1 week. RESULTS: Forty-one patients (21 randomized to prednisone and 20 randomized to placebo) experienced a serologic flare. Analysis of severe flares occurring 40 mg/day and/or the addition of an immunosuppressive agent. Furthermore, improvement in scores on the Systemic Lupus Erythematosus Disease Activity Index, decreased levels of anti-dsDNA antibodies, and increased levels of C4 occurred 1 month after initiation of prednisone treatment. CONCLUSION: These preliminary data support our hypothesis that in a subset of clinically stable SLE patients with a combination of elevated C3a and anti-dsDNA levels, short-term corticosteroid therapy may avert a severe flare.