Immune responses and disease biomarker long-term changes following COVID-19 mRNA vaccination in a cohort of rheumatic disease patients (preprint)

Objective. To evaluate seroreactivity and disease biomarkers after 2 or 3 doses of COVID-19 mRNA vaccines in a cohort of patients with rheumatic diseases. Methods. We collected biological samples longitudinally before and after 2-3 doses of COVID-19 mRNA vaccines from a cohort of patients with systemic lupus erythematosus (SLE), psoriatic arthritis, Sjogrens syndrome, ankylosing spondylitis, and inflammatory myositis. Anti-SARS-CoV-2 spike IgG and IgA and anti-dsDNA concentration were measured by ELISA. A surrogate neutralization assay was utilized to measure antibody neutralization ability. Lupus disease activity was measured by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Expression of type I interferon signature was measured by real-time PCR. The frequency of extrafollicular double negative 2 (DN2) B cells was measured by flow cytometry. Results. Most of the patients generated high SARS-CoV-2 spike-specific neutralizing antibodies comparable to those in healthy controls after 2 doses of mRNA vaccines. The antibody level declined over time but recovered after the third dose of the vaccine. Rituximab treatment substantially reduced antibody level and neutralization ability. Among SLE patients, no consistent increase in SLEDAI scores was observed post-vaccination. The changes in anti-dsDNA antibody concentration and expression of type I IFN signature genes were highly variable but did not show consistent or significant increases. Frequency of DN2 B cells remained largely stable. Conclusion. Rheumatic disease patients without rituximab treatment have robust antibody responses toward COVID-19 mRNA vaccination. Disease activity and disease-associated biomarkers remain largely stable over 3 doses of vaccines, suggesting that COVID-19 mRNA vaccines may not exacerbate rheumatic diseases.

Peripherally Inserted Central Catheter-Related Infectious Myositis: A Case Report.

BACKGROUND Peripherally inserted central catheters (PICCs) are commonly used by clinicians in daily practice as a safe and reliable alternative to central venous catheters. While there are advantages to the use of PICCs, such as a low insertion-related complication rate and cost-effectiveness, using PICCs may expose patients to life-threatening severe complications such as a central line-associated bloodstream infection and deep venous thrombosis (DVT). There have been no reports of infectious myositis associated with PICC insertion. CASE REPORT We report a case of infectious myositis related to PICC insertion complicated by brachial DVT in a 43-year-old immunocompromised patient with myelodysplastic syndrome. Despite the administration of broad-spectrum antibiotics, the patient's condition did not improve. He developed septic shock and required emergency excision of the infected and necrotic muscles. Although the pathogen responsible for the infection was unknown, infectious myositis and myonecrosis were observed intraoperatively. Furthermore, histopathological examination revealed evidence of infectious myositis in the biceps brachii and brachial muscles. The septic shock resolved with treatment and the patient survived with residual elbow joint dysfunction. CONCLUSIONS We present a case of infectious myositis related to PICC insertion. We believe that urgent resection of infected and necrotic tissues, rather than broad-spectrum antimicrobial therapy alone, was essential to save the patient's life.

A case of antisynthetase syndrome presenting solely with life-threatening interstitial lung disease.

A previously fit and well 38-year-old man presented during the COVID-19 pandemic with dyspnoea, cough and palpitations. C-reactive protein was elevated and chest X-ray demonstrated bilateral lower zone consolidation. SARS CoV-2 swab was negative. He was diagnosed with community-acquired pneumonia and treated with oral antibiotics. He developed severe type 1 respiratory failure and was admitted to the high-dependency unit for non-invasive ventilation. CTPA was negative for pulmonary embolism, instead demonstrating bilateral organising pneumonia. Empirical treatment for swab-negative COVID-19 pneumonitis was started; however, further deterioration ensued and prompted intubation and ventilation. Microbiological testing did not yield any positive results, thereby raising suspicion for the presence of an autoimmune disease. Pulsed intravenous methylprednisolone was administered with good effect. ENA screen was positive for anti-Jo1 and myositis-specific autoantibodies were positive for Ro-52, Ku and PL-12. The patient was extubated and did not exhibit any muscle weakness on clinical examination. Creatine kinase was only mildly elevated. He was diagnosed with amyopathic antisynthetase syndrome - frequently considered as a form of idiopathic inflammatory myopathy (IIM) - and treated with further intravenous methylprednisolone and cyclophosphamide. Oxygen therapy was gradually weaned and the patient discharged on mycophenolate mofetil and a weaning course of oral steroids.

Inflammatory Myopathies.

PURPOSE OF REVIEW: This article outlines the salient clinical, serologic, electrophysiologic, imaging, and histopathologic findings and treatment options for the idiopathic inflammatory myopathies, including those related to immune checkpoint inhibitors and SARS-CoV-2. RECENT FINDINGS: The classification of idiopathic inflammatory myopathies has improved with the integration of myositis-specific antibodies and histopathologic findings. Characteristic features of immune checkpoint inhibitor-related myositis have been identified, allowing early recognition and treatment of the syndrome. The COVID-19 pandemic has had a profound impact on the care of patients with idiopathic inflammatory myopathies, and several mechanisms of virus-related muscle injury have been proposed. SUMMARY: A comprehensive evaluation including clinical examination, EMG, imaging, antibody testing, muscle biopsy, and cancer screening, when appropriate, can lead to an earlier accurate diagnosis and an individualized treatment approach for patients with idiopathic inflammatory myopathies.

Necrotizing autoimmune myositis following coronavirus disease 2019 infection: a case report.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 may be associated with late-onset necrotizing myositis, mimicking autoimmune inflammatory myositis; however, the exact underlying pathogenesis of severe acute respiratory syndrome coronavirus 2-induced myositis is still unclear. CASE PRESENTATION: Herein, we report a rare case of necrotizing autoimmune myositis in a 67-year-old middle eastern male following coronavirus disease 2019 infection, who presented with muscle weakness. The patient had positive anti-NXP2. The diagnosis of necrotizing autoimmune myositis was made according to muscle weakness, increased liver enzymes, electromyography and nerve conduction velocity results, and muscle biopsy. The patient underwent a full malignancy evaluation, which was unremarkable, and was discharged in relatively well condition with a daily dose of 1 mg/kg prednisolone and azathioprine 150 mg (2 mg/kg). CONCLUSION: Our report highlights the already known possible protracted sequence of coronavirus disease 2019 infection and the potential for delayed-onset necrotizing myositis.

Factors associated with severe COVID-19 in people with idiopathic inflammatory myopathy: results from the COVID-19 Global Rheumatology Alliance physician-reported registry.

OBJECTIVES: To investigate factors associated with severe COVID-19 in people with idiopathic inflammatory myopathy (IIM). METHODS: Demographic data, clinical characteristics and COVID-19 outcome severity of adults with IIM were obtained from the COVID-19 Global Rheumatology Alliance physician-reported registry. A 3-point ordinal COVID-19 severity scale was defined: (1) no hospitalisation, (2) hospitalisation (and no death) and (3) death. ORs were estimated using multivariable ordinal logistic regression. Sensitivity analyses were performed using a 4-point ordinal scale: (1) no hospitalisation, (2) hospitalisation with no oxygen (and no death), (3) hospitalisation with oxygen/ventilation (and no death) and 4) death. RESULTS: Of 348 patients, 48% were not hospitalised, 39% were hospitalised (and did not die) and 13% died. Older age (OR=1.59/decade, 95% CI 1.31 to 1.91), high disease activity (OR=3.50, 95% CI 1.25 to 9.83; vs remission), ≥2 comorbidities (OR=2.63, 95% CI 1.39 to 4.98; vs none), prednisolone-equivalent dose >7.5 mg/day (OR=2.40, 95% CI 1.09 to 5.28; vs no intake) and exposure to rituximab (OR=2.71, 95% CI 1.28 to 5.72; vs conventional synthetic disease-modifying antirheumatic drugs only) were independently associated with severe COVID-19. In addition to these variables, in the sensitivity analyses, male sex (OR range: 1.65-1.83; vs female) was also significantly associated with severe outcomes, while COVID-19 diagnosis after 1 October 2020 (OR range: 0.51-0.59; vs on/before 15 June 2020) was significantly associated with less severe outcomes, but these associations were not significant in the main model (OR=1.57, 95% CI 0.95 to 2.59; and OR=0.61, 95% CI 0.37 to 1.00; respectively). CONCLUSIONS: This is the first large registry data on outcomes of COVID-19 in people with IIM. Older age, male sex, higher comorbidity burden, high disease activity, prednisolone-equivalent dose >7.5 mg/day and rituximab exposure were associated with severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with IIM.

What Is in the Myopathy Literature?

ABSTRACT: We cover intensive care unit-acquired neuromuscular disorders associated with coronavirus disease 2019. Outcomes may be worse than expected in these patients, and there is some evidence that coronavirus disease 2019 causes myopathy directly. Corticosteroid regimens in Duchenne muscular dystrophy are addressed including outcomes in pulmonary and cardiac function. A recent article notes a continued diagnostic delay in Duchenne muscular dystrophy. An interesting report of a Canary Islands cohort of patients with oculopharyngeal muscular dystrophy is discussed. Features and clinical pearls related to a series of patients with limb-girdle muscle dystrophy R12 (anoctaminopathy) and a misdiagnosis of idiopathic inflammatory myopathy are provided. The last section on autoimmune myopathy includes articles on clinical and pathologic features associated with myositis-specific antibodies and dermatomyositis, the epidemiology of immune-mediated necrotizing myopathies (IMNMs) in Olmsted County, Minnesota, and features of a German cohort of hydroxy-3-methylglutaryl coenzyme A reductase-associated IMNM. A recent article proposes the benefit of early intravenous immunoglobulin use for adults with IMNM. We also highlight a report of 2 unusual cases of antisignal recognition particle myopathy presenting with asymmetric distal weakness.

Covid-19 associated shoulder girdle calcific myositis: a novel entity.

OBJECTIVE: To investigate the prevalence, describe the radiological features, and consider the clinical sequelae of COVID-19- associated shoulder girdle calcific myositis. METHODS: All patients who underwent a CT pulmonary angiogram study at our institution (Queen Alexandra Hospital, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom) in April and May 2020, January 2021, and July 2021 were included. A total of 1239 CT pulmonary angiogram studies for 1201 patients were reviewed. Patients with COVID-19 and associated shoulder girdle calcific myositis were identified. Their electronic patient records were reviewed. The patients' demographics, serum inflammatory markers, and proning history were recorded. RESULTS: Of the 364 patients in Wave 1, 71 patients (19.5%) had COVID-19, and of those, 2 patients (2.8%) had shoulder girdle calcific myositis. Of the 521 patients in Wave 2, 354 patients (67.9%) had COVID-19, and of those, 3 patients (0.8%) had shoulder girdle calcific myositis. Of the 316 patients in Wave 3, 37 patients (11.7%) had COVID-19, and of those, 1 patient (2.7%) had shoulder girdle calcific myositis. The overall prevalence was 1.3%. The most common site of calcific myositis was within the subscapularis muscle. CONCLUSION: COVID-19-associated shoulder girdle calcific myositis is a rare extrapulmonary musculoskeletal manifestation of COVID-19. Early recognition and increased awareness of this disease entity, in our experience, aids in reducing patient morbidity and improving long-term functional outcome. ADVANCES IN KNOWLEDGE: We have reported a novel disease entity associated with COVID-19, in the form of shoulder girdle calcific myositis. We have described the common imaging features and discussed our experience of management and clinical sequelae.

Anti-MDA5 Antibody Linking COVID-19, Type I Interferon, and Autoimmunity: A Case Report and Systematic Literature Review.

Introduction: The SARS-CoV-2 infection has been advocated as an environmental trigger for autoimmune diseases, and a paradigmatic example comes from similarities between COVID-19 and the myositis-spectrum disease associated with antibodies against the melanoma differentiation antigen 5 (MDA5) in terms of clinical features, lung involvement, and immune mechanisms, particularly type I interferons (IFN). Case Report: We report a case of anti-MDA5 syndrome with skin manifestations, constitutional symptoms, and cardiomyopathy following a proven SARS-CoV-2 infection. Systematic Literature Review: We systematically searched for publications on inflammatory myositis associated with COVID-19. We describe the main clinical, immunological, and demographic features, focusing our attention on the anti-MDA5 syndrome. Discussion: MDA5 is a pattern recognition receptor essential in the immune response against viruses and this may contribute to explain the production of anti-MDA5 antibodies in some SARS-CoV-2 infected patients. The activation of MDA5 induces the synthesis of type I IFN with an antiviral role, inversely correlated with COVID-19 severity. Conversely, elevated type I IFN levels correlate with disease activity in anti-MDA5 syndrome. While recognizing this ia broad area of uncertainty, we speculate that the strong type I IFN response observed in patients with anti-MDA5 syndrome, might harbor protective effects against viral infections, including COVID-19.

Relapses of idiopathic inflammatory myopathies after vaccination against COVID-19: a real-life multicenter Italian study.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination plays a crucial role as pivotal strategy to curb the coronavirus disease-19 (COVID-19) pandemic. The present study described the clinical status of patients affected by idiopathic inflammatory myopathies (IIM) after COVID-19 vaccination to assess the number of relapses. We included all patients affected by IIM and followed by Myositis Clinic, Rheumatology and Respiratory Diseases Units, Siena University Hospital, Bari University Hospital, Policlinico Umberto I, Sapienza University, Rome, and Policlinico Paolo Giaccone, Palermo. They underwent a telephone survey. A total of 119 IIM patients (median, IQR 58 (47-66) years; 32males; 50 dermatomyositis, 39 polymyositis and 30 anti-synthetase syndrome) were consecutively enrolled. Except four patients who refused the vaccination, 94 (81.7%) received Comirnaty, 16 (13.9%) Spikevax, 5 (4.4%) Vaxzevria. Seven (6.1%) patients had flare after vaccination. One of them had life-threatening systemic involvement and died two months after second dose of COVID-19 vaccination. From logistic regression analysis, Chi2-log ratio = 0.045,the variable that most influences the development of flare was the number of organs involved (p = 0.047). Sixty-eight patients received the third dose of COVID-19 vaccination: 51(75%) Comirnaty and 17 (25%) Moderna. No patients had flares after third dose. Our study represents the largest cohort of IIM patients in which the incidence of recurrence after anti-SARS-CoV-2 vaccine was assessed. In line with real-life data from other diseases, we found a clinical non-statistically significant risk of relapse in our patients, which occurred seldom, usually mild and in patients with a more severe and aggressive course of disease.

Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate wide-spread non-receptor mediated immune cell recruitment (preprint)

Leukocyte recruitment from the vasculature into tissues is a crucial component of the immune system, but is also key to inflammatory disease. Chemokines are central to this process but have yet to be therapeutically targeted during inflammation, due to a lack of mechanistic understanding. Specifically, CXCL4 (PF4) has no established receptor that explains its function. Here we use biophysical, in vitro and in vivo techniques to determine the mechanism underlying CXCL4 mediated leukocyte recruitment. We demonstrate that CXCL4 binds to glycosaminoglycan (GAG) sugars within the endothelial extracellular matrix resulting in increased vascular permeability and non-specific recruitment of a range of leukocytes. Furthermore, GAG sulphation confers selectivity onto chemokine localisation. These findings represent a new understanding of chemokine biology, providing novel mechanisms for future therapeutic targeting. One sentence summary CXCL4 binds to extracellular matrix proteoglycans resulting in increased vascular permeability and recruitment of a wide range of different leukocytes via a non-canonical mechanism.

What Do We Need to Know About Musculoskeletal Manifestations of COVID-19?: A Systematic Review.

¼: COVID-19 is a disease that is challenging science, health-care systems, and humanity. An astonishingly wide spectrum of manifestations of multi-organ damage, including musculoskeletal, can be associated with SARS-CoV-2. ¼: In the acute phase of COVID-19, fatigue, myalgia, and arthralgia are the most common musculoskeletal symptoms. ¼: Post-COVID-19 syndrome is a group of signs and symptoms that are present for >12 weeks. The associated musculoskeletal manifestations are fatigue, arthralgia, myalgia, new-onset back pain, muscle weakness, and poor physical performance. ¼: Data on COVID-19 complications are growing due to large absolute numbers of cases and survivors in these 2 years of the pandemic. Additional musculoskeletal manifestations encountered are falls by the elderly, increased mortality after hip fracture, reduced bone mineral density and osteoporosis, acute sarcopenia, rhabdomyolysis, Guillain-Barré syndrome, muscle denervation atrophy, fibromyalgia, rheumatological disease triggering, septic arthritis, adhesive capsulitis, myositis, critical illness myopathy, onset of latent muscular dystrophy, osteonecrosis, soft-tissue abscess, urticarial vasculitis with musculoskeletal manifestations, and necrotizing autoimmune myositis. ¼: A wide range of signs and symptoms involving the musculoskeletal system that affect quality of life and can result in a decrease in disability-adjusted life years. This powerful and unpredictable disease highlights the importance of multimodality imaging, continuing education, and multidisciplinary team care to support preventive measures, diagnosis, and treatment.

Unaltered T cell responses to common antigens in individuals with Parkinson’s disease (preprint)

Background and Objectives Parkinson’s disease (PD) is associated with a heightened inflammatory state, including activated T cells. However, it is unclear whether these PD T cell responses are antigen specific or more indicative of generalized hyperresponsiveness. Our objective was to measure and compare antigen-specific T cell responses directed towards antigens derived from commonly encountered human pathogens/vaccines in patients with PD and age-matched healthy controls (HC). Methods Peripheral blood mononuclear cells (PBMCs) from 20 PD patients and 19 age-matched HCs were screened. Antigen specific T cell responses were measured by flow cytometry using a combination of the activation induced marker (AIM) assay and intracellular cytokine staining. Results Here we show that both PD patients and HCs show similar T cell activation levels to several antigens derived from commonly encountered human pathogens/vaccines in the general population. Similarly, we also observed no difference between HC and PD in the levels of CD4 and CD8 T cell derived cytokines produced in response to any of the common antigens tested. These antigens encompassed both viral (coronavirus, rhinovirus, respiratory syncytial virus, influenza, cytomegalovirus) and bacterial (pertussis, tetanus) targets. Conclusions These results suggest the T cell dysfunction observed in PD may not extend itself to abnormal responses to commonly encountered or vaccine-target antigens. Our study supports the notion that the targets of inflammatory T cell responses in PD may be more directed towards autoantigens like α-synuclein (α-syn) rather than common foreign antigens.

COVID-19 vaccine-associated myositis -- a case report. (preprint)

Myositis is one of the uncommon adverse events following COVID–19 vaccination, and its mechanism is still unclear. In the hope of aiding in its better understanding, we present a case of myositis following the first dose of the ChAdOx1 nCoV-19 Corona Virus Vaccine, evidenced by serology and MRI.

Myocarditis, Pulmonary Hemorrhage, and Extensive Myositis with Rhabdomyolysis 12 Days After First Dose of Pfizer-BioNTech BNT162b2 mRNA COVID-19 Vaccine: A Case Report.

BACKGROUND The COVID-19 pandemic is a current global crisis, and there are hundreds of millions of individuals being vaccinated worldwide. At present, there have been few reports of COVID-19 vaccine-induced autoimmune processes manifested as myositis, thrombocytopenia, and myocarditis. CASE REPORT A 37-year-old man presented to the Emergency Department (ED) with a 3-day history of back pain and a 1-day history of left upper limb swelling with paresthesia and shortness of breath, 12-days after receiving the first dose of Pfizer/BioNTech BNT162b2 mRNA COVID-19 vaccine. He was diagnosed with severe myositis complicated with rhabdomyolysis and non-oliguric acute kidney injury, thrombocytopenia, myocarditis with pulmonary edema, and pulmonary hemorrhage. Screens for potential toxic, infectious, paraneoplastic, and autoimmune disorders were unremarkable. The patient was treated with a 5-day course of intravenous methylprednisolone and intravenous immunoglobulin, with a good response. He was hospitalized for 16 days and discharged home on a tapering dose of oral prednisolone for 6 weeks. CONCLUSIONS The case describes a possible link between Pfizer/BioNTech BNT162b2 mRNA COVID-19 vaccine and immune-mediated myocarditis, pulmonary vasculitis, myositis, and thrombocytopenia. However, further data are required to confirm such an association.