Integrative Systems Immunology Analysis Reveals Elevated Anti-AGTR1 Levels with Accumulating COVID-19 Symptoms (preprint)

The coronavirus disease 2019 (COVID-19) displays a broad spectrum of symptoms, with the underlying reasons for this variability still not fully elucidated. Our study investigates the potential association between specific autoantibodies (AABs), notably those that targeting G protein-coupled receptors (GPCRs) and renin-angiotensin system (RAS) related molecules, and the diverse clinical manifestations of COVID-19, commonly observed in patients with autoimmune conditions, including rheumatic diseases, such as systemic sclerosis. In a cross-sectional analysis, we explored the relationship between AAB levels and the presence of key COVID-19 symptoms. Hierarchical clustering analysis revealed a robust correlation between certain AABs and symptoms such as fever, muscle ache, anosmia, and dysgeusia, which emerged as significant predictors of disease severity. Specifically, AABs against CHRM5 and CXCR3 were strongly linked to fever, while AABs against CHRM5 and BDKRB1 correlated with muscle ache. Anosmia was predominantly associated with AABs against F2R and AGTR1, while dysgeusia was linked to AABs against BDKRB1 and AGTR1. Furthermore, we observed a rise in AAB levels with the accumulation of these symptoms, with the highest levels detected in patients presenting all four predictors. Multinomial regression analysis identified AABs targeting AGTR1 as a key predictor for one or more of these core symptoms. Additionally, our study indicated that anti-AGTR1 antibodies triggered a concentration-dependent degradation of eGC, which could be mitigated by the AGTR1 antagonist Losartan. This suggests a potential mechanistic connection between eGC degradation, the observed COVID-19 symptoms, and rheumatic diseases. In conclusion, our research underscores a substantial correlation between AABs, particularly those against GPCRs and RAS-related molecules, and the severity of COVID-19 symptoms. These findings open avenues for potential therapeutic interventions in the management of COVID-19.

COVID-19 with rheumatic diseases: a report of 5 cases.

The coronavirus disease 2019 (COVID-19), the result of an infection with the new virus, SARS-CoV-2, is rapidly spreading worldwide. It is largely unknown whether the occurrence of COVID-19 in patients with rheumatic immune diseases has some specific manifestations, or makes them more prone to rapidly progress into severe COVID-19. In this case report, we describe the clinical features of 5 rheumatic immune disease patients with the concomitant presence of COVID-19. Amongst these patients, 4 had rheumatoid arthritis (RA) and 1 had systemic sclerosis (SSc). Two patients had a history of close contact with a COVID-19 patient. The age of the patients ranged between 51 and 79 years. Fever (80%), cough (80%), dyspnea (40%), and fatigue (20%) were the most common presenting symptoms. Laboratory investigations revealed leukopenia and lymphopenia in 2 patients. In all the patients, chest computerized tomography (CT) revealed patchy ground glass opacities in the lungs. During the hospital stay, the condition of two patients remained the same (i.e., mild COVID-19), two patients progressed to the severe COVID-19, and one patient worsened to the critically ill COVID-19. These patients were treated with antiviral agents for COVID-19, antibiotics for secondary bacterial infections, and immunomodulatory agents for rheumatic immune diseases. All the patients responded well, were cured of COVID-19, and subsequently discharged.

Exploring research team members' and trial participants' perceptions of acceptability and implementation within one videoconference-based supportive care program for individuals affected by systemic sclerosis during COVID-19: a qualitative interview study.

The SPIN-CHAT Program was designed to support mental health among individuals with systemic sclerosis (SSc; commonly known as scleroderma) and at least mild anxiety symptoms at the onset of COVID-19. The program was formally evaluated in the SPIN-CHAT Trial. Little is known about program and trial acceptability, and factors impacting implementation from the perspectives of research team members and trial participants. Thus, the propose of this follow-up study was to explore research team members' and trial participants' experiences with the program and trial to identify factors impacting acceptability and successful implementation. Data were collected cross-sectionally through one-on-one, videoconference-based, semi-structured interviews with 22 research team members and 30 purposefully recruited trial participants (Mage = 54.9, SD = 13.0 years). A social constructivist paradigm was adopted, and data were analyzed thematically. Data were organized into seven themes: (i) getting started: the importance of prolonged engagement and exceeding expectations; (ii) designing the program and trial: including multiple features; (iii) training: research team members are critical to positive program and trial experiences; (iv) offering the program and trial: it needs to be flexible and patient-oriented; (v) maximizing engagement: navigating and managing group dynamics; (vi) delivering a videoconference-based supportive care intervention: necessary, appreciated, and associated with some barriers; and (vii) refining the program and trial: considering modification when offered beyond the period of COVID-19 restrictions. Trial participants were satisfied with and found the SPIN-CHAT Program and Trial to be acceptable. Results offer implementation data that can guide the design, development, and refinement of other supportive care programs seeking to promote psychological health during and beyond COVID-19.

The Scleroderma Patient-centered Intervention Network COVID-19 Home-isolation Activities Together (SPIN-CHAT) Program, a videoconference-based supportive care program, was designed to protect and enhance mental health in individuals affected by systemic sclerosis (commonly known as scleroderma) with at least mild anxiety symptoms during the COVID-19 pandemic. A trial was conducted to evaluate the SPIN-CHAT Program, and results were generally positive. However, important gaps in knowledge remained. Specifically, research team members' and participants' perceptions of SPIN-CHAT Trial acceptability (including satisfaction) and factors impacting implementation of the SPIN-CHAT Program had not yet been explored. To fill this gap, we conducted one-on-one, videoconference-based, semi-structured interviewed with 22 research team members and 30 purposefully recruited trial participants. Interviews sought to gain insights into research team members' and trial participants' experiences within the SPIN-CHAT Program, delivery preferences, and aspects that were/were not beneficial. Findings suggest research team members and participants valued the SPIN-CHAT Program and found the trial to be acceptable. Results also highlight important factors to consider when designing, developing, and/or refining videoconference-based supportive care programs.

Incidence and prevalence of systemic sclerosis in Thailand in year 2017-2020: a database from the Ministry of Public Health.

BACKGROUND: A better understanding of the epidemiological profile of systemic sclerosis (SSc) in Thais could improve care, human resource deployment, and public health budgeting. OBJECTIVES: We aimed to determine the incidence and prevalence of SSc in Thailand between 2017 and 2020. METHODS: A descriptive epidemiological study was performed using the Information and Communication Technology Center, Ministry of Public Health database, comprising all types of healthcare providers during the study period. Demographic data of patients having a primary diagnosis of M34 systemic sclerosis and over 18 years of age between 2017 and 2020 were reviewed. The incidence and prevalence of SSc were calculated as well as their respective 95% confidence intervals (CIs). RESULTS: The number of SSc cases in 2017 was 15,920 from a total Thai population of 65,204,797. The prevalence of SSc in 2017 was 24.4 per 100,000 populations (95% CI 24.0-24.8). The prevalence of SSc among women was 2 times greater than among men (32.7 vs. 15.8 per 100,000). The incidence of SSc was stable from 2018 to 2019 but dropped slightly in 2020 (7.2, 7.6, and 6.8 per 100,000 person-years, respectively). Most SSc cases were in northeastern Thailand (11.6, 12.1, and 11.1 per 100,000 person-years from 2018 to 2020, respectively) and the peak was between 60 and 69 years of age (24.6, 23.8, and 20.9 per 100,000 person-years from 2018 to 2020, respectively). CONCLUSION: SSc is a rare disease among Thais. The disease was commonly revealed in late middle-aged women with a peak at age 60-69 years, mainly from the northeast regions. The incidence remained stable during the study period, albeit during the emergence of the coronavirus pandemic a slight decline was recorded. Key Points • The incidence and prevalence of systemic sclerosis (SSc) vary across ethnic populations. • There is a lack of epidemiology research of SSc since the 2013 ACR/EULAR Classification Criteria for Scleroderma was adopted among Thais included Asia-Pacific population as the population has some different clinical features than those reported among Caucasians. • SSc is a rare connective disease among Thais and commonly presents in late middle-aged group of both genders, mainly in Thailand's northern and northeastern regions. • When compare to the epidemiology of SSc in Asia-Pacific, the prevalence of SSc in Thais was higher than among East Asians and the Indian population and the incidence of SSc among Thais was greater than the other Asia-Pacific population including Australian.

Glomerulonephritis associated with systemic sclerosis: a case report.

BACKGROUND: Systemic sclerosis is a multiorgan autoimmune disease that can overlap with other rheumatologic disorders; however, co-occurrence with antineutrophil cytoplasmic antibody-associated vasculitis is rare. CASE PRESENTATION: A 39-year-old Persian female patient with systemic sclerosis according to American College of Rheumatology/European League Against Rheumatism 2013 criteria with a disease duration of 6 years was admitted to the hospital due to a rise in creatinine level in July 2021. She had complaints of nasal speech and feeling of nasal perforation. The first symptoms of antineutrophil cytoplasmic antibody-associated vasculitis had started 5 years earlier with palpable purpura in the lower limbs, hemoptysis, and positive perinuclear (p)-antibody-associated vasculitis level (> 300 AU/mL). Still, the diagnosis was not achieved due to the patient's reluctance to undergo a biopsy. She was treated with azathioprine (150 mg/day) and prednisolone (10 mg/day) during the 5-year follow-up. Her renal biopsy results showed cortical renal tissue with a cellular crescent in more than 50% of the specimen, rupture of the Bowman capsule and the glomerular basement membrane, peri-glomerular inflammation, and mild tubular atrophy in microscopic examinations. The immunofluorescence study resulted in a granular pattern of immune deposits along the glomerular basement membrane, mesangial tissue, and tubular basement membranes. CONCLUSION: We reported a rare case of comorbid systemic sclerosis and antineutrophil cytoplasmic antibody-associated vasculitis with nasal perforation. Her renal biopsy showed immune deposits along the glomerular basement membrane, mesangial tissue, and tubular basement membranes. Overlapping with other collagen vascular diseases can occur in rheumatology patients with uncommon manifestations. In systemic sclerosis, renal involvement in the form of glomerulonephritis is infrequent, and comorbid systemic lupus erythematosus or antineutrophil cytoplasmic antibody-associated vasculitis should be considered.

Systemic sclerosis and COVID-19 vaccine safety: short-term insights from the global COVID-19 vaccination in autoimmune disease (COVAD) survey.

The safety profile of COVID-19 vaccines is understudied in patients with systemic sclerosis (SSc). We compared short-term adverse events (AEs) 7 days following vaccination in patients with SSc vs other rheumatic (AIRDs), non-rheumatic autoimmune diseases (nrAIDs), and healthy controls (HCs). The COVID-19 Vaccination in autoimmune diseases (COVAD) self-reporting e-survey was circulated by a group of > 110 collaborators in 94 countries from March to December 2021. AEs were analyzed between different groups using regression models. Of 10,679 complete respondents [73.8% females, mean age 43 years, 53% Caucasians], 478 had SSc. 83% had completed two vaccine doses, Pfizer-BioNTech (BNT162b2) (51%) was the most common. Minor and major AEs were reported by 81.2% and 3.3% SSc patients, respectively, and did not differ significantly with disease activity or different vaccine types, though with minor symptom differences. Frequencies of AEs were not affected by background immunosuppression, though SSc patients receiving hydroxychloroquine experienced fatigue less commonly (OR 0.4; 95% CI 0.2-0.8). Frequency of AEs and hospitalisations were similar to other AIRDs, nrAIDs, and HC except a higher risk of chills (OR 1.3; 95% CI 1.0-1.7) and fatigue (OR 1.3; 95% CI 1.0-1.6) compared to other AIRDs. COVID-19 vaccines were largely safe and well tolerated in SSc patients in the short term. Background immunosuppression and disease activity did not influence the vaccination-related short-term AEs.

Systemic sclerosis following COVID-19 infection with recurrent corticosteroid-induced scleroderma renal crisis.

Systemic sclerosis is a complex multisystem connective tissue disease resulting in fibrosis of the skin and internal organs. Exposure to corticosteroids can trigger scleroderma renal crisis, a life-threatening complication of the disease. Autoimmune disease following infection with COVID-19 is being increasingly recognised. The mechanisms of post-COVID-19 autoimmunity are likely multifactorial, involving immune dysregulation, molecular mimicry and the development of cross-reactive antibodies. There are currently only two reported cases of systemic sclerosis occurring post-COVID-19 infection.We present the case of a female patient who developed systemic sclerosis post-COVID-19 infection. Following exposure to corticosteroids, the patient developed scleroderma renal crisis complicated by thrombotic microangiopathy, seizures and acute renal failure. Despite an antibody profile not typically associated with renal crisis (anti-topoisomerase positive, anti-RNA-polymerase III negative), the patient developed recurrent renal crisis with repeated exposure to corticosteroid therapy, highlighting the risk of steroid use in all patients with systemic sclerosis.

A systematic review of the incidence, management and prognosis of new-onset autoimmune connective tissue diseases after COVID-19.

A literature review on new-onset autoimmune connective tissue diseases (ACTDs) following COVID-19 is lacking. We evaluated potential associations between COVID-19 and the development of new-onset ACTDs. The "population" was adults with disease terms for ACTDs, including systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis (SSc), idiopathic inflammatory myositis (IIM), anti-synthetase syndrome, mixed CTD and undifferentiated CTD, and "intervention" as COVID-19 and related terms. Databases were searched for English-language articles published until September 2022. We identified 2236 articles with 28 ultimately included. Of the 28 included patients, 64.3% were female, with a mean age was 51.1 years. The USA reported the most cases (9/28). ACTD diagnoses comprised: 11 (39.3%) IIM (including four dermatomyositis); 7 (25%) SLE; four (14.3%) anti-synthetase syndrome; four (14.3%) SSc; two (7.1%) other ACTD (one lupus/MCTD overlap). Of eight, four (14.3%) patients (including that with lupus/MCTD) had lupus nephritis. The average time from COVID-19 to ACTD diagnosis was 23.7 days. A third of patients were admitted to critical care, one for treatment of haemophagocytic lymphohistiocytosis in SLE (14 sessions of plasmapheresis, rituximab and intravenous corticosteroids) and nine due to COVID-19. 80% of patients went into remission of ACTD following treatment, while three (10%) patients died-one due to macrophage activation syndrome with anti-synthetase syndrome and two from unreported causes. Our results suggest a potential association between COVID-19 and new-onset ACTDs, notably in young females, reflecting more comprehensive CTD epidemiology. The most common diagnosis in our cohort was IIM. The aetiology and mechanisms by which ACTDs emerge following COVID-19 remain unknown and require further research.

Systemic sclerosis: one year in review 2022.

Systemic sclerosis (SSc) is an autoimmune disease characterised by microvasculopathy, immune dysregulation, and skin and visceral organ fibrosis. Every year novel insights into the pathogenesis, organ involvement and treatment of this severe disease are published in the scientific community.In this review we report an overview of some of the most relevant contributions published in 2021.

Antinuclear antibodies in individuals with COVID-19 reflect underlying disease: Identification of new autoantibodies in systemic sclerosis (CDK9) and malignancy (RNF20, RCC1, TRIP13).

A high prevalence of antinuclear antibodies (ANA) in COVID-19 has been insinuated, but the nature of the target antigens is poorly understood. We studied ANA by indirect immunofluorescence in 229 individuals with COVID-19. The target antigens of high titer ANA (≥1:320) were determined by immunoprecipitation (IP) combined with liquid-chromatography-mass spectrometry (MS). High titer ANA (≥1:320) were found in 14 (6%) of the individuals with COVID-19. Of the 14 COVID-19 cases with high titer ANA, 6 had an underlying autoimmune disease and 5 a malignancy. IP-MS revealed known target antigens associated with autoimmune disease as well as novel autoantigens, including CDK9 (in systemic sclerosis) and RNF20, RCC1 and TRIP13 (in malignancy). The novel autoantigens were confirmed by IP-Western blotting. In conclusion, in depth analysis of the targets of high titer ANA revealed novel autoantigens in systemic sclerosis and in malignant disease.

Acute limb ischemia in an adolescent with COVID-19 and systemic scleroderma: a case report.

BACKGROUND: Juvenile Scleroderma is a rare autoimmune disease of the connective tissue. Its concurrence with COVID-19 can lead to limb ischemia as both disease entities are pro-inflammatory and pro-thrombotic. To date, there is no case report describing the symptomatology and course of disease in patients with juvenile Scleroderma and COVID-19. CASE PRESENTATION: An adolescent with acute limb ischemia presented with a history of generalized hypo-and-hyperpigmented skin lesions and mild, non-productive cough. She tested positive for SARS-CoV-2 on nasopharyngeal swab RT-PCR. Further work-up revealed elevated anti-phospholipid antibodies, anti-nuclear antibody, and D-dimer; low Protein S activity; and evidence of peripheral arterial disease on imaging studies. She was started on peripheral vasodilators, Methotrexate, and anticoagulation. Close monitoring of the affected limbs and other organs involved was done. Control of limb ischemia was achieved after 4 months of regular Cyclophosphamide infusion. Continued multi-disciplinary care was ensured for this patient. CONCLUSION: There is evolving knowledge about the interplay of COVID-19 hyperinflammatory state and rheumatologic disorders. COVID-19 is thought to exacerbate cutaneous manifestations of autoimmune disorders via antigen protein mimicry and cytokine imbalance. Moreover, COVID-19 is characterized by complex hematopathologic processes that put a patient in a hypercoagulable state. Elevated D-dimer can be seen in both COVID-19 and systemic sclerosis owing to their pro-thrombotic sequela. There is scarcity of data on the association of Protein S activity with COVID-19 and systemic sclerosis. More studies need to be carried out to ultimately arrive at a consensus on thrombosis prophylaxis for patients with Scleroderma and COVID-19.

Sudden winter iloprost withdrawal in scleroderma patients during COVID-19 pandemic.

INTRODUCTION: Intravenous iloprost is currently recommended in the treatment of Raynaud's phenomenon (RP) refractory to oral therapy and of digital ulcers (DUs) related to systemic sclerosis (SSc). In real-life practice there is a huge heterogeneity about the Iloprost regimens used. METHODS: A survey was carried out on SSc patients that interrupted Iloprost infusion to compare acral vascular symptoms just before Iloprost withdrawal and just after the missed infusion. Severity, and frequency of RP, new DUs onset or aggravation of those pre-existing were reported. Last available capillaroscopic images were also evaluated. RESULTS: The analysis includes 50 patients. After iloprost withdrawal, 11 patients reported a RP worsening because of enhanced intensity (p = 0.007). Only 8 patients of them also complained of an increased frequency (p = 0.07). None of the patients experienced digital ulcers for the first-time during quarantine. Among the 27 patients with a history of digital ulcers, 9 reported worsening and 7 recurrence of DUs. Overall, 17 patients (34.0 %) complained of a worsening of SSc vascular acral manifestations, namely RP or DUs. Reduced capillary density was associated with RP worsening, in particular, each unit increase of capillary density corresponds to an average 44 % decrease in the odds of RP worsening (OR 0.56, CI 95 % 0.36-0.97, p = 0.037). As for RP worsening, the aggravation of DU was associated with a lower capillary density. CONCLUSIONS: Low capillary density can predict a worsening of both RP and DUs in controlled quarantine conditions within a month after iloprost discontinuation in SSc patients.

Generalized morphea following the COVID vaccine: A series of two patients and a bibliographic review.

The appearance of morphea after vaccination has been reported to date as single and deep lesions that appear exactly at the site of the skin puncture. It was therefore postulated that the origin could be the trauma related to the injection. The aim of this article is to review the various hypotheses offered in the published literature about generalized morphea following vaccination. We present two cases of generalized morphea after COVID-19 vaccination and review the published literature on immune-related cutaneous reactions. As previously reported, antigenic cross-reactivity between vaccine spike proteins and human tissues could cause certain immune-mediated diseases, including generalized morphea. Herein we report two cases of generalized morphea probably induced by the COVID-19 vaccine, given the temporal relationship with its administration. In summary, environmental factors such as vaccination against SARS-COV-2 could induce an immune system dysregulation, which would have an important role in the pathogenesis of morphea. We present two cases of generalized morphea probably induced by the COVID-19 vaccine, given the time elapsed between vaccination and the onset of the skin lesions.