Risk and prognosis of SARS-CoV-2 infection and vaccination against SARS-CoV-2 in rheumatic and musculoskeletal diseases: a systematic literature review to inform EULAR recommendations.

OBJECTIVES: Perform a systematic literature review (SLR) on risk and prognosis of SARS-CoV-2 infection and vaccination against SARS-CoV-2 in patients with rheumatic and musculoskeletal diseases (RMDs). METHODS: Literature was searched up to 31 May 2021, including (randomised) controlled trials and observational studies with patients with RMD. Pending quality assessment, data extraction was performed and risk of bias (RoB) was assessed. Quality assessment required provision of (1) an appropriate COVID-19 case definition, and (2a) a base incidence (for incidence data) or (2b) a comparator, >10 cases with the outcome and risk estimates minimally adjusted for age, sex and comorbidities (for risk factor data). RESULTS: Of 5165 records, 208 were included, of which 90 passed quality assessment and data were extracted for incidence (n=42), risk factor (n=42) or vaccination (n=14). Most studies had unclear/high RoB. Generally, patients with RMDs do not face more risk of contracting SARS-CoV-2 (n=26 studies) or worse prognosis of COVID-19 (n=14) than individuals without RMDs. No consistent differences in risk of developing (severe) COVID-19 were found between different RMDs (n=19). Disease activity is associated with worse COVID-19 prognosis (n=2), possibly explaining the increased risk seen for glucocorticoid use (n=13). Rituximab is associated with worse COVID-19 prognosis (n=7) and possibly Janus kinase inhibitors (n=3). Vaccination is generally immunogenic, though antibody responses are lower than in controls. Vaccine immunogenicity is negatively associated with older age, rituximab and mycophenolate. CONCLUSION: This SLR informed the July 2021 update of the European Alliance of Associations for Rheumatology recommendations for the management of RMDs in the context of SARS-CoV-2.

Long COVID: rheumatologic/musculoskeletal symptoms in hospitalized COVID-19 survivors at 3 and 6 months.

OBJECTIVE: To document the detailed characteristics including severity, type, and locations of rheumatic and musculoskeletal symptoms along with other COVID-19 persistent symptoms in hospitalized COVID-19 survivors at 3 and 6 months. METHODS: In this extension cohort study, two telephone surveys at 3 and 6 months following the hospitalization were carried out. In these telephone surveys, participants were asked regarding their symptoms through a previously designed standard questionnaire. RESULTS: At 3 months, 89.0% of survivors had at least one symptom, 74.6% had at least one rheumatic and musculoskeletal symptom, and 82.1% had at least one other COVID-19 symptom. At 6 months, 59.6% of survivors had at least one symptom, 43.2% had at least one rheumatic and musculoskeletal symptom, and 51.2% had at least one other COVID-19 symptom. Regarding the rheumatic and musculoskeletal symptoms, 31.6% had fatigue, 18.6% had joint pain, and 15.1% had myalgia; and regarding the other-COVID-19-symptoms, 25.3% had dyspnea, 20.0% had hair loss, and 17.2% sweat at 6 months. In an adjusted model, female patients were more likely to have fatigue (OR: 1.99, 95% CI: 1.18-3.34), myalgia (3.00, 1.51-5.98), and joint pain (3.39, 1.78-6.50) at 6 months. CONCLUSION: Approximately 3 in 5 patients had at least one symptom with ≈2 in 5 patients had at least one rheumatic and musculoskeletal symptom. Fatigue, joint pain, and myalgia were the most frequent rheumatic and musculoskeletal symptoms. Joint pain and myalgia were mostly widespread. This information guide rheumatologists to understand the nature and features of persistent rheumatic and musculoskeletal symptoms in hospitalized COVID-19 survivors and may contribute to better management of these individuals. Key Points • Approximately 3 in 5 patients had at least one symptom with ≈2 in 5 patients had at least one rheumatic and musculoskeletal symptom at 6 months • Fatigue, joint pain, and myalgia were the most frequent rheumatic and musculoskeletal symptoms followed by back pain, low back pain, and neck pain • Dyspnea, hair loss, and sweat were the most frequent other-COVID-19-symptoms.

Cluster analysis reveals three main patterns of beliefs and intention with respect to SARS-CoV-2 vaccination in patients with autoimmune and inflammatory diseases.

INTRODUCTION: Given the COVID-19 pandemic, it is crucial to understand the underlying behavioural determinants of SARS-CoV-2 vaccine hesitancy in patients with autoimmune or inflammatory rheumatic diseases (AIIRDs). We aimed to analyse patterns of beliefs and intention regarding SARS-CoV-2 vaccination in AIIRD patients, as a mean of identifying pragmatic actions that could be taken to increase vaccine coverage in this population. METHODS: Data relating to 1258 AIIRD patients were analysed using univariate and multivariate logistic regression models, to identify variables associated independently with willingness to get vaccinated against SARS-CoV-2. Subsets of patients showing similar beliefs and intention about SARS-CoV-2 vaccination were characterized using cluster analysis. RESULTS: Hierarchical cluster analysis identified three distinct clusters of AIIRD patients. Three predominant patient attitudes to SARS-COV-2 vaccination were identified: voluntary, hesitant and suspicious. While vaccine willingness differed significantly across the three clusters (P < 0.0001), there was no significant difference regarding fear of getting COVID-19 (P = 0.11), the presence of comorbidities (P = 0.23), the use of glucocorticoids (P = 0.21), or immunocompromised status (P = 0.63). However, patients from cluster #2 (hesitant) and #3 (suspicious) were significantly more concerned about vaccination, the use of a new vaccine technology, lack of long-term data in relation to COVID-19 vaccination, and potential financial links with pharmaceutical companies (P < 0.0001 in all) than patients from cluster #1 (voluntary). DISCUSSION: Importantly, the differences between clusters in terms of patient beliefs and intention was not related to the fear of getting COVID-19 or to any state of frailty, but was related to specific concerns about vaccination. This study may serve as a basis for improved communication and thus help increase COVID-19 vaccine coverage among AIIRD patients.

Risk of coronavirus disease 2019 hospitalization and mortality in rheumatic patients treated with hydroxychloroquine or other conventional disease-modifying anti-rheumatic drugs in Italy.

OBJECTIVES: To ascertain if the use of hydroxychloroquine(HCQ)/cloroquine(CLQ) and other conventional DMARDs (cDMARDs) and rheumatic diseases per se may be associated with COVID-19-related risk of hospitalization and mortality. METHODS: This case-control study nested within a cohort of cDMARD users was conducted in the Lombardy, Veneto, Tuscany and Lazio regions and Reggio Emilia province. Claims databases were linked to COVID-19 surveillance registries. The risk of COVID-19-related outcomes was estimated using a multivariate conditional logistic regression analysis comparing HCQ/CLQ vs MTX, vs other cDMARDs and vs non-use of these drugs. The presence of rheumatic diseases vs their absence in a non-nested population was investigated. RESULTS: A total of 1275 patients hospitalized due to COVID-19 were matched to 12 734 controls. Compared with recent use of MTX, no association between HCQ/CLQ monotherapy and COVID-19 hospitalization [odds ratio (OR) 0.83 (95% CI 0.69, 1.00)] or mortality [OR 1.19 (95% CI 0.85, 1.67)] was observed. A lower risk was found when comparing HCQ/CLQ use with the concomitant use of other cDMARDs and glucocorticoids. HCQ/CLQ was not associated with COVID-19 hospitalization as compared with non-use. An increased risk for recent use of either MTX monotherapy [OR 1.19 (95% CI 1.05, 1.34)] or other cDMARDs [OR 1.21 (95% CI 1.08, 1.36)] vs non-use was found. Rheumatic diseases were not associated with COVID-19-related outcomes. CONCLUSION: HCQ/CLQ use in rheumatic patients was not associated with a protective effect against COVID-19-related outcomes. The use of other cDMARDs was associated with an increased risk when compared with non-use and, if concomitantly used with glucocorticoids, also vs HCQ/CLQ, probably due to immunosuppressive action.

Incidence and severeness of COVID-19 hospitalization in patients with inflammatory rheumatic disease: a nationwide cohort study from Denmark.

OBJECTIVES: To estimate the incidence of COVID-19 hospitalization in patients with inflammatory rheumatic disease (IRD); in patients with RA treated with specific DMARDs; and the incidence of severe COVID-19 infection among hospitalized patients with RA. METHODS: A nationwide cohort study from Denmark between 1 March and 12 August 2020. The adjusted incidence of COVID-19 hospitalization was estimated for patients with RA; spondyloarthritis including psoriatic arthritis; connective tissue disease; vasculitides; and non-IRD individuals. Further, the incidence of COVID-19 hospitalization was estimated for patients with RA treated and non-treated with TNF-inhibitors, HCQ or glucocorticoids, respectively. Lastly, the incidence of severe COVID-19 infection (intensive care, acute respiratory distress syndrome or death) among hospital-admitted patients was estimated for RA and non-IRD sp - individudals. RESULTS: Patients with IRD (n = 58 052) had an increased partially adjusted incidence of hospitalization with COVID-19 compared with the 4.5 million people in the general population [hazard ratio (HR) 1.46, 95% CI: 1.15, 1.86] with strongest associations for patients with RA (n = 29 440, HR 1.72, 95% CI: 1.29, 2.30) and vasculitides (n = 4072, HR 1.82, 95% CI: 0.91, 3.64). There was no increased incidence of COVID-19 hospitalization associated with TNF-inhibitor, HCQ nor glucocorticoid use. COVID-19 admitted patients with RA had a HR of 1.43 (95% CI: 0.80, 2.53) for a severe outcome. CONCLUSION: Patients with IRD were more likely to be admitted with COVID-19 than the general population, and COVID-19 admitted patients with RA could be at higher risk of a severe outcome. Treatment with specific DMARDs did not affect the risk of hospitalization.

Outcomes of COVID-19 in a cohort of pediatric patients with rheumatic diseases.

BACKGROUND: There are few reports of COVID-19 in pediatric patients with rheumatic diseases. This study describes the clinical presentation and outcomes of COVID-19 in this population. METHODS: We analyzed a single-center case series of pediatric patients with rheumatic diseases and laboratory-confirmed COVID-19. Demographic, baseline and COVID-19 associated clinical features were compared between ambulatory and hospitalized patients using univariate analysis. RESULTS: Fifty-five cases were identified: 45 (81.8%) in the ambulatory group and 10 (18.2%) hospitalized. African American race (OR 7.78; 95% CI [1.46-55.38]; p = 0.006) and cardiovascular disease (OR 19.40; 95% CI 2.45-254.14; p = 0.001) predominated in hospitalized patients. Active rheumatic disease (OR 11.83; 95% CI 1.43-558.37; p = 0.01), medium/high-dose corticosteroid use (OR 14.12; 95% CI [2.31-106.04]; p = 0.001), mycophenolate use (OR 8.84; 95% CI [1.64-63.88]; p = 0.004), rituximab use (OR 19.40; 95% CI [2.45-254.14]; p = 0.001) and severe immunosuppression (OR 34.80; 95% CI [3.94-1704.26]; p = < 0.001) were associated with increased odds of hospitalization. Fever (OR 7.78; 95% CI [1.46-55.38]; p = 0.006), dyspnea (OR 26.28; 95% CI [2.17-1459.25]; p = 0.003), chest pain (OR 13.20; 95% CI [1.53-175.79]; p = 0.007), and rash (OR 26.28; 95% CI [2.17-1459.25]; p = 0.003) were more commonly observed in hospitalized patients. Rheumatic disease flares were almost exclusive to hospitalized patients (OR 55.95; 95% CI [5.16-3023.74]; p < 0.001).. One patient did not survive. CONCLUSIONS: Medium/high-dose corticosteroid, mycophenolate and rituximab use, and severe immunosuppression were risk factors for hospitalization. Fever, dyspnea, chest pain, and rash were high-risk symptoms for hospitalization. Rheumatic disease activity and flare could contribute to the need for hospitalization.

How to Manage COVID-19 Vaccination in Immune-Mediated Inflammatory Diseases: An Expert Opinion by IMIDs Study Group.

Since March 2020, the outbreak of Sars-CoV-2 pandemic has changed medical practice and daily routine around the world. Huge efforts from pharmacological industries have led to the development of COVID-19 vaccines. In particular two mRNA vaccines, namely the BNT162b2 (Pfizer-BioNTech) and the mRNA-1273 (Moderna), and a viral-vectored vaccine, i.e. ChAdOx1 nCoV-19 (AstraZeneca), have recently been approved in Europe. Clinical trials on these vaccines have been published on the general population showing a high efficacy with minor adverse events. However, specific data about the efficacy and safety of these vaccines in patients with immune-mediated inflammatory diseases (IMIDs) are still lacking. Moreover, the limited availability of these vaccines requires prioritizing some vulnerable categories of patients compared to others. In this position paper, we propose the point of view about the management of COVID-19 vaccination from Italian experts on IMIDs and the identification of high-risk groups according to the different diseases and their chronic therapy.

COVID-19 Outcomes in Patients With Systemic Autoimmune Rheumatic Diseases Compared to the General Population: A US Multicenter, Comparative Cohort Study.

OBJECTIVE: Patients with systemic autoimmune rheumatic diseases (ARDs) continue to be concerned about risks of severe coronavirus disease 2019 (COVID-19) outcomes. This study was undertaken to evaluate the risks of severe outcomes in COVID-19 patients with systemic ARDs compared to COVID-19 patients without systemic ARDs. METHODS: Using a large multicenter electronic health record network, we conducted a comparative cohort study of patients with systemic ARDs diagnosed as having COVID-19 (identified by diagnostic code or positive molecular test result) compared to patients with COVID-19 who did not have systemic ARDs, matched for age, sex, race/ethnicity, and body mass index (primary matched model) and additionally matched for comorbidities and health care utilization (extended matched model). Thirty-day outcomes were assessed, including hospitalization, intensive care unit (ICU) admission, mechanical ventilation, acute renal failure requiring renal replacement therapy, ischemic stroke, venous thromboembolism, and death. RESULTS: We initially identified 2,379 COVID-19 patients with systemic ARDs (mean age 58 years; 79% female) and 142,750 comparators (mean age 47 years; 54% female). In the primary matched model (2,379 patients with systemic ARDs and 2,379 matched comparators with COVID-19 without systemic ARDs), patients with systemic ARDs had a significantly higher risk of hospitalization (relative risk [RR] 1.14 [95% confidence interval (95% CI) 1.03-1.26]), ICU admission (RR 1.32 [95% CI 1.03-1.68]), acute renal failure (RR 1.81 [95% CI 1.07-3.07]), and venous thromboembolism (RR 1.74 [95% CI 1.23-2.45]) versus comparators but did not have a significantly higher risk of mechanical ventilation or death. In the extended model, all risks were largely attenuated, except for the risk of venous thromboembolism (RR 1.60 [95% CI 1.14-2.25]). CONCLUSION: Our findings indicate that COVID-19 patients with systemic ARDs may be at a higher risk of hospitalization, ICU admission, acute renal failure, and venous thromboembolism when compared to COVID-19 patients without systemic ARDs. These risks may be largely mediated by comorbidities, except for the risk of venous thromboembolism.

Herpes zoster following BNT162b2 mRNA COVID-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series.

OBJECTIVES: As global vaccination campaigns against COVID-19 disease commence, vaccine safety needs to be closely assessed. The safety profile of mRNA-based vaccines in patients with autoimmune inflammatory rheumatic diseases (AIIRD) is unknown. The objective of this report is to raise awareness of reactivation of herpes zoster (HZ) following the BNT162b2 mRNA vaccination in patients with AIIRD. METHODS: The safety of the BNT162b2 mRNA vaccination was assessed in an observational study monitoring post-vaccination adverse effects in patients with AIIRD (n = 491) and controls (n = 99), conducted in two rheumatology departments in Israel. RESULTS: The prevalence of HZ was 1.2% (n = 6) in patients with AIIRD compared with none in controls. Six female patients aged 49 ± 11 years with stable AIIRD: RA (n = 4), Sjogren's syndrome (n = 1), and undifferentiated connective disease (n = 1), developed the first in a lifetime event of HZ within a short time after the first vaccine dose in five cases and after the second vaccine dose in one case. In the majority of cases, HZ infection was mild, except a case of HZ ophthalmicus, without corneal involvement, in an RA patient treated with tofacitinib. There were no cases of disseminated HZ disease or postherpetic neuralgia. All but one patient received antiviral treatment with a resolution of HZ-related symptoms up to 6 weeks. Five patients completed the second vaccine dose without other adverse effects. CONCLUSION: Epidemiologic studies on the safety of the mRNA-based COVID-19 vaccines in patients with AIIRD are needed to clarify the association between the BNT162b2 mRNA vaccination and reactivation of zoster.

Autoimmune and Rheumatic Manifestations Associated With COVID-19 in Adults: An Updated Systematic Review.

Background: Numerous cases of the coronavirus disease 2019 (COVID-19) with autoimmune and rheumatic manifestations have been reported. Despite the available reviews that summarized its autoimmune/rheumatic manifestations, a systematic approach is still lacking. Therefore, we conducted a comprehensive systematic review in order to give an overview upon these rare but clinically significant manifestations. Methods: We performed a literature search of PubMed and EMBASE as of October 9, 2020. All articles relevant to either systemic or organ-specific autoimmune and rheumatic manifestations potentially associated with COVID-19 were collected. The reviewed literature were limited to adults ≥18 years. Results: Although most of the existing evidence was based on case reports or case series without a long-term follow-up, a variety of autoimmune/rheumatic manifestations were associated with COVID-19. The manifestations that have a consistent association with COVID-19 include autoimmune cytopenia, cutaneous vasculitis, encephalitis, and Guillain-Barre syndrome. Such association is conflicting as regards to antiphospholipid syndrome, hemophagocytic lymphohistiocytosis, and myasthenia gravis. Conclusion: Our systematic review indicated the potential of the COVID-19 virus to trigger a myriad of autoimmune and rheumatic manifestations, which should be considered amid global efforts to combat COVID-19.

Association of Race and Ethnicity With COVID-19 Outcomes in Rheumatic Disease: Data From the COVID-19 Global Rheumatology Alliance Physician Registry.

OBJECTIVE: Racial/ethnic minorities experience more severe outcomes of coronavirus disease 2019 (COVID-19) in the general US population. This study was undertaken to examine the association between race/ethnicity and COVID-19 hospitalization, ventilation status, and mortality in people with rheumatic disease. METHODS: US patients with rheumatic disease and COVID-19 were entered into the COVID-19 Global Rheumatology Alliance physician registry between March 24, 2020 and August 26, 2020 were included. Race/ethnicity was defined as White, African American, Latinx, Asian, or other/mixed race. Outcome measures included hospitalization, requirement for ventilatory support, and death. Multivariable regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for age, sex, smoking status, rheumatic disease diagnosis, comorbidities, medication use prior to infection, and rheumatic disease activity. RESULTS: A total of 1,324 patients were included, of whom 36% were hospitalized and 6% died; 26% of hospitalized patients required mechanical ventilation. In multivariable models, African American patients (OR 2.74 [95% CI 1.90-3.95]), Latinx patients (OR 1.71 [95% CI 1.18-2.49]), and Asian patients (OR 2.69 [95% CI 1.16-6.24]) had higher odds of hospitalization compared to White patients. Latinx patients also had 3-fold increased odds of requiring ventilatory support (OR 3.25 [95% CI 1.75-6.05]). No differences in mortality based on race/ethnicity were found, though power to detect associations may have been limited. CONCLUSION: Similar to findings in the general US population, racial/ethnic minorities with rheumatic disease and COVID-19 had increased odds of hospitalization and ventilatory support. These results illustrate significant health disparities related to COVID-19 in people with rheumatic diseases. The rheumatology community should proactively address the needs of patients currently experiencing inequitable health outcomes during the pandemic.

Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry.

OBJECTIVES: To determine factors associated with COVID-19-related death in people with rheumatic diseases. METHODS: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. RESULTS: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. CONCLUSION: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.

Syndemics & syndemogenesis in COVID-19 and rheumatic and musculoskeletal diseases: old challenges, new era.

People with rheumatic and musculoskeletal diseases (RMDs) are facing several challenges during the COVID-19 pandemic, such as poor access to regular health services and drug shortages, particularly in developing countries. COVID-19 represents a syndemic, synergistic condition that interacts with and exacerbates pre-existing diseases such as RMDs, other co-morbidities and social conditions. The emerging evidence on both biological and non-biological factors implicated in worse outcomes in people with RMDs affected by the COVID-19 pandemic, whether infected by the virus or not, calls for the need to use more novel and holistic frameworks for studying disease. In this context, the use of a syndemic framework becomes particularly relevant. We appeal for a focus on the identification of barriers and facilitators to optimal care of RMDs in the context of the COVID-19 pandemic, in order to tackle both the pandemic itself and the health inequities inherent to it.