Update on autoinflammatory diseases.

PURPOSE OF REVIEW: Although the concept of systemic autoinflammatory diseases (SAIDs) is still very young, our knowledge about them is exponentially growing. In the current review, we aim to discuss novel SAIDs and autoinflammatory pathways discovered in the last couple of years. RECENT FINDINGS: Advances in immunology and genetics have led to the discovery of new pathways involved in autoinflammation, as well as several new SAIDs, including retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache (ROSAH syndrome), vacuoles, E1 enzyme, X-linked autoinflammatory somatic (VEXAS) syndrome, TBK1 deficiency, NEMO deleted exon 5 autoinflammatory syndrome (NDAS), and disabling pansclerotic morphea. Progress in immunobiology and genetics has also brought forth novel treatments for SAIDs. Personalized medicine has made significant progress in areas such as cytokine-targeted therapies and gene therapies. However, much work remains, especially in measuring and improving the quality of life in patients with SAIDs. SUMMARY: In the current review, we discuss the novelties in the world of SAIDs, including mechanistic pathways of autoinflammation, pathogenesis, and treatment. We hope this review helps rheumatologists to gain an updated understanding of SAIDs.

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.

The COVID-19 Global Rheumatology Alliance: evaluating the rapid design and implementation of an international registry against best practice.

OBJECTIVES: As the coronavirus disease 2019 pandemic developed there was a paucity of data relevant to people living with rheumatic disease. This led to the development of a global, online registry to meet these information needs. This manuscript provides a detailed description of the coronavirus disease 2019 Global Rheumatology Alliance registry development, governance structure, and data collection, and insights into new ways of rapidly establishing global research collaborations to meet urgent research needs. METHODS: We use previously published recommendations for best practices for registry implementation and describe the development of the Global Rheumatology Alliance registry in terms of these steps. We identify how and why these steps were adapted or modified. In Phase 1 of registry development, the purpose of the registry and key stakeholders were identified on online platforms, Twitter and Slack. Phase 2 consisted of protocol and data collection form development, team building and the implementation of governance and policies. RESULTS: All key steps of the registry development best practices framework were met, though with the need for adaptation in some areas. Outputs of the registry, two months after initial conception, are also described. CONCLUSION: The Global Rheumatology Alliance registry will provide highly useful, timely data to inform clinical care and identify further research priorities for people with rheumatic disease with coronavirus disease 2019. The formation of an international team, easily able to function in online environments and resulting in rapid deployment of a registry is a model that can be adapted for other disease states and future global collaborations.

Microbiome is not linked to clinical disease severity of familial Mediterranean fever in an international cohort of children.

OBJECTIVES: The severity of familial Mediterranean fever (FMF) may vary in different areas, suggesting a role for environmental factors. We analysed the composition of gut microbiota among children with FMF and healthy controls from Turkey and the USA and determined its effect on disease severity. METHODS: Children with FMF with pathogenic MEFV mutations and healthy controls from Turkey and the USA were enrolled. FMF disease activity was evaluated with the Autoinflammatory Disease Activity Index (AIDAI). Gut bacterial diversity was assessed by sequencing 16S rRNA gene libraries. RESULTS: We included 36 children from Turkey (28 patients with FMF, 8 healthy controls), and 21 patients and 6 controls from the USA. In the Turkish group, 28.6% of patients had severe disease, while 13.3% of US group patients had severe disease. As expected, we observed substantial differences between the gut microbiota of children from the two geographic regions, with Turkish patients and controls exhibiting higher relative abundances of Bacteriodia, while US patients and controls exhibited higher relative abundances of Clostridia. Alpha- and betadiversity did not differ significantly between FMF patients and controls, and neither was predictive of disease severity within each geographic region. We observed differences between FMF patients and controls in the relative abundance of some bacterial taxa at the amplicon sequence variant (ASV) level, but these differences received mixed statistical support. CONCLUSIONS: Among an international cohort of children with FMF, we did not find a strong effect of gut microbiota composition on disease severity. Other environmental or epigenetic factors may be operative.

Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry.

OBJECTIVES: COVID-19 outcomes in people with rheumatic diseases remain poorly understood. The aim was to examine demographic and clinical factors associated with COVID-19 hospitalisation status in people with rheumatic disease. METHODS: Case series of individuals with rheumatic disease and COVID-19 from the COVID-19 Global Rheumatology Alliance registry: 24 March 2020 to 20 April 2020. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Age, sex, smoking status, rheumatic disease diagnosis, comorbidities and rheumatic disease medications taken immediately prior to infection were analysed. RESULTS: A total of 600 cases from 40 countries were included. Nearly half of the cases were hospitalised (277, 46%) and 55 (9%) died. In multivariable-adjusted models, prednisone dose ≥10 mg/day was associated with higher odds of hospitalisation (OR 2.05, 95% CI 1.06 to 3.96). Use of conventional disease-modifying antirheumatic drug (DMARD) alone or in combination with biologics/Janus Kinase inhibitors was not associated with hospitalisation (OR 1.23, 95% CI 0.70 to 2.17 and OR 0.74, 95% CI 0.37 to 1.46, respectively). Non-steroidal anti-inflammatory drug (NSAID) use was not associated with hospitalisation status (OR 0.64, 95% CI 0.39 to 1.06). Tumour necrosis factor inhibitor (anti-TNF) use was associated with a reduced odds of hospitalisation (OR 0.40, 95% CI 0.19 to 0.81), while no association with antimalarial use (OR 0.94, 95% CI 0.57 to 1.57) was observed. CONCLUSIONS: We found that glucocorticoid exposure of ≥10 mg/day is associated with a higher odds of hospitalisation and anti-TNF with a decreased odds of hospitalisation in patients with rheumatic disease. Neither exposure to DMARDs nor NSAIDs were associated with increased odds of hospitalisation.

Burden of illness in hereditary periodic fevers: a multinational observational patient diary study.

OBJECTIVES: This study aimed to characterise the burden of illness of patients with inadequately controlled hereditary periodic fevers (HPFs), during and outside of flares. It was focused on the burden to the patients and also considered the wider impact on their caregivers and families. METHODS: The target population was patients or caregivers of patients with clinically/genetically confirmed colchicine resistant FMF (crFMF), mevalonate kinase deficiency/hyperimmunoglobinaemia D with periodic fever syndrome (MKD/HIDS) or TRAPS, who were expected to flare at least once in a 6-month period based on patient history. Disease burden was captured during and between flares using an electronic diary (e-diary) with questions on patient functioning, emotional/social well-being and pain, using validated instruments. RESULTS: HPF-related symptoms such as fever, joint, muscle or bone pain and tiredness and fatigue were reported by patients both during and outside of a flare. The SF-10 Health Survey (SF-10v2) (paediatric patients) and SF-12 Health Survey (SF-12v2) (adult patients) showed that flares negatively impacted patients' psychosocial and physical health. Negative effect of on-flare status on health utility index score assessed by the Short-Form Six-Dimension (SF-6D) was significant only for crFMF patients. Furthermore, the Sheehan Disability Score (SDSv3) showing the on-flare status resulted in significant functional impairment in all 3 disease cohorts through assessment of impact on work/school, social and family life. CONCLUSIONS: crFMF, MKD/HIDS and TRAPS negatively affected the quality of life (QoL) of adult and paediatric patients, including their physical, mental, psychosocial health, and social functioning. There remains, however, a high number of unmet needs for these patients to reduce their disease burden.

Targeting cytokines to treat autoinflammatory diseases.

Autoinflammatory diseases are rare group of conditions manifested by recurrent fevers, systemic inflammation, and dysfunctions of the innate immune system. These conditions are characterized by overproduction or lack of inhibition of various cytokines, and the advent of biologic drugs that block specific cytokines involved in these conditions has revolutionized their treatment. In this review, I will discuss the most common autoinflammatory conditions of adulthood including familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), mevalonate kinase deficiency/hyperimmunoglobulinemia D Syndrome (MKD/HIDS), TNF receptor-associated autoinflammatory syndrome (TRAPS), and systemic juvenile idiopathic arthritis/adult-onset Still's disease (SJIA/AOSD). I will discuss how IL-1, IL-6, IL-18, and TNF play pathogenic roles in these conditions and will review the evidence behind cytokine blockade for these diseases. Throughout the paper, I will reflect on gaps in knowledge of autoinflammatory diseases and will highlight the latest advances and newest drugs in development.

Physicians' perspectives on the diagnosis and management of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome.

To assess the practice patterns of pediatric rheumatology and infectious diseases subspecialists in the diagnosis and treatment of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. An online survey assessing diagnostic and treatment approaches was sent to 424 members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and 980 members of the Pediatric Infectious Disease Society (PIDS). 277 physicians (123 from CARRA and 154 from PIDS representing 21% of the total membership) completed the survey. To diagnose PFAPA, most respondents agreed that patients must have the following features of the diagnostic criteria: stereotypical fever episodes (95%), asymptomatic intervals between episodes (93%), and normal growth and development (81%). However, 71% of the respondents did not require age of onset <5 years, 33% did not require regular intervals between episodes, and 79% did not require the concomitant signs of aphthous stomatitis, adenitis, or pharyngitis during episodes as long as episodes were regular. Over half (58%) considered episode resolution with steroids to be diagnostic of PFAPA. Corticosteroids, antipyretics, tonsillectomy, and cimetidine were the most commonly prescribed treatments, while steroids and tonsillectomy were most effective. Subspecialists in pediatric rheumatology and infectious diseases showed limited adherence to the complete published criteria for diagnosing PFAPA suggesting heterogeneity in the characteristics of patients diagnosed with the disorder. These findings emphasize the need to develop consensus diagnostic and treatment guidelines in well-characterized patient populations.

Impact of Risk Factors on COVID-19 Outcomes in Unvaccinated People With Rheumatic Diseases: A Comparative Analysis of Pandemic Epochs Using the COVID-19 Global Rheumatology Alliance Registry.

OBJECTIVE: Approximately one third of individuals worldwide have not received a COVID-19 vaccine. Although studies have investigated risk factors linked to severe COVID-19 among unvaccinated people with rheumatic diseases (RDs), we know less about whether these factors changed as the pandemic progressed. We aimed to identify risk factors associated with severe COVID-19 in unvaccinated individuals in different pandemic epochs corresponding to major variants of concern. METHODS: Patients with RDs and COVID-19 were entered into the COVID-19 Global Rheumatology Alliance Registry between March 2020 and June 2022. An ordinal logistic regression model (not hospitalized, hospitalized, and death) was used with date of COVID-19 diagnosis, age, sex, race and/or ethnicity, comorbidities, RD activity, medications, and the human development index (HDI) as covariates. The main analysis included all unvaccinated patients across COVID-19 pandemic epochs; subanalyses stratified patients according to RD types. RESULTS: Among 19,256 unvaccinated people with RDs and COVID-19, those who were older, male, had more comorbidities, used glucocorticoids, had higher disease activity, or lived in lower HDI regions had worse outcomes across epochs. For those with rheumatoid arthritis, sulfasalazine and B-cell-depleting therapy were associated with worse outcomes, and tumor necrosis factor inhibitors were associated with improved outcomes. In those with connective tissue disease or vasculitis, B-cell-depleting therapy was associated with worse outcomes. CONCLUSION: Risk factors for severe COVID-19 outcomes were similar throughout pandemic epochs in unvaccinated people with RDs. Ongoing efforts, including vaccination, are needed to reduce COVID-19 severity in this population, particularly in those with medical and social vulnerabilities identified in this study.

Implementing a Virtual Flipped Classroom in a Rheumatology Fellowship Program.

OBJECTIVE: Active learning opportunities within graduate medical education may be underused. We aimed to assess whether active learning strategies increase after implementing a faculty development workshop and transitioning rheumatology fellowship didactics to a virtual flipped classroom. METHODS: We measured baseline faculty use of active learning strategies during lectures within the Introductory Rheumatology Curriculum by calculating an "active learning score" from a cognitive learning theory assessment tool. We held a faculty development workshop demonstrating active teaching strategies and encouraged using a flipped classroom for fellowship didactics. Because of the COVID-19 pandemic, the strategies were discussed in a virtual classroom setting where the intervention phase would occur. We compared active learning scores before and after the intervention for lectures within the Introductory Rheumatology Curriculum. The primary outcome was the change in active teaching scores preintervention versus postintervention. RESULTS: Active learning scores increased in 14 of the 16 lectures, with a mean score increase of 4.7 of 24 points (95% confidence interval 2.3-7.2). Paired t-test analyses comparing active learning scores preintervention and postintervention for each lecture confirmed that results were highly statistically significant (P < 0.001). Despite faculty hesitancy to teach within a virtual environment, faculty satisfaction remained high postintervention. CONCLUSION: A virtual flipped classroom increased the use of active learning strategies within the Introductory Rheumatology Curriculum. Faculty satisfaction remained high despite modest increases in time spent updating their presentations. Fellows and faculty reported a largely positive experience within the virtual classroom.

Association Between Race/Ethnicity and COVID-19 Outcomes in Systemic Lupus Erythematosus Patients From the United States: Data From the COVID-19 Global Rheumatology Alliance.

OBJECTIVE: To determine the association between race/ethnicity and COVID-19 outcomes in individuals with systemic lupus erythematosus (SLE). METHODS: Individuals with SLE from the US with data entered into the COVID-19 Global Rheumatology Alliance registry between March 24, 2020 and August 27, 2021 were included. Variables included age, sex, race, and ethnicity (White, Black, Hispanic, other), comorbidities, disease activity, pandemic time period, glucocorticoid dose, antimalarials, and immunosuppressive drug use. The ordinal outcome categories were: not hospitalized, hospitalized with no oxygenation, hospitalized with any ventilation or oxygenation, and death. We constructed ordinal logistic regression models evaluating the relationship between race/ethnicity and COVID-19 severity, adjusting for possible confounders. RESULTS: We included 523 patients; 473 (90.4%) were female and the mean ± SD age was 46.6 ± 14.0 years. A total of 358 patients (74.6%) were not hospitalized; 40 patients (8.3%) were hospitalized without oxygen, 64 patients (13.3%) were hospitalized with any oxygenation, and 18 (3.8%) died. In a multivariable model, Black (odds ratio [OR] 2.73 [95% confidence interval (95% CI) 1.36-5.53]) and Hispanic (OR 2.76 [95% CI 1.34-5.69]) individuals had higher odds of more severe outcomes than White individuals. CONCLUSION: Black and Hispanic individuals with SLE experienced more severe COVID-19 outcomes, which is consistent with findings in the US general population. These results likely reflect socioeconomic and health disparities and suggest that more aggressive efforts are needed to prevent and treat infection in this population.

Incidence and Risk Factors for Eosinophilia and Lung Disease in Biologic-Exposed Children With Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: Although interleukin-1 (IL-1)/IL-6 inhibitors are effective therapies for systemic juvenile idiopathic arthritis (JIA), some patients develop eosinophilia and lung disease during treatment. This study was undertaken to retrospectively evaluate incidence and risk factors for eosinophilia and describe lung disease outcomes in IL-1/IL-6 inhibitor-exposed patients with systemic JIA. METHODS: Among JIA patients at our institution exposed to interleukin-1 (IL-1)/IL-6 inhibitors (1995-2022), we compared incidence rate of eosinophilia in systemic JIA compared to other JIA, stratified by medication class (IL-1/IL-6 inhibitors, other cytokine inhibitors, methotrexate). We used Cox models to identify predictors of eosinophilia during IL-1/IL-6 inhibitor use and summarized treatment changes and outcomes after eosinophilia, including lung disease. HLA typing was performed on a clinical or research basis. RESULTS: There were 264 new medication exposures in 75 patients with systemic JIA and 41 patients with other JIA. A total of 49% of patients with systemic JIA with HLA typing (n = 45) were positive for HLA-DRB1*15 alleles. Eosinophilia was common during IL-1/IL-6 inhibitor use and did not differ by systemic JIA compared to other JIA (0.08 and 0.07 per person-year, respectively; P = 0.30). Among systemic JIA patients, pretreatment macrophage activation syndrome (MAS) was associated with a higher rate of subsequent eosinophilia on biologic therapy (unadjusted hazard ratio 3.2 [95% confidence interval 1.2-8.3]). A total of 4 of 5 patients who switched therapy within 10 weeks of eosinophilia experienced disease flare compared to none of the patients who continued the original therapy. A total of 8 of 25 patients with pulmonary evaluations had lung disease, and all had severe manifestations of systemic JIA (MAS, intensive care unit stay). One death was attributed to systemic JIA-lung disease. CONCLUSION: Eosinophilia is common in JIA patients using IL-1/IL-6 inhibitors. Severe disease may be associated with eosinophilia and lung disease in systemic JIA.

Engaging trainees within the virtual classroom: Teaching strategies for rheumatologists in a pandemic.

Social distancing during the COVID-19 pandemic has led to unprecedented challenges in medical education, including for rheumatology training programs. Many programs have adapted by transitioning educational curricula into virtual classrooms. Herein, we review strategies to optimize learning within the virtual classroom. We introduce the flipped virtual classroom as a framework for facilitating higher-order thinking and improving long-term learning. We provide recommendations to maximize interactions between learners, elevate group discussions, and encourage problem solving. Once implemented, these techniques can lead to more productive teaching and learning experiences while maintaining a sense of community for rheumatology training programs.

The Promises and Perils of Social Media for Pediatric Rheumatology.

The advent of social media has revolutionized and empowered communities of people living with rare diseases. Social media has enabled families of children with similar pediatric rheumatic diseases (PRDs) to meet regardless of geographic distance, allowing them to support each other and join together to advocate on behalf of their children. Researchers have also leveraged social media to learn about the health of patients and their communities. This article reviews the promises and perils of social media related to health, focusing on its potential use to support research and care of children with PRD.

Features predicting colchicine efficacy in treatment of children with undefined systemic autoinflammatory disease: A retrospective cohort study.

OBJECTIVE: Patients with undefined systemic autoinflammatory diseases (uSAIDs) are challenging to manage, as there are no guidelines or recommendations for targeted therapy. We aimed to evaluate the efficacy of empiric treatment with colchicine in our single-center uSAID population in the United States, as well as the patient characteristics associated with the most robust colchicine response. METHODS: Children with uSAID 18 years old at initial evaluation during 2000-2019 were included if they received 3 months of colchicine therapy. Data on demographics, clinical features, laboratory/ genetic studies, and treatment responses were collected. Most statistics were based on chi-square analyses for categorical data. Complete response to colchicine was defined as resolution of episodes or the presence of minor residual symptoms that did not require any further therapy. A partial response was defined as a decrease in the frequency, severity, or length of episodes but still necessitating additional therapy. Patients were considered nonresponders if they did not experience any improvement with colchicine at target therapeutic dosing. RESULTS: We identified 133 children diagnosed with uSAID who met our inclusion criteria. The median time to starting empiric colchicine was 5 months from the diagnosis of autoinflammatory disease. 92.5% (n = 123) of patients had a beneficial response to colchicine, including 46.6% (n = 62) partial responders and 45.9% (n = 61) complete responders. The presence of a nonurticarial rash was associated with an incomplete colchicine response (29.2% (n = 21) vs 13.1% (n = 8), P = .025). The presence of a heterozygous MEFV mutation in patients who did not fit Familial Mediterranean Fever diagnostic criteria (n = 25) appeared to be associated with a greater likelihood of complete colchicine response, although this was not statistically significant (62.5% (n = 14) vs 42.6% (n =11), P = .08). In MEFV mutation-negative patients, a nonurticarial rash was even more strongly associated with incomplete colchicine response, with an OR of 27.53 (CI [1.59-477], P = .023). The presence of oral ulcers also corresponded to incomplete colchicine response, although this did not reach clinical significance (38.9% (n = 28) vs 24.6% (n = 15), P = .08). There was no significant association between episode duration or frequency and colchicine response. CONCLUSION: Colchicine leads to clinical benefits in most children with uSAID. We, thus, recommend an early trial of colchicine in newly diagnosed patients with uSAID.

Feasibility and Efficacy of Online Strategies to Recruit Parents of Children With Rheumatic Diseases for Research.

OBJECTIVE: We aimed to determine the feasibility and efficacy of online strategies to recruit parents of children with pediatric rheumatic diseases (PRDs) for research and to evaluate the degree to which known features of various rheumatic disease groups were present in the online cohort. METHODS: We studied two cohorts; the first was composed of respondents from a cross-sectional parental survey of children with PRDs contacted through patient support groups and social media platforms, and the second cohort was composed of participants from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) legacy clinical registry. RESULTS: In the social media cohort, 712 complete surveys were analyzed. Most (65.9%) were referred from Facebook. The most common rheumatic disease was juvenile idiopathic arthritis (JIA) (27.1%), followed by juvenile dermatomyositis (22.1%). In the CARRA registry cohort, 7985 records were included. JIA was the largest disease group (70.3%), followed by systemic lupus erythematosus (12.0%). The age at disease onset for most PRDs was similar between those in the social media and CARRA registry cohorts (mean difference = 1.3 years). CONCLUSION: Recruitment through Facebook was the most fruitful. The clinical characteristics of the social media cohort were similar to those of patients recruited through a clinical registry, suggesting the utility of online recruitment for engaging disease-relevant cohorts. Parents of children with rare PRDs were overrepresented in the social media cohort, perhaps reflecting the increased need of those parents to find online information and receive emotional support. Social media recruitment for research studies may help expand the number and diversity of participants in clinical research, especially by including those with rare diseases.