Vitamin D in Rheumatic Diseases: Interpretation and Significance

The pleiotropic effects of vitamin D on the various metabolic, anticancer, and immunomodulatory functions of the body based on the presence of vitamin D receptors (VDR) on various cell types has been recognized worldwide now. Of few understood mechanisms of immunomodulatory actions of vitamin D are the suppressive action on the maturation of antigen-presenting cells and decrease in the levels of pro-inflammatory cytokines. Vitamin D deficiency has been implicated in the immune diseases like rheumatic diseases, asthma, psoriasis, and multiple sclerosis. Vitamin D deficiency has been associated with increased frequency and severity of disease flares in rheumatic diseases like lupus and rheumatoid arthritis. Other studies have shown higher prevalence of persistence and evolution in to more definite rheumatic disorder in undifferentiated arthritis and undifferentiated connective tissue disorder patients with vitamin D deficiency. Multiple factors like avoidance of sunlight, the use of corticosteroids and hydroxychloroquine, skin pigmentation, etc. should be considered when evaluating vitamin D levels in these patients, needless to say the consideration of higher-dose supplement for these patients. It is thus prudent that all patients with established or undifferentiated rheumatic diseases are evaluated for vitamin D status and an adequate supplementation is recommended to prevent the associated consequences

Early Undifferentiated Arthritis: A Developing Country Perspective from Nepal

Early undifferentiated arthritis is a group of inflammatory joint disease of less than 3 months duration that do not classify under any of the specific rheumatic or connective tissue disorder. Previously, inflammatory arthritis used to be treated only when there was a clear evidence of damage or deformity occurring with it. Use of disease modifying anti-rheumatic drugs were considered potentially harmful early in the course of arthritis which could be self-limiting. However, with the abundance of data on outcomes of early arthritis and identification of factors that can help to predict those outcomes lead to earlier use of such DMARDs. Better understanding of serological tests like anti-CCP antibodies and imaging modalities like high frequency ultrasound with power doppler and magnetic resonance imaging has increased the diagnostic and prognostic yield of such early arthritis cases. It is now imperative that the risk be assessed early in the course of disease and early DMARDs be instituted for better outcome in these cases. This review analyses the historical evolution of evidence in the management of early undifferentiated arthritis and summarises the treatment approach, monitoring and disease outcomes till date

A Simplified Understanding of the Black Swan: Anti-phospholipid Antibody Syndrome

Anti-phospholipid antibody syndrome is caused by the presence of specific antibodies against phospholipid-binding plasma proteins in serum of patient, with or without underlying autoimmune diseases, that causes prolongation of tests of coagulation. High index of clinical suspicion is required for diagnosis. Stroke or myocardial infarction in young, unprovoked recurrent deep vein thrombosis and recurrent pregnancy loss are typical scenarios where it should be suspected. Presence of non-criteria manifestations like livedoreticularis, skin ulcers, nephropathy, valvular-heart disease and thrombocytopenia adds to diagnostic clue for presence of the syndrome. Therapeutic anti-coagulation with heparin followed by warfarin is required for patients with acute thrombosis. Those with venous thrombosis are given moderate-intensity warfarin(INR 2-3), whereas those with arterial thrombosis or recurrent venous thrombosis even on warfarin are treated with high intensity warfarin (INR 3-4). Similarly, anticoagulation with heparin is advised throughout pregnancy and up to six weeks postpartum. Treatment recommendations are still not clear for asymptomatic patients and in those with non-criteria manifestations of the disease. Steroids, intravenous immunoglobulin and immunosuppressant are reported to be effective in catastrophic cases characterized by rapid small vessel thrombotic involvement of multiple organ systems. Studies are evaluating the efficacy of direct thrombin inhibitors in the management of refractory cases

COVID-19 vaccination-related delayed adverse events among people with rheumatoid arthritis: results from the international COVAD survey

This study aimed to assess COVID-19 vaccination-related AEs in patients with rheumatoid arthritis (RA), in the COVID-19 Vaccination in Autoimmune Diseases (COVAD)-2 study. An online international cross-sectional survey captured self-reported data on COVID-19 vaccination-related adverse events (AEs) in people with RA, autoimmune diseases (AIDs; rheumatic [r] and non-rheumatic [nr]) and healthy controls (HCs). The survey was circulated by the COVAD study group, comprising 157 collaborators across 106 countries, from February to June 2022. Delayed AEs among RA were compared with other rAIDs, nrAIDs and HCs using multivariable binary regression. A total of 7203 participants were included (1423 [19.7%] RA, 2620 [36.4%] rAIDs, 426 [5.9%] nrAIDs, 2734 [38%] HCs), with 75% female. Compared to HCs, individuals with RA reported higher overall major AEs [OR 1.3 (1.0-1.7)], and an increased number of several minor AEs. Compared to nrAIDs, people with RA had several increased reported minor AEs including myalgia and joint pain. People with active RA had increased major AEs [OR 1.8 (1.1-3.0)] and hospitalisation [OR 4.1 (1.3 - 13.3)] compared to inactive RA. RA patients without autoimmune comorbidities had significantly fewer major and minor AEs than those with other rAIDs. A decreased incidence of hospitalisation was seen in patients taking methotrexate or TNF inhibitors compared to patients not taking these medications. COVID-19 vaccination is associated with minimal to no risks of delayed AEs in patients with RA compared to HCs, and fewer compared to other rAIDs. Active RA and presence of co-existing rAIDs were associated with an increased risk of delayed AEs

Disease burden in inflammatory arthritis: an unsupervised machine learning approach of the COVAD-2 e-survey dataset

OBJECTIVES To comprehensively compare the disease burden among patients with RA, PsA and AS using Patient-Reported Outcome Measurement Information System (PROMIS) scores and to identify distinct patient clusters based on comorbidity profiles and PROMIS outcomes. METHODS Data from the global COVID-19 Vaccination in Autoimmune Diseases (COVAD) 2 e-survey were analysed. Patients with RA, PsA or AS undergoing treatment with DMARDs were included. PROMIS scores (global physical health, global mental health, fatigue 4a and physical function short form 10a), comorbidities and other variables were compared among the three groups, stratified by disease activity status. Unsupervised hierarchical clustering with eXtreme Gradient Boosting feature importance analysis was performed to identify patient subgroups based on comorbidity profiles and PROMIS outcomes. RESULTS The study included 2561 patients (1907 RA, 311 PsA, 343 AS). After adjusting for demographic factors, no significant differences in PROMIS scores were observed among the three groups, regardless of disease activity status. Clustering analysis identified four distinct patient groups: low burden, comorbid PsA/AS, low burden with depression and high-burden RA. Feature importance analysis revealed PROMIS global physical health as the strongest determinant of cluster assignment, followed by depression and diagnosis. The comorbid PsA/AS and high-burden RA clusters showed a higher prevalence of comorbidities (56.47% and 69.7%, respectively) and depression (41.18% and 41.67%, respectively), along with poorer PROMIS outcomes. CONCLUSION Disease burden in inflammatory arthritis is determined by a complex interplay of factors, with physical health status and depression playing crucial roles. The identification of distinct patient clusters suggests the need for a paradigm shift towards more integrated care approaches that equally emphasize physical and mental health, regardless of the underlying diagnosis

COVID-19 vaccination-related delayed adverse events among people with rheumatoid arthritis: results from the international COVAD survey

This study aimed to assess COVID-19 vaccination-related AEs in patients with rheumatoid arthritis (RA), in the COVID-19 Vaccination in Autoimmune Diseases (COVAD)-2 study. An online international cross-sectional survey captured self-reported data on COVID-19 vaccination-related adverse events (AEs) in people with RA, autoimmune diseases (AIDs; rheumatic [r] and non-rheumatic [nr]) and healthy controls (HCs). The survey was circulated by the COVAD study group, comprising 157 collaborators across 106 countries, from February to June 2022. Delayed AEs among RA were compared with other rAIDs, nrAIDs and HCs using multivariable binary regression. A total of 7203 participants were included (1423 [19.7%] RA, 2620 [36.4%] rAIDs, 426 [5.9%] nrAIDs, 2734 [38%] HCs), with 75% female. Compared to HCs, individuals with RA reported higher overall major AEs [OR 1.3 (1.0–1.7)], and an increased number of several minor AEs. Compared to nrAIDs, people with RA had several increased reported minor AEs including myalgia and joint pain. People with active RA had increased major AEs [OR 1.8 (1.1–3.0)] and hospitalisation [OR 4.1 (1.3 – 13.3)] compared to inactive RA. RA patients without autoimmune comorbidities had significantly fewer major and minor AEs than those with other rAIDs. A decreased incidence of hospitalisation was seen in patients taking methotrexate or TNF inhibitors compared to patients not taking these medications. COVID-19 vaccination is associated with minimal to no risks of delayed AEs in patients with RA compared to HCs, and fewer compared to other rAIDs. Active RA and presence of co-existing rAIDs were associated with an increased risk of delayed AEs

Flares in IIMs and the timeline following COVID-19 vaccination: a combined analysis of the COVAD-1 and 2 surveys

OBJECTIVES: Disease flares in the post COVID-19 vaccination period represent a prominent concern, though risk factors are poorly understood. We studied these flares among patients with idiopathic inflammatory myopathies (IIMs) and other autoimmune rheumatic diseases (AIRDs). METHODS: The COVAD-1 and -2 global surveys were circulated in early 2021 and 2022 respectively, and we captured demographics, comorbidities, AIRDs details, COVID-19 infection history, and vaccination details.Flares of IIMs were defined as a. patient self-reported, b. immunosuppression (IS) denoted, c. clinical sign directed, and d. with >7.9-point MCID worsening of PROMISPF10a score. Risk factors of flares were analyzed using regression models. RESULTS: Of 15165 total respondents, 1278 IIMs (age 63 years, 70.3% female, 80.8% Caucasians), and 3453 AIRDs were included. Flares of IIM were seen in 9.6%, 12.7%, 8.7%, and 19.6% patients by definitions a-d respectively with a median time to flare of 71.5 (10.7-235) days, similar to AIRDs. Patients with active IIMs pre-vaccination (OR:1.2; 95%CI:1.03-1.6, p = 0.025) were prone to flares, while those receiving Rituximab (OR:0.3; 95%CI:0.1-0.7, p = 0.010) and Azathioprine (OR:0.3, 95%CI:0.1-0.8, p = 0.016) were at lower risk. Female gender and comorbidities predisposed to flares requiring changes in immunosuppression. Asthma (OR: 1.62; 95%CI: 1.05-2.50, p = 0.028) and higher pain VAS (OR: 1.19; 95%CI: 1.11-1.27, p < 0.001) were associated with disparity between self-reported and IS-denoted flares. CONCLUSION: A diagnosis of IIMs confers an equal risk of flares in the post COVID-19 vaccination period to AIRDs, with active disease, female gender, and comorbidities conferring a higher risk. Disparity between patient and physician reported outcomes represents a future avenue for exploration

Latitude gradient influences the age of onset of rheumatoid arthritis : a worldwide survey

The age of onset of rheumatoid arthritis (RA) is an important outcome predictor. Northern countries report an age of RA onset of around 50 years, but apparently, variability exists across different geographical regions. The objective of the present study is to assess whether the age of onset of RA varies across latitudes worldwide. In a proof-of-concept cross-sectional worldwide survey, rheumatologists from preselected cities interviewed 20 consecutive RA patients regarding the date of RA onset (RAO, when the patient first noted a swollen joint). Other studied variables included location of each city, rheumatologist settings, latitudes (10A degrees increments, south to north), longitudes (three regions), intracountry consistency, and countries' Inequality-adjusted Human Development Index (IHDI). Data from 2481 patients (82% females) were obtained from 126 rheumatologists in 77 cities of 41 countries. Worldwide mean age of RAO was 44 +/- 14 years (95% CI 44-45). In 28% of patients, RA began before age 36 years and before age 46 years in 50% of patients. RAO was 8 years earlier around the Tropic of Cancer when compared with northern latitudes (p <0.001, 95% CI 3.5-13). Multivariate analysis showed that females, western cities, and latitudes around the Tropic of Cancer are associated with younger age of RAO (R (2) 0.045, p <0.001). A positive correlation was found between the age of RAO and IHDI (r = 0.7, p <0.01, R (2) 0.5). RA often begins at an early age and onset varies across latitudes worldwide. We postulate that countries' developmental status and their geographical and geomagnetic location influence the age of RAO.Peer reviewe

Takayasu Arteritis: A Case Series from Tertiary Rheumatology Center from Nepal

Background Takayasu arteritis (TA) is an idiopathic, granulomatous, large-vessel arteritis that predominantly involves the aorta, its major branch arteries. Then objective is to evaluate the clinical features, angiographic findings and response of treatment Method 12 patients with TA were studied at the NCRD between 2018 and 2023 and were followed for 3 months to 5 years. Data on clinical features, angiographic and laboratory findings, disease course, and response to therapy were all recorded and stored in a computer-based retrieval system. Result TA was more common in females (54%). The mean age at disease onset was 37.08± 16.91 years. The clinical presentation ranged from asymptomatic to catastrophic with uncontrolled hypertension, gradual loss of vision. The most common clinical finding was a fatigue and dizziness. Hypertension was most often associated with renal artery stenosis (4 out of 12). Almost 50% of the patients had systemic symptoms on presentation. Medical therapy was required for all of the patients. Immunosuppressive treatment with glucocorticoids helped achieve remission (ITAS-0) whereas remaining had decrease in disease activity with one reported mortality. Conclusion In Nepal, Takayasu arteritis is a rare disease. It is heterogeneous in presentation, progression, and response to therapy. Although mortality was low, substantial morbidity occurred in most patients