Delay in diagnosis of rheumatoid arthritis: reasons and trends over a decade.

INTRODUCTION: Delay in diagnosis and treatment initiation often lead to poorer outcomes in rheumatoid arthritis (RA). Most of the data on delay in diagnosis and management are from western population with no data from India. Additionally, with improved health care services, whether the delay has changed over years is not known. In this longitudinal observational study, we investigated delay to diagnosis and disease-modifying antirheumatic drugs (DMARDs) initiation over past 9 years. METHODS: Patients aged ≥ 18 years having RA fulfilling 2010 ACR/EULAR criteria were enrolled from January to June in years 2012, 2017 and 2021. Diagnoses received before presenting to clinic, socioeconomic status, educational level and other demographic variables were recorded. RESULTS: Each year, 323 patients (mean age 49.5-52.01 years) were enrolled. There was a significant reduction in delay in diagnosis from a median (IQR) of 36 (12-84, range 1-288) months in 2012 to 12 (4-36, range 1-180) months in 2017 and 10 (5-24, range 1-120) months) in 2021 (p < 0.0001). A significant improvement in time to initiating DMARDs from 2012 [48 (24-96) months] to 2017 [12 (6-36) months] (p < 0.0001) and from 2017 to 2021 [12 (5-24) months] (p = 0.03) was seen. Higher education, more patients opting for treatment from rheumatologists, and urbanisation contributed significantly to improvement in delay. There was no impact of age or gender on delay. CONCLUSION: Delay in diagnosis has improved significantly between 2012 and 2021. However, delay still remains long as most patients miss the 3-month therapeutic window. Future work focussing on reasons for delays in the patient pathway could help improve consultation pathways in India.

Efficacy and safety of curcumin in maintaining remission during disease-modifying antirheumatic drug withdrawal in rheumatoid arthritis at 52 weeks: a phase III double-blind, randomized placebo-controlled trial.

Curcumin has anti-inflammatory properties but current evidence is limited to advocate its use in rheumatoid arthritis (RA). We explored whether curcumin could maintain remission in patients with RA while tapering conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARD). In this patient-and investigator-blinded trial, adults with RA in sustained remission for more than six months were randomized to oral curcumin (1 g) with piperine (5 mg) twice daily or matching placebo. Patients who had received biological DMARDs or curcumin supplements in the last 6 months were excluded. csDMARD were tapered and stopped sequentially as per a fixed protocol. The primary outcome was flare-free survival at 52 weeks. The secondary outcomes were flare rate, correlation of serum curcuminoid levels with flares and safety. 200 patients (100 per arm) entered the trial with comparable baseline characteristics. Per protocol analysis included 92 and 93 participants in the curcumin and the placebo group, respectively. Flare-free survival at week 52 was similar between both groups (60% versus 64%; p = 0.76). The median time to flare was similar [Curcumin: 219 days (IQR: 123) versus placebo: 214 days (95.8); p = 0.067]. Cox proportionate regression modelling showed that the flare-free survival was independent of serum curcuminoid levels [adjusted HR = 0.99 (95% CI: 0.97-1.0)]. The model showed that flare-free survival was not associated with age, gender, seropositivity, or csDMARD used at baseline. No serious adverse effects were noted. Curcumin did not impact the flare-free survival in patients with RA in remission during the tapering of csDMARDs despite achieving adequate serum levels.Trial registration: CTRI/2018/04/013279.

Postvaccination antibody titres predict protection against COVID-19 in patients with autoimmune diseases: survival analysis in a prospective cohort.

INTRODUCTION: To assess the incidence and risk factors for breakthrough COVID-19 infection in a vaccinated cohort of patients with autoimmune rheumatic diseases (AIRDs) and determine whether antibodies to receptor binding domain of spike protein (anti-RBD) serve as a reliable predictor of susceptibility to such infections. METHODS: Patients with AIRDs who had completed two doses of SARS-CoV2 vaccines were included and anti-RBD antibodies were determined 4-6 weeks post the second vaccine dose and stratified into good responders (GR) (>212 IU), inadequate responders (IR) (0.8-212 IU) and non-responders (NR) (<0.8 IU). Patients who had completed a minimum of 8 weeks interval after the second dose of vaccine were followed up every 2 months to identify breakthrough infections. All sero converted patients who had contact with COVID-19 were also analysed for neutralising antibodies. RESULTS: We studied 630 patients of AIRDs (mean age 55.2 (±11.6) years, male to female ratio of 1:5.2). The majority of patients had received AZD1222 (495, 78.6%) while the remaining received the BBV152 vaccine. The mean antibody titre was 854.1 (±951.9), and 380 (60.3%) were GR, 143 (22.7%) IR and 107 (16.9%) NR.Breakthrough infections occurred in 47 patients (7.4%) at a mean follow-up of 147.3 (±53.7) days and were proportionately highest in the NR group (19; 17.75%), followed by the IR group (13; 9.09%) and least in the GR group (15; 3.95%). On log-rank analysis, antibody response (p<0.00001), vaccine(p=0.003) and mycophenolate mofetil (p=0.007) were significant predictors of breakthrough infections. On multivariate Cox regression, only NR were significantly associated with breakthrough infections (HR: 3.6, 95% CI 1.58 to 8.0, p=0.002). In sero converted patients with contact with COVID-19, neutralisation levels were different between those who developed and did not develop an infection. CONCLUSION: Breakthrough infections occurred in 7.4% of patients and were associated with seronegativity following vaccination. This provides a basis for exploring postvaccination antibody titres as a biomarker in patients with AIRD.

Hamman's Syndrome - in Young Asthmatic Female.

Spontaneous pneumomediastinum (SPM) is a rare condition where there is presence of air in the mediastinum without any precipitating trauma, surgery or other conditions. It usually develops after alveolar rupture and air penetration into the pulmonary interstitium, the hilum and the mediastinum. It is commonly seen in young males, asthmatics on inhalational drugs, or following severe vomiting, parturition, weight lifting. A young female, known case of bronchial asthma presented to us with history of breathlessness and cough of 3 days and mild swelling of the face and neck of 2 days duration. On examination, she was dyspneic, had subcutaneous swelling of the face, neck and chest bilaterally with palpable crepitus. Respiratory examination showed diffuse polyphonic rhonchi and crepitations. CT thorax showed pneumomediastinum, pneumoperitoneum, pneumothorax and pneumorrhachis. A diagnosis of Hamman's syndrome was made and patient was treated symptomatically and recovered.

Withholding methotrexate after vaccination with ChAdOx1 nCov19 in patients with rheumatoid or psoriatic arthritis in India (MIVAC I and II): results of two, parallel, assessor-masked, randomised controlled trials.

Background: There is a necessity for an optimal COVID-19 vaccination strategy for vulnerable population groups, including people with autoimmune inflammatory arthritis on immunosuppressants such as methotrexate, which inhibit vaccine-induced immunity against SARS-CoV-2. Thus, we aimed to assess the effects of withholding methotrexate for 2 weeks after each dose of ChAdOx1 nCov-19 (Oxford-AstraZeneca) vaccine (MIVAC I) or only after the second dose of vaccine (MIVAC II) compared with continuation of methotrexate, in terms of post-vaccination antibody titres and disease flare rates. Methods: MIVAC I and II were two parallel, independent, assessor-masked, randomised trials. The trials were done at a single centre (Dr Shenoy's Centre for Arthritis and Rheumatism Excellence; Kochi, India) in people with either rheumatoid arthritis or psoriatic arthritis with stable disease activity, who had been on a fixed dose of methotrexate for the preceding 6 weeks. Those with previous COVID-19 or who were positive for anti-SARS-CoV-2 nucleocapsid antibodies were excluded from the trials. People on high-dose corticosteroids and rituximab were also excluded, whereas other disease-modifying antirheumatic drugs were allowed. In MIVAC I, participants were randomly assigned (1:1) to stop methotrexate treatment for 2 weeks after each vaccine dose or to continue methotrexate treatment. In MIVAC II, participants who had continued methotrexate during the first dose of vaccine were randomly assigned (1:1) to withhold methotrexate for 2 weeks after the second dose of vaccine or to continue to take methotrexate. The treating physician was masked to the group assignments. The primary outcome for both MIVAC I and MIVAC II was the titre (absolute value) of anti-receptor binding domain (RBD) antibody measured 4 weeks after the second dose of vaccine. All analyses were done per protocol. The trials were registered with the Clinical Trials Registry- India, number CTRI/2021/07/034639 (MIVAC I) and CTRI/2021/07/035307 (MIVAC II). Findings: Between July 6 and Dec 15, 2021, participants were recruited to the trials. In MIVAC I, 250 participants were randomly assigned and 158 completed the study as per the protocol (80 in the methotrexate hold group and 78 in the control group; 148 [94%] were women and 10 [6%] were men). The median post-vaccination antibody titres in the methotrexate hold group were significantly higher compared with the control group (2484·0 IU/mL, IQR 1050·0-4388·8 vs 1147·5 IU/mL, 433·5-2360·3; p=0·0014). In MIVAC II, 178 participants were randomly assigned and 157 completed the study per protocol (76 in the methotrexate hold group and 81 in the control group; 135 [86%] were women and 22 [14%] were men). The methotrexate hold group had higher post-vaccination antibody titres compared with the control group (2553·5 IU/ml, IQR 1792·5-4823·8 vs 990·5, 356·1-2252·5; p<0·0001). There were no reports of any serious adverse events during the trial period. Interpretation: Withholding methotrexate after both ChAdOx1 nCov-19 vaccine doses and after only the second dose led to higher anti-RBD antibody titres compared with continuation of methotrexate. However, withholding methotrexate only after the second vaccine dose resulted in a similar humoral response to holding methotrexate after both vaccine doses, without an increased risk of arthritis flares. Hence, interruption of methotrexate during the second dose of ChAdOx1 nCov-19 vaccine appears to be a safe and effective strategy to improve the antibody response in patients with rheumatoid or psoriatic arthritis. Funding: Indian Rheumatology Association.