SARS-CoV-2 seroprevalence in patients with autoimmune rheumatic diseases versus family controls: a multi-city cross-sectional survey.

There is uncertainty regarding the effect of the SARS-CoV-2 infection on patients with autoimmune rheumatic diseases (AIRD) who are on immunosuppressive drugs. We did a multicity cross-sectional seroprevalence study conducted in five different cities in India before COVID-19 immunization. Patients with a diagnosis of AIRD and DMARDs were included. Relatives of the patients, preferably staying in the same household with no known rheumatic diseases served as controls. Serum IgG antibodies to SARS-CoV-2 Receptor Binding Domain (RBD) of the spike protein and nucleoprotein (NP) were assayed in eight hundred and eighty nine sera (subjects with disease = 379 and in subjects without disease = 510). IgG antibodies to either RBD and/or NP were positive in 135 (36%) subjects with AIRD as compared to 196 (38%) controls. The seroprevalence of anti-RBD and anti-NP varied between different cities but was not significantly different between subjects with and without disease in Mumbai, Ahmedabad, Bengaluru and Bhubaneswar. However, the occurrence of IgG antibodies to RBD was significantly (p < 0.05) lower in subjects with disease (28/65;43%) as compared to subjects without disease (42/65;65%) in Kolkata, where the positivity rate was lower in connective tissue disease group than in inflammatory arthritis group. Overall, patients with rheumatic diseases on DMARDs have IgG antibodies to RBD and NP of SARSCoV-2 at a comparable level with that of subjects without disease, but the level of antibodies to RBD is lower in patients with connective tissue disease on immunosuppressive drugs in one centre.

Blockades in the Pathway of Specialty Care in Rheumatoid Arthritis: A Report Based on Indian Rheumatology Association Database.

AIM: The study aims to identify factors influencing referral patterns and delays in rheumatoid arthritis (RA) patients across clinical settings in India. MATERIALS AND METHODS: A prospective, multicenter, observational study collected data from eight centers using the Indian Rheumatology Association (IRA) database. Patient-related factors and referral factors were determined based on patient narration. The modified PRASAD scale categorized patients' socioeconomic status. RESULTS: The study included 4,643 RA patients from eight centers. Data from 35 patients were excluded due to inconsistent reporting of diagnosis and delay. Lack of awareness was the predominant factor causing the delay in referral. Approximately, 39% of patients were referred to the rheumatology specialty within 6 months of disease onset, while 26% reported later, and 34% reported over 2 years. Referral delays were linked to socioeconomic factors in Madhya Pradesh (21.43%) and West Bengal (28.57%). Lack of awareness about the disease and rheumatology specialty was highest in West Bengal (100%), followed by Delhi and Rajasthan (93.70%). Misconceptions about modern medicine, reluctance to refer patients to the rheumatologist, and previous treatment by other specialities were other factors influencing referral delay. Primary care clinicians' unawareness of the rheumatology specialty was the primary reason for referral delay in Gujarat (33.56%) and Delhi and Rajasthan (25.18%). CONCLUSION: Both patient and healthcare professional-related factors contribute to referral delays in RA patients. Major factors causing referral delays include reluctance to refer and inadequate knowledge about rheumatology among primary care physicians and the general public. Patients' education and occupation also influence the timing of referrals to specialty care.

Interleukin-17 as a predictor of subclinical synovitis in the remission state of rheumatoid arthritis.

OBJECTIVES: To compare the level of pro and anti-inflammatory cytokines, and angiogenic mediators between Rheumatoid arthritis (RA) patients with and without subclinical synovitis (SS) in remission state, to find the correlation of these mediators with Greyscale synovitis (GSS) and power Doppler (PD) scores, and to find the probable predictor/s of SS. METHODS: 52 RA patients in remission state were recruited and subdivided into with and without SS group by Ultrasonography (USG) of 14 joints. Total GSS and PD scoring was done. The serum levels of the pro/anti-inflammatory cytokines and angiogenic mediators were compared between groups, and correlation and regression analysis were done with GSS and PD scores. RESULT: 63.46% patients had USG evidence of SS. Patients with SS had significantly higher levels of pro-inflammatory and angiogenic mediators [matrix-metalloproteinase -3 (p = 0.0001), Tumour necrosis factor-α (p = 0.0001), Interleukin (IL)-6 (p = 0.001), IL-1b (p = 0.0001), IL-17 (p = 0.0005), IL-33 (p = 0.0003), Tie-2 (p = 0.0001), vascular endothelial growth factor (VEGF (p = 0.03)], and lower anti-inflammatory cytokines [IL-27 (p = 0.0003), IL-10(p = 0.0001)]. A strong positive correlation of GSS score was noted with IL-17(r = 0.7), IL-6 (r = 0.7), IL-1b (r = 0.7), and IL-33 (r = 0.6). Multiple linear regression model identified IL-17 and IL-6 as predictors of GSS score, and TNF-α and VEGF as predictors of PD score. IL-17 level > 249 picogram/millilitre (pg/ml) could predict the SS with high specificity (89.5%). CONCLUSION: Patients with SS in the remission state of RA showed altered expression of some of the pro/anti-inflammatory/angiogenic markers compared to those not having SS. IL-17, IL-6, VEGF, and TNF-α could be the predictors of USG synovial scores.

Recurrent macrophage activation syndrome as the initial manifestation of paediatric systemic lupus erythematosus.

Introduction: Macrophage Activation Syndrome (MAS) is a rare but potentially fatal complication in rheumatic diseases. Here, we report the case of a 14-year-old girl with MAS as the primary manifestation of Systemic Lupus Erythematosus (SLE). She had three episodes of MAS during the course of her treatment. This case is unique as recurrent MAS in pediatric SLE is rare.Methods: Demographic, clinical, laboratory features and outcomes of our patient was noted. We also reviewed the two reported cases of recurrent MAS in pediatric SLE. Literature review was performed on PubMed search forum. Search items included Macrophage activation syndrome, pediatric systemic lupus erythematosus, recurrent MAS.Conclusion: The diagnosis and management of MAS are challenging as it can simulate an infectious complication or can be the exacerbation of the underlying disease. Early detection and prompt treatment can reduce morbidity in these patients.

Methotrexate and theaflavin-3, 3'-digallate synergistically restore the balance between apoptosis and autophagy in synovial fibroblast of RA: an ex vivo approach with cultured human RA FLS.

BACKGROUND: Imbalance between apoptosis and autophagy in fibroblast-like synoviocytes (FLS) is one of the pathogenic mechanisms responsible for their abnormal proliferation in rheumatoid arthritis (RA). Methotrexate (MTX) demonstrated limited efficacy in amending this imbalance in fluid-derived (fd)-FLS. The active compound of black tea Theaflavin 3,3'-digallate (TF3) may be effective in restoring apoptosis-autophagy imbalance in (fd)-FLS. The combined effect of MTX + TF3 upon the same is yet to be elucidated. OBJECTIVE: To evaluate the effect of MTX + TF3 on fd-FLS to induce apoptosis and inhibit autophagy through Endoplasmic Reticulum (ER) stress-mediated pathways. METHODS: FLS from synovial fluid of 11 RA and 10 osteoarthritis patients were cultured after treatment with MTX/TF3 or a combination of MTX (125 nM) and TF3(10 µM) and the following parameters were evaluated. C-reactive protein, cytokines (TNF-α, IL-6), angiogenic markers were quantified by ELISA. fd-FLS viability was determined by MTT assay and apoptosis by flow cytometry. ER stress markers were estimated by RT-PCR (IRE1A, spliced-XBP-1) and immunoblotting (Grp78, Hsp70, CHOP, HIF-1α). Immunoblot studies were done to evaluate apoptotic (Bcl-2, Bax, Caspases) and autophagic (Beclin1, LC3b, p62) proteins. RESULTS: MTX (IC25) and TF3 (IC50) both in single doses could down-regulate the levels of pro-inflammatory and angiogenic markers. Combinatorial treatment modulated autophagosomal proteins in fd-FLS and induced apoptosis by regulating ER stress response. CONCLUSION: Disruption in homeostasis between apoptosis and autophagy in fd-FLS might be an underlying phenomenon in the progression of pathophysiology in RA. Co-administration of MTX + TF3 successfully restored the homeostasis by inducing apoptosis.

Quality of life among female patients with systemic lupus erythematosus in remission.

The objective is to assess quality-of-life (QoL) parameters among Indian female systemic lupus erythematosus (SLE) patients with durable remission. Indian female SLE patients in remission determined by the European consensus criteria and age-matched female control participants were included in the study. All included participants underwent measurements of QoL [Medical Outcomes Study Short-Form-12 (SF12)], Fatigue Severity Scale, and structured interview with a clinical psychologist. The population comprised of 126 female SLE patients [median age: 27.5 years [interquartile range (IQR): 11]; median disease duration: 36 months (IQR 26)] and 110 female controls [median age 30 years (IQR 9)]. Clinical remission was seen in 65.9% (83/126) and complete remission in 34.1% (43/126). Significant fatigue was present in 18.3% (23/126). Both SF-12 physical component summary (PCS) and mental component summary (MCS) were similar between SLE patients and controls [median PCS: 50.3 (IQR: 16.2) vs. 48.6 (IQR: 11.6); median MCS: 57.2 (IQR: 4.8) vs. 57.9 (IQR: 7.6)]. In generalised linear modelling, PCS was associated with fatigue [odd's ratio (OR) 0.012, 95% confidence interval (CI) 0.006-0.025, p < 0.001], disease duration ≥ 5 years (OR 23.16, 95% CI 1.548-346.58, p = 0.023), and complete remission (OR 33.16, 95% CI 4.43-248.15, p = 0.001); MCS with fatigue (OR 0.53, 95% CI 0.34-0.84, p = 0.007) and absence of depression (OR 3.65, 95% CI 1.07-12.44, p = 0.038). Patients with SLE in remission report significant fatigue in 18.3% of subjects. Both PCS and MCS scores are similar to healthy controls. Better PCS was associated with less fatigue, longer disease duration, and complete remission. Better MCS was associated with less fatigue and absence of depression.

Cyclophosphamide Versus Mycophenolate Versus Rituximab in Lupus Nephritis Remission Induction: A Historical Head-to-Head Comparative Study.

OBJECTIVE: We report comparative efficacy between high-dose cyclophosphamide (HDCyC), low-dose cyclophosphamide (LDCyC), mycophenolate mofetil (MMF) and rituximab in patients with lupus nephritis (LN). METHODS: We analyzed comparative efficacy of 4 induction regimens of biopsy-proven LN: LDCyC: 500 mg fortnightly, HDCyC: 750 to 1200 mg monthly, MMF: 1.5 to 3 g/d, and rituximab. Outcomes of 4 groups were analyzed at the sixth month. RESULTS: Among a total 222 patients, 26 received LDCyC (3-g total dose), 113 received HDCyC (mean, 5.1-g total dose), 61 received MMF (mean, 2.2 g/d), and 22 received rituximab (mean, 1.9-g total dose). Relapsing/refractory LN was 11 in HDCyC, 1 in LDCyC, 10 in MMF, and 14 in the rituximab group. Overall 16.2% had no improvement of proteinuria, 18% had partial response, and 65.8% (146/222) had complete response. Renal response (RR) was higher in HDCyC (90.3%) and rituximab (90.9%) groups compared with LDCyC (73%) and MMF (72%) groups. Rituximab was effective in relapsing disease (100% RR). Infection was highest with the HDCyC, followed by LDCyC and rituximab (p = 0.15), whereas the MMF group had a higher incidence of gastrointestinal adverse effects (p < 0.001). The following predictors of RR were identified: rituximab (odds ratio [OR], 20.4; 95% confidence interval [CI], 1.9-215.7; p = 0.012), renal Baseline Systemic Lupus Erythematosus Disease Activity Index at baseline (OR, 0.86; 95% CI, 0.75-0.99; p = 0.034), and duration of disease (OR, 0.98; 95% CI, 0.97-0.99; p = 0.009). CONCLUSIONS: High-dose cyclophosphamide and rituximab were the most effective therapeutic strategies in patients with LN, especially in the Indian context. Rituximab was highly effective in relapsing disease.

Intravenous cyclophosphamide vs rituximab for the treatment of early diffuse scleroderma lung disease: open label, randomized, controlled trial.

Objectives: SSc is characterized by fibrotic changes in the skin and lung, and the mainstay of treatment has been CYC. B cell involvement suggests that rituximab (RTX) may also be of therapeutic benefit. The aim of the study was to compare the efficacy and safety of RTX compared with CYC in retarding the progression of interstitial lung disease and skin manifestations of primary SSc. Methods: We randomly assigned 60 patients of dcSSc, age 18-60 years with skin and lung involvement, to monthly pulses of CYC 500 mg/m2 or RTX 1000 mg × 2 doses at 0, 15 days. Primary outcomes were forced vital capacity (FVC) percent predicted at 6 months. Secondary outcomes were: absolute change in litres (FVC-l) at 6 months; modified Rodnan skin scores at 6 months, 6-min walk test, Medsgers score and new onset or worsening of existing pulmonary hypertension by echocardiographic criteria. Results: The FVC [%mean (s.d.)] in the RTX group improved from 61.30 (11.28) to 67.52 (13.59), while in the CYC group it declined from 59.25 (12.96) to 58.06 (11.23) at 6 months (P = 0.003). The change of FVC was 1.51 (0.45) l to 1.65 (0.47) l in the RTX group, compared with 1.42 (0.49) to 1.42 (0.46) l in the CYC group. The mRSS changed from 21.77 (9.86) to 12.10 (10.14) in the RTX group and 23.83 (9.28) to 18.33 (7.69) in the CYC group after 6 months. Serious adverse events were more common in the CYC group. Conclusion: RTX is a safe and effective alternative to CYC in the primary therapy of skin and lung manifestations of scleroderma. Trial registration: Clinical Trials Registry - India, www.ctri.nic.in, CTRI/2017/07/009152.

Assessment of nail unit structures by ultrasound in patients with psoriatic arthritis and their correlations with disease activity indices: a case-control study.

Ultrasound (USG) of nail was performed to assess, (1) morphological alterations of nail plates in psoriatic arthritis (PsA) patients, (2) differences of nail unit parameters [nail bed thickness (NBT), nail matrix thickness (NMT) and nail plate distance (NPD)] in PsA patients from healthy controls (3) correlation of nail unit parameters with PsA disease activity indices. Total of 895 fingernails (448 nails of 45 PsA patients and 447 of 45 controls) were evaluated by USG. Psoriasis Area and Severity Index (PASI), Disease Activity in Psoriatic Arthritis (DAPSA), and Nail Psoriasis Severity Index (NAPSI) were calculated in PsA patients. Nail unit parameters were compared between two study groups. Correlation study was done between nail unit parameters and disease activity indices. All PsA patients showed ultrasound evidence of nail plate changes (87.95% of the total fingernails and 75.34% of the clinically normal nails). Loosening of the ventral nail plate border was most common (51.79%). Mean NBT (PsA: 0.19 ± 0.035 cm, control: 0.17 ± 0.018 cm, p = 0.003) and mean NMT (PsA: 0.32 ± 0.041 cm, control: 0.28 ± 0.031 cm, p = < 0.0001) were significantly increased in the PsA patients. Moderately positive correlation was observed between NAPSI score and mean NMT (Spearman r = 0.411, 95% confidence interval: 0.125-0.634, p = 0.005). USG evidence of nail plate alterations was frequent among PsA patients, even in clinically normal nails. Increased mean nail bed and matrix thickness were noted in PsA patients. Mean NMT had a moderately positive correlation with NAPSI score.

Temporal evolution of urate crystal deposition over articular cartilage after successful urate-lowering therapy in patients with gout: An ultrasonographic perspective.

OBJECTIVE: To detect evolution of ultrasonographic signs of deposition of monosodium urate crystals (MSUC) in gouty joints by serial ultrasonography after initiation of urate-lowering therapy (ULT). METHODS: Adult gout patients were examined by serial ultrasonography after initiation of ULT with target serum uric acid (SUA) < 6 mg/dL. RESULTS: Thirty-eight male patients with gout with mean age of 50 ± 11 years, median disease duration of 48 months and baseline mean SUA level of 8.8 ± 1.5 mg/dL were recruited. Ultrasonographic evidence of MSUC deposition was detected in 89.74% of first metatarsophalangeal (MTP) joints and 27.63% of knee joints. Double contour sign (DCS), tophi, and hyperechoic spots (HES) were detected in 77.63%, 43.42%, and 19.74% of first MTPs, respectively. SUA level normalizes and plateaus after fourth month of follow-up. DCS thickness reduced significantly throughout the follow-up period. Overall, 86.25% DCS and 100% HES disappeared with median time of 6 months and 5.7 months, respectively. SUA normalization was the only significant predictor of DCS disappearance. CONCLUSIONS: Serial ultrasonographic determination of DCS, tophi, or HES during hypouricemic therapy is a noninvasive, effective method to detect the lowering of burden of urate load in gouty joints.

Ultrasonography as a useful modality for documenting sacroiliitis in radiographically negative inflammatory back pain: a comparative evaluation with MRI.

OBJECTIVES: The aims of this study were to identify and characterize features of sacroiliitis in patients with non-radiographic inflammatory low back pain by ultrasonography (USG) and to correlate the findings with that of MRI. METHODS: MRI and USG of SI joints were performed on 29 patients who fulfilled the definition of inflammatory low back pain according to the Assessment of SpondyloArthritis International Society 2009 criteria for axial SpA but were X-ray negative for sacroiliitis. Increased vascularity, low resistive index (RI) and hyperechogenicity of the joint space were considered USG features of sacroiliitis. The findings were compared with those of 32 controls. USG features of sacroiliitis were compared with MRI by κ statistics. RESULTS: Receiver operating characteristic analysis revealed cut-off values for flow signals and RI of 3 and 0.605, respectively. There was a significant difference in the number of flow signals, RI and echogenicity of the SI joint between MRI-proven cases and controls. The Cohen's κ for flow signals, RI and hyperechogenicity when compared with MRI were 0.816 (95% CI 0.676, 0.937) and 0.821 (95% CI 0.662, 0.965) and 0.403 (95% CI 0.108, 0.695). Taking both flow signals and RI parameters as criteria for determining sacroiliitis, comparison with MRI returned a κ of 0.816 (95% CI 0.601, 0.963). CONCLUSION: Three or more flow signals and a RI ≤0.605 can be applied as USG criteria for sacroiliitis. USG can be a cost-effective and non-inferior modality compared with MRI in documenting sacroiliitis in early SpA.

Efficacy and safety of an early response-based tapering regimen of tocilizumab in children with systemic juvenile idiopathic arthritis.

INTRODUCTION: Systemic juvenile idiopathic arthritis (sJIA) is a distinct disease subset, with a poorer prognosis compared with other JIA subsets. Tocilizumab has an important role in the management of sJIA refractory to standard initial therapy. However, no specific guidelines exist for the tapering of tocilizumab therapy in sJIA, which could have implications on the overall cost and side effects of treatment. METHODS: This was an observational study which included 21 children with refractory sJIA, who were initially put on injection tocilizumab every 2 weekly, with subsequent dosing tapered to 4 weekly and 6 weekly intervals based on JIA ACR 70 responses at 12 and 24 weeks, respectively. The primary outcome at week 36 included JIA ACR 30, 50, 70, and 90 response rates with other efficacy and safety measures as secondary outcomes. RESULTS: At 36 weeks, JIA ACR 30, 50, 70, and 90 responses were observed in 90.5%, 90.5%, 71.4%, and 52.4% patients respectively along with significant improvement in hematological and inflammatory parameters. The mean prednisolone dose could be reduced from 0.54 to 0.13 mg/kg/day and around 29% patients were able to discontinue steroids altogether. No serious adverse events were recorded. With drug tapering, we could curtail on 26% of the total tocilizumab dose that would have been otherwise required on the continuous 2 weekly protocol. CONCLUSIONS: Tocilizumab, used in an early response-based tapering regimen, was both safe and efficacious in children with sJIA refractory to standard therapy. Larger and longer duration studies are required to further validate our observations.

Two Concomitant Rare Extraglandular Manifestations of Primary Sjögren's Syndrome: IgA Nephropathy and Autoimmune Hepatitis.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease and can rarely present with multiple extraglandular manifestations. Here we report a case of pSS with concomitant IgA nephropathy and autoimmune hepatitis as the initial manifestations. She presented with polyarthralgia, sicca symptoms and persistent fatigue but was asymptomatic for renal and liver involvement. Autoimmune diseases can have overlapping clinical features and occasionally, manifest nonspecific symptoms leading to delay in diagnosis. It is therefore imperative to thoroughly evaluate any patient of pSS for early recognition of the diverse extraglandular features and initiate prompt treatment to improve outcome.