Human leukocyte antigen association in systemic sclerosis patients: our experience at a tertiary care center in North India.

Introduction: Systemic sclerosis (SSc) is a chronic multisystem autoimmune rheumatic disease of unknown etiology. Several studies have established that SSc is triggered by a dynamic interplay between genetic factors and environmental stimuli. In the present study, we aimed to study the association of human leukocyte antigen (HLA) with familial and non-familial SSc patients [limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc)] from North India. Methods: The HLA-A, B, DRB1, and DQB1 genotyping of 150 (70 lcSSc and 80 dcSSc) adult-onset SSc patients and 150 age-gender-matched healthy controls were performed with sequence-specific oligonucleotide (SSO) typing kits using the luminex platform. HLA typing for HLA class I (A, B, and C) and II (DRB1, DQB1, and DPB1) in five North Indian families consisting of parent-child/sibling pairs affected with SSc or overlap syndrome was performed by Next Generation Sequencing (NGS) with Illumina MiniSeq. Rseults: Among the non-familial SSc patients, HLA- DRB1*11 (P = 0.001, OR: 2.38, P c = 0.01) was identified as a risk allele, and DRB1*12 (P = .0001, OR: 0.00, P c = 0.001) as a protective allele. There was no statistical association found with HLA-DQB1*. Also, no significant association was observed between HLA antigens and different clinical subsets (lcSSc and dcSSc) of SSc. Two cases of familial SSc patients had the DRB1*11 allele. The DRB1*12 allele was absent in all the familial SSc patients. Discussion: HLA DRB1*11 (risk allele) and DRB1*12 (protective allele) were found to be strongly associated with non-familial SSc patients and partially explain the disease's familial clustering, supporting the susceptible genetic background theory for SSc development. The study also indicates the HLA allele as a common genetic risk factor in distinct autoimmune diseases contributing to overlap syndrome or polyautoimmunity.

Predictors of COVID-19 severity and outcomes in Indian patients with rheumatic diseases: a prospective cohort study.

Objective: There is dearth of data regarding the outcomes of coronavirus disease 2019 (COVID-19) among rheumatic and musculoskeletal disease (RMD) patients from Southeast Asia. We report the clinicodemographic profile and identify predictors of COVID-19 outcomes in a large cohort of Indian RMD patients. Methods: This prospective cohort study, carried out at the Postgraduate Institute of Medical Education and Research, Chandigarh (a tertiary care centre in India), included RMD patients affected with COVID-19 between April 2020 and October 2021. Demographic and clinical and laboratory details of COVID-19 and underlying RMD were noted. Predictors of mortality, hospitalization and severe COVID-19 were identified using stepwise multivariable logistic regression. Results: A total of 64 severe acute respiratory syndrome coronavirus-2-infected RMD patients [age 41.5 (19-85) years; 46 (72%) females] were included. Eighteen (28%) patients had severe COVID-19. Twenty-three (36%) required respiratory support [11 (17%) required mechanical ventilation]. Thirty-six (56%) patients required hospitalization [median duration of stay 10 (1-42) days]; 17 (27%) required intensive care unit admission. Presence of co-morbidities [odds ratio (OR) = 4.5 (95% CI: 1.4, 14.7)] was found to be an independent predictor of COVID-19 severity. Co-morbidities [OR = 10.7 (95% CI: 2.5, 45.4)] and underlying lupus [OR = 7.0 (95% CI: 1.2, 40.8)] were independently associated with COVID-19 hospitalization. Ongoing rheumatic disease activity [OR = 6.8 (95% CI: 1.3, 35.4)] and underlying diagnosis of lupus [OR = 7.1 (95% CI: 1.2, 42.4)] and SSc [OR = 9.5 (95% CI: 1.5, 61.8)] were found to be strong independent predictors of mortality. Age, sex, underlying RMD-associated interstitial lung disease and choice of immunosuppressive therapy were not associated with COVID-19 severity or adverse outcomes. Conclusion: The presence of co-morbidities was independently associated with COVID-19 severity and hospitalization. Ongoing rheumatic disease activity and the presence of lupus or SSc independently predicted mortality. Age, sex, type of immunosuppressive therapy and presence of RMD-associated interstitial lung disease did not affect COVID-19 severity or outcomes in Indian RMD patients.

Detection of Epstein-Barr virus in systemic sclerosis patients: A molecular and serological based study.

OBJECTIVE: This study aimed to evaluate an association between Epstein-Barr virus (EBV) and systemic sclerosis (SSc). METHODOLOGY: One hundred and fifty (138 female, 12 male) consecutive adult SSc patients fulfilling the American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) criteria were included in this cross-sectional study. Serological analysis by line blot for class immunoglobulin G (IgG) and IgM antibodies against EBV antigen (EBV capsid antigen [VCA] gp125, VCA p19, EBNA-1, p22, EA-D) and quantification of EBV DNA in whole blood by real-time polymerase chain reaction was performed. RESULTS: Class IgM antibodies against VCA gp125 (22.8% vs 0%, P < .0002), VCA p19 (55.7% vs 4.4%, P < .0001), EBNA1 (35.7% vs 0%, P < .0001), p22 (24.2% vs 0%, P < .0001), EA-D (14.2% vs 2.2%, P < .04), and class IgG antibodies against p22 (95.7% vs 82.2%, P < .02) and EA-D (54.2% vs 0%, P < .0001) reactivities were significantly higher in SSc patients than in controls. The past infection was significantly associated with the control group (42.8% vs 91%, P < .0001); and the viral reactivation was significantly associated with the SSc group (55.7% vs 4.4%, P < .0001). Only three (2%) out of 150 SSc patients were positive for EBV DNA, similar to the control group (2%) (P > .9). CONCLUSION: The study shows a strong serological association of EBV (reactivation stage) with SSc patients in the absence of viral DNA in the circulation, indicating the EBV reservoir or tropism presence elsewhere.

Managing ANCA-associated vasculitis during COVID-19 pandemic: a single-center cross-sectional study.

The objective of the study is to report the outcomes of COVID-19 in ANCA-associated vasculitis (AAV) patients. This was a registry-based observational study conducted at a tertiary care center in north India. AAV patients with at least one follow-up visit between March 2020 and September 2021 were included. Demographic features, clinical manifestations, disease activity, and treatment details of underlying AAV were noted in all patients. Details of COVID-19 infection including severity, treatment, and outcomes were noted. Predictors of COVID-19 severity were determined using univariate analysis. A total of 33 (18.3%) out of 180 AAV patients contracted COVID-19 infection. Moderate COVID-19 infection was seen in 33.3% and severe or critical infection was seen in 36.3% of patients. Seventeen patients (51.5%) required supplemental oxygen therapy. Nine patients had active disease at the time of COVID-19 infection and three of them died due to COVID-19 infection. The risk of COVID-19 infection and its severity did not differ between patients receiving different immunosuppressants including rituximab induction. Hypothyroidism (p = 0.046) and ocular (p = 0.038) involvement due to AAV predicted the development of moderate to severe/critical COVID-19. Three (9.1%) patients died from COVID-19 and the rate of AAV flare after COVID-19 was similar to that in non-COVID-19 patients (15.3/100 person-year vs. 15.6/100 person-year, p = 0.95). Majority of the patients with AAV had moderate to severe or critical COVID-19 infection. The rate of death due to COVID-19 in AAV is higher than in general population. Use of standard remission induction regimens did not lead to increased risk of COVID-19 infection in our AAV cohort.

Comparison of two dose escalation strategies of methotrexate in active rheumatoid arthritis: a multicentre, parallel group, randomised controlled trial.

OBJECTIVES: There are no head-to-head trials of different dose escalation strategies of methotrexate (MTX) in RA. We compared the efficacy, safety and tolerability of 'usual' (5 mg every 4 weeks) versus 'fast' (5 mg every 2 weeks) escalation of oral MTX. METHODS: This multicentre, open-label (assessor blinded) RCT included patients 18-55 years of age having active RA with disease duration <5 years, and not on DMARDs. Patients were randomized 1:1 into usual or fast escalation groups, both groups starting MTX at 15 mg/week till a maximum of 25 mg/week. Primary outcome was EULAR good response at 16 weeks, secondary outcomes were ΔDAS28 and adverse effects (AE). Analyses were intention-to-treat. RESULTS: 178 patients with mean DAS28-CRP of 5.4(1.1) were randomized to usual (n=89) or fast escalation groups (n=89). At 16 weeks, there was no difference in good EULAR response in the usual (28.1%) or fast escalation (22.5%) groups (p=0.8). There was no difference in mean ΔDAS28-CRP at 8 weeks (-0.9, -0.8, p=0.72) or 16 weeks (-1.3, -1.3, p=0.98). Even at 24 weeks (extended follow-up), responses were similar. There were no inter-group differences in ΔHAQ, or MTX-polyglutamates 1-3 levels at 8 or 16 weeks. Gastrointestinal AE were higher in the fast escalation group over initial 8 weeks (27%, 40%, p=0.048), but not over 16 weeks. There was no difference in cytopenias, transaminitis, or drug discontinuation/dose reduction between the groups. No serious AE were seen. CONCLUSION: A faster MTX escalation strategy in RA was not more efficacious over 16-24 weeks, and did not significantly increase AE, except higher gastrointestinal AE initially. TRIAL REGISTRATION NUMBER: CTRI/2018/12/016549.

Anti-Jo-1 Syndrome Often Misdiagnosed as Rheumatoid Arthritis (for Many Years): A Single-Center Experience.

BACKGROUND: Antisynthetase syndrome is characterized by a triad of myositis, arthritis, and interstitial lung disease. Anti-Jo-1 is the most common associated autoantibody. This study planned to look at the presentation of anti-Jo-1 antisynthetase syndrome in a single Indian center. METHODS AND MATERIALS: This was a medical records review single-center study that included patients with anti-Jo-1 antisynthetase syndrome over 10 years. RESULTS: This study included 27 patients with anti-Jo-1 antisynthetase syndrome, with mean age of 40 ± 9.2 years and female preponderance (female-to-male ratio, 4:1). At presentation, the characteristic triad was present in only 4 patients. A majority presented with the incomplete form, with 2 clinical features (of triad) in 11 and single feature (of triad) being present in 12 patients at initial presentation. Seven presented only with polyarthritis, out of which 6 had been earlier diagnosed as rheumatoid arthritis. Time gap from diagnosis of "rheumatoid arthritis" to antisynthetase syndrome ranged from 3 to 20 years. In patients who had only arthritis in the beginning, there was a significantly longer delay to diagnosis of antisynthetase syndrome, higher frequency of rheumatoid factor, and lower frequency of anti-Ro-52. Overall, outcome was good, with Eastern Cooperative Oncology Group class 1 or 2 in most except 2 patients. CONCLUSIONS: Anti-Jo-1 antisynthetase syndrome commonly presented as incomplete (not a triad) and often only with arthritis. These patients are diagnosed and treated as rheumatoid arthritis for many years, before a diagnosis of antisynthetase syndrome is made. Being aware of this presentation may help in earlier diagnosis by actively searching for subtle clues.

Prognostic Role of Measurement of Renal Resistive Index in Systemic Sclerosis.

OBJECTIVE: The spectrum of vascular involvement in systemic sclerosis (SSc) includes digital ulcers, gangrene, Raynaud's phenomenon, renovascular disease, and pulmonary hypertension (PH). Recognition of markers of subclinical vascular disease in SSc is an area of active research, but such studies are limited. This study assesses the role of measurement of the renal resistive index (RRI) as an early marker of renal and systemic vasculopathy. It is a step forward towards examining the possibility of a "unified vascular phenotype' in SSc. METHODS: In this single-centre prospective study, RRI was calculated for SSc patients >18 years age. Elevated RRI (>0.7) was correlated with renal function (eGFR and proteinuria) and systemic vasculopathy manifestations like digital ulcers, digital infarcts, and PH. RESULTS: A total of 73 patients with mean (SD) age 41.8(10.9) years were included. Mean (SD) RRI in the right and left renal artery was 0.65(0.08) and 0.66(0.07), respectively. 16 (21.9%) patients had elevated RRI (>0.7). A strong negative correlation was noted between elevated RRI and eGFR (r= -0.96, p=0.03). The percentage of patients with overt proteinuria was higher in the group with elevated RRI (20% versus 7%) (p=0.16). Similarly, digital ulcers (56% vs 33%) and digital pitting (50% vs 35%.) were numerically higher in the group with raised RRI, although statistical significance was not reached because of small numbers (p=0.09 and 0.28, respectively). No correlation of RRI with PH was identified. CONCLUSION: RRI correlates well with asymptomatic renal dysfunction and holds promise in the assessment of systemic vasculopathy. However, validation in studies with a larger sample size is needed.

Ovarian dysfunction with moderate-dose intravenous cyclophosphamide (modified NIH regimen) and mycophenolate mofetil in young adults with severe lupus: a prospective cohort study.

BACKGROUND: Ovarian toxicity is a dreaded complication of cyclophosphamide (CYC). With the use of lower cumulative doses of intravenous CYC (modified NIH regimens) and availability of better markers of ovarian toxicity, the incidence of ovarian dysfunction needs reassessment. Lupus disease activity, by itself, is also believed to affect ovarian function negatively. METHODS: This single-centre prospective cohort study recruited 50 female patients of severe lupus aged 18-40 years. Twenty-five patients each received induction with either monthly intravenous CYC (0.5-0.75 g/m2) for 6-9 months or daily oral mycophenolate mofetil (MMF). Details of menstrual irregularities; serum levels of FSH, LH, estradiol, AMH, and inhibin B; and sonographic assessment of ovarian volume and antral follicular count were done at baseline and 6 months after treatment. Amenorrhoeic patients were re-evaluated at 1 year. RESULTS: Mean (SD) age of subjects in the CYC and MMF groups was 31.4 (6.3) and 28.4 (4.4) years, respectively. Mean (SD) SLEDAI at the initiation of therapy was 7.2 (2.5) in the CYC group and 5.8 (3.4) in the MMF group. The mean cumulative dose of CYC used was 4.6 (1.8) g. Three patients in the CYC group (versus none in MMF) had amenorrhoea at 6 months-two of these regained menses within 6 months, while only one (4%) developed sustained amenorrhoea (lasting more than 12 months) at 41 years of age, likely menopause. Serum FSH levels increased (p = 0.03), while AMH (p = 0.002) and inhibin B (p < 0.001) levels decreased significantly with 6 months of CYC therapy. Ovarian volume also reduced significantly (p = 0.005) with 6 months of CYC therapy, while antral follicular count reduced numerically (p = 0.32). Levels of AMH, inhibin-B, estradiol, ovarian volume, and antral follicular count after 6 months therapy were significantly lesser in the CYC group compared to the MMF group, despite being similar before the start of therapy. CONCLUSIONS: Ovarian dysfunction with monthly intravenous CYC (modified NIH regimen) was predominantly subclinical, with a negative effect on ovarian reserve. No premature ovarian failure was noted at 1 year. No ovarian dysfunction occurred in the MMF group, despite having patients with severe background lupus. Use of intravenous CYC for induction may thus not be restricted in young lupus females with incomplete families for fear of gonadotoxicity, especially in life- or organ-threatening situations, where the benefits outweigh this subclinical risk.

Efficacy and safety of pirfenidone in systemic sclerosis-related interstitial lung disease-a randomised controlled trial.

To assess the efficacy and safety of pirfenidone in systemic sclerosis-related interstitial lung disease (SSc-ILD). This was a double-blind, randomised, placebo-controlled, pilot study. Subjects with SSc-ILD and forced vital capacity (FVC) between 50 and 80% of the predicted (%pred) value were randomised in 1:1 ratio to receive either pirfenidone (2400 mg/day) or placebo for 6 months. Primary outcome was the proportion of subjects with either stabilisation or improvement in FVC at 6 months. Secondary outcomes were the absolute change in the %pred FVC, Mahler's dyspnoea index, 6-min walk distance (6MWD), modified Rodnan skin score (MRSS) and serum levels of tumour necrosis factor α (TNF-α) and transforming growth factor ß (TGF-ß). Thirty-four subjects with median (range) age of 41 (20-63) years (91.2% women) and median (range) %pred FVC of 65 (51-78) were enrolled. Stabilisation/improvement in FVC was seen in 16 (94.1%) and 13 (76.5%) subjects in the pirfenidone and placebo groups, respectively (p = 0.33). The median (range) absolute change in %pred FVC was - 0.55 (- 9 to 7%) and 1.0 (- 42 to 11.5%) in the treatment and control groups, respectively (p = 0.51). The changes in 6MWD, dyspnoea scores, MRSS, and levels of TNF-α and TGF-ß were not significantly different between groups. Common adverse events were gastrointestinal disturbances and skin rash. We failed to find a significant beneficial effect of pirfenidone over placebo in improving/stabilising FVC, exercise capacity, symptoms, or skin disease. Study is underpowered to provide conclusive evidence. Larger studies with longer follow-up periods are required.

Effect of mycophenolate mofetil (MMF) on systemic sclerosis-related interstitial lung disease with mildly impaired lung function: a double-blind, placebo-controlled, randomized trial.

The efficacy and safety of mycophenolate mofetil (MMF) has been studied in patients with systemic sclerosis (SSc)-related interstitial lung disease (ILD) with moderate-severe impairment. There is no study on its use in patients with mildly impaired lung function. The objective of this study is to determine the efficacy and safety of MMF for treating mild SSc-ILD (forced vital capacity (FVC) ≥ 70% predicted). This was a double-blind, randomized, placebo-controlled pilot trial. The subjects with SSc-ILD with FVC ≥ 70% were randomized to receive either MMF (2 g/day) or placebo for 6 months. FVC, diffusing capacity of lungs for carbon monoxide (DLCO), modified Rodnan skin score (mRSS), Short Form-36 (SF36v2), Mahler's Dyspnoea Index (MDI), and 6-min walk distance (6MWD) were recorded at baseline and at 6 months. Forty-one subjects were included in the study (MMF: 20, placebo: 21). FVC decreased by a median of 2.7% (range - 21 to 9) in MMF arm and increased by 1% (range - 6 to 10) in placebo arm (p = 0.131). SF36v2 scores improved in both the groups. Median change in MDI (3 vs 3), DLCO (1% vs 1.5%), and 6MWD (0 m vs 0 m) was similar between the study groups. MMF was effective in improving mRSS (- 5 vs - 1, p = 0.045) compared to placebo. Adverse events occurred with similar frequency in both the study groups. In this pilot study, MMF did not result in significant improvement in lung function in SSc-ILD with minimally impaired lung function, but was effective in reducing the skin tightness. Larger studies are needed to confirm these findings. This study was registered at ClinicalTrials.gov (NCT02896205).

Chikungunya: A rheumatologist's perspective.

Chikungunya (CHIK), a viral infection, is transmitted by Aedes mosquitoes. It is characterized by a phase of acute infection, which is sometimes followed by chronic rheumatisim in the form of arthralgia or myalgia that can last for months and even years. Several studies have been conducted to understand the mechanisms underlying inflammation associated with CHIK infection, persistence of viruses in monocytes-macrophages, and their relationship to the chronic symptoms. Chronic arthritis is one of the serious complications of CHIK infection, which is characterized by swelling and acute pain that poorly responds to treatment with analgesics. Such debilitating chronic joint pain mimics that of rheumatic arthritis and significantly compromises the quality of life. Diagnosis is primarily based on the initial viral detection using molecular methods or the use of virus culture, and on the basis of an immune response in the later stages. In the absence of published guidelines, physicians are often limited to prescribing analgesics and steroids for symptomatic care, as there is no accurate approach for the treatment and management of pain. This review aims to focus on the need for appropriate guidelines that will aid in developing suitable pharmacologic treatment to manage pain associated with post-CHIK chronic inflammatory rheumatism.

Gastrointestinal Dysmotility and Infections in Systemic Sclerosis- An Indian Scenario.

INTRODUCTION: Systemic Sclerosis is known to involve the gastrointestinal system and can lead to multitude of problems predominantly affecting the GI motility. METHODS: It was a prospective, observational, single centre study of fifty consecutive patients with SSc who presented to rheumatology clinic. Gut score was assessed using UCLA SCTC GIT 2.0 questionnaire. 35 patients underwent esophago- gastro duodenoscopy(UGIE), 31 underwent esophageal manometry, 37 underwent lactulose breath test to assess orocaecal transit time (OCTT) and glucose breath test for detecting small intestinal bacterial overgrowth (SIBO) and 36 underwent gastric emptying scintigraphy to measure gastric emptying time. RESULTS: GI involvement was seen in 98% of patients, with most common symptom being regurgitation (78%). Mean T score of the GUT score was 0.60±0.27. In UGIE, esophagitis was seen in 30, of which 3 had candidiasis and 1 had HSV esophagitis. Hiatus hernia was noted in 10 patients. Mean lower esophageal sphincter pressure was 16.1± 12.7 mmHg with hypotensive sphincture in twelve patients. Esophageal peristaltic abnormalities were observed in 28(90%) patients. Gastric emptying was delayed in10/36 patients. OCTT was prolonged in 23/ 37 patients whereas SIBO was noted in 7/37. CONCLUSION: GI involvement is common in SSc with esophagus being most commonly affected. Motility abnormalities make them prone for super added infections especially infectious esophagitis and SIBO and should be investigated for early detection and treatment.

Use of Biologics and Biosimilars in Rheumatology.

Prior to the availability of biologics, synthetic DMARDs (Disease modifying anti-rheumatic drugs) were the mainstay of the treatment in rheumatology. With the introduction of biologics, the scenario is changing to become more promising. These drugs have innovative mechanism of action, based on the targeted inhibition of specific molecular or cellular targets directly involved in disease pathogenesis. The biosimilars are highly similar copies of originator biologics approved through pre-defined, stringent regulatory processes after rigorous physicochemical, non-clinical, and clinical evaluations. Low cost and resulting wider patient access as compared to innovators goes in favor of biosimilars. Regulatory guidelines for biosimilar development and approval are rigorous and undergoing constant refinement. Approval of several biosimilars in across the world in last few years bears testimony to the increased regulatory acceptance of these agents. This article addresses development of biosimilars, regulatory process, benefits and concerns about their usage in rheumatologic practice.