Rheumatoid arthritis synovial fluid shows enrichment of T-cells producing GMCSF which are polyfunctional for TNFα and IFNγ.

OBJECTIVES: GMCSF+T-cells may be involved in pathogenesis of rheumatoid arthritis (RA), and polyfunctionality may be a marker of pathogenicity. Although, higher frequencies of CD4+GMCSF+ T-cells have been reported, there are no data on CD8+GMCSF+ T-cells or polyfunctionality.Our objective was to enumerate frequencies of CD8+GMCSF+ T cells in RA blood and synovial fluid (SF), and assess their polyfunctionality, memory phenotype and cytotoxic ability. METHODS: This study included RA patients (blood samples,in some with paired synovial fluid (SF)), healthy controls (HC) (blood) and SpA patients (SF). In some RA patients' blood was sampled twice, before and 16-24 weeks after methotrexate (MTX) treatment. After mononuclear cell isolation from blood and SF, ex-vivo stimulation using PMA/Ionomycin was done, and cells were stained (surface and intracellular after permeabilisation/fixation). Subsequently, frequencies of GMCSF+CD8+ and CD4+ T-cells, polyfunctionality (TNFα, IFNγ, IL-17), phenotype (memory) and perforin/granzyme expression were assessed by flowcytometry. RESULTS: There was no significant difference in frequencies of GMCSF+CD8+ (3.7, 4.1%, p=0.540) or GMCSF+CD4+ T-cells (4.5, 5.2%, p=0.450) inblood of RA and HC. However, there was significant enrichment of both CD8+GMCSF+ (5.8, 3.9%, p=0.0045) and CD4+GMCSF+ (8.5, 4.5%, p=0.0008) T-cells inSF compared to blood in RA patients. Polyfunctional triple cytokine positive TNFα+IFNγ+GMCSF+CD8+T-cells (81, 36%, p=0.049) and CD4+T-cells (48, 32%, p=0.010) was also higher in SF compared to blood in RA. CD8+ T cells showed higher frequency of effector-memory phenotype and granzyme-B expression in RA-SF. On longitudinal follow-up, blood CD4+GMCSF+ T-cells significantly declined (4.6, 2.9%, p=0.0014) post-MTX. CONCLUSIONS: We report a novel finding of enrichment of CD8+GMCSF+ in addition to CD4+GMCSF+ T-cells in RA-SF. These cells showed higher polyfunctionality for TNFα and IFNγ, and effector memory phenotype suggesting their involvement in RA pathogenesis.

Severity and determinants of psychosocial comorbidities in granulomatosis with polyangiitis and their impact on quality of life.

Depression, anxiety, sleep disturbances, and fatigue are inadequately addressed comorbidities in granulomatosis with polyangiitis (GPA). We determined the prevalence, severity, determinants, and the impact of these comorbidities on quality-of-life (QoL) in GPA. This observational study included adult GPA patients; patients with RA and lupus were included as comparators. Patient Health Questionnaire-9 for depression, Generalized Anxiety Disorder 7-item scale for anxiety, Epworth Sleepiness Scale for sleep disturbances, and Fatigue Severity Scale for fatigue were administered prospectively to estimate prevalence and severity. QoL and disability were estimated using PROMIS-HAQ, HAQ-health and HAQ-pain. Correlations among these parameters were assessed. Stepwise regression analyses were performed to identify determinants of depression, anxiety, excessive sleepiness, and fatigue. One hundred eighty-one patients-62 GPA [mean age 43 (13) years], 57 RA and 62 SLE- were included. The prevalence of depression (47%), excessive sleepiness (21%), and fatigue (39%) in GPA were comparable to RA and lupus; anxiety was less prevalent (29% versus 46% and 53%, p = 0.02). Severity was mostly mild-moderate. Younger age [OR = 0.93 (0.89-0.98)], higher BMI [OR = 1.2 (1.0-1.4)], and greater disease damage [OR = 2.0 (1.3-3.3)] independently predicted presence of depression. Higher BMI [OR = 1.3 (1.1-1.5)] and concomitant FMS [OR = 80.9 (5.1-1289.2)] were independently associated with excessive sleepiness. No association with disease activity, duration, or gender was seen. GPA patients with depression, anxiety, excessive sleepiness, and fatigue had worse PROMIS-HAQ, HAQ-pain, and HAQ-health. In conclusion, depression, anxiety, sleep disturbances, and fatigue are common in GPA. Although their severity is mostly mild-moderate, they impair QoL significantly. Potentially modifiable determinants that can form targets for future interventions have been identified.

Long-term persistence of oral methotrexate and associated factors in rheumatoid arthritis: a retrospective cohort study.

There is little data on long-term persistence/continuation of methotrexate among Indian Rheumatoid arthritis patients. We assembled a retrospective single-center cohort consisting of RA patients (fulfilling 1987 ACR criteria) started on methotrexate as part of three academic studies (including two RCTs) from 2011 to 2016. Oral methotrexate was started at 7.5 or 15 mg per week with a target dose of 25 mg per week. Between August and December 2020, all patients were contacted (telephonically) and data were obtained from clinic files to evaluate self-reported continuation/persistence of methotrexate and reasons for discontinuation. Survival analysis using Kaplan-Meier and cox-regression were used to assess methotrexate continuation rates and factors associated with its discontinuation. This study included 317 patients with rheumatoid arthritis, with mean age and disease duration (at enrollment) of 43 years and 2 years; And positive rheumatoid factor and anti-CCP in 69 and 75%. At follow-up, 16 patients (5%) had died, whereas 103 (32.5%) had discontinued methotrexate. On Kaplan-Meier survival analysis, the mean survival (continuation) time for methotrexate was 7.3 years (95% CI 7-7.6 years). The actuarial continuation/persistence of methotrexate at 3, 5 and 9 years was 92, 81 and 51%, respectively. Among those who discontinued methotrexate, common reasons were remission of disease, symptomatic adverse effects (intolerance), perceived lack of efficacy and socioeconomic reasons. On multivariable cox-regression, symptomatic adverse effects during the first 12-24 weeks (Hazard ratio, 95% CI 1.8 (1.2-2.8)) and anti-CCP positivity (Hazard ratio, 95% CI 0.6 (0.3-1.0)) were significantly associated with hazard of discontinuation. Persistence or continuation of methotrexate was found to be good and comparable to reports in other centers world-wide. Apart from remission, the most important cause of methotrexate discontinuation was symptomatic adverse effects (intolerance).

ANCA-associated vasculitis following ChAdOx1 nCoV19 vaccination: case-based review.

For the foreseeable future, vaccines are the cornerstone in the global campaign against the Coronavirus Disease-19 (COVID-19) pandemic. As the number and fatalities due to COVID-19 decline and the lockdown anywise rescinded, we recognize an increase in the incidence of autoimmune disease post-COVID-19 vaccination. However, the causality of the most vaccine-induced side effects is debatable and, at best, limited to a temporal correlation. We herein report a case of a 51-year-old gentleman who developed Anti-Neutrophil Cytoplasmic Antibody (ANCA)-associated vasculitis (AAV) 2 week post-COVID-19 vaccination. The patient responded favorably to oral steroids and rituximab. Additionally, we conducted a case-based review of vaccine-associated AAV describing their clinical manifestations and treatment response of this emerging entity.

Clinical presentation and treatment outcomes of arterial involvement in Behçet's disease: a single-centre experience.

Arterial involvement, although rare, accounts for significant mortality and morbidity in patients of Behçet's disease (BD). There is paucity of data on arterial BD. The objective of this 5-year retrospective cohort study was to examine the clinical presentation, pattern of arterial involvement, and treatment outcome in Indian arterial BD patients. Data on demography, clinical presentation, radiology, instituted therapy, vascular interventions and treatment outcomes were recorded and analyzed. Ten (16.9%) out of 59 patients with BD had arterial involvement in 13 vascular territories [mean age 30 (8) years, 9 (90%) males]. Pulmonary artery was most commonly involved (46%), followed by abdominal aorta (15%), femoral artery (15%), descending thoracic aorta (8%), common iliac (8%), and dorsalis pedis artery (8%). Two patients had multi-territory involvement. The median interval between disease onset and development of arterial aneurysms was 3 years (3 months-12 years). Concomitant deep vein thrombosis was seen in 60% cases. Prednisolone and cyclophosphamide were the most common immunosuppressive therapy used; one patient who relapsed on cyclophosphamide responded to infliximab. Five surgical or endovascular interventions were performed. Four patients (40%) died due to aneurysm rupture-all had a delayed diagnosis, and three had pulmonary artery involvement, with death due to massive hemoptysis. Based on the present study, we concluded that arterial involvement in BD is seen predominantly in males and has a high mortality. Early detection and aggressive treatment with immunosuppression and surgical or endovascular interventions are essential for good outcomes.

Efficacy of a step-down regimen of oral prednisolone in axial spondyloarthritis: result of a double-blind randomized controlled trial (COBRA-AS Study).

OBJECTIVES: To evaluate the efficacy and safety of a step-down regimen of oral prednisolone over 24 weeks in patients of axial SpA (axSpA). METHODS: This proof-of-concept double-blind randomized controlled trial enrolled patients with active axSpA (BASDAI ≥4) having predominantly axial disease (≤1 active joint currently) and inadequate response to NSAIDs. They were randomized to receive either oral prednisolone (n = 32) or placebo (n = 33) at a dose of 60, 40, 30, 20, 15 and 10 mg daily for 1 week each, following which they received 5 mg prednisolone (or placebo) daily for 18 weeks. The primary endpoint was a 50% improvement in the BASDAI (BASDAI50) at week 24. Analysis was intention to treat. RESULTS: A BASDAI50 was achieved by 12 of 32 patients (37.5%) in the prednisolone arm and 3 of 33 patients (9.1%) in the placebo arm at 24 weeks [difference 28.4% (95% CI 7.9, 46.7)]. However, there was no difference in achieving a 20 or 40% improvement in the Assessment of SpondyloArthritis international Society response between the groups. Although there was a significant intergroup difference in adjusted ΔBASDAI and ΔAnkylosing Spondylitis Disease Activity Score with CRP at 24 weeks, there was no difference at 12 weeks. There was also no significant difference in ΔBASFI, ΔBAS-G or ΔBASMI at 12 or 24 weeks. No serious adverse events were noted. There was significant weight gain in the first 12 weeks in the prednisolone group vs placebo [0.9 (s.d. 0.4) kg], but not at 24 weeks. CONCLUSIONS: In this small study, oral prednisolone was efficacious in axSpA in achieving the primary outcome, but many crucial secondary outcomes such as functional improvement were not met. Its impact on bone loss was not studied.Trial registration: CTRI/2018/01/011342.

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.

Fluorodeoxyglucose positron emission tomography/computed tomography in the diagnosis, assessment of disease activity and therapeutic response in relapsing polychondritis.

OBJECTIVE: To evaluate 18F-fluorodeoxyglucose (FDG) PET/CT in the assessment of disease activity, extent of the disease and response to therapy in relapsing polychondritis. METHODS: Twenty-five patients (9 men, 16 women) with a mean age of 38.2 years (s.d. 13.7; range 18-62), diagnosed to have relapsing polychondritis according to Damiani and Levine's modification of McAdam's criteria, who underwent PET/CT examination were included. Ten patients underwent a second PET/CT examination after therapy or during follow-up. Clinical symptoms and auxiliary examination findings were recorded. PET/CT findings were reviewed and correlated with the clinical symptoms. RESULTS: The major symptoms were aural pain (n = 21), nasal pain (n = 10), stridor (n = 5), cough (n = 9), fever (n = 8) and laryngeal tenderness (n = 8). The initial PET/CT was positive in 23/25 patients. PET/CT revealed involvement of auricular (n = 14), nasal (n = 8), laryngeal (n = 7), tracheobronchial (n = 6) and Eustachian (n = 3) cartilages with a mean maximum standardized uptake value (SUVmax) of 4.1 (s.d. 2.5; range 1.7-12.7). Fair correlation of aural/nasal pain/stridor with FDG avidity of cartilage involvement on PET/CT was noted. The key finding was detection of asymptomatic large airway involvement in seven patients (28%). Re-examination PET in 10 patients revealed complete therapeutic response (n = 5), partial response (n = 1), stable disease (n = 1), progressive disease (n = 1) and disease recurrence (n = 2). CONCLUSION: FDG PET/CT is a useful tool for the assessment of the disease activity and extent. It identified activity in clinically inaccessible sites that are of clinical significance. It is also useful in assessing treatment response and finding relapse.

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).

Cerebrospinal Fluid Viral Escape on Highly Active Antiretroviral Therapy: Analysis from Single Tertiary Care Centre.

HIV-infected individuals receiving regular antiretroviral therapy (ART) can present with a high viral load in cerebrospinal fluid (CSF) at times when it is suppressed in blood. This study presents data of HIV-infected patients who had undetectable or low plasma viral load in blood but presented with neurological signs and symptoms and were diagnosed to have CSF HIV viral escape. Records were reviewed for clinical manifestations, details of opportunistic or coinfection, and HIV viral copies in plasma and CSF at time of diagnosis of CSF escape. A total of 10,200 HIV-infected individuals were registered in HIV care till December 31, 2021. Nineteen individuals (14 virologically confirmed and 5 clinically) were diagnosed with high viral copies in CSF from June 2014 to December 2021. Mean age was 41.5 ± 9.2 (median, 39.5; range, 30-62) years. Average duration of antiretroviral treatment received at the time of diagnosis of CSF escape was 10.1 years. Median plasma HIV-viral copies were 2,469.8 (undetectable to 29,418) and in CSF were 12,773.7 (n = 14, range, 1,340-48,530) copies/mL. HIV viral copies in CSF were significantly higher than in plasma at the time of presentation (p = .003). ART regimen switch was done after identification of HIV CSF escape. Seventeen patients were alive with a regular follow-up of average 35 (range 7-66) months. All had documented clinical improvement with reversal of neurological impairment after ART switch. There was one death and one lost to follow-up. Early identification and timely intervention in CSF viral escape could revert severe neurological impairment and improves treatment outcome.

Efficacy, Tolerability, and Compliance of Direct Acting Antivirals in Patients with HIV and Hepatitis C Coinfection: A Real-Life Experience.

Effective management of HIV and hepatitis C virus (HCV) coinfection warrants special emphasis on interactions between direct acting antivirals (DAAs) and antiretroviral therapy (ART) along with maintenance of treatment compliance. All HIV-HCV coinfected adult patients (2015-2020) were included in this real-life retrospective study. Prevalence of coinfection, proportion of coinfected patients treated, compliance rate, sustained virological response at week 12 (SVR12) after the end of therapy, and adverse events were assessed. Among 4578 HIV patients, 232 (5.1%) had HCV coinfection. Ninety-two (39.7%) were intravenous drug users. One hundred twenty-eight (55.1%) patients presented to the liver clinic. Seventy-six (32.8%) patients [mean age: 36.6 ± 10.4 years; 65 (85.5%) males; mean CD4 count: 396 ± 246 cells/mL] completed DAA therapy, whereas 52 (22.4%) patients defaulted and 75 (32.3%) were lost to follow-up. Sixty-seven (82.2%) patients had chronic hepatitis and 9 (11.8%) had compensated cirrhosis. Median (range) HCV-RNA was 5.9 × 106 IU/mL (2.4 × 105-9.9 × 105). Among 15 (19.5%) treatment experienced patients, 14 were pegylated interferon experienced and one was NS5A-inhibitor experienced. ART regimens comprised a combination of tenofovir (T), lamivudine (L), efavirenz (E), nevirapine (N), and/or zidovudine (Z) at dosage and modifications as applicable [TLE: 63 (82.9%), ZLN:11 (14.5%), and ZLE: 2 (2.6%)]. Overall, 74 (97.4%) out of 76 patients who completed DAA therapy achieved SVR12. Adverse events were minor and well-tolerated. HIV-HCV-coinfected patients demonstrate excellent SVR12 and tolerability with available DAAs, with no major adverse events.

Association of immunological features with clinical manifestations in primary Sjogren's syndrome: a single-center cross-sectional study.

The objectives of this study were to describe the clinical features and evaluate the utility of immunological features as predictors of organ involvement and disease severity in patients with primary Sjogren's syndrome (pSS). In this single-center observational cross-sectional study, subjects fulfilling the 2012 AECG criteria or 2016 ACR/EULAR criteria for pSS were included. Details of glandular, extra-glandular manifestations, ESSDAI, ESSPRI, ANA, anti-Ro/La antibodies, rheumatoid factor (RF), complement (C3 and C4) levels and hyperglobulinemia were noted. Chi-square and Mann-Whitney U tests were performed for determining associations and relative risk (RR) was calculated. Sixty-four subjects with pSS were included in the study. Females constituted 92% and median age at onset was 37.5 (15-74) years. Ocular or oral sicca was noted in 61 (95.3%) subjects and parotidomegaly was noted in 17 (26.5%) subjects. Extra-glandular manifestations noted were: constitutional (85.9%), articular (65.6%), renal (29.6%), hematological (26.6%), cutaneous (12.5%), peripheral nerves (9.3%) and pulmonary (4.7%). Immunological features noted were: ANA (85.9%), anti-Ro (81.3%), anti-La (60.9%), RF (84.4%), hypocomplementemia (39.1%) and hyperglobulinemia (62.5%). Median ESSDAI was 6 (0-23) and ESSPRI was 7 (0-10). ANA was associated with younger age and renal involvement (RR 1.25). Anti-Ro was associated with younger age, renal involvement (RR 1.36) and high ESSDAI. Anti-La was associated with high renal (RR 3.4) and low articular involvement (RR 2.75). RF was associated with hematological involvement and hyperglobulinemia was associated with younger age. Certain immunological features can help predict the organ involvement in patients with pSS. Larger, prospective follow-up studies are needed to clearly understand these associations.

Experience with similar biologic rituximab in 77 patients of granulomatosis with polyangiitis-a real-life experience.

OBJECTIVES: To present single centre experience on the efficacy and safety of similar biologic of rituximab in patients with granulomatosis with polyangiitis (GPA). METHODS: This was a retrospective study of GPA patients who received similar biologic of rituximab as either remission induction or maintenance agent. Demographic parameters, Birmingham Vasculitis Activity Score (BVAS-v3), vasculitis damage index, relapse and adverse events were retrieved from patient records. Outcomes noted were remission at 6 months in remission induction group and rates of relapses, adverse events, serious infections and mortality in both remission induction and maintenance groups. RESULTS: Seventy-seven GPA patients were enrolled. Sixty received rituximab for induction and 57 for maintenance; 69% were anti PR-3 positive. In the induction group, median BVAS-v3 reduced from 12 (IQR 6-21.5) to 0 (0-1) at 6 months. At 6 months, 60% patients attained remission, 40% in primary induction group and 74% in re-induction group (p = 0.016%). In the maintenance group, seven (12%) patients had relapses with median time to relapse of 12 (6-22) months. Median relapse free survival was 21 (6-22) months on rituximab maintenance. There were 12 deaths (15.6%) and 18 serious infections. CONCLUSION: Similar biologic of rituximab was an effective agent for remission induction and remission maintenance in patients with GPA. Head to head trials with innovator molecule are needed to confirm these results. KEY POINTS: • Remission was achieved in 60% of GPA patients who received similar biologic of rituximab as remission induction therapy. • Relapse rate during maintenance phase was 12% with similar biologic of rituximab. Serious infections and mortality with similar biologic of rituximab were comparable with that reported previously in AAV trials.