IL-21/23 axis modulates inflammatory cytokines and RANKL expression in RA CD4+ T cells via p-Akt1 signaling.

Introduction: CD4+ T cells are critically involved in the pathogenesis of Rheumatoid Arthritis; an autoimmune disorder characterized by joint inflammation and bone degeneration. In this study, we focused on the critical role of cytokines, IL-21 and IL-23 in facilitating the aberrant status of RA Th17-like cells and report their significant contribution(s) in modulating the expression of inflammatory cytokines and RANKL. Methods: Blood and synovial fluid collected from a total of 167 RA patients and 25 healthy volunteers were assessed for various inflammatory markers and RANKL expression in plasma and CD4+ T cells. Subsequent ex vivo studies examined the role of specific cytokines, IL-21 and IL-23 in mediating inflammation and RANKL upregulation by blocking their expression with neutralizing antibodies in RA CD4+ T cells and terminally differentiated human Th17 cells. Further, the role of p-Akt1 as a signalling target downstream of IL-21 and IL-23 was evinced with IL-21 and IL-23 inhibition and phospho Akt-1/2 kinase inhibitor. Results: Our observations highlighted the augmented inflammatory cytokine levels in plasma and an aberrant CD4+ T cell phenotype expressing exaggerated inflammatory cytokines and membrane RANKL expression in RA as opposed to healthy controls. Neutralization of either IL-21 or IL-23 (p19 and p40) or both, resulted in downregulation of the cytokines, TNF-α, IFN-γ and IL-17 and RANKL expression in these cells, signifying the critical role of IL-21/23 axis in modulating inflammation and RANKL. Subsequent dissection of the signaling pathway found p-Akt1 as the key phosphoprotein downstream of both IL-21 and IL-23, capable of increasing inflammatory cytokines and RANKL production. Discussion: Our findings unequivocally identify IL-21/23 axis in RA CD4+ T cells as a key regulator dictating two critical processes i.e. exaggerated inflammation and higher RANKL expression and provide critical targets in their downstream signalling for therapeutic approaches.

Restless leg syndrome in rheumatic conditions: Its prevalence and risk factors, a meta-analysis.

INTRODUCTION: Restless leg syndrome (RLS) is a neurological disorder characterized by an uncontrollable desire to move legs along with abnormal sensations, particularly at night, which can lead to sleep disturbance. RLS may mimic rheumatic diseases or can be associated with them, hence their identification and treatment are important to improve sleep quality and overall quality of life in rheumatic diseases. METHODS: We conducted a search of the PubMed, SCOPUS, and EMBASE databases to identify studies reporting a prevalence of RLS in patients with rheumatic disease. Two authors independently screened, selected, and extracted the data. Heterogeneity was assessed using I2 statistics and random effect method of the meta-analysis was used to synthesize the results. RESULTS: Out of 273 unique records, 17 eligible studies including 2406 rheumatic patients were identified. RLS prevalence (95% CI) among patients of rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, fibromyalgia and ankylosing spondylitis are found to be 26.6% (18.6 34.6); 32.5% (23.1-41.9), 4.4% (2.0-6.8), 38.1% (31.3-45.0) and 30.8% (23.48-39.16) respectively. RLS prevalence was similar for males and females. CONCLUSION: Our study indicates a high prevalence of RLS in patients with rheumatic diseases. Early detection and treatment of RLS in patients with rheumatic conditions could be beneficial in improving their overall health and quality of life.

Nintedanib vs pirfenidone in the management of COVID-19 lung fibrosis: A single-centre study.

BACKGROUND: COVID-19 pneumonia is complicated with residual lung fibrosis, as evidenced by imaging and postmortem pathological findings. In addition to steroids, we compared the efficacy of nintedanib and pirfenidone in the management of COVID-19 lung fibrosis measured by CT severity score (CTSS). METHODS: All cases of COVID-19 pneumonia diagnosed as COVID-19 positive by RT-PCR having SpO2 ⩽ 96% and CTSS ⩾ 10 even after 15 days were included in the study. The patients were divided into three groups. All three groups received steroids at a dose of 1 mg/kg body weight of prednisolone or equivalent. The first group received steroids alone, the second group received pirfenidone with steroids and the third group received nintedanib with steroids. All patients were followed up at 6 and 12 weeks. The primary endpoint of our study was to find out any improvement in CTSS. RESULTS: Out of 90 patients, 56 patients completed the study. Among three groups, 19 (33.9%) patients received steroids (control) only, 16 (28.6%) patients received steroids with pirfenidone and 21 (37.5%) patients received steroids with nintedanib. The study population had a mean (±SD) age of 52.5 ± 10.1 years, mean (±SD) C-reactive protein of 97.1 ± 102.2 mg/L (normal <6 mg/L), mean (±SD) serum ferritin 459.4 ± 305.5 ng/mL (normal <250 ng/mL), mean (±SD) serum d-dimer level 2.1 ± 2.6 µg/mL (normal <0.5 µg/mL) and mean (±SD) CTSS of 16.9 ± 4.3. There was significant improvement in CTSS in group receiving nintedanib compared to pirfenidone at 12 weeks (3.67 ± 1.21 vs 9.07 ± 1.12) with a p-value <0.01. CONCLUSION: Along with steroids in the treatment of COVID-19 lung fibrosis, there was a significant improvement in lung CTSS with nintedanib compared to pirfenidone.

Secukinumab therapy in reactive arthritis: Report of two cases.

Reactive arthritis (ReA) is an immune-mediated aseptic synovitis resulting either from genitourinary or gastrointestinal tract, commonly presenting as oligoarthritis of the lower limbs and rarely urethritis and conjunctivitis. The treatment options include nonsteroidal anti-inflammatory drugs, conventional disease-modifying antirheumatic drugs, and biologics in severe cases. We report successful use of secukinumab in two cases of chronic severe ReA who initially failed to treatment with tumour necrosis factor inhibitor.

Unusual Presentation of Systemic Lupus Erythematosus in a Young Male: A Case Report.

Hepatic involvement in systemic lupus erythematosus (SLE) is common but described infrequently. Liver is usually never the primary organ to be affected in lupus. Again hepatic involvement probably does not carry much prognostic importance though it may correlate with lupus activity. We here report a case of 21-year-old man with no prior comorbidity or addiction who presented to us with acute hepatic illness with jaundice. He also had malar rash and arthralgia. Viral markers were negative. Antinuclear antibody and anti-double-stranded DNA (dsDNA) were strongly positive. Liver biopsy was consistent with autoimmune hepatitis, whereas skin biopsy was suggestive of SLE. He had a brisk and complete recovery with prompt use of immunosuppressive agents (corticosteroids and azathioprine). Cyclophosphamide was started latter in view of lupus nephritis. This is probably the fourth reported case of SLE presenting as acute hepatic illness with jaundice.

Increased Extracellular ATP in Plasma of Rheumatoid Arthritis Patients Activates CD8+T Cells.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disorder with genetic and environmental causes often linked with the disease etiology. A disrupted metabolism has often been a characteristic of RA and an altered metabolic state of immune cells has been associated with their phenotypic and functional changes. The energy in the form of ATP produced by the metabolically active cells may thus initiate a cascade of immune responses there by influencing the disease pathogenesis or progression. AIM OF THE STUDY: Through this study we have focused on determining the role of ATP in etiology of RA and aberrant cellular functions. METHODS: Blood samples of 80 healthy controls (HC) and 95 RA patients were screened for extracellular ATP concentration, transcriptome analyses, an inflammatory mediator and the results were statistically analysed. RESULTS: In this study, ATP is shown to be excessive in the plasma of RA patients (453.5 ± 16.09% in RA vs. 233.9 ± 10.07% in HC, p <0.0001) and significantly increases with the disease severity. The abundant extracellular ATP could activate circulating cytotoxic CD8+T cells in RA patients to produce Granzyme B. CONCLUSION: Plasma ATP is thus identified to have a significant potential in progression and prognosis of RA and may thus be studied further to design better therapeutic approaches for the disease.

Acute onset paraplegia in a case of granulomatosis with polyangitis (GPA) - an unusual complication.

Granulomatosis with polyangiitis (GPA) is a rare multisystem autoimmune disease of unknown aetiology with only a few reported cases about spinal cord involvement in the literature. We report on the case of an established GPA presented with acute onset bilateral lower limb weakness, urinary retention and faecal incontinence consistent with transverse myelitis. Contrast-enhanced MRI scanning revealed T2 hyperintensity extending from the T1 to conus medularis, without any gadolinium enhancement features suggestive of long segment myelitis. He was successfully treated with I.V IG followed by Rituximab.

Mixed Connective Tissue Disease With Retroperitoneal Fibrosis: A Rare Occurrence.

Mixed connective tissue disease (MCTD) is an autoimmune condition characterized by mixed clinical features of connective tissue diseases like systemic lupus erythematosus, polymyositis or systemic sclerosis with high titers of anti-U1 small nuclear ribonucleoprotein. Interstitial lung disease is a frequent manifestation of MCTD. Retroperitoneal fibrosis (RPF) is a rare fibro-inflammatory process involving the retroperitoneum. Majority of the cases are idiopathic and the rest are secondary to malignancies, infections or drugs. In this article, we describe a rare occurrence of RPF with MCTD.

Altered mitochondrial proteome and functional dynamics in patients with rheumatoid arthritis.

The autoimmune inflammatory disease, Rheumatoid arthritis (RA), has known imbalances in energy metabolism and superoxide levels thus may have an etiology associated with mitochondrial dysfunction. We thus evaluated the presence of a differential mitochondrial proteome as well as other characteristics including mitochondrial mass, membrane potential (Ψm), total cellular ATP and superoxide levels. Eighteen mitochondrial proteins were down-regulated while four were up-regulated in RA patients in comparison to the healthy controls (HC). A significant decrease in mitochondrial Ψm, superoxides and cellular ATP levels was observed in RA with constant mitochondrial mass suggesting mitochondrial dysfunction responsible for functional disparity in RA.

Rheumatic manifestations as initial presentation of malignancy: A case series from a tertiary care center in India.

OBJECTIVE: Malignant neoplasms can be associated with a wide variety of rheumatological manifestations that may be caused by direct tumor invasion into bones and joints, as a paraneoplastic syndrome, and through altered immune surveillance. To identify the relationship between rheumatic manifestations in various malignancies. METHODS: Twenty patients with various malignancies presenting with rheumatic conditions in our tertiary medical care were studied retrospectively from case records at the Kalinga Institute of Medical Sciences from 2013 to 2018. RESULTS: In the present study, total of 20 patients including 12 males and 8 females with mean age at diagnosis of was 46.3±22.2 years with various malignancy associated rheumatic diseases were included. In total 20% of patients with were current smokers. Seven (35%) had hematological malignancies whereas 13 (65%) had solid malignancies. Most common presenting feature was arthritis (40%), followed by weight loss (20%), skin rash (10%), fever (15%) and muscle weakness (10%) at the time of diagnosis. All of them developed malignancy within 24 months of diagnosis. Among the autoantibodies, only 6 patients (30%) were positive for both ANA (n= 4, 20%) and RF (n=2, 10%), other antibodies were negative. The patients in the hematological malignancies had significantly higher serum levels of LDH, Mean±SD U/L compared to solid malignancy group (716.8±169.6 vs. 249.9±161.6, p<0.001). CONCLUSION: In our cohort, all the patients developed malignancies within 2 years of diagnosis of rheumatic condition. Higher serum LDH levels helpful to differentiates between hematological and solid malignancies. Hence early detection of malignancy is of major importance in these patients.

Clinical features and outcome of acute exacerbation in connective tissue disease-associated interstitial lung disease: A single-center study from India.

BACKGROUND: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is associated with high mortality, but there is limited clinical data on AE of interstitial lung disease (ILD) in connective tissue disease-associated ILD (CTD ILD). The present study was conducted to provide prevalence and clinical features of AE, as well as various risk factors associated with mortality among AE CTD ILD patients. METHODS: Between May 2013 and April 2018, 15 patients who developed AE among 105 consecutive patients with CTD with chronic ILD were included. AE was defined using the criteria recently proposed by the IPF net, with slight modification for adaptation to CVD-IP6 (collagen vascular disease-associated interstitial pneumonia), and patients having CTD with AE met all the criteria. RESULTS: Fifteen patients with mean age of 45.8 ± 13.9 years developed AE; the most common subgroup (n = 5, 33%) was systemic sclerosis. The mean duration (months) between diagnosis of ILD and AE was 56.5 ± 38.0 with mean follow-up duration of 24 ± 18.1 months. The baseline arterial oxygen pressure (PaO2 ) was 81.7 ± 8.1 mm Hg and mean forced vital capacity (%) was 57.9 ± 8.9. Five patients requiring mechanical ventilation died. Patients with shorter duration (months) of disease between onset of ILD to AE had higher mortality, 40.4 ± 45.1 vs 64.6 ± 33.6. Those who had significantly lower baseline PaO2 (mean ± SD), 72.6 ± 3.4 vs 86.2 ± 5.3 mm Hg (P = .002) had higher mortality. CONCLUSIONS: In our study, the majority of patients with AE CTD ILD had systemic sclerosis. Patients with lower baseline PaO2 and those requiring mechanical ventilation had higher mortality.

Direct recognition of LPS drive TLR4 expressing CD8+ T cell activation in patients with rheumatoid arthritis.

Aberrant immune responses characterize autoimmune disorders like Rheumatoid Arthritis (RA) wherein lymphocytes are recognized as key players. Role of CD8+ T cells in RA has been less defined however we found that these cells are activated in RA patients with increased expression of cytolytic granules and inflammatory mediators thereby modulating immune responses contributing to disease severity. Though unconventional expression of different Toll Like Receptors (TLRs) on CD8+ T cells has been proposed but their expression and role in T cell activation and differentiation in RA still remains obscure. Herein we report, for the first time, an increased expression of TLR4 on peripheral CD8+ T cells of RA patients and its role in skewing CD8+ T cells towards activated and inflammatory phenotype thereby playing a significant role in pathogenesis and progression of RA. We found that the surface expression of TLR4 on CD8+ T cells directly correlates with disease severity. Moreover, these CD8+ T cells respond to the TLR4 ligand LPS and express robust amounts of cytotolytic and inflammatory molecules including TNFα and IFNγ. Our study hence identifies an important role for CD8+ T cells in orchestrating RA through TLR4 mediated activation and differentiation.

Unilateral Migratory Relapsing Orbital Myositis While on Immunosuppressant Therapy: An Uncommon Entity.

A young healthy female presented with acute onset left ocular pain, restricted ocular motility, and binocular diplopia. CT imaging showed left lateral rectus myositis that resolved with oral corticosteroids. Two sequential relapses occurred subsequently involving the superior rectus-levator complex followed by the medial rectus. Biopsy revealed orbital inflammatory disease with lymphocytic vasculitis. Detailed systemic work up was normal. The second relapse was seen while on long-term oral methotrexate although initial disease remission had been achieved with the same drug. A changeover to oral azathioprine was able to achieve disease remission after the second relapse. All relapses involved the same side and the contralateral orbit was not affected. This report presents the curious phenomenon of unilateral migratory relapsing orbital myositis of unknown cause that recurred even while on immunosuppressant therapy. It highlights the unpredictable nature of this uncommon entity and the challenges faced in managing such cases.

Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells.

Reactive oxygen species (ROS) signaling is critical in T helper (Th) cell differentiation; however its role in differentiated Th cell functions is unclear. In this study, we investigated the role of oxidative stress on the effector functions of in vitro differentiated mouse Th17 and Th1 cells or CD4+ T cells from patients with Rheumatoid Arthritis using pro-oxidants plumbagin (PB) and hydrogen peroxide. We found that in mouse Th cells, non-toxic concentration of pro-oxidants inhibited reactivation induced expression of IL-17A in Th17 and IFN-γ in Th1 cells by reducing the expression of their respective TFs, RORγt and T-bet. Interestingly, in both the subsets, PB increased the expression of IL-4 by enhancing reactivation induced ERK1/2 phosphorylation. We further investigated the cytokine modulatory effect of PB on CD4+ T cells isolated from PBMCs of patients with Rheumatoid Arthritis, a well-known Th17 and or Th1 mediated disease. In human CD4+ T cells from Rheumatoid Arthritis patients, PB reduced the frequencies of IL-17A+ (Th17), IFN-γ+ (Th1) and IL-17A+/IFN-γ+ (Th17/1) cells and also inhibited the production of pro-inflammatory cytokines TNF-α and IL-6. N-Acetyl Cysteine (NAC) an antioxidant completely reversed PB mediated cytokine modulatory effects in both mouse and human cells indicating a direct role for ROS. Together our data suggest that oxidative microenvironment can alter cytokine response of terminally differentiated cells and thus altering intracellular ROS could be a potential way to target Th17 and Th1 cells in autoimmune disorders.

Severe calcinosis cutis with cutaneous ulceration in juvenile dermatomyositis.

BACKGROUND: Calcinosis cutis is usually seen in long standing and untreated cases of juvenile dermatomyositis. CASE CHARACTERISTICS: 7-year-old girl with severe calcinosis cutis who developed cutaneous ulceration, rash and myopathy. OBSERVATION: Myopathic changes in EMG, muscle edema in MRI, elevated muscle enzymes and Jo-1 positive antibodies. OUTCOME: Treatment with prednisolone and methotrexate resulted in improvement of the lesion. MESSAGE: Calcinosis cutis may be a presenting feature of juvenile dermatomyositis even in the absence of characteristic findings of rash and weakness.