Safety and Efficacy of Golimumab in Indian Patients with Active Spondyloarthritis of Ankylosing Spondylitis or Psoriatic Arthritis: A Multicenter, Noncomparative, Open-Label, Real-World Study.

BACKGROUND: The safety and efficacy of tumor necrosis factor-α (TNF-α) inhibitor therapy for most common rheumatological diseases, ankylosing spondylitis (AS), and psoriatic arthritis (PsA) in controlled clinical trials is well-studied. This study evaluated subcutaneous (SC) golimumab in Indian patients with active spondyloarthritis (SpA) of AS or PsA in a real-world setting. MATERIALS AND METHODS: This phase 4, multicenter, prospective, non-comparative, interventional, 24-week study was performed in patients (age ≥18 years) with active SpA of AS or PsA (NCT03733925). Golimumab 50 mg was given subcutaneously to the patients every 4 weeks. Safety was assessed. The proportion of patients with AS and PsA achieving ≥20% improvement in the Assessment of SpA International Society 20 (ASAS20) criteria and American College of Rheumatology 20 (ACR20) responses, respectively, at weeks 14 and 24 were efficacy endpoints. RESULTS: Of the 100 patients enrolled (men: 78 [78.0%]; mean age: 36.7 [12.02] years), 94 (94.0%) patients completed the study. Treatment-emergent adverse events with golimumab were observed in 29/100 (29.0%) patients, and nasopharyngitis and upper respiratory tract infection (5.0% each) were the most common (≥5%). Deaths were not reported. At week 14, 74.5% (95% confidence interval [CI]: 59.7; 86.1%) of patients with AS and 84.6% (95% CI: 69.5; 94.1%) of patients with PsA achieved ASAS20 and ACR20 responses, which were sustained at week 24 (ASAS20: 66.0% [95% CI: 50.7, 79.1%]; ACR20: 93.2% [95% CI: 81.3, 98.6%]), respectively. CONCLUSION: Golimumab (50 mg) administered subcutaneously was safe and effective in Indian patients with active SpA of AS or PsA during the 24-week study period with no new safety signals.

Effect of neuronavigated repetitive Transcranial Magnetic Stimulation on pain, cognition and cortical excitability in fibromyalgia syndrome.

BACKGROUND: Fibromyalgia syndrome is a widespread chronic pain condition identified by body-wide pain, fatigue, cognitive fogginess, and sleep issues. In the past decade, repetitive transcranial magnetic stimulation has emerged as a potential management tool.. In the present study, we enquired whether repetitive transcranial magnetic stimulation could modify pain, corticomotor excitability, cognition, and sleep. METHODS: Study is a randomized, sham-controlled, double-blind, clinical trial; wherein after randomizing thirty-four fibromyalgia patients into active or sham therapy (n = 17 each), each participant received repetitive transcranial magnetic stimulation therapy. In active therapy was given at 1 Hz for 20 sessions were delivered on dorsolateral prefrontal cortex (1200 pulses, 150 pulses per train for 8 trains); while in sham therapy coil was placed at right angle to the scalp with same frequency. Functional magnetic resonance imaging was used to identify the therapeutic site. Pain intensity, corticomotor excitability, cognition, and sleep were examined before and after therapy. RESULTS: Baseline demographic and clinical parameters for both active and sham groups were comparable. In comparison to sham, active repetitive transcranial magnetic stimulation showed significant difference in pain intensity (P < 0.001, effect size = 0.29, large effect) after intervention. Other parameters of pain perception, cognition, and sleep quality also showed a significant improvement after the therapy in active therapy group only, as compared to sham. CONCLUSIONS: Findings suggest that repetitive transcranial magnetic stimulation intervention is effective in managing pain alongside cognition and sleep disturbances in patients of fibromyalgia. It may prove to be an important tool in relieving fibromyalgia-associated morbidity.

HLA sequencing identifies novel associations and suggests clinical relevance of DPB1*04:01 in ANCA-associated Granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease. Major contributions of HLA genes have been reported; however, HLA typing-based diagnosis or risk prediction in GPA has not been established. We have performed a sequencing-based HLA genotyping in a north Indian GPA cohort and controls to identify clinically relevant novel associations. PR3-ANCA-positive 40 GPA patients and 40 healthy controls from north India were recruited for the study. Targeted sequencing of HLA-A,-B,-C,-DRB1,-DQB1, and -DPB1 was performed. Allelic and haplotypic associations were tested. Molecular docking of susceptibility HLA alleles with reported super-antigen epitopes was performed. The association of substituted amino acids located at the antigen-binding domain of HLA was evaluated. Genetic association of five HLA-alleles was identified in GPA. The novel association was identified for C*15:02 (p = 0.04; OR = 0.27(0.09-0.88)). The strongest association was observed for DPB1*04:01 (p < 0.0001; OR = 6.2(3.08-11.71)), previously reported in European studies. 35 of 40 GPA subjects had at least one DPB1*04:01 allele, and its significant risk was previously not reported from the Indian population. Significantly associated haplotypes DRB1*03:01-DQB1*02:01-DPB1*04:01 (p = 0.02; OR = 3.46(1.11-12.75)) and DRB1*07:01-DQB1*02:02-DPB1*04:01 (p = 0.04; OR = 3.35(0.95-14.84)) were the most frequent in GPA patients. Ranging from 89 % to 100 % of GPA patients with organ involvement can be explained by at least one DPB1*04:01 allele. A strong interaction between the HLA and three epitopes of the reported super antigen TSST-1 of Staphylococcus aureus was confirmed. Our study highlighted the potential applicability of HLA typing for screening and diagnosis of GPA. A large multi-centric study and genotype-phenotype correlation analysis among GPA patients will enable the establishment of HLA-typing based GPA diagnosis.

Yoga maintains Th17/Treg cell homeostasis and reduces the rate of T cell aging in rheumatoid arthritis: a randomized controlled trial.

The pathogenesis of rheumatoid arthritis (RA) is characterized by a Th17/Treg cell imbalance. A pro-inflammatory cytokine milieu that promotes the continued proliferation of Th17 cells is related to the development of autoinflammation. In RA, T cells have several hallmarks of cellular aging, and they accumulate DNA damage, predisposing to the occurrence of mutations and epigenetic alterations. Since the onset, progression, and treatment response are influenced by a variety of external stressors and environmental factors, this study aimed to evaluate the impact of 8-week yoga practice on disease severity, T cell subsets, markers of T cell ageing and inflammation, epigenetic alterations and gene expression patterns in active RA patients on standard disease-modifying anti-rheumatic drugs (DMARDs). A total of 64 participants with active RA were randomized into 2 groups, yoga group (n = 32) or non-yoga group (n = 32); that were assessed for disease severity, at baseline and after 8 week duration, for Disease Activity Score (DAS28-ESR), T cell subsets [Th17 (CD3+ CD4+ IL17+ RORγt+) cells and Treg (CD3+ CD4+ CD25+ CD127-Foxp3+) cells], markers of T cell aging [aged Th17 cells (CD3+ CD4+ IL17+ RORγt+ CD28-) and aged Treg cells (CD3+ CD4+ CD25+ CD127-Foxp3+ CD28-)], pro-inflammatory markers [IL-6, and IL-17], anti-inflammatory markers [TGF-ß, and IL-10], epigenetic alterations [5-methyl cytosine, 5-hydroxymethyl cytosine, and HDAC1] and gene expression patterns [RORγt, FoxP3, IL-17, IL-6, TGF-ß, CXCL2, CXCR2, and JUN]. In yoga group, there was a significant improvement in DAS28-ESR scores at the end of 8-weeks of yoga program. The Th17 cells and aged T cell subsets showed a significant decline whereas Treg cell population showed a significant elevation in yoga group. There were significant improvements observed in epigenetic markers as well as inflammatory markers post 8-weeks of yoga practice. The yoga group showed downregulation of RORγt, IL-17, IL-6, CXCL2, CXCR2, and upregulation of FoxP3 and TGF-ß transcripts. Yoga enables the maintenance of immune-homeostasis as evident by increased Treg cell population and reduced Th17 cell population. Yoga reduces the rate of immunological aging in T cells, as seen by the reduction in population of aged Th17 cells and aged Treg cells. Yoga positively modifies transcriptome and epigenome by normalization of various inflammatory markers, gene expression patterns and epigenetic alterations. Taken together, yoga reduces RA severity, and aids in immune-modulation and hence can be beneficial as an adjunct therapy.

Effect of Motor Imagery on Corticomotor Excitability and Pain Status in Rheumatoid Arthritis Patients.

OBJECTIVES: Rheumatoid arthritis (RA) has been defined by the American College of Rheumatology in 1987 as a chronic inflammatory disease characterised by joint swelling, joint tenderness, and destruction of synovial joints leading to severe disability and premature mortality. There is a paucity of literature assessing corticomotor excitability in RA patients. This study aimed to assess the effect of motor imagery on corticomotor excitability and pain status in RA patients. The specific objectives were to study the effect of motor imagery on corticomotor excitability and pain status in RA patients. We also wanted to compare the corticomotor excitability between RA patients with healthy controls. The correlation between the measures of corticomotor excitability and pain status in RA patients has also been done. METHODS: The study was designed as a pilot clinical trial with a case-control design. Forty participants were recruited for the study. Twenty RA patients were recruited from the Department of Rheumatology and Department of Physical Medicine and Rehabilitation (PMR), AIIMS, New Delhi, and 20 healthy controls. Testing was performed at the Pain Research & rTMS Lab, Department of Physiology, AIIMS, New Delhi. The study was approved by the Institute Ethics Committee, AIIMS New Delhi, and registered in the Clinical Trials Registry-India (CTRI). For the subjective assessment of pain, the visual analogue scale (VAS), Short-Form McGill Pain Questionnaire, WHO-Quality of Life Brief questionnaire (WHO-QOL-BREF), and Rheumatoid Arthritis Pain Scale were used. For the objective assessment of pain, hot and cold pain thresholds were assessed using thermo-tactile quantitative sensory testing (QST) using the method of limits and corticomotor excitability using a transcranial magnetic stimulation device. All participants were also asked to perform motor imagery tasks which consisted of a metronome-paced thumb opposition paradigm.  Results: The resting motor threshold (RMT) decreased significantly after motor imagery when compared to the mental calculation group. The amplitude of motor evoked potential (MEP) and QST parameter value was comparable in both the groups before and after motor imagery and mental calculation. RMT was found to be significantly higher whereas MEP values were found to be significantly lower in RA compared to controls. CONCLUSION: We conclude that patients suffering from RA have decreased corticomotor excitability compared to controls. Motor imagery was effective in improving corticomotor excitability in these patients and can be used as rehabilitation in RA to relieve their pain.

Anti-inflammatory potential of selective small compounds by targeting TNF-α & NF-kB signaling: a comprehensive molecular docking and simulation study.

Tumor necrosis factor alpha (TNF-α) is the major cause of inflammation in autoimmune diseases like rheumatoid arthritis (RA). It's mechanisms of signal transduction through nuclear factor kappa B (NF-kB) pathway via small molecules such as metabolite crosstalk are still elusive. In this study, we have targeted TNF-α and NF-kB through metabolites of RA, to inhibit TNF-α activity and deter NF-kB signaling pathways, thereby mitigating the disease severity of RA. TNF-α and NF-kB structure was obtained from PDB database and metabolites of RA were selected from literature survey. In-silico studies were carried out by molecular docking using AutoDock Vina software and further, known TNF-α and NF-kB inhibitors were compared and revealed metabolite's capacity to targets the respective proteins. Most suitable metabolite was then validated by MD simulation to verify its efficiency against TNF-α. Total 56 known differential metabolites of RA were docked with TNF-α and NF-kB compared to their corresponding inhibitor compounds. Four metabolites such as Chenodeoxycholic acid, 2-Hydroxyestrone, 2-Hydroxyestradiol (2-OHE2), and 16-Hydroxyestradiol were identified as a common TNF-α inhibitor's having binding energies ranging from -8.3 to -8.6 kcal/mol, followed by docking with NF-kB. Further, 2-OHE2 was selected because of having binding energy -8.5 kcal/mol, found to inhibit inflammation and the effectiveness was validated by root mean square fluctuation, radius of gyration and molecular mechanics with generalized born and surface area solvation against TNF-α. Thus 2-OHE2, an estrogen metabolite was identified as the potential inhibitor, attenuated inflammatory activation and can be utilized as a therapeutic target to disseminate severity of RA.

Translational implications of humoral and cellular immune dysfunction in granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA) is a rare systemic ANCA (Anti-neutrophil cytoplasmic antibodies) associated vasculitis (AAV). In the last couple of decades, GPA has emerged as a disease of concern due to rapid increase in the prevalence and incidence especially in developing countries. Unknown aetiology and rapid progression have made GPA a critical disease. Thus, establishing specific tools to facilitate early and faster disease diagnosis and efficient disease management has immense importance. GPA may develop in genetically predisposed individuals on receiving the external stimulus (i.e. microbial pathogen, pollutant etc.) that triggers the immune response. B-cell activating factor (BAFF) produced by the neutrophils, promotes the B-cell maturation and survival which leads to increased ANCA production. Abnormal B-cell and T-cell proliferation and their cytokine response plays a major role in disease pathogenesis and granuloma formation. ANCA interacts with neutrophils and induces the neutrophil extracellular traps (NETs) formation and reactive oxygen species (ROS) production which leads to the endothelial cell injury. This review article summarizes the critical pathological events and how cytokines and immune cells shape the GPA pathogenesis. Decoding this complex network would facilitate in developing tools for diagnosis, prognosis and disease management. Recently developed specific monoclonal antibodies (MAbs) targeting cytokines and immune cells are being used for safer treatment and achieving longer remission.

Case report: Characterization of a rare pathogenic variant associated with loss of COL3A1 expression in vascular Ehlers Danlos syndrome.

The vascular subtype of Ehlers Danlos Syndrome (vEDS) is a rare connective tissue disorder characterized by spontaneous arterial, bowel or organ rupture. The diagnosis of vEDS is established in a proband by identification of a heterozygous pathogenic variant in the alpha-1 gene of type III collagen (COL3A1) by molecular analysis. In this report, we present a case of vEDS with life threatening, spontaneous arterial dissections in association with an uncharacterized rare variant of COL3A1, exon19:c.1340G > A. Primary culture of patient skin fibroblasts followed by immunofluorescence revealed a complete absence of COL3A1 protein expression as well as altered morphology. Electron microscopy of the cultured fibroblasts showed abnormal vacuoles in the cytoplasm suggestive of a secretory defect. In this study, we have performed functional characterization of the COL3A1 exon19:c.1340G > A variant for the first time and this may now be classified as likely pathogenic in vEDS. *Both JM and LRL contributed equally in the manuscript and should both be considered as the first author.

HLA-G 3'UTR polymorphisms & response to a yoga-based lifestyle intervention in rheumatoid arthritis: A randomized controlled trial.

Background & objectives: Human leucocyte antigen (HLA)-G plays a vital role in immunomodulation in rheumatoid arthritis (RA). The mounting evidence suggests a link between HLA-G gene polymorphisms, disease susceptibility and methotrexate treatment response. Various environmental factors influence the onset and progression of RA and its treatment outcomes. The aim is to identify the treatment response of HLA-G 3' untranslated region polymorphisms to yoga-based lifestyle intervention (YBLI). Methods: In this eight-week single-blinded randomized controlled trial (CTRI/2017/05/008589), patients with RA (n=140) were randomized into two groups namely, yoga group or non-yoga group. Baseline genomic DNA was isolated using salting-out method. PCR-based methods were used for genotyping. The levels of soluble (s) HLA-G and disease activity were assessed by ELISA and disease activity score-28-erythrocyte sedimentation rate (DAS28-ESR), respectively, at baseline (day 0) and after eight weeks of intervention. Results: Low-producing sHLA-G genotypes, i.e. +3142GG and 14 bp ins/ins, showed a significant increase in sHLA-G levels after YBLI. The association analysis between HLA-G polymorphisms and treatment for RA showed no considerable differential treatment remission in either of the groups (P>0.05). The percentages of improvement were higher in the yoga group as compared to the non-yoga group in both the HLA-G +3142G>C and 14 bp ins/del polymorphisms irrespective of their respective genotypes. No significant association was found between sHLA-G levels and disease activity with respect to genotypes. Interpretation & conclusions: Yoga intervention results in improvement and reduced severity of RA in patients irrespective of the HLA-G 14 bp ins/del or +3142G>C polymorphisms. YBLI may be used as an adjunct therapy in RA independent of the genotypes.

Stratification of rheumatoid arthritis cohort using Ayurveda based deep phenotyping approach identifies novel genes in a GWAS.

BACKGROUND AND AIM: Genome wide association studies have scaled up both in terms of sample size and range of complex disorders investigated, but these have explained relatively little phenotypic variance. Of the several reasons, phenotypic heterogeneity seems to be a likely contributor for missing out genetic associations of large effects. Ayurveda, the traditional Indian system of medicine is one such tool which adopts a holistic deep phenotyping approach and classifies individuals based on their body constitution/prakriti. We hypothesized that Ayurveda based phenotypic stratification of healthy and diseased individuals will allow us to achieve much desired homogeneous cohorts which would facilitate detection of genetic association of large effects. In this proof of concept study, we performed a genome wide association testing of clinically diagnosed rheumatoid arthritis patients and healthy controls, who were re-phenotyped into Vata, Pitta and Kapha predominant prakriti sub-groups. EXPERIMENTAL PROCEDURE: Genotypes of rheumatoid arthritis cases (Vata = 49; Pitta = 117; Kapha = 78) and controls (Vata = 33; Pitta = 175; Kapha = 85) were retrieved from the total genotype data, used in a recent genome-wide association study performed in our laboratory. A total of 528461 SNPs were included after quality control. Prakriti-wise genome-wide association analysis was employed. RESULTS AND CONCLUSION: This study identified (i) prakriti-specific novel disease risk genes of high effect sizes; (ii) putative candidates of novel therapeutic potential; and (iii) a good correlation between genetic findings and clinical knowledge in Ayurveda. Adopting Ayurveda based deep phenotyping may facilitate explaining hitherto undiscovered heritability in complex traits and may propel much needed progress in personalized medicine.

Meta-analysis confirmed genetic susceptibility conferred by multiple risk variants from CTLA4 and SERPINA1 in granulomatosis with polyangiitis.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease. Smaller sample size and complex nature of the disease pathogenesis has made it challenging to perform well-powered genetic investigations. We performed a systematic review based meta-analysis in GPA to investigate the genetic susceptibility conferred by non-human leukocyte antigen (non-HLA) candidate genes. METHODS: A systematic review was performed using web-based literature search and eligible studies were included following inclusion-exclusion criteria. Studies were evaluated for their quality of evidence and study outcome was assessed using the Newcastle-Ottawa Scale and Grades of Research, Assessment, Development and Evaluation tools. Reviewer's agreement was accessed through Cohen's κ value. Meta-analyses were performed using RevMan 5 tool. Meta-odds ratio (meta-OR) and Z test P value were evaluated to estimate the genetic susceptibility for each of the variants. RESULTS: Eighteen studies were found eligible and 7 genetic variants from only 4 genes, namely CTLA4, PRTN3, SERPINA1 and PTPN22 could be studied for meta-analysis. rs231775-G (49-G) (Meta-OR = 1.42 [1.14-1.76]; P = .001) of CTLA4 and rs7151526-A (Meta-OR = 2.70 [1.51-4.85]; P = .0008) of SERPINA1 were confirmed to be predisposing alleles, and rs5742909-C (318-C) (Meta-OR = 0.65 [0.44-0.97]; P =.03) of CTLA4 was found to be protective for GPA. In concordance with the genetic association of rs7151526-A, serological marker for the same variant "Z" allele of SERPINA1 was found to be predisposing (Meta-OR = 12.60 [5.01-31.68]; P < .00001) for GPA. CONCLUSION: Genetic variants confirmed in this study play critical roles in T-cell mediated immune function and could be significantly implicated in GPA. Molecular pathology studies are warranted to confirm their role. These markers could be used for efficient patient classification and disease management.

Potential Role of Yoga Intervention in the Management of Chronic Non-malignant Pain.

Pain is an unpleasant and upsetting experience. Persistent pain has an impact on an individual's quality of life which causes stress and mood disorders. There are currently no pain-relieving techniques available that can eliminate pain and offer relief without causing any adverse effects. These factors draw attention to traditional treatments like yoga and meditation, which can reduce biological stress and hence increase immunity, as well as alleviate the psychological and emotional suffering produced by pain. Yoga reduces the stress response and the pain cascade via the downregulation of the hypothalamus-pituitary-adrenal (HPA) axis and vagal stimulation. Yoga is a cost-effective growing health practice that, unlike pharmaceuticals, has no side effects and can help patients stay in remission for longer periods of time with fewer relapses. Yoga not only reduces stress and depression severity but also improves functional status and reduces pain perception. This article highlights the impact of yoga on pain management and on a malfunctioning immune system, which leads to improved health, pain reduction, disease management, and improvement in overall quality of life.

Haemoglobin drives inflammation and initiates antigen spread and nephritis in lupus.

Haemoglobin (Hb) has well-documented inflammatory effects and is normally efficiently scavenged; clearance mechanisms can be overwhelmed during erythrocyte lysis. Whether Hb is preferentially inflammatory in lupus and triggers broad anti-self responses was assessed. Peripheral blood mononuclear cells (PBMCs) derived from SLE patients secreted higher levels of lupus-associated inflammatory cytokines when incubated with human Hb than did PBMCs derived from healthy donors, an effect negated by haptoglobin. Ferric murine Hb triggered the preferential release of lupus-associated cytokines from splenocytes, B cells, CD4 T cells, CD8 T cells and plasmacytoid dendritic cells isolated from ageing, lupus-prone NZM2410 mice, and also had mitogenic effects on B cells. Pull-downs, followed by mass spectrometry, revealed interactions of Hb with several lupus-associated autoantigens; co-incubation of ferric Hb with apoptotic blebs (structures that contain packaged autoantigens) revealed synergies-in terms of cytokine release and autoantibody production in vitro-that were also restricted to the lupus genotype. Murine ferric Hb activated multiple signalling pathways and, in combination with apoptotic blebs, preferentially triggered MAP kinase signalling specifically in splenocytes isolated from lupus-prone mice. Infusion of murine ferric Hb into lupus-prone mice led to enhanced release of lupus-associated cytokines, the generation of a spectrum of autoantibodies and enhanced-onset glomerulosclerosis. Given that the biased recognition of ferric Hb in a lupus milieu, possibly in concert with lupus-associated autoantigens, triggers inflammatory responses and the generation of lupus-associated cytokines, and also stimulates the generation of potentially pathogenic lupus-associated autoantibodies, neutralization of Hb could have beneficial effects.

Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine-mapping in the MHC and genomewide.

Because transethnic analysis may facilitate prioritization of causal genetic variants, we performed a genomewide association study (GWAS) of psoriasis in South Asians (SAS), consisting of 2,590 cases and 1,720 controls. Comparison with our existing European-origin (EUR) GWAS showed that effect sizes of known psoriasis signals were highly correlated in SAS and EUR (Spearman ρ = 0.78; p < 2 × 10-14). Transethnic meta-analysis identified two non-MHC psoriasis loci (1p36.22 and 1q24.2) not previously identified in EUR, which may have regulatory roles. For these two loci, the transethnic GWAS provided higher genetic resolution and reduced the number of potential causal variants compared to using the EUR sample alone. We then explored multiple strategies to develop reference panels for accurately imputing MHC genotypes in both SAS and EUR populations and conducted a fine-mapping of MHC psoriasis associations in SAS and the largest such effort for EUR. HLA-C*06 was the top-ranking MHC locus in both populations but was even more prominent in SAS based on odds ratio, disease liability, model fit and predictive power. Transethnic modeling also substantially boosted the probability that the HLA-C*06 protein variant is causal. Secondary MHC signals included coding variants of HLA-C and HLA-B, but also potential regulatory variants of these two genes as well as HLA-A and several HLA class II genes, with effects on both chromatin accessibility and gene expression. This study highlights the shared genetic basis of psoriasis in SAS and EUR populations and the value of transethnic meta-analysis for discovery and fine-mapping of susceptibility loci.

Efficacy and safety of intravenous and subcutaneous immunoglobulin therapy in idiopathic inflammatory myopathy: A systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis on the efficacy and safety of intravenous (IVIg) and subcutaneous (SCIg) immunoglobulin (Ig) therapy in the treatment of idiopathic inflammatory myopathy (IIM) and juvenile dermatomyositis (JDM). METHODS: PubMed, Embase and SCOPUS were searched to identify studies on Ig therapy in patients with IIM and/or JDM (2010-2020). Outcome measures were complete response (CR) or partial response (PR) in terms of muscle power and extramuscular disease activity measures on the International Myositis Assessment and Clinical Studies Group (IMACS) core set domains. RESULTS: Twenty-nine studies were included (n = 576, 544 IIM, 32 JDM). Muscle power PR with pooled Ig therapy was 88.5% (95% confidence interval (CI): 80.6-93.5, n = 499) and PR with SCIg treatment was 96.61% (95% CI: 87.43-99.15, n = 59). Pooled PR with first-line use of IVIg was 77.07% (95% CI: 61.25-92.89, n = 80). Overall, mean time to response was 2.9 months (95% CI: 1.9-4.1). Relapse was seen in 22.76% (95% CI: 14.9-33). Studies on cutaneous disease activity and dysphagia showed significant treatment responses. Glucocorticoid and immunosuppressant sparing effect was seen in 40.9% (95% CI: 20-61.7) and 42.2% (95% CI: 20.4-64.1) respectively. Ig therapy was generally safe with low risk of infection (1.37%, 95% CI: 0.1-2.6). CONCLUSIONS: Add-on Ig therapy improves muscle strength in patients with refractory IIM, but evidence on Ig therapy in new-onset disease and extramuscular disease activity is uncertain.

Transthyretin and Receptor for Advanced Glycation End Product's Differential Levels Associated with the Pathogenesis of Rheumatoid Arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic autoimmune, inflammatory joint disease. The identification of multifaceted etiological changes at the protein level in RA remains an important need. We aimed to identify differential proteins (DPs) and gene profiles to uncover inflammatory indicators and their association to RA pathogenesis. METHODS: 2-DE and SWATH-MS were used to identify DPs in RA and healthy control plasma. Fluorescence phenylboronate gel electrophoresis (Flu-PAGE) with mass spectrometry was used for protein glycation in RA plasma. Disease specificity of identified DPs was confirmed by ELISA and Western blot analysis. The gene expressions of selected DPs were evaluated by qRT-PCR in PBMCs of RA, systemic lupus erythematosus (SLE), spondyloarthritis (SpA), and osteoarthritis (OA). The functional implication of glycated protein was determined by in- silico and validated by in vitro analysis in fibroblast-like synoviocytes. RESULTS: A total of 150 DPs (127 increased and 23 decreased) were identified by 2-DE and SWATH-MS analysis in RA plasma compared to healthy control (HC). Nine proteins were identified as glycated by Flu-PAGE LC-MS/MS. Transthyretin (TTR), serotransferrin, and apolipoprotein-A1 (Apo-A1) were found to be differential and glycated. ELISA and Western blot results revealed the disease-specific increased expression of TTR and RAGE in RA. The qRT-PCR results signify the aberrant gene expression of TTR and RAGE, found to be associated with RA when compared with SLE, SpA, and OA PBMCs. TTR-RAGE interactions were predicted by in-silico and validated by in- vitro analysis using RA-FLS. The increased levels of pro-inflammatory cytokines IL-6, IL-1ß, TNF-α, and differently expressed TTR and RAGE were confirmed in fibroblast-like synoviocytes under inflammatory conditions. CONCLUSION: Our findings showed that the level of TTR was increased in RA plasma, along with an altered glycation rate. TTR and RAGE aberrant gene expression in PBMCs are the key events associated with RA, and TNF-α activates the NF-KB pathways and promote TTR and RAGE differential expressions that may have pathogenic/inflammatory significance.

Epidemiology and genetics of granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA) previously known as Wegener's granulomatosis (WG) is a rare rheumatic disease affecting subjects of all ages. Prevalence and incidence of this systemic disease greatly varies across different ethnic groups. GPA is the commonest form of ANCA-associated vasculitis (AAV) with PR3 positivity among 85-95% of the cases. Scientific investigations of GPA is warranted because its severity, clinical heterogeneity, fast disease manifestation and end-organ damage. The etiology of GPA is still unknown. Major role of HLA and non-HLA genes with immune functions were identified, however, very limited replication was observed in different ethnic populations. In the present review, we have discussed the updates on the global epidemiology and contribution of HLA and major non-HLA genes/loci in GPA. We have also highlighted the cross disease association of GPA associated genes that may help in better disease management and predictive medicine. We proposed that high-resolution HLA typing and development of genetic risk model would help in early disease diagnosis and understanding the prognosis.

Clinical and laboratory evidence of Lyme disease in North India, 2016-2019.

BACKGROUND: Lyme disease is endemic to parts of the Americas, Europe and Asia. However, only a handful of sporadic cases have been reported from India. In this study, we systematically evaluated the clinical and epidemiological features of Lyme disease in North India. METHOD: All samples were tested by using the standard two-tiered testing algorithm (STTA). Paired serum and cerebrospinal fluid (CSF) were used for demonstrating Borrelia burgdorferi specific intrathecal IgG antibody synthesis (AI). In addition, a commercial tick-borne bacterial flow chip (TBFC) system and a real-time PCR were also used to detect Borrelia species and Anaplasma phagocytophilum in patients who were positive by STTA. RESULTS: The diagnosis of Lyme disease was confirmed in 18 (7.14%) of the 252 clinically suspected cases by STTA. Neurological involvement was reported in 14 (77.78%) patients, whereas joint and heart involvement was reported in five (27.78%) and three (16.67%) patients, respectively. Lymphocytic pleocytosis (median 37.5 cells/mm3; range 12-175 cells/mm3) in the CSF was seen in 11 of 14 Lyme neuroborreliosis (LNB) patients. Intrathecal production of Borrelia specific IgG antibodies was demonstrated in 9 (64.28%, n = 14) patients, a highly specific finding for neuroborreliosis. Two patients (11.11%) were also found to be co-infected with human granulocytic anaplasmosis. CONCLUSIONS: The results of this study show clinical and laboratory evidence of endemic Lyme disease in North India and thus, highlight the importance for travel medicine practitioners and physicians to evaluate for Lyme disease in patients with compatible symptoms and a history of travel to tick risk areas.