16s RNA-based metagenomics reveal previously unreported gut microbiota associated with reactive arthritis and undifferentiated peripheral spondyloarthritis.

OBJECTIVES: Reactive arthritis (ReA) provides a unique opportunity to comprehend how a mucosal infection leads to inflammatory arthritis at a distant site without the apparent invasion of the pathogen. Unfortunately, conventional stool cultures after ReA provide limited information, and there is a dearth of metagenomic studies in ReA. The objective of this study was to identify gut microbiota associated with the development of ReA. METHODS: Patients with ReA or undifferentiated peripheral spondyloarthritis (UpSpA) were included if they presented within 4 weeks of the onset of the current episode of arthritis. Metagenomic DNA was extracted from the stools of these patients and of 36 age- and sex-similar controls. Sequencing and analysis were done using a standard 16S ribosomal pipeline. RESULTS: Of 55 patients, there was no difference between the gut microbiota of postdiarrheal ReA(n = 20) and of upSpA (n = 35). Comparing the gut microbiota of patients vs healthy controls, the patients had significantly higher alpha and beta diversity measures. After stringency filters, Proteobacteria had high abundance while Firmicutes had lesser as compared with the controls. Six families were overexpressed in patients, while another five were overexpressed in controls. Sixteen genera and 18 species were significantly different between patients and controls. At the species level there was strong association of Staphylococcus aureus, Clostridium septicum Klebsiella pneumoniae, Escherichia coli, Empedobacter brevis, Roseburia hominis, Bacillus velezensis, and Crassaminicella with ReA. CONCLUSION: The microbiota of classical gut-associated ReA and upSpA is similar. Patients have higher diversities in their gut microbiota compared with healthy controls. Both known and previously unreported species associated with ReA/upSpA were identified.

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

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

Parkinsonism as the presenting manifestation of lupus: A case-based review.

INTRODUCTION: Neuropsychiatric manifestations in systemic lupus erythematosus (SLE) occur in about half of the patients; however, movement disorders like Parkinsonism are rare. We describe a case of SLE who presented solely with features of Parkinsonism. CASE REPORT: 50-year-old female presented with global slowing of movements and slowing of speech since 2 months. On examination, she had mask-like facies with a faint malar rash sparing the nasolabial folds, hard palate ulcer, cog-wheel rigidity, and proximal muscle weakness. Lab evaluation revealed lymphopenia, high ESR, elevated lactate dehydrogenase, creatinine phosphokinase, AST, and ALT levels. She had high anti-dsDNA levels with low complements. Urinalysis showed proteinuria and hematuria. ANA was positive at a titer of 1:320, and she had positive anti-ribosomal-P antibody. She had severe flare with a SLEDAI of 33. She was treated with pulse IV methylprednisolone followed by cyclophosphamide (NIH protocol). At 4 weeks follow-up, she had dramatic improvement in her Parkinsonian symptoms and her proximal muscle weakness. DISCUSSION: The prevalence of movement disorders in cases of neuropsychiatric SLE is very low at 0.7%, with chorea being most frequent and Parkinsonism rare. The pathogenesis is multifactorial including anti-dopaminergic antibodies or associated anti-phospholipids causing microvascular thrombosis or vasculitis of the thalamostriatal arteries or disease activity itself. As in our case, immunosuppression and optimal treatment of active lupus reverts symptoms in most cases. CONCLUSION: A high index of suspicion needs to be exercised in cases of SLE presenting with Parkinsonism as adequate immunosuppression translates to near-complete recovery.

Assessment of cutaneous disease activity in early lupus and its correlation with quality of life: a cross-sectional study.

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with varied dermatological manifestations that are almost universal. Overall, lupus disease has a major effect on the quality of life in these patients. We assessed the extent of cutaneous disease in early lupus and correlated it with the SLE quality-of-life (SLEQoL) index and disease activity measures. Patients diagnosed as SLE with the skin involved were recruited at the first presentation and were assessed for cutaneous and systemic disease activity using the cutaneous lupus erythematosus disease area and severity index (CLASI) and the Mexican-SLE disease activity index (Mex-SLEDAI), respectively. Quality of life was assessed with the SLEQoL tool while systemic damage was captured by the SLICC damage index. Fifty-two patients with SLE who had cutaneous involvement were enrolled (40, 76.9% females) with a median disease duration of 1 month (1-3.7). The median age was 27.5 years (IQR: 20-41). Median Mex-SLEDAI and SLICC damage index were 8(IQR: 4.5-11) and 0 (0-1), respectively. The median CLASI activity and damage scores were 3 (1-5) and 1 (0-1), respectively. Overall, there was no correlation between SLEQoL with CLASI or CLASI damage. Only the self-image domain of SLEQoL correlated with total CLASI (ρ = 0.32; p = 0.01) and CLASI-D (ρ = 0.35; p = 0.02). There was a weak correlation of CLASI with the Mexican-SLEDAI score (ρ = 0.30; p = 0.03) but not with the SLICC damage index. In this cohort of early lupus, cutaneous disease activity in lupus had a weak correlation with systemic disease. Cutaneous features did not appear to influence the quality of life except in the self-image domain.

Toll-like receptor-7 activation in CD8+ T cells modulates inflammatory mediators in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology with aberrant immunological responses leading to inflammation, swelling and pain of the joints. CD8+ T cells have been known to be one of the major immune modulators in the progression of RA and the presence of toll-like receptors (TLRs) on these cells further accentuate their role in RA. Herein, we report an increased expression of TLR7 in the endosomes of CD8+ T cells of RA patients correlating with disease severity. The stimulation of TLR7 with Imiquimod (IMQ) in these CD8+ T cells drives the signalling cascade via NFkB and pERK activation and hence an increase in the mRNA transcripts of signature cytokines and cytolytic enzymes. However, a parallel synthesis of Tristetraprolin (TTP), an mRNA destabilizing protein prevents the translation of the mRNA transcripts, leading to a rapid degeneration of the target mRNA. We thus report that a direct TLR7 ligation by its agonist increases cytokine transcript signature but not an equivalent protein surge.

Update on Post-Streptococcal Reactive Arthritis: Narrative Review of a Forgotten Disease.

PURPOSE OF THE REVIEW: This topical review attempts to build the concepts of PSRA as an independent entity and discuss prevalent diagnostic criteria. It utilizes a search strategy to collate all clinical features of PSRA reported from across the world and also discusses laboratory and treatment options in brief. RECENT FINDINGS: There are several immune-mediated diseases described after acute streptococcal infections. Post-streptococcal reactive arthritis (PSRA) is a sterile, self-limiting arthritis that occur as an immune sequelae to streptococcal infection. Though PSRA resembles the arthritis of acute rheumatic fever superficially, it is a separate entity in its own right. It is different from classical reactive arthritis too. It was being recognized worldwide and more frequently in the recent past, possibly due to heightened awareness amongst clinicians. However, research on this enigmatic immune phenomenon is limited. Most acceptable hypotheses suggest molecular mimicry sensitizing the immune system towards synovial peptides such as keratin, vimentin and laminin, leading to arthritis in a genetically predisposed individual. There is still much to be learnt from this unique disease about the vagaries of the immune system.

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.

Extensive thoracoabdominal aortic aneurysm as initial presentation in Takayasu arteritis: case series and literature review.

Background: Aortic aneurysm as a presenting feature in Takayasu's arteritis is very rare. Here, we report three cases of extensive thoracoabdominal aortic aneurysm in Takayasu's arteritis as initial presentation. Case summary: All three cases were males and presented with complaints of abdominal pain and refractory hypertension. The diagnosis was made from the finding of thickened and calcified aortic wall, stenosis of visceral arteries, and age < 40 years at diagnosis. Case 1 was a 34 years male with aortic aneurysm extending from left subclavian artery to infrarenal aorta. He underwent endovascular repair of aneurysm by sandwich chimney technique in view of impending aneurysm rupture. Case 2, a 37 years male had aortic aneurysm from descending thoracic aorta (D4 vertebral body) to infrarenal aorta (L4 level). While being evaluated for repair, he had sudden death probably due to ruptured aneurysm. Case three, a 40 years male had aortic aneurysm extending from left subclavian artery to aortic bifurcation and stenosis of visceral arteries. He did not consent for repair and died one year later due to chronic kidney disease and related complications. Discussion: Thoracoabdominal aortic aneurysm is a very rare manifestation in Takayasu's arteritis; more common in males. Endovascular repair is challenging but feasible. Long-term monitoring and repeat intervention may be needed due to young age of patients and disease progression.

Successful Use of Tofacitinib in Scleroderma Arthropathy.

Musculoskeletal manifestations of systemic sclerosis (SSc) are frequent and may be one of the early manifestations of the disease. However, arthralgia, pain and stiffness without frank arthritis usually constitute the clinical picture, while overlap syndromes such as rheumatoid-like polyarthritis can dominate when the arthritis is erosive. Hereby, we report a case of primary SSc presenting as frank erosive arthritis involving small and large joints mimicking rheumatoid arthritis, unresponsive to methotrexate, which was successfully treated with tofacitinib.

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.

Successful Use of Tofacitinib in Refractory Takayasu Arteritis: A Case Series.

Objective: To study the clinical effectiveness and safety of Tofacitinib in refractory Takayasu arteritis (TAK). Methods: This study was conducted from September 2021 to June 2022. Ten cases of refractory TAK patients were enrolled. TAK patients who required >7.5mg prednisolone or equivalent per day and those who failed to achieve remission despite being on conventional immunomodulators, with an Indian Takayasu Activity Score 2010 (ITAS 2010) of > 1 were included in this study. Tofacitinib was used at a dose of 5 mg twice daily after ruling out latent tuberculosis. The patients were followed up at 1, 3 and 6 months. ESR, CRP and ITAS 2010 were recorded at each visit. Complete blood counts, liver, and kidney function tests were done to assess the adverse effects at baseline and follow up. Results: There was a mean decline in ESR from 60.7 ± 20.05 mm/1st hour at baseline to 11.9 ± 2.38mm/1st hour at 6 months, CRP from 28.9 ± 16.77 mg/L at baseline to 6.8 ± 7.52 mg/L at 6 months, ITAS 2010 from 6.2 ± 2.74 at baseline to 0.6 ± 1.26 at 6 months (p value 0.016). All the patients tolerated tofacitinib well without any adverse effects. Conclusions: The results of our research indicate that tofacitinib is safe and effective for treating patients with refractory TAK.

Tofacitinib in Refractory Scleritis: A Case Series.

Tofacitinib, a Janus kinase inhibitor, has been recently investigated as a potential therapy for refractory scleritis. Despite treatment with systemic immunosuppressive agents, scleritis is refractory to conventional therapy in a significant number of patients. Hereby, we report the use of tofacitinib as a steroid-sparing immunomodulatory agent in three patients with refractory scleritis who were either recalcitrant or intolerant to conventional therapy.

Lactobacillus rhamnosus reduces CD8+T cell mediated inflammation in patients with rheumatoid arthritis.

BACKGROUND: The T cells, components of adaptive immunity participate in immune pathology of the autoimmune inflammatory disorder called rheumatoid arthritis (RA). The presence of TLRs on the surface of the CD8+ T cells and their ability to recognize bacterial moieties adds to the inflammatory burden in case of RA. It has been reported that the gut microbiome is necessary for the crucial shift in the balance between proinflammatory and anti-inflammatory cytokines. The altered gut microbiome and the presence of TLRs emphasizes on the microbiome driven inflammatory responses in case of RA. METHODS: Eighty-nine RA patients participated in this study. Clinical variations like disease duration, number of actively inflamed joints, number and type of bone deformities, CRP, RF, Anti-CCP, ESR, DAS 28 score were recorded for each patient. Co-culture of CD8+T cells and bacteria has been performed with proper culture condition. TLRs and inflammatory mediators' expression level were checked by both qPCR and flow cytometry analysis. RESULTS: We observed in the suppression of pro-inflammatory molecules like Granzyme B and IFNƳ and expression of TLR2 in CD8 + T cells upon treatment with Lactobacillus rhamnosus (L. rhamnosus). Moreover, L. rhamnosus activated CD8+T cells such that they could induce FOXP3 expression in CD4+T cells thereby skewing T cell population towards a regulatory phenotype. On the contrary, TLR4 engagement on CD8+T cell by Escherichia coli (E.coli) increased in inflammatory responses following ERK activation. CONCLUSIONS: Thus, we conclude that L. rhamnosus can effectively suppress CD8+T cell mediated inflammation by a simultaneous decrease of Th1 cells that may potentiate better treatment modalities for RA.

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.