Pulukool Sandhya

Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis

The human body is an environmental niche which is home to diverse co‐habiting microbes collectively referred as the human microbiome. Recent years have seen the in‐depth characterization of the human microbiome and associations with diseases. Linking of the composition or number of the human microbiota with diseases and traits date back to the original work of Elie Metchnikoff. Recent advances in genomic technologies have opened up finer details and dynamics of this new science with higher precision. Microbe‐rheumatoid arthritis connection, largely related to the gut and oral microbiomes, has showed up as a result – apart from several other earlier, well‐studied candidate autoimmune diseases. Although evidence favouring roles of specific microbial species, including Porphyromonas, Prevotella and Leptotricha, has become clearer, mechanistic insights still continue to be enigmatic. Manipulating the microbes by traditional dietary modifications, probiotics, and antibiotics and by currently employed disease‐modifying agents seems to modulate the disease process and its progression. In the present review, we appraise the existing information as well as the gaps in knowledge in this challenging field. We also discuss the future directions for potential clinical applications, including prevention and management of rheumatoid arthritis using microbial modifications.

Influence of geolocation and ethnicity on the phenotypic expression of primary Sjögren's syndrome at diagnosis in 8310 patients : a cross-sectional study from the Big Data Sjögren Project Consortium

Objectives To analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögrens syndrome (SjS) at diagnosis. Methods The Big Data Sjögren Project Consortium is an international, multicentre registry designed in 2014. By January 2016, 20 centres from five continents were participating. Multivariable logistic regression analyses were performed. Results We included 7748 women (93%) and 562 men (7%), with a mean age at diagnosis of primary SjS of 53 years. Ethnicity data were available for 7884 patients (95%): 6174 patients (78%) were white, 1066 patients (14%) were Asian, 393 patients (5%) were Hispanic, 104 patients (1%) were black/African-American and 147 patients (2%) were of other ethnicities. SjS was diagnosed a mean of 7 years earlier in black/African-American compared with white patients; the female-to-male ratio was highest in Asian patients (27:1) and lowest in black/African-American patients (7:1); the prevalence of sicca symptoms was lowest in Asian patients; a higher frequency of positive salivary biopsy was found in Hispanic and white patients. A north-south gradient was found with respect to a lower frequency of ocular involvement in northern countries for dry eyes and abnormal ocular tests in Europe (OR 0.46 and 0.44, respectively) and Asia (OR 0.18 and 0.49, respectively) compared with southern countries. Higher frequencies of antinuclear antibodies (ANAs) were reported in northern countries in America (OR=1.48) and Asia (OR=3.80) while, in Europe, northern countries had lowest frequencies of ANAs (OR=0.67) and Ro/La (OR=0.69). Conclusions This study provides the first evidence of a strong influence of geolocation and ethnicity on the phenotype of primary SjS at diagnosis.

Eosinophilic esophagitis and pharyngitis presenting as mass lesion in a patient with inactive rheumatoid arthritis.

We describe here a case of longstanding rheumatoid arthritis (RA) presenting with recurrent episodes of epigastric pain, melena, nonprogressive dysphagia, and hoarseness associated with persistent peripheral blood eosinophilia. Her RA was clinically inactive, but she had significant lymphadenopathy and hepatosplenomegaly. Computed tomographic scan of the thorax revealed circumferential wall thickening extending from the oropharynx to the gastroesophageal junction with a large polypoidal mass projecting into the lumen of the stomach. Histology revealed infiltration of the esophageal mucosa by eosinophils with a density of 40 to 80 per high-power field. The stratified squamous epithelium of the pharyngeal mucosa was also infiltrated by eosinophils with a density of more than 100 per high-power field. Eosinophilic esophagitis and pharyngitis were diagnosed, and the patient was administered corticosteroids and hydroxyurea, following which her symptoms resolved. On repeat imaging, there was significant reduction in esophageal wall thickening and luminal dilatation. There are few reports of tissue eosinophilia in association with RA, but the pathogenesis and any definite association with RA are not clear.

Clinical Characteristics and Outcome of Primary Sjogren’s Syndrome: ALarge Asian Indian Cohort

Objective : To characterise the clinical features, immunological profile and outcome in a cohort of Asian Indian patients with primary Sjögrens syndrome (SS). Methods : Electronic medical records from a tertiary care teaching hospital in south India were screened for SS between 2004 and 2011. Patients fulfilling American European Consensus group (AECG) 2002 or American College of Rheumatology (ACR) 2012 classification criteria were included. Agglomerative hierarchical cluster analysis to identify patterns of associations between clinical and immunological features was done. Multivariate logistic regression to identify predictors of major systemic involvement was performed. Data on treatment and outcome were retrieved from electronic records. Results : Of 423 patients suspected to have SS, 332 fulfilled inclusion criteria. Only 8.3% of patients complained of sicca symptoms on their own at initial presentation. Younger age of onset, higher female to male ratio, paucity of cryoglobulinemia, Raynaud’s phenomenon and hyperglobulinemia were unique to this cohort. Cluster analysis revealed two subsets: The first cluster comprised of patients having a major systemic illness with high antibody titers and the second comprised of seronegative patients with mild disease. Over a third of SS cases had severe systemic manifestations necessitating treatment with immunosuppressants. In multivariate logistic regression analysis, anti-Ro and anti-La antibody positivity was associated with higher odds for systemic disease features (OR=2.67, P=0.03 and OR=3.25, P=0.003, respectively) whereas chronic pain was associated with lower odds (OR=0.4, p=0.032). Clinical improvement including symptomatic benefit in sicca and musculoskeletal features was noted with immunomodulators in the majority. Conclusion : Our cohort of patients with SS has characteristic clinical features; some of them are in contrast with previous observations reported in European patients. This cohort consisted of two distinct patient clusters. The first cluster was associated with major systemic illness and high antibody titers, where as the second cluster comprised of seronegative patients with mild disease. Association of antibody positivity with systemic features was further confirmed on logistic regression analysis.

Gut inflammation and microbiome in spondyloarthritis

Spondyloarthritis (SpA) is chronic inflammatory disease involving joints and the spine. Bowel inflammation is common in SpA, which may be classified as acute or chronic. Chronic gut inflammation is most common in SpA patients with axial involvement as compared to those presenting with peripheral involvement alone. The pathogenesis of gut inflammation in SpA could be explained by two factors—over-activation of immunological cells and altered gut microbiome. This is exemplified by SpA animal models, namely HLA-B27-expressing transgenic animals and SKG mice models. Immunological mechanisms include homing of activated T cells from gut into synovium, excess pro-inflammatory cytokines secretion by immune cells such as IL-23 and genetic variations in immunological genes. The evidence for role of gut microbiome in SpA is gradually emerging. Recently, metagenomic study of gut microbiome by sequencing of microbial nucleic acids has enabled identification of new microbial taxa and their functions in gut of patients with SpA. In SpA, the gut microbiome could emerge as diagnostic and prognostic marker of disease. Modulation of gut microbiome is slated to have therapeutic potential as well.

Long noncoding RNAs could be potential key players in the pathophysiology of Sjögren's syndrome.

Long noncoding RNAs (lncRNAs) are a recently discovered class of noncoding functional RNAs encoded by metazoan genomes. Recent studies suggest a larger regulatory role for lncRNAs in critical biological and disease processes. Mounting evidence on the role of lncRNAs in regulating key processes of the immune system prompted us to hypothesize the role of lncRNAs as key regulators of the pathophysiology of Sjögrens syndrome (SS). We used two similar approaches based on reanalysis of microarray expression datasets and curation of lncRNA‐protein coding gene interactions from literature to derive support for our hypothesis. We also discuss potential caveats to our approach and suggest approaches to validate the hypothesis. Our analysis suggests the potential larger and hitherto unknown role of lncRNA regulatory networks in modulating the expression of key genes involved in the pathogenesis of SS and thereby modulating the pathophysiology of SS.

Sjögren’s, Renal Tubular Acidosis And Osteomalacia - An Asian Indian Series

Objective: To study the profile of Renal Tubular Acidosis (RTA) in Asian Indian patients with Primary Sjögrens Syndrome (pSS). Methods: The Electronic medical records of patients with a diagnosis of pSS seen between 2003 and 2010 at our tertiary care teaching hospital were screened for RTA. Clinical features, immunological profile, acid-base balance and electrolyte status, 25-hydroxyvitamin D (25(OH) D3) levels, histopathological changes in minor salivary gland biopsy samples and radiological findings were retrieved. RTA was diagnosed in cases of hyperchloremic metabolic acidosis with urinary pH values higher than 5.5. Those with known features suggestive of RTA including hypokalemic paralysis, hyperchloremia and nephrocalcinosis without acidosis were defined as incomplete RTA. Results: Of the 380 patients with clinically suspected pSS, 25 had RTA. The median age was 32 (18-60) years. Nineteen patients had complete RTA. Six had incomplete RTA. Only 10 patients (40%) had symptoms related to RTA at presentation. Sixteen patients (64%) had present or past history of hypokalemic paralysis. Pseudofractures were seen in 7 patients and an additional 2 had subclinical radiological osteomalacia. Majority of the patients (61.2%) had a normal 25(OH) D3 level. Those with osteomalacia had significantly lower serum phosphate, blood ph and higher alkaline phosphatase. Serum calcium and 25(OH) D3 levels were not significantly different between patients with osteomalacia and those without. Conclusion: Most patients were asymptomatic for RTA inspite of clinically overt and elicitable features. Skeletal manifestation was a common finding in patients with Sjögren and RTA, despite normal levels of 25 (OH) D3 in a majority.

Paraneoplastic palmar fasciitis in carcinoma breast.

A 50-year-old lady presented to the rheumatology clinic with pain and deformity of her hands for 6 months. There was no involvement of any other joints. She was not diabetic. On examination, she had contractures of fingers bilaterally. There was diffuse thickening of the palmar fascia, but no nodules or puckering of skin was present (Fig. 1A, B). There was no Raynaud phenomenon, digital pitting scars, synovitis, rheumatoid nodule, or neuropathy. Examination revealed a hard, 4 5 cm lump in the inner and upper quadrant of the left breast. Therewas no lymphadenopathyor hepatosplenomegaly. Findings on the rest of the physical examinationwere unremarkable. Fine-needle aspiration confirmed the diagnosis of carcinoma of the breast. Mammography revealed 2 irregular spiculated mass lesions in the left breast (Fig. 1C). There was diffuse thickening of palmar fascia in ultrasound of hands. Paraneoplastic palmar fasciitis was diagnosed, and she was referred to the oncology department. She received 4 cycles of neoadjuvant chemotherapy (cyclophosphamide + fluorouracil + epirubicin) followed by modified radical mastectomy. There was significant reduction in pain but no improvement in deformity was noted. Paraneoplastic palmar fasciitis was first described in 1982 in association with ovarian cancer. Around 40 cases have been described till date mainly in association with breast, ovarian, and gastric malignancies. It can precede, accompany, or follow the diagnosis of malignancy. Most cases described in literature have reported improvement in pain and fasciitis following treatment of the underlying malignancy but no improvement in contractures. In only 1 patient with gastric carcinoma, complete resolution has been described after total gastrectomy. Rheumatoid arthritis, scleroderma, reflex sympathetic dystrophy, and Dupuytren contracture are common differential diagnoses of this presentation. The aggressive course and the severity of contractures are pointers toward malignancy, and a detailed evaluation is warranted.

Update on Pathogenesis of Sjogren's Syndrome

Sjogrens syndrome is a common autoimmune disease that presents with sicca symptoms and extraglandular features. Sjogrens syndrome is presumably as common as RA; yet it is poorly understood, underdiagnosed and undertreated. From the usual identity as an autoimmune exocrinopathy to its most recent designate as an autoimmune epithelitis - the journey of SS is complex. We herein review some of the most important milestones that have shed light on different aspects of pathogenesis of this enigmatic disease. This includes role of salivary gland epithelial cells, and their interaction with cells of the innate and adaptive immune system. Non-immune factors acting in concert or in parallel with immune factors may also be important. The risk genes identified so far have only weak association, nevertheless advances in genetics have enhanced understanding of disease mechanisms. Role of epigenetic and environmental role factors is also being explored. SS has also some unique features such as congenital heart block and high incidence of lymphoma; disease mechanisms accounting for these manifestations are also reviewed.

AB0188 Systematic Analysis of the Oral Microbiome in Primary SjÖgren's Syndrome Suggest Enrichment of Distinct Microbes

Background Dysbiosis has been hypothesized to play a role in the pathogenesis of autoimmune disease. Primary Sjögrens syndrome (pSS) is an autoimmune disease characterized by sicca symptoms resulting from salivary and lacrimal gland dysfunction. This could result in dysbiosis of oral cavity. At the same time, dysbiosis could also be hypothesized to have a causative role. Previous studies using culture dependent approaches have provided evidence for altered oral microflora in pSS. However culture dependent approaches have caveats which have been abrogated with the advent of culture independent methodologies. Objectives To systematically evaluate the microbiome in the oral cavity in patients with pSS using a culture independent shotgun metagenome sequencing Methods Cases included adult patients fulfilling criteria for pSS by American-European Consensus Group (AECG) 2002 or American College of Rheumatology (ACR) 2012 classification criteria, while controls included healthy volunteers. Neither cases nor controls had oral disease or other obvious co morbidities, recent antibiotic intake. Individuals who had chronic intake of alcohol and tobacco were excluded. Saliva was collected in sterile tubes with buffer. DNA was extracted using Qiagen DNA isolation kit. Libraries were prepared and sequenced on Illumina Hiseq 2500 (Illumina Inc, USA). Reads mapping to the Human reference genome (hg19) were tagged. Reads were further reference mapped to the core oral microbiome sequences available from the Human Oral Microbiome Database. The read counts were normalized for the input reads as well as the genome size of the organism. A fold change (FC) of >2 and p value <0.05 by Students t-test was considered significant. Results Oral microbiome of 13 pSS patients and 12 healthy controls were analysed. Organisms significantly enriched in pSS included the following (FC; p-value) Capnocytophaga (2.09; 0.01), Dialister (2.13; 0.02), Fusobacterium (2.84; 0.04), Helicobacter (4.83; 0.03), Streptococcus (3.33; 0.01) and Veilonella (3.82; 0.006) spp. A paucity of Pseudomonas (8.9;0.03) spp. was noted compared to controls. Conclusions A distinct subset of organisms was enriched in the oral cavity of patients with pSS. This subset includes Capnocytophaga previously shown to be associated with the pathogenesis and T cell activation in pSS. References Almståhl A, Kroneld U, Tarkowski A, Wikström M. Oral microbial flora in Sjögrens syndrome. J Rheumatol. 1999;26:110-4. Almståhl A, Wikström M, Kroneld U. Microflora in oral ecosystems in primary Sjögrens syndrome. J Rheumatol. 2001;28:1007-13. Szymula A, Rosenthal J, Szczerba BM, Bagavant H, Fu SM, Deshmukh US.T cell epitope mimicry between Sjögrens syndrome Antigen A (SSA)/Ro60 and oral, gut, skin and vaginal bacteria. Clin Immunol. 2014;152:1-9. Acknowledgements Authors acknowledge colleagues at Department of Clinical Immunology and Rheumatology, CMC Vellore for help in recruiting volunteers for the study. Authors VS and SS acknowledge funding from CSIR, India through Grant OLP1105 (EMPOWER). Disclosure of Interest None declared