[Show abstract][Hide abstract] ABSTRACT: 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 Sj€ ogren's 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.
International Journal of Rheumatic Diseases 10/2015; DOI:10.1111/1756-185X.12752 · 1.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
International Journal of Rheumatic Diseases 09/2015; DOI:10.1111/1756-185X.12728 · 1.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To characterise the clinical features, immunological profile and outcome in a cohort of Asian Indian patients with primary Sjögren's syndrome (SS).
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.
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.
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.
The Open Rheumatology Journal 06/2015; 9(1):36-45. DOI:10.2174/1874312901409010036
[Show abstract][Hide abstract] ABSTRACT: Background Dysbiosis has been hypothesized to play a role in the pathogenesis of autoimmune disease. Primary Sjögren's 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 Student's 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.
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
Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):953.3-954. DOI:10.1136/annrheumdis-2015-eular.5721 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Paucity of growth retardation has been observed by us in patients with juvenile-onset ankylosing spondylitis (JAS) in a tertiary care health centre in south India. We, therefore, undertook this pilot study to assess and compare anthropometry of patients with JAS who were 15 yr and older with that of adult onset ankylosing spondylitis (AAS) and matching Indian reference population.
Consecutive male patients (December 2009- October 2012) with JAS and AAS fulfilling Modified New York Criteria were selected after applying inclusion and exclusion criteria. Demography and anthropometry were noted. Height of both patient groups as well as their parents and siblings were compared with that of the reference population. Mid-parental height and delta height were derived. Those with delta height of >8.5 cm were compared with the remaining. Multivariate logistic regression was done for variables that were found to be significant by chi-square in bivariate analysis. Similar analysis was done for BMI also.
There was no significant difference in anthropometric variables between JAS and AAS groups. Twenty eight of the 30 (93.33%) JAS patients were taller as compared to the reference population. Twenty six (86.67%) AAS patients were taller than the reference population. The mean heights of JAS (170.67 ± 6.94 cm) and AAS (168.2 ± 5.94 cm) patients were significantly higher than the reference value of 163.11 cm; both p0 <0.001. Logistic regression revealed that tallness in JAS was associated positively with hypermobility (OR=23.46,95%CI 1.2-447.2, p0 =0.036). No significant association was detected for height in AAS and for BMI in both JAS and AAS groups.
No growth retardation was seen in patients with JAS in our study. Majority of patients with JAS and AAS were taller than reference population. The difference between mean height of JAS and AAS was not significant. Larger studies involving different populations are required to confirm these findings.
The Indian Journal of Medical Research 04/2015; 141(4):446-53. DOI:10.4103/0971-5916.159295 · 1.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To study the profile of Renal Tubular Acidosis (RTA) in Asian Indian patients with Primary Sjögren's Syndrome (pSS).
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.
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.
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.
The Open Rheumatology Journal 12/2014; 8(1):103-9. DOI:10.2174/1874312901408010103
[Show abstract][Hide abstract] ABSTRACT: Immune mechanisms alone cannot directly account for exocrine gland dysfunction and extraglandular features such as renal tubular acidosis, neuropathy, hearing loss and fatigue in Sjögren's syndrome (SS). Absence of Vacuolar ATPase (V-ATPase) has been reported in SS related renal tubular acidosis (RTA). We hypothesise how defect in V-ATPase could account for decreased neurotransmitter release leading onto exocrine dysfunction, neuroendocrine manifestations and hearing loss which are well described manifestations in SS. S-phase-kinase-associated protein-1 (Skp1) is a constituent of RAVE which is involved in V-ATPase assembly. It is also a component of SCF ligase which is crucial in NFκB signalling. SKP1 also interacts with TRIM 21/Ro 52 which is an autoantigen in SS. By virtue of these interactions, we postulate how a defective skp1 could fit into the existing pathogenesis of SS and also account for increased risk of lymphoma in SS as well as congenital heart block in fetus of mothers with SS.
Medical Hypotheses 01/2014; 82(3). DOI:10.1016/j.mehy.2013.12.019 · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Juvenile ankylosing spondylitis (JAS) is a chronic autoimmune disorder which causes considerable morbidity when left untreated; it occurs predominantly in men. We describe an Asian Indian woman who had JAS with phenotypic features of Turner syndrome (TS) and was found to be a mosaic for 45, X/46, X, psu idic (X) (p11) by karyotyping and fluorescence in situ hybridization (FISH) studies of peripheral blood. The absence of Y chromosome material was confirmed by FISH. Haplo-insufficiency of the X chromosome can predispose to autoimmunity. To the best of our knowledge, this is the first report of JAS in association with mosaic Turner syndrome. This case highlights the possible effects of gene dosage in development of an autoimmune disease.
The National medical journal of India 11/2013; 26(6):338-9. · 0.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background & objectives:
Tumour necrosis factor-alpha (TNF-α)- 308 promoter gene polymorphism has been shown to be associated with several autoimmune disorders and infections such as tuberculosis. There is no study on TNF-α gene polymorphism in Takayasu's arteritis (TA) till date. We aimed to study this polymorphism in TA, a granulomatous vasculitis, probably triggered by Mycobacterium tuberculosis.
TNF-α - 308 gene polymorphism was studied in 34 patients with TA and 39 healthy controls recruited from Christian Medical College, India. PCR was done followed by enzyme digestion. G and A polymorphisms were analysed. Occurrence of alleles in the disease group was compared with controls as well as with historical controls.
GG allele was most frequent in TA and in controls. GA allele was detected in four controls but only in one patient who was the oldest in the study group. AA polymorphism was detected in one control but not in TA. When compared with controls from other populations, it was found that our allelic frequency was similar to that in Japan as well as from USA with mixed population. However, predominantly Caucasian population studied from Netherlands, Germany and England, where TA is rare, had a higher frequency of A allele as compared to our controls.
Interpretation & conclusions:
Our preliminary results indicated that G allele at TNF-α - 308 was more common in TA patients and controls similar to that in other Indian as well as Japanese population. Compared to the western population, A allele was relatively less common in our study subjects.
The Indian Journal of Medical Research 04/2013; 137(4):749-752. · 1.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of clinical rheumatology: practical reports on rheumatic & musculoskeletal diseases 12/2011; 18(1):33-5. DOI:10.1097/RHU.0b013e31823e6b54 · 1.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of the study is to evaluate the outcome of patients with seronegative spondyloarthritis continuing on sulphasalazine (SSZ) and methotrexate (MTX) after a short course of infliximab. Patients with seronegative spondyloarthritis on MTX and SSZ were given short course of infliximab therapy at 0, 2, 6 and 14 weeks. Outcome of these patients while continuing on MTX and SSZ was assessed. Clinical features, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were noted at baseline (pre-infliximab), 1 month, 3 months and last follow-up after last dose of infliximab infusion. Twenty-four patients were included in this study. The mean duration of follow-up was 9.1 months. Statistically significant reduction in tender and swollen joint count was noted at all the three visits as compared to baseline. Fall in ESR and CRP was statistically significant at 1 and 3 months, but not at last follow-up. Mean reduction in BASDAI at 1 month ,3 month and last follow-up after last infliximab dose were 3.907 (95% CI 2.98-4.83; p < 0.001), 4.53 (95% CI 3.56-5.49; p < 0.001) and 2.48 (95% CI 1.12-3.84; p = 0.002), respectively. Mean reduction in BASFI at 1 month, 3 months and last follow-up after last infliximab dose were 4.13 (95% CI 3.23-5.04; p < 0.001), 4.34 (95% CI 2.8-5.88; p < 0.001) and 2.38 (95% CI 0.86-3.90; p = 0.005), respectively. Continuing SSZ and MTX after short course of infliximab results in sustained improvement in our patients with seronegative spondyloarthritis in India.