Clinical features, severity and outcome of acute pancreatitis in systemic lupus erythematosus.

Acute pancreatitis (AP) is a rare but life threatening manifestation of Systemic Lupus Erythematosus (SLE). The current study aims to study the clinical characteristics, severity, mortality, and outcome of SLE-related AP in Indian population. We retrospectively reviewed medical records of patients with SLE who had AP in the past. Data from 13 rheumatology centers across India were compiled. All patients satisfied SLICC criteria for SLE and ATLANTA criteria for AP. AP was classified in to mild, moderate and severe using revised Atlanta classification. Patients with known risk factors like gall stone and alcohol were excluded.Sixty-six patients (six, children) were studied. Majority of patients were females (82%). The median age of presentation was 24 (11-63) years and most patients (57.5%) presented within first year of diagnosis of lupus. AP occurred mostly in the setting of active lupus (89%). Active nephritis was seen in 39% while a fourth had CNS disease. Patients with severe AP had lower C3. Ascites and sepsis were most common local and systemic complications, respectively. Mortality was 17%. Hypocalcemia, presence of sepsis and shock predicted mortality. In the multivariate analysis, only presence of shock remained as independent predictor of death (OR 63.0, 95% CI: 5.2-760.3). Pancreatitis is an early manifestation of SLE and is associated with active disease. Significant mortality is seen particularly with severe pancreatitis.

Autoimmune polyendocrine syndrome type 1 (APECED) in the Indian population: case report and review of a series of 45 patients.

BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) or autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive genetic disease due to mutations in the AIRE (AutoImmune REgulator) gene. The clinical diagnosis is classically based on the presence of at least two of the three main components: chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency. Patients often suffer from other endocrine or non-endocrine autoimmune conditions throughout life. APECED etiopathogenesis is mediated by T lymphocytes. Autoantibodies against proteins of the affected organs are found in the serum of APECED patients as well as neutralizing antibodies against cytokines. We report here the clinical and genetic characteristics of 45 Indian APECED patients in comparison to Finnish, Sardinian, Turkish and North/South American cohorts from their published results. We also report a new case of APECED of Indian origin, a 2-year old child suffering from chronic mucocutaneous candidiasis since the age of 8 months, with confirmatory AIRE homozygous mutation c.274C > T (p.R92W). CONCLUSION: With the inherent limitations of a retrospective study, analysis of Indian APECED patients suggested that compared to classic criteria, application of Ferre/Lionakis criteria validated in North/South American patients could help in earlier diagnosis in 3 of 8 (37.5%) patients for whom adequate information for evaluation was available.

Immunological biomarkers in neuropsychiatric systemic lupus erythematosus: a comparative cross-sectional study from a tertiary care center in South India.

INTRODUCTION: The prevalence of various immunological biomarkers in neuropsychiatric systemic lupus erythematosus (NPSLE) differs among various patients with varied neuropsychiatric manifestations and different populations. We studied the prevalence of these biomarkers; especially the neuron specific autoantibodies in patients with systemic lupus erythematosus (SLE) and compared them among patients with and without neuropsychiatric involvement. METHODOLOGY: This is a comparative cross-sectional study conducted in a tertiary care hospital in South India. The prevalence of immunological biomarkers including complement levels, systemic and brain specific autoantibodies (anti-myelin antibody, anti-myelin oligodendrocyte glycoprotein and anti-myelin-associated glycoprotein antibody) were assessed and compared among those with and without NPSLE and with different NPSLE manifestations. RESULTS: A total of 522 SLE patients were enrolled in the study. The mean age of the study participants was 28.5 ± 8.8 years and 93.5% were women. Neuropsychiatric manifestations were seen in 167 (32%) patients. Seizure was the most common neuropsychiatric manifestation seen in 41.3%, followed by psychosis (18.6%), mood disorder (16.8%), stroke (10.8%), mononeuropathy (10.2%), headache (9.6%), acute confusional state (6.6%) and aseptic meningitis (5.4%). Patients with NPSLE had a higher SLE disease activity index score. Most of the autoantibodies, that is anticardiolipin antibody (aCL), anti-ß2 glycoprotein 1 antibody (ß2GP1), lupus anticoagulant (LA), anti-nucleosome, anti-ribosomal P, anti-Ro52, anti-Ro60 and anti-La, were seen in higher proportion in the NPSLE group, although the difference failed to reach statistical significance. On subgroup analysis, psychosis was significantly higher in patients with anti-ribosomal P positivity than without (11.8% versus 4.1%, p.0.007; odds ratio (OR) 3.1, confidence interval (CI) 1.4-6.8), while stroke had a higher proportion among those with positive b2GP1 IgG (6.3% versus 1.8%, p.0.03; OR 3.6, CI 1.2-11.0). A higher proportion of demyelination was seen among the LA positive than the negative (10.3% versus 0.2%, p.0.03; OR 5.39, CI 1.15-24.17) and anti-myelin oligodendrocyte glycoprotein in mood disorder (14.3% versus 3.4%, p = 0.03; OR 4.66, CI 1.13-19.13). CONCLUSION: No single biomarker correlated with NPSLE. Among different NPSLE manifestations, the prevalence of IgG ß2GP1 in stroke, LA in demyelination, anti-ribosomal P in psychosis and anti-myelin oligodendrocyte glycoprotein in mood disorder were higher. Further studies on the pathogenic mechanisms underlying NPSLE and its different manifestations may help us to identify better biomarkers.

Association of NKG2D gene variants with susceptibility and severity of rheumatoid arthritis.

NKG2D (KLRK1) is a C-type lectin receptor present on natural killer (NK) cells, γδ, CD8+ and CD4+ T cells. Upon ligand binding, NKG2D mediates activatory and co-stimulatory signals to NK cells and activated CD4+ T cells, respectively. Polymorphisms in NKG2D predispose to infectious diseases, cancer, transplantation and autoimmune disorders. We studied the influence of this NK receptor polymorphism on predisposition to and modification of the disease phenotype in patients with rheumatoid arthritis (RA). Eight different single nucleotide polymorphisms (SNP) in the NKG2 gene were genotyped in 236 patients with RA and 187 controls using Taqman 5' nuclease assays. NKG2D genotype/allele frequency did not differ between patients and controls. Subgroup analysis showed that the frequency of A allele of NKG2D9 and T allele of NKG2D10 was significantly higher in patients with deformities (a marker of severe disease) [11 versus 5%, Pc = 0·03, odds ratio (OR) = 2·44, 95% confidence interval (CI) = 1·09-5·98 and 10 versus 4%, Pc = 0·04, OR = 2·45, 95% CI = 1·05-6·39, respectively], while the frequency of alleles G of NKG2D9 and A of NKG2D10 was greater in patients without deformities (Pc = 0·03, OR = 0·41, 95% CI = 0·17-0·91 and Pc = 0·04, OR = 0·41, 95% CI = 0·16-0·96). Similar trends of association were observed with deforming phenotype of RA in female patients and deforming young onset RA subgroups. Haplotype analysis revealed that the frequency of haplotype G-C-A-G-A-T-C-C was higher in patients than in controls (12 versus 8%, P = 0·04, OR = 1·61, 95% CI = 1·01-2·55), suggesting that it may predispose to RA. Our study suggests that the NKG2D gene polymorphisms may modify the risk of development and severity of RA.

Urinary haptoglobin, alpha-1 anti-chymotrypsin and retinol binding protein identified by proteomics as potential biomarkers for lupus nephritis.

The study was aimed at identification by proteomics and validation by enzyme-linked immunosorbent assay (ELISA) of potential urinary biomarkers for lupus nephritis. Study subjects comprised 88 systemic lupus erythematosus (SLE) patients and 60 controls (rheumatoid arthritis, diabetes mellitus and healthy individuals). Based on the SLE disease activity index (SLEDAI), patients were classified as active renal (AR), active non-renal (ANR) or inactive disease (ID). Urinary proteins from a group of patients with AR or ID were resolved by two-dimensional gel electrophoresis and identified by matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS/MS). The selected biomarkers were validated by ELISA using samples from all patients and controls. AR patients were followed-up for 12 months after start of therapy. Three urinary proteins, alpha-1 anti-chymotrypsin (ACT), haptoglobin (HAP) and retinol binding protein (RBP), were detected in patients with AR and not ID. Upon validation, ACT levels were higher in AR patients than the other groups (P < 0·001) and showed good correlation with renal SLEDAI (r = 0·577, P < 0·001) as well as SLEDAI (r = 0·461, P < 0·001). Similarly, HAP levels were > 10-fold higher in AR than other groups (P < 0·001) and correlated well with renal SLEDAI (r = 0·594, P < 0·001) and SLEDAI (r = 0·371, P < 0·01). RBP levels were also higher in AR patients than in other groups (P < 0·05), except diabetes, and showed moderate correlation with renal SLEDAI (r = 0·284, P < 0·008) and SLEDAI (r = 0·316, P < 0·003). Upon follow-up with treatment, levels of all three proteins declined at 6 and 12 months (P < 0·01). Multiple logistic regression identified ACT as the best marker to differentiate AR from ANR. Urinary HAP, ACT and RBP are potential biomarkers for lupus nephritis activity.

Pharmacogenetic markers to predict the clinical response to methotrexate in south Indian Tamil patients with psoriasis.

INTRODUCTION: Despite the advent of several new systemic therapies, methotrexate remains the gold standard for the treatment of moderate to severe psoriasis. However, there exists a significant heterogeneity in individual response to methotrexate. There are no consistently reliable markers to predict methotrexate treatment response till date. OBJECTIVES: We aimed to demonstrate the association of certain genetic variants in the HLA (HLA-A2, HLA-B17, and HLA-Cw6) and the non-HLA genes including T-helper (Th)-1, Th-2, Th-17 cytokine genes (IFN-γ, IL-2, IL-4, IL-10, IL-12B, and IL-23R), and T-regulatory gene (FOXP3) with the methotrexate treatment response in South Indian Tamil patients with psoriasis. METHODS: Of the 360 patients recruited, 189 patients with moderate to severe psoriasis were treated with methotrexate. Of the 189 patients, 132 patients responded to methotrexate and the remaining 57 patients were non-responders. We analyzed the association of aforesaid polymorphisms with the methotrexate treatment outcome using binary logistic regression. RESULTS: We observed that there were significant differences between genotype frequencies of HLA-Cw6 and FOXP3 (rs3761548) among the responders compared to non-responders, with conservative estimation. We observed that pro-inflammatory cytokines such as IFN-γ, IL-2, IL-12, and IL-23 were markedly reduced with the use of methotrexate, in comparison to the baseline levels, while the plasma IL-4 levels were increased posttreatment. CONCLUSION: Our results serve as preliminary evidence for the clinical use of genetic markers as predictors of response to methotrexate in psoriasis. This might aid in the future in the development of a point-of-care testing (POCT) gene chip, to predict optimal treatment response in patients with psoriasis, based on their individual genotypic profile.

Polymorphisms in the promoter region of iNOS predispose to rheumatoid arthritis in south Indian Tamils.

Nitric oxide synthase (NOS) catalyses the production of nitric oxide (NO) from L-Arginine, which participates in diverse biological processes including inflammation and apoptosis. Macrophages, chondrocytes, osteoblasts and osteoclasts express inducible NOS (iNOS) at the site of synovial inflammation. NO produced at the inflamed joint may contribute to peri-articular bone loss, mediate apoptosis and regulate Th1/Th2 balance in rheumatoid arthritis (RA). Variations in the promoter region of NOS gene regulate the nitric oxide synthase expression and iNOS (NOS2) polymorphisms have been associated with susceptibility to autoimmune disorders. Hence, this study was conducted to identify the possible contributions of NOS2 -1659G/A, -1026C/A, -277A/G promoter polymorphisms towards development of RA in South Indian Tamils. A total of 242 (219 females, 23 males) patients with RA (mean age 41.2 ± 10.9 years, disease duration 8.5 ± 4.3 years) and 279 age- and sex-matched healthy individuals of South Indian Tamil ethnicity were genotyped for NOS2 -1659C/T, -1026G/T and -277A/G promoter polymorphisms by TaqMan chemistry. Nature of disease (erosive or nonerosive), the presence of extra-articular manifestations, seropositivity for rheumatoid factor and anticyclic citrullinated peptide, serum C-reactive protein (CRP) level and response to therapy were assessed for all patients. The three single nucleotide polymorphisms (SNPs) were in Hardy-Weinberg equilibrium. The frequency of GG genotype and G allele of NOS2-277 was higher in patients (pc = 5.7 × 10-9 , OR = 6.09, 95% CI = 3.09-12.8 and pc = 4 × 10-13 , OR = 2.37, 95% CI = 2.06-3.62, respectively) compared to controls. Similarly, the frequency of NOS2-1026 (rs2779249) GT genotype and the T allele was higher in patients with RA (pc = .01, OR = 1.61, 95% CI = 1.09-2.36, and pc = .04, OR = 1.40, 95% CI = 1.02-1.91, respectively). However, no significant difference in frequency of NOS2-1659C/T polymorphism was observed between patients and controls. None of the studied SNPs were associated with erosive disease, seropositivity or extra-articular manifestations. The -277A/G and -1026 G/T promoter polymorphisms in iNOS may confer susceptibility to RA in South Indian Tamils.

Urinary osteoprotegerin: a potential biomarker of lupus nephritis disease activity.

OBJECTIVES: Urinary biomarkers may help in identification, treatment and assessment of response in patients with lupus nephritis (LN). Osteoprotegerin (OPG) is produced by the kidneys and lymphoid cells and may reflect renal disease activity better. The data on its utility are sparse. METHODS: Fifty-eight patients with active LN (AN), 24 with active non-renal disease (ANR) and 39 with inactive disease (ID) were included. Median disease duration was 32 (1-204) months and median age was 27 (12-50) years. AN patients were followed up every three months for one year. Urine and serum samples were collected for OPG measurement by ELISA (pg/ml) and urinary values were normalised for creatinine excretion (pg/mg). Urine samples from 24 healthy individuals (HCs) and 20 patients each of rheumatoid arthritis (RA) and diabetic nephropathy (DM) served as controls. Variables were expressed as median (range). RESULTS: At baseline, normalised urinary OPG (uOPG) was significantly higher (p < 0.001) in AN (1229 (0-8577)) than ANR (236 (0-14713)), ID (463 (7-4253)), HCs (366 (120-2849)) and DM (350 (127-1577)) but it was not different from RA (1511 (122-8849)). uOPG correlated modestly with rSLEDAI (r = 0.4, p < 0.001) and SLEDAI (r = 0.31, p < 0.001) but not with serum OPG (sOPG). uOPG but not sOPG could differentiate between AN and ANR groups. In the longitudinal study, uOPG and sOPG decreased significantly with treatment at all follow-up visits but the trend of fall in sOPG was erratic. uOPG values at baseline, 3, 6, 9 and 12 months were 1229 (0-8577), 466 (3-4874), 104 (0-1598), 325 (0-4025) and 555 (6-6771) pg/mg, respectively. uOPG but not sOPG rose before conventional markers in three patients who had a relapse of LN. In two patients who developed chronic kidney disease, uOPG remained persistently high. For differentiating AN from ANR patients, uOPG performed the best on receiver operator characteristics analysis (AUC = 0.72) when compared with anti-dsDNA antibodies, C3, C4 and sOPG. CONCLUSION: uOPG is derived from kidneys and helps differentiate active SLE patients with and without LN. It shows modest correlation with disease activity and has a potential to predict poor response to therapy and relapse of LN.

Human leukocyte antigen-G polymorphism influences the age of onset and autoantibody status in rheumatoid arthritis.

The study was conducted to investigate the frequency of three gene polymorphisms in the 3'-untranslated region (3'-UTR) of human leucocyte antigen-G (HLA-G) gene in south Indian patients with rheumatoid arthritis (RA) and analyze their influence on disease susceptibility, phenotype and treatment response. HLA-G 14 bp insertion (Ins)/deletion (del) (rs66554220), HLA-G +3142G>C (rs1063320) and +3187A>G (rs9380142) polymorphism was analyzed in 221 RA patients and 200 healthy controls. Frequency of HLA-G genotypes or alleles did not differ between patients and controls. Analysis based on rheumatoid factor (RF) status revealed that the frequency of allele 'A' (rs9380142) was significantly higher in RF-positive than in RF-negative patients [84% vs 74%, Yates-corrected P value (Pc) = 0.04, odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.0-3.2]. A similar difference was maintained in RF-positive female patients than their RF-negative counterparts (83% vs 71%, Pc = 0.02, OR = 1.9, 95% CI = 1.0 to 3.4) and between RF-positive and RF-negative young onset RA (YORA) patients (84% vs 73%, Pc = 0.03, OR = 1.9, 95% CI = 1.0-3.2), suggesting that rs9380142 polymorphism influenced RF status. The 14 bp Ins allele of rs66554220 was significantly more prevalent in RF-positive YORA than in RF-positive late onset RA (LORA) patients (51% vs 25%, P = 0.03, OR = 3.1, 95% CI = 1.1-9.8). Frequency of the four major haplotypes [InsGA (48%), DelGA (22%), DelCG (18%), DelCA (9.7%)] observed did not differ between cases and controls. HLA-G does not appear to be a risk factor for development of RA in south Indian Tamils but may act as a genetic modifier of clinical phenotype in terms of autoantibody production, gender preference and age at disease onset.

TNFAIP3 and TNIP1 polymorphisms confer psoriasis risk in South Indian Tamils.

Psoriasis is a chronic inflammatory skin disease with genetic and environmental factors having an important role in its aetiology. Several genome-wide association studies have reported the association of the genes of the TNFα signalling, tumour necrosis factor alpha-induced protein 3 (TNFAIP3), TNFAIP3-interacting protein 1 (TNIP1) with psoriasis in Western and Chinese populations. The aim of this study is to demonstrate whether the TNFAIP3 and TNIP1 genes contribute to the risk of psoriasis in the ethnically distinct South Indian population. 360 psoriatic subjects and 360 healthy controls were recruited in this case control study. TNFAIP3 (rs610604) and TNIP1 (rs17728338) polymorphisms were typed by using TaqMan 5 allele discrimination assay. The results demonstrated that the SNPs rs610604 and rs17728338 of the TNFAIP3 and TNIP1 genes, respectively, were associated with psoriasis in our population at both allelic and genotypic levels. Thus, our results suggest that TNFAIP3 (rs610604) and TNIP1 (rs17728338) polymorphisms confer increased risk of psoriasis and may play a vital role in its pathogenesis in our ethnic South Indian Tamils.

The CTLA4 +49 A/G (rs231775) polymorphism influences susceptibility to SLE in South Indian Tamils.

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with complex etiology. Loss of immune tolerance and synthesis of autoantibodies against nuclear antigens contributes to the disease. Genetic aberrations disrupting the functions of immune regulatory receptors may facilitate the development of autoimmune diseases. Cytotoxic T-lymphocyte antigen 4 (CTLA4) is an inhibitory receptor for T cells and this study was carried out to analyze the influence of CTLA4 +49A/G (rs231775) polymorphism on susceptibility to SLE in ethnic Tamils. Three hundred SLE patients and 460 age and sex similar, ethnicity-matched controls were screened for the +49 A/G polymorphism by real time polymerase chain reaction (PCR). The wild allele (A) frequency in controls and cases was 63% and 47%, respectively. The presence of heterozygous (AG) and homozygous mutant (GG) genotype was associated with a significant risk to develop SLE (P = 0.0001, OR-2.29, 95% confidence interval (CI), 1.6-3.3) and (P = 0.0001, OR-4.3, 95% CI, 2.8-6.99). The frequency of mutant allele (G) in patients was also significantly associated with SLE (P = 0.0001, OR-1.9, 95% CI, 1.5-2.4). However, this polymorphism did not influence the clinical or serological phenotypes in our study. Therefore the CTLA4 +49 A/G polymorphism is a potential genetic risk factor for lupus susceptibility in South Indian Tamils, but does not appear to influence either the clinical or serological phenotype.

IRF5rs2004640 single nucleotide polymorphism is associated with susceptibility to rheumatoid arthritis in South Indian Tamils.

Polymorphism of interferon regulatory factor 5 (IRF5), a latent transcription factor gene has been associated with various auto-immune diseases. Our aim was to study the IRF5rs2004640 gene polymorphism and its association with disease susceptibility, disease phenotype and treatment response in South Indian Tamil patients with rheumatoid arthritis (RA).The study was conducted on 217 RA patients fulfilling the American College of Rheumatology (ACR) 2010 criteria and 482 healthy controls (HCs) without family history of autoimmune disease. The IRF5rs2004640 genotyping was performed using a TaqMan 5' allelic discrimination assay. We found that the IRF5rs2004640T allele [P < 0.0001, odds ratio (OR) 3.25, 95% confidence interval (CI) 2.55-4.12] and TT genotype (P < 0.0001, OR 4.60, 95% CI 3.23-6.57) were significantly more frequent in RA patients as compared with HCs. No association was found between IRF5rs2004640 polymorphism, clinical manifestations, autoantibody profile and treatment response. IRF5rs2004640 T (mutant) allele may be a susceptibility factor conferring risk for RA in South Indian Tamils, whereas G allele (wild type) may be protective.

Immunoglobulin-like transcripts 6 (ILT6) polymorphism influences the anti-Ro60/52 autoantibody status in South Indian SLE patients.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with complex etiology. Loss of immune tolerance against self-antigens results in activation of the immune system to produce autoantibodies, which in turn contribute to the clinical manifestations of the disease. Immune cells harbor a plethora of regulatory receptors. Immunoglobulin-like transcripts (ILTs) exhibit both immune activation and inhibitory properties. Genetic defects in genes encoding these receptors may predispose to development of autoimmune diseases secondary to loss of their function. The aim of our study was to analyze the presence or absence of the 6.7 kb segment in the ILT6 gene and its association with susceptibility to SLE and its different manifestations. METHOD: A total of 188 SLE patients and 192 age-, sex similar-, ethnicity-matched controls were recruited. They were genotyped to test the presence or absence of the 6.7 kb segment of the ILT6 gene by polymerase chain reaction. RESULTS: The mutant allele lacking the 6.7 kb gene segment had an equal frequency in patients as well as controls (20% and 18%, respectively). The mutant allele was not associated with SLE or its clinical manifestations. However, the mutant allele was associated with the presence of anti-Ro60 (p = 0.0005, OR 3.5, 95% CI 1.8-7.1) and anti-Ro52 (p = 0.0027, OR 2.99, 95% CI 1.5-6.06) autoantibodies. CONCLUSION: ILT6 deletion polymorphism does not appear to be a lupus susceptibility gene in South Indian Tamils, but may behave as a genetic modifier of autoantibody phenotype by influencing the production of anti-Ro60 and anti-Ro52 autoantibodies and thus indirectly contribute to autoimmune responses in SLE.

Q222R polymorphism in DNAse I gene is a risk factor for nephritis in South Indian SLE patients.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a multisystem disorder in which defective apoptotic clearance is considered to be an important factor in pathogenesis. DNAse I is associated with disposal of apoptotic nuclear debris. The defective enzyme production due to +2373 A to G (Q222R) in exon 8 is reported to be a genetic risk factor for SLE. SLE in Indians is reported to be severe. There are no genetic studies reported from India which have explored this aspect of DNAseI gene. This study aimed to analyze whether Q222R is a susceptibility factor for SLE and to study its influence on clinical manifestations and autoantibody production in South Indian Tamils. METHOD: Three hundred SLE cases (based on ACR 1982 criteria) and 530 age, sex similar and ethnicity matched controls were recruited. All the cases and controls were genotyped for DNAse I Q222R polymorphism using PCR-RFLP method. RESULTS: DNAse I Q222R polymorphism is prevalent in our population. We observed higher frequency of Q/R in patients compared with controls (60% vs. 53%). This was found to be a genetic risk for SLE susceptibility (p = 0.04, odds ratio 1.5, 95% confidence interval 1-2.1). It also conferred a significant risk for development of nephritis (p = 0.007, odds ratio 1.93, 95% confidence interval 1.2-3.2). CONCLUSION: DNAse I Q222R polymorphism is a potential genetic risk factor for SLE in South Indian Tamils. In addition, the mutant allele confers a significant risk for lupus nephritis.

Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India.

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India. METHODS: A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects. RESULTS: In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one-half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported. CONCLUSION: This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults.

Activation of NF-kappaB in lymphocytes and increase in serum immunoglobulin in hyperthyroidism: possible role of oxidative stress.

This study evaluated oxidative stress, serum IgM and IgG, and nuclear factor (NF)-kappaB signaling in lymphocytes of hyperthyroidism patients. GSH content in lymphocytes was significantly lower and serum malondialdehyde, IgM and IgG levels were significantly higher in hyperthyroidism as compared to controls. In lymphocytes, the NF-kappaB signaling pathway was studied by western blot analysis of p65 and p-IkappaBalpha. Density of p-IkappaBalpha and p65 (in nuclear fraction) was significantly higher in hyperthyroidism as compared to controls. The density of p-IkappaBalpha and p65 had significant positive correlation with serum malondialdehyde level and negative correlation with lymphocyte GSH level in hyperthyroid cases. The serum IgG and IgM levels were correlated significantly with density of p-IkappaBalpha and p65. As immunoglobulin production is regulated by the NF-kappaB pathway, we conclude that the oxidative stress-induced activation of the NF-kappaB pathway might play a role in the rise of serum immunoglobulin level in hyperthyroidism.

Synthesis and biological evaluation of naphthalene-1,4-dione derivatives as potent antimycobacterial agents.

The recent increase in the incidence of tuberculosis with the emergence of multi-drug resistant (MDR) cases has lead to the search for new drugs that are effective against MDR strains of Mycobacterium tuberculosis (M. tb) and can augment the potential of existing drugs against tuberculosis. In the present study a series of naphthalene-1,4-dione derivatives were synthesized and evaluated for their in vitro antimycobacterial activity against M. tb H37Rv strain. Preliminary results indicated that most of the compounds demonstrated significant antimycobacterial activities. The most effective compounds of the series 7, 8 and 10 have MIC values of 3.13 microg/mL and growth inhibition of 99%. Compound 7 has an IC50 value of 0.49 microg/mL. Compounds 1, 3 and 18 with MIC values of 3.13 microg/mL also showed 96-98% growth inhibition. The objective of our study is to generate new leads through different mode of action and to optimize their structure to display the potent efficacy.

The Serological and Biochemical Markers of Adrenal Cortex and Endocrine Pancreas Dysfunction in Patients with Hashimoto's Thyroiditis: A Hospital-based Pilot Study.

BACKGROUND: The prevalence of both islet cell and adrenal autoimmunity among Asian Indian hypothyroidism patients with Hashimoto's thyroiditis (HT) is lacking in literature. OBJECTIVES: The objective of this study was to assess the proportion of Addison's disease (AD) and type 1 diabetes mellitus (T1DM) in patients with HT. MATERIALS AND METHODS: The patients with hypothyroidism due to HT were included in this study over 2 years. Primary hypothyroidism was defined as high serum thyroid-stimulating hormone (>5.5 mIU/L) with or without low thyroxine level. HT was defined by the presence of high thyroid peroxidase antibody (Ab) titer (>35 IU/ml). Autoimmune markers of AD and T1DM, i.e., adrenal (21-hydroxylase) Ab, glutamic acid decarboxylase (GAD) Ab, and insulinoma-associated antigen-2 (IA-2) Ab were measured among them. In addition, 250 µg adrenocorticotropic hormone (ACTH) stimulation test was done in patients with adrenal Ab. Similarly, beta cell function was assessed in patients with GAD and/or IA-2 Ab. RESULTS: Out of 150 patients screened, 136 patients were included in this study. Seven patients had adrenal Ab while 15 had IA-2 Ab. The GAD Ab was not present in any of the patients in the study. ACTH stimulation test was done in four of seven patients with adrenal Ab and beta cell function was assessed in 8 of 15 patients with islet cell Ab. All patients with adrenal Ab had normal adrenal function and 1 out of 15 with IA-2 Ab developed diabetes mellitus during follow-up. CONCLUSIONS: Either adrenal or islet cell Ab was found in 16% Asian Indian hypothyroidism patients with HT.

An exploratory study of immune markers in acute and transient psychosis.

The aim of this study was to look into the balance of pro-inflammatory (TNF-α, IL-6) and anti-inflammatory (TGF-ß) cytokines and their association with stress, alterations in HPA axis activity and the disease severity in acute psychosis. Socio-demographic and clinical details were collected from 41 in-patients with a diagnosis of Acute and Transient Psychotic Disorder. Holmes and Rahe Stress Scale for stress in the preceding year, and Brief Psychiatric Rating Scale at baseline and follow up (4-12 weeks) for psychopathology were applied. IL-6, TNF-α (pro-inflammatory), TGF-ß (anti-inflammatory) and Cortisol (morning and afternoon values) were measured at baseline and follow up. A total of 30 out of 41 cases recruited had follow up data available. The levels of IL-6 (p<0.001), TNF-α (p<0.001) and TGF-ß (p<0.001) at baseline were all found to be significantly elevated compared to 42 age and gender matched healthy controls. There was a significant increase in the levels of TNF-α (p=0.020) and morning levels of cortisol (p=0.009) and a significant decrease in the levels of TGF-ß (p=0.004) and afternoon levels of cortisol (p=0.043) from baseline to follow up. This study showed that there was an increased level of both pro and anti-inflammatory cytokines at baseline and a prolonged pro - inflammatory compared to anti - inflammatory response which warrants larger prospective studies and comparative studies to patients with schizophrenia and bipolar disorders.

HLA class II alleles influence rheumatoid arthritis susceptibility and autoantibody status in South Indian Tamil population.

Rheumatoid arthritis (RA) is a complex multifactorial autoimmune disease characterized by inflammatory arthritis. The precise etiology and pathogenesis of RA remains elusive but evidence points towards stochastic interactions between genetic and environmental factors. This study investigated the distribution of human leucocyte antigen (HLA)-DRB1/DQB1 alleles in South Indian patients with rheumatoid arthritis (RA) and their influence on RA susceptibility and clinical phenotype. Low resolution HLA-DRB1 and -DQB1 typing was performed in 271 RA patients and 233 healthy controls by polymerase chain reaction (PCR) using sequence-specific primers (SSP). HLA-DRB1*10 was found to be more frequent in patients (Pc = 0.004, OR = 2.23, 95% CI = 1.5-3.34) than controls. This difference persisted in RF positive (Pc = 9 × 10-6 , OR = 2.45, 95% CI = 1.62-3.74), ACPA positive (Pc = 0.007, OR = 2.10, 95% CI = 1.35-3.29), ACPA negative (Pc = 0.001, OR = 2.45, 95% CI = 1.50-3.97) and both RF and ACPA positive subgroup of patients (Pc = 0.003, OR = 2.22, 95% CI = 1.41-3.51). On the contrary, the HLA-DRB1*13 (Pc = 0.01, OR = 0.43, 95% CI = 0.25-0.73) and HLA-DRB1*14 (Pc = 0.003, OR = 0.43, 95% CI = 0.26-0.69) alleles were over-represented in controls than patients. Further, distribution of the prominent Caucasian RA risk allele DRB1*04 did not differ between patients and controls in our study population. We did not find any association between DQB1 alleles and RA susceptibility or autoantibody status. The haplotypes DQB1*05-DRB1*10 (P = 6.8 × 10-6 , OR = 2.46, 95% CI = 1.63-3.79) and DQB1*06-DRB1*15 (P = 0.03, OR = 1.41, 95% CI = 1.02-1.96) were more frequent in patients while DQB1*05-DRB1*14 (P = 8.4 × 10-4 , OR = 0.44, 95% CI = 0.26-0.74) and DQB1*06-DRB1*13 (P = 9.5 × 10-4 , OR = 0.40, 95% CI = 0.21-0.72) were higher in controls. To conclude, HLA-DRB1*10 is associated with RA while HLA-DRB1*13 and HLA-DRB1*14 alleles confer protection in south Indian Tamils.