Outcome of critically ill patients with systemic lupus erythematosus from a medical intensive care unit in Southern India.

OBJECTIVE: Systemic lupus erythematosus (SLE) has become the most prevalent autoimmune condition requiring admission in the intensive care units (ICU) in the last two decades. Here we analysed the clinical outcomes of SLE patients admitted to our ICU between 2011 and 2021, and studied the prognostic role of high-density lipoprotein (HDL) and procalcitonin in those enrolled after August 2019. METHODS: Systemic lupus erythematosus (ACR/SLICC 2012) were enrolled, 72 retrospectively and 30 prospectively. Data on indications for ICU admission, complications, infections, and disease activity were recorded. Outcome was mortality at 90 days (prospective) whereas in the retrospective analysis outcome was hospital discharge or death in hospital. Serum HDL and procalcitonin (PCT) was estimated in the prospectively enrolled 30 patients and compared with 30 non ICU-SLE patients. RESULTS: Indications for ICU admissions were respiratory causes in 78/102 (76.5%) patients; for haemodynamic monitoring and for invasive procedures in the remaining. Pneumonia was the primary reason for mechanical ventilation, followed by diffuse alveolar haemorrhage (DAH). Eighty-three (81.3%) patients died; infections (n = 54) and SLE related causes (n = 29). APACHE-II >16 (p = .026), lymphopenia (p = .021), infection (p = .002), creatinine >1.3 mg/dL (p = .023), and hypotension requiring vasopressor support (p = .006) emerged as significant predictors of non-survival on multivariable analysis. HDL (mg/dL) day 1 was significantly lower in SLE-ICU patients compared to non ICU-SLE (31.8 ± 14.3 vs 38.8 ± 11.4 mg/dl); p = .045. On day 1, PCT (ng/mL) in SLE-ICU was significantly higher when compared to non-ICU SLE; median (IQR): 0.53 (0.26-5.27) versus 0.13 (0.05-0.47), p < .001), respectively. It was also significantly higher on day 5 in SLE-ICU than non-ICU SLE (median (IQR): 4.18 (0.20-14.67) versus 0.10 (0.08-0.46), p = .004. CONCLUSION: The mortality of SLE patients admitted to the ICU in this study is high, and infections were the principal reason for death. Baseline low HDL and higher procalcitonin are potential biomarkers to identify critically ill SLE patients.

Liver Abnormalities in Systemic Lupus Erythematosus: A Prospective Observational Study.

Objectives In this study, we aimed to examine and analyze liver abnormalities among patients with systemic lupus erythematosus (SLE), including both newly diagnosed patients and those being followed up, as well as the prevalence of lupus hepatitis. Methods This was a prospective observational study. Clinical data, liver function tests (LFTs), and the findings from the ultrasonography of the abdomen among the patients were prospectively recorded and evaluated. Results Overall, 28 of the total 135 (20.7%) patients had liver abnormalities, including biochemical and those detected via ultrasonography. Ten patients had transaminitis, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >2 times the upper limit of normal (ULN). Nine patients had elevated alkaline phosphatase (ALP) or gamma-glutamyl transferase (GGT) of >2 times ULN. In three patients, transaminitis was due to anti-tubercular therapy (ATT)-induced hepatitis; in seven (5.2%), no specific cause for transaminitis could be identified, and hence they were classified as cases of lupus hepatitis. On comparing clinical features between patients with (n=7) and without lupus hepatitis (n=128), the condition was more prevalent in newly diagnosed SLE patients compared to those who had been on follow-up [six (85.7%) vs. 30 (23.6%), p=0.002]. All seven patients with lupus hepatitis had complete resolution of the transaminitis on follow-ups. However, one patient who had received ATT (isoniazid, rifampicin, ethambutol, and pyrazinamide) died. Ultrasonography showed fatty liver in seven patients and chronic liver disease in one patient. Conclusion In this study, transaminitis due to lupus hepatitis was seen in newly diagnosed lupus patients and was not associated with disease activity. Before diagnosing lupus hepatitis, drug-induced liver disease has to be ruled out, and if persistent LFT abnormalities are present, further workup is suggested to rule out overlap with primary biliary cirrhosis and/or autoimmune hepatitis.

Pulmonary Manifestations in Systemic Sclerosis: Hospital-Based Descriptive Study.

Introduction Prevalence of systemic sclerosis (SSc)-related organ injury is difficult to estimate as it occurs early in SSc, even though patients are often asymptomatic. As the patients with organ damage have a poor prognosis, all the patients should be carefully evaluated and followed­up in the initial periods. This facilitates the early identification and initiation of appropriate therapy. This study emphasizes on different clinical manifestations and early predictors of lung involvement by using clinical, radiological, and pulmonary function tests in a tertiary care centre.   Materials and methods A total of 53 SSc cases, who satisfied American College of Rheumatology (ACR) 2013 criteria, without any overlap syndromes were included in the study. All patients underwent thorough clinical examination along with Modified Rodnan Scoring (MRS) assessment, nailfold capillaroscopy (NFC), chest X-ray (CXR), HRCT thorax, 2D-echocardiography, spirometry and diffusion lung study by carbon monoxide (DLco). Results Out of 53 patients, four were male and 49 were female. Twenty-one patients had limited SSc (lcSSc) and 32 had diffuse SSc (dcSSc). Eighty-three per cent of subjects presented with skin manifestations and 34% with respiratory complaints. Reticulonodular opacities and ground glassing were the predominant radiological abnormalities suggestive of non-specific interstitial pneumonia (NSIP) followed by usual interstitial pneumonia (UIP). Pulmonary hypertension was predominant in patients with lcSSc. Thirty-eight patients had a restrictive pattern of spirometry. Forty-four patients showed deranged DLco, among which two patients showed an isolated decrease in DLco. Thirty-seven patients had abnormal NFC among which dropout pattern was predominant. MRS was significantly correlated with pulmonary involvement by DLco and HRCT. Conclusions SSc can affect the lungs even before developing obvious clinical pulmonary manifestations. DLco and HRCT play a critical role in detecting early lung involvement and predicting the outcomes in SSc. Higher modified Rodnan's score, which has a significant correlation with DLco and HRCT can be used to predict early visceral involvement in resource-limited settings.

Folyl polyglutamate synthethase (FPGS) gene polymorphisms may influence methotrexate adverse events in South Indian Tamil Rheumatoid Arthritis patients.

The aim of the study was to look for the association of FPGS 2752 G > A (rs1544105), FPGS 1994 A > G (rs10106), and GGH 452 C > T (rs 11545078), GGH -401C > T (rs 3758149) gene polymorphisms with methotrexate (MTX) treatment response and MTX-induced adverse events in South Indian Tamil patients with rheumatoid arthritis (RA). Further the influence of these gene polymorphisms on MTX polyglutamate levels was analyzed. A total of 330 patients with RA were investigated. FPGS gene polymorphisms were analyzed by TaqMan 5'nuclease assay and GGH gene polymorphisms were analyzed by PCR-RFLP. Methotrexate polyglutamates (nmol/L of packed erythrocytes) were measured by liquid chromatography mass spectrometry (LCMS/MS) method. We found that the heterozygous genotype of FPGS rs1544105 [p = 0.02, OR 1.93, 95% CI (1.15-3.35)] and FPGS rs10106 AG genotype [p = 0.01, OR 2.11, 95% CI (1.20-3.71)] were associated with MTX adverse events. FPGS rs1544105 and GGH -401C > T SNPs influenced the polyglutamate levels. None of the investigated SNPs seems to be associated with MTX treatment outcome.

Arthritis in sarcoidosis: A multicentric study from India.

INTRODUCTION: Ten to 15% of patients with sarcoidosis have associated arthritis. Chronic arthritis is fairly uncommon. There is a paucity of data on articular manifestations of the disease from India. METHODS: Case records of adult patients with sarcoidosis presenting to 11 rheumatology centers from 2005 to 2017 were retrospectively reviewed. Joint involvement was assessed clinically, classified as acute or chronic depending on duration of symptoms less or greater than 6 months, respectively. RESULTS: A total of 117 patients with sarcoid arthritis were reviewed. Forty-five patients were classified as having Lofgren's syndrome. The pattern of joint involvement revealed the ankle to be most commonly affected in both the groups. Shoulder, wrist, metacarpophalangeal, proximal interphalangeal joints of hands and knee joint involvement were significantly more common in chronic sarcoid arthritis. Peripheral lymphadenopathy and uveitis were significantly more frequent in chronic sarcoid arthritis. Forty out of 49 patients with acute arthritis followed up over a median of 1.8 years had achieved complete remission. Twelve out of 16 chronic sarcoid arthritis (median follow up 2.5 years) had achieved complete remission with 15, 12 and five patients on steroids, methotrexate and hydroxychloroquine, respectively. One patient with acute sarcoid arthritis with concomitant interstitial lung disease had died due to lung infection. CONCLUSION: Acute oligoarthritis was the commonest presentation with the ankle being the most commonly affected joint. Upper limb joint (predominantly distal) and knee involvement were more common as reported in our largest series worldwide of chronic sarcoid arthritis in adults. Hilar adenopathy and erythema nodosum were common extra-articular features in both acute and chronic sarcoid arthritis. A limitation of the study was the retrospective nature of the analysis.

Association of MICA-129 polymorphism and circulating soluble MICA level with rheumatoid arthritis in a south Indian Tamil population.

INTRODUCTION: Rheumatoid arthritis (RA) is a clinically heterogeneous chronic inflammatory disorder characterized by synovitis leading to joint destruction. Both genetic and environmental factors are involved in the pathogenesis of RA. Significant dysregulation of NKG2D, an activating receptor of natural killer and certain autoreactive T cells as well as its ligand major histocompatibility complex class I chain-related gene A (MICA) has been implicated in perpetuating the pathology of RA. Since the genetic polymorphism in MICA gene (MICA-129 met/val polymorphism at codon 129) is known to affect its binding affinity to NKG2D, we explored its influence on RA susceptibility and disease severity. METHODS: The MICA-129 met/val polymorphism was examined in 270 patients with RA and 232 healthy controls by TaqMan 5'-nuclease assay. Serum soluble MICA (sMICA) was measured in a subset of 89 patients and 80 controls by enzyme-linked immunosorbent assay. RESULTS: We observed that the frequency of MICA-129 val allele (73% vs. 65%, Pc = 0.006, odds ratio = 1.48, 95% CI = 1.12-1.95) was higher in patients than in controls. sMICA levels were significantly higher in patients with RA than in controls (P < 0.0001). sMICA levels were higher in patients with val/val genotype than in those with met/val or met/met genotype (P = 0.03). The MICA-129 val/val genotype was associated with high titers of sMICA in patients with deforming RA phenotype (P = 0.02), suggesting a role in determination of severity of RA. CONCLUSION: MICA-129 val/val genotype, associated with higher levels of circulating sMICA, may influence disease susceptibility and associate with increased severity of RA in south Indian Tamils.

Nonassociation of homocysteine gene polymorphisms with treatment outcome in South Indian Tamil Rheumatoid Arthritis patients.

The aim of the study was to look for any association of MTR 2756A>G and MTRR 66A>G gene polymorphisms with clinical phenotype, methotrexate (MTX) treatment response, and MTX-induced adverse events in South Indian Tamil patients with rheumatoid arthritis (RA). A total of 335 patients with RA were investigated. MTR 2756A>G gene polymorphism was analyzed by PCR-RFLP, and MTRR 66A>G SNP was analyzed by TaqMan 5' nuclease assay. The allele frequencies were compared with HapMap groups. MTR 2756G allele was found to be associated with risk of developing RA. The allele frequencies of MTR 2756A>G and MTRR 66A>G SNPs in controls differed significantly when compared with HapMap groups. Neither of the SNPs influenced the MTX treatment outcome and adverse effects. Neither of the SNPs seems to be associated with MTX treatment outcome and adverse events in South Indian Tamil patients with RA.

ATIC 347C>G gene polymorphism may be associated with methotrexate-induced adverse events in south Indian Tamil rheumatoid arthritis.

AIM: To find the association of ATIC 347C>G gene polymorphism with methotrexate (MTX) treatment response and MTX-induced adverse events in south Indian Tamil patients with rheumatoid arthritis. PATIENTS & METHODS: A total of 319 rheumatoid arthritis and 310 healthy controls were recruited for the study and ATIC 347C>G gene polymorphism was analyzed by PCR-RFLP method. RESULTS: The genotype and allele frequencies of ATIC 347 C>G SNP did not differ between good and nonresponders and hence this SNP was not found to be associated with MTX treatment response. However, the ATIC 347 GG genotype (p = 0.02; odds ratio [OR]: 4.46; 95% CI: 1.28-15.52) and mutant G allele was associated with MTX-induced gastrointestinal adverse events (p = 0.01; OR: 2.60; 95% CI: 1.27-5.35). CONCLUSION:  ATIC 347C>G gene polymorphism may be associated with the development of MTX induced gastrointestinal adverse events.

Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism is not a risk factor for hypertension in SLE nephritis.

SLE is a systemic autoimmune disease with high prevalence of hypertension. Around 40-75 % of SLE patients develop nephritis, a major cause of hypertension and mortality. Angiotensin-converting enzyme (ACE) maintains the blood pressure and blood volume homeostasis. An insertion/deletion (I/D) polymorphism in intron 16 of ACE gene was reported to influence the development of hypertension, nephritis, and cardiovascular diseases in different ethnic populations. Despite compelling evidence for the high prevalence of hypertension in individuals with SLE, underlying factors for its development are not well studied. With this background, we analyzed the influence of ACE insertion/deletion polymorphism on susceptibility to SLE, development of nephritis and hypertension, other clinical features and autoantibody phenotype in South Indian SLE patients. Three hundred patients with SLE and 460 age and sex similar ethnicity matched individuals were included as patients and healthy controls, respectively. The ACE gene insertion/deletion polymorphism was analyzed by PCR. Insertion (I) and deletion (D) alleles were observed to be equally distributed among patients (57 and 43 %) and controls (59 and 41 %), respectively. The mutant (D) allele did not confer significant risk for SLE (II vs. ID: p = 0.4, OR 1.15, 95 % CI 0.8-1.6; II vs. DD: p = 0.34, OR 1.22, 95 % CI 0.8-1.85). There was no association of the ACE genotype or the allele with development of lupus nephritis (II vs. ID: p = 0.19, OR 1.41, 95 % CI 0.84-2.36; II vs. DD: p = 0.41, OR 0.74, 95 % CI 0.38-1.41) or hypertension (II vs. ID: p = 0.85, OR 0.9, 95 % CI 0.43-1.8; II vs. DD: p = 0.66, OR 1.217, 95 % CI 0.5-2.8). The presence of mutant allele (D) was not found to influence any clinical features or autoantibody phenotype. The insertion/deletion polymorphism of the ACE gene is not a genetic risk factor for SLE and does not influence development of hypertension or lupus nephritis in South Indian Tamils.

Susceptibility to SLE in South Indian Tamils may be influenced by genetic selection pressure on TLR2 and TLR9 genes.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with complex etiology. Genetics plays an important role in lupus pathogenesis through its influence on clinical and autoantibody phenotype of the disease. Toll like receptors (TLR) recognize molecular patterns of pathogens and activate the innate immune system. Their ability to identify nucleic acids makes them suitable candidates for investigation of their role in lupus pathogenesis. Hence, this study was carried out to analyze the G to A and C to T transitions in TLR2 and TLR9 genes respectively and to test their association with lupus susceptibility, clinical and autoantibody phenotypes in South Indian Tamils. METHOD: Three hundred SLE patients fulfilling ACR 2012 criteria for SLE and 460 age, sex similar, ethnicity matched controls were recruited as cases and controls. TLR2 (R753Q) and TLR9 (-1237C/T) polymorphisms were analyzed by real time PCR. RESULTS: The TLR2 gene remained monomorphic in patients and controls, the frequency of the homozygous wild type allele being 100% and 99.6% respectively. Hence, it did not confer susceptibility to SLE. The more frequent T allele of TLR9 gene conferred a significant risk to develop SLE (p=0.011, OR 1.69, 95% CI 1.1-2.6). Both the polymorphisms did not influence clinical or autoantibody phenotype of the disease. CONCLUSION: Prevailing endemic infections in the Indian subcontinent may have exerted a selection pressure resulting in TLR2 gene remaining monomorphic and the TLR9 adapting to a mutation for its increased expression. These may have an additive effect in the presence of other genetic and environmental risk factors to confer susceptibility to SLE in South Indian Tamils.

Anaplastic large cell lymphoma in a patient with systemic onset juvenile arthritis: case report and review of literature.

The association of malignancy with autoimmune rheumatic diseases has been a subject of investigation. It has been shown that there is increased risk of malignancies, mainly non-Hodgkin lymphoma, in patients with autoimmune disorders. There is scarcity of data about malignancy in juvenile idiopathic arthritis (JIA). We report the occurrence of anaplastic large cell lymphoma in a patient with systemic onset juvenile idiopathic arthritis treated with low dose methotrexate (MTX). A relationship between MTX treatment and the occurrence of lymphoma in autoimmune diseases has been suggested. The hypothesis that MTX has a role in the aetiology of lymphoproliferative disorders is supported by the observation of spontaneous remission of lymphoma in few cases on cessation of MTX therapy. However, systemic onset juvenile idiopathic arthritis patients receiving MTX must be periodically examined for the development of lymphoproliferative disorder especially if the disease is difficult to control or patient develop new symptoms on therapy.

Complement C1q and C2 polymorphisms are not risk factors for SLE in Indian Tamils.

INTRODUCTION: Complement system is an important effector component of the innate immune system. More than 30 plasma proteins undergo a cascade of enzymatic reactions to produce effector molecules to clear infectious microbes, immune complexes, post apoptotic cellular debris and thus participate in prevention of autoimmunity. Absolute deficiency of individual complement components and selective deficiency of classical pathway complement components are reported to be associated with severe infections and a high risk for lupus like syndromes. Genetic defects in gene encoding for complement components were reported to be associated with complement deficiency. This study was carried out to investigate whether C1q and C2 polymorphisms are risk factors for SLE in south Indian Tamils. MATERIALS AND METHODS: Three hundred SLE patients fulfilling ACR criteria for SLE and 460 age and sex similar ethnicity matched individuals were included as patients and healthy controls respectively. The genomic DNA obtained from both the groups was screened for two polymorphisms including a C/T transition in exon 2 of C1qA (rs121909581) by PCR-RFLP and a 28bp deletion in sixth exon of C2 gene by PCR. RESULTS: C1q exon 2 C/T polymorphism analysis revealed that homozygous CC was the most common genotype in patients and controls. A single SLE patient was found to have heterozygous variant (CT). None of the patients or healthy controls were found to have 28bp deletion variant of C2 gene. CONCLUSION: The C/T polymorphism in exon 2 of C1qA and a 28bp deletion in sixth exon of C2 gene were found to be rare in south Indian Tamil SLE patients. They do not appear to be susceptibility factors for SLE in Indian Tamils.

Rabson-Mendenhall syndrome with recurrent cerebral infarcts caused by a novel INSR mutation.

Rabson-Mendenhall syndrome (RMS) is an autosomal recessive disorder characterized by extreme insulin resistance and certain characteristic phenotypic features. The primary defect lies in the insulin receptor and involves biallelic mutations that lead to a loss of function through various postulated defects. We present a 9-year-old female patient with RMS complicated by multiple cerebral infarcts, in whom genetic analysis revealed a novel insulin receptor mutation.

Asymptomatic right atrial thrombus in a case of nephrotic syndrome.

Hypercoagulable state in nephrotic syndrome can be complicated by thrombosis in unusual sites. We describe the case of a steroid-responsive nephrotic syndrome in an adult patient complicated by isolated thrombus in the right atrium which was completely asymptomatic. The patient was treated with steroids, anticoagulation and excision of the intracardiac thrombus with complete resolution. The case is presented in view of its rarity and to highlight the importance of routine echocardiography in all cases of nephrotic syndrome.