Performance of Clinical and Biochemical Parameters in Identifying Renal Histopathology and Predictors of One-Year Renal Outcome in Lupus Nephritis-A Single Centre Study from India.

Objectives: To assess the performance of clinical and biochemical parameters in identifying renal histopathology. To assess the performance of a combination of demographic, clinical, serological and histopathological parameters in determining renal response at one year. Methods: Data of biopsy-proven (ISN/RPS­2003 criteria) Lupus Nephritis (LN) were extracted from the institute database. Demographic, clinical and biochemical parameters at the time of biopsy were noted, and their associations with histopathological class, activity and chronicity scores were evaluated. Follow-up data at one year were collected. Complete, partial or no response (CR, PR, NR) for renal outcomes at one year and the predictors of NR were assessed. Results: Out of the 333 renal biopsies, 240 (71.8%) were Class III/IV. More patients with Class III/IV LN had hypertension (52.1%) and low eGFR (p < 0.001). Among Class III/IV, AS correlated weakly with UPCR (r = 0.31, p < 0.01), eGFR (r = −0.172; p < 0.01) and CS with eGFR (r = −0.212; p < 0.01). The presence of either hypertension, UPCR > 0.5 g/day, active urinary sediments or serum creatinine >1.3 g/dL had a sensitivity of >96% and specificity of <9% in detecting proliferative LN, crescents, interstitial inflammation and chronicity. NR was higher in males (aOR:3.9, 95% CI:1.4−11.0, p < 0.001), those with abnormal baseline creatinine (aOR: 1.9, 95% CI: 1.1−3.2, p < 0.001), higher renal SLEDAI (p < 0.05), higher AS, CS (p < 0.001) and interstitial inflammation (p < 0.005). In the binary logistic regression, the combination of male sex, baseline creatinine, UPCR and CS performed best in predicting NR (AUC: 0.762; 95% CI: 0.684−0.840, p < 0.001). Conclusions: Clinical and biochemical parameters alone have a poor specificity in identifying renal histopathology. A combination of demographic, clinical and histopathology parameters can better predict renal outcomes at one year.

The IRF5 rs2004640 (G/T) polymorphism is not a genetic risk factor for systemic lupus erythematosus in population from south India.

Background & objectives: Genetic aberrations disrupting toll-like receptor and interferon homeostasis enhance the risk of systemic lupus erythematosus (SLE). Raised serum interferon-alpha (IFN-α) levels in SLE patients have been ascribed to polymorphism (rs2004640 G/T) in interferon regulatory factor 5 (IRF5) gene, resulting in enhanced transcript splicing. A positive association between IRF5 polymorphism and SLE risk has been reported in many populations. This study was aimed to find out frequency of IRF5 rs2004640 G/T polymorphism in patients with SLE and healthy controls and to assess its influence on susceptibility, clinical and serological characteristics of SLE. Methods: IRF5 rs2004640 (G/T) polymorphism was analyzed in 300 SLE patients and 460 age and sex matched controls by real-time PCR. Results: The IRF5 rs2004640 (G/T) polymorphism did not confer risk of SLE or influence clinical or serological phenotype. However, the mutant allele conferred a borderline risk to develop thrombocytopenia (odds ratio: 2.05, 95% confidence interval: 0.97-4.3, P=0.06) in patients with SLE. Interpretation & conclusions: Our study revealed that the IRF5 rs2004640 polymorphism was not a risk factor for SLE in population from south India. It may, however, be a useful genetic marker for thrombocytopenia in SLE patients. Although we could not demonstrate susceptibility toward lupus in the presence of IRF5 rs2004640 (G/T) polymorphism, further exploration of the genetic variability of IRF5 may help uncover its pathogenic role in Indian SLE patients.

Comparing the efficacy of low-dose vs high-dose cyclophosphamide regimen as induction therapy in the treatment of proliferative lupus nephritis: a single center study.

Cyclophosphamide (CYC) has been the backbone immunosuppressive drug to achieve sustained remission in lupus nephritis (LN). The aim was to evaluate the efficacy and compare adverse effects of low and high dose intravenous CYC therapy in Indian patients with proliferative lupus nephritis. An open-label, parallel group, randomized controlled trial involving 75 patients with class III/IV LN was conducted after obtaining informed consent. The low dose group (n = 38) received 6 × 500 mg CYC fortnightly and high dose group (n = 37) received 6 × 750 mg/m2 CYC four-weekly followed by azathioprine. The primary outcome was complete/partial/no response at 52 weeks. The secondary outcomes were renal and non-renal flares and adverse events. Intention-to-treat analyses were performed. At 52 weeks, 27 (73%) in high dose group achieved complete/partial response (CR/PR) vs 19 (50%) in low dose (p = 0.04). CR was higher in the high dose vs low dose [24 (65%) vs 17 (44%)], although not statistically significant. Non-responders (NR) in the high dose group were also significantly lower 10 (27%) vs low dose 19 (50%) (p = 0.04). The change in the SLEDAI (Median, IQR) was also higher in the high dose 16 (7-20) in contrast to the low dose 10 (5.5-14) (p = 0.04). There was significant alopecia and CYC-induced leucopenia in high dose group. Renal relapses were significantly higher in the low dose group vs high dose [9 (24%) vs 1(3%), (p = 0.01)]. At 52 weeks, high dose CYC was more effective in inducing remission with decreased renal relapses in our population. TRIAL REGISTRATION: The study was registered at http://www.clintrials.gov . NCT02645565.

Antifibrillarin Antibodies Are Associated with Native North American Ethnicity and Poorer Survival in Systemic Sclerosis.

OBJECTIVE: To examine the clinical correlates and survival in patients with antifibrillarin antibodies (AFA) in a large international study population consisting of well-characterized systemic sclerosis (SSc) cohorts from Canada, Australia, and the United States. METHODS: Baseline clinical data from the prospective cohorts (Canadian Scleroderma Research Group, the Australian Scleroderma Cohort Study, and the American Genetics versus Environment in Scleroderma Outcome Study) were investigated. Clinical variables were harmonized and sera were tested for AFA using a commercially available SSc profile line immunoassay, regardless of the immunofluorescence staining pattern. Association of demographic and clinical features with AFA was investigated by logistic or linear regression. Further, a survival analysis was performed by Cox regression analysis. RESULTS: A total of 1506 patients with SSc with complete serological profiles were included in the study. Fifty-two patients (3.5%) had antibodies detected against fibrillarin. Patients of African descent and Native North American ethnicity were more likely to be AFA-positive compared with other ethnicities. After adjustment for demographic factors, diffuse involvement, and intestinal bacterial overgrowth requiring antibiotics, gastrointestinal reflux disease showed a trend for association with AFA. Further, AFA positivity was associated with shorter survival independently of demographic factors and disease type (HR 1.76, 95% CI 1.11-2.79, p = 0.016). CONCLUSION: In this large multinational SSc cohort, AFA was associated with Native American ethnicity and was an independent predictor of mortality.

The spectrum of anti-chromatin/nucleosome autoantibodies: independent and interdependent biomarkers of disease.

Autoantibodies directed to chromatin components date back to the discovery of the LE cell and the LE cell phenomenon circa 1950, and subsequent evidence that major components of that reaction were chromatin components and histones in particular. Over time, immunoassays ranging from ELISA and line immunoassays to more modern bead-based assays incorporated histone and DNA mixtures, purified histones, and purified nucleosomes leading to a more thorough understanding of the genesis and pathogenetic relationships of antibodies to chromatin components in systemic lupus erythematosus and other autoimmune conditions. More recently, interest has focussed on other components of chromatin such as high mobility group (HMG) proteins both as targets of B cell responses and pro-inflammatory mediators. This review will focus on immunoassays that utilize chromatin components, their clinical relationships, and newer evidence implicating HMG proteins and DNA neutrophil extracellular traps (NETs) as important players in systemic autoimmune rheumatic diseases.

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.

Hirudin anticoagulation allows more rapid determination of P2Y12 inhibition by the VerifyNow P2Y12 assay.

VerifyNow (VN) P2Y12 is a point-of-care assay used to assess response to P2Y12 inhibitors. Sodium citrate (citrate) is the standard anticoagulant used for this assay but requires a pre-incubation period. Hirudin is an alternative anticoagulant for platelet function studies that maintains physiological divalent cation levels. We investigated whether hirudin anticoagulation might allow more rapid testing of P2Y12 inhibition at the time of percutaneous coronary intervention (PCI). Blood was collected from the arterial sheath of aspirin-treated patients undergoing elective, urgent or emergency coronary angiography±PCI and aliquots were anticoagulated with either citrate or hirudin. For each anticoagulant, VN P2Y12 was performed both immediately and after 20 minutes. A total of 98 patients were included in this study following pre-treatment with clopidogrel (n=88), prasugrel (n=6) or no P2Y12 inhibitor (n=4). PRU with hirudin immediately (PRU_H_Imm) and PRU with citrate 20 minutes post sampling (PRU_C_20) were very strongly correlated (R=0.95) though PRU_H_Imm tended to be lower than PRU_C_20 so that optimal correlation was estimated by the equation PRU_H_Imm=0.95xPRU_C_20 (p<0.001). Bland-Altman plots showed good agreement between PRU_H_Imm and (0.95xPRU_C_20). Platelet reactivity was more stable over the studied time course with hirudin as compared to citrate. We therefore conclude that VN P2Y12 with hirudin anticoagulation can be performed more rapidly and results are strongly correlated with delayed citrate measurements. Further studies are warranted to assess the utility of this method for improving clinical outcomes in patients undergoing PCI.

Autoantibodies in systemic sclerosis.

Autoantibodies directed against a variety of nuclear, cytoplasmic and extracellular autoantigens are a serological hallmark of systemic sclerosis. This review provides an overview of the history and clinical association of many of the autoantibodies identified in SSc sera to date. Some of these autoantibodies predate the clinical diagnosis of SSc, some are pathogenic while others have no apparent role in pathogenesis. It was once thought that the autoantibody spectrum of individual SSc sera were less complex than other systemic autoimmune rheumatic diseases with respect to heterogeneous B cell responses reflected in circulating autoantibodies. However, with the advent of array technologies, there is now an unprecedented capability to detect multiple autoantibodies in an individual serum and this long held tenet of clinical diagnostic immunology is being reexamined.

Biologics in SLE: the current status.

Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, hydroxychloroquine, mycophenolate mofetil, azathioprine, cyclophosphamide, and very recently belimumab have been approved for SLE therapy. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. B-cells abnormalities leading to autoantibody production play a central role in Systemic Lupus Erythematosus (SLE) pathogenesis. The targets of these biological therapies are directed toward the B cell depletion, interference in the co-stimulation signals and the blockade of cytokines. Biologic agents targeting specific pathways (i.e. T-B lymphocyte interaction, cytokines and complement) have been also proposed as new tools for SLE treatment. B-cell targeted therapies, including anti-B lymphocyte stimulator (BLyS) and anti-CD20 monoclonal antibodies are at forefront of new SLE treatment. Results from randomized trials in systemic lupus erythematosus (SLE) have been very disappointing, with lack of efficacy for some drugs and development of severe side-effects such as infections for others. Fortunately, as more and more trials of biologics in the treatment of lupus are being performed, the first promising results have been achieved. Today, belimumab is expected to become the first approved drug for use in lupus in several decades. In this review we will focus on biological drugs whose potential efficacy have been evaluated in open-label and randomized clinical trials. Biologics provide encouraging results that represent a possible option in the treatment of refractory lupus. Thus we review recent clinical trials in patients with systemic lupus erythematosus (SLE), with emphasis on outcomes and on mechanisms by which the biological agents suppress autoimmunity.

Dermatomyositis: a rare presentation of HIV seroconversion illness.

Dermatomyositis is a rare autoimmune inflammatory myopathy with proximal muscle weakness and skin affection. Only 4 cases of HIV that subsequently developed dermatomyositis have been reported. This is the first case of dermatomyositis being the initial presentation of an acute seroconversion illness. We highlight the pathophysiology of dermatomyositis in HIV infection along with the complex issues of treatment in such cases. We report a case of a 50-year-old woman who presented with a 2 months' history of proximal muscle weakness with classic signs of dermatomyositis and consistent electromyographic and muscle biopsy. HIV (by enzyme-linked immunosorbent assay) was initially nonreactive, indeterminate at 4 weeks, and positive at 8 weeks. It was further confirmed by Western blot and polymerase chain reaction. She was treated with prednisolone and antiretroviral therapy. A high degree of suspicion is required to diagnose HIV seroconversion when an individual presents with dermatomyositis. A fine balance of immunosuppressants and antiretroviral therapy needs to be maintained in the treatment of such cases.