Incidence of cardiac conduction disorders in patients with rheumatic disease receiving hydroxychloroquine

Background: Hydroxychloroquine (HCQ) used for long-term management of rheumatic diseases. Prolonged use of antimalarials has been implicated in the development of conduction disorders particularly with chloroquine. Since limited data are available with HCQ, we studied electrocardiograms (ECG’s) of 122 patients with rheumatic diseases treated with HCQ. This is the first study with large cohort evaluating conduction disorders in those receiving HCQ.Methods: To evaluate cardiac conduction disorders in patients receiving HCQ as a part of their treatment, during 1-year follow-up and to note other related adverse reactions with a hypothesis to determine, how common are conduction disorders with HCQ. This is longitudinal prospective observational study over 1-year in the tertiary referral of south India. All patients who were started on HCQ (200-400 mg/day) as a part of their treatment were included. Patients with established cardiac diseases, electrolyte abnormalities and who were on drugs that cause conduction disorders were excluded. All ECG’s were cross-checked by a cardiologist.Results: A total of 276 patients were screened at baseline and 270 patients were enrolled in the study. Patients of rheumatoid arthritis, lupus, Sjogren’s syndrome, undifferentiated connective tissue disease, palindromic rheumatism were included after satisfying respective classification criteria. The mean age is 38.85 (standard deviation [SD] 8.34) years. Females are 82.8% (n=101) and males are 17.2% (n=21). The baseline mean heart rate is 81.4 beats/min (SD=11.04), PR interval is 141.5 ms (SD=13.90), QRS is 84.8 ms (SD=13.90), QTc is 421.5 ms (SD=35.65). At 6 months, mean heart rate is 80.4 beats/min (SD=9.99), PR interval is 141.9 ms (SD=16-37), QRS is 81.5 ms (SD=11.82), QTc is 427.4 ms (SD=34.56). At the end of study period, mean heart rate is 81.8 beats/min (SD=9.49), PR interval is 140 ms (SD=21.33), QRS is 84.6 ms (SD=15.72), QTc is 422.7 ms (SD=36.2). During study period four events occurred. A young girl with lupus developed ventricular ectopics on hiking dose of HCQ from 200 mg to 400 mg with a cumulative drug intake of 9.8 g, which has resolved completely on stopping drug without any other intervention. A lupus patient died at home and the cause was not known. A 36-year-old male with rheumatoid arthritis of 4 years duration developed prolonged PR interval with 6 months of drug intake with cumulative was drug intake of 30.6 g with no available follow-up data. A 30-year-old female with undifferentiated arthritis developed skin rash which is pruritic, exfoliative with tiny blisters, 3 days after starting drug. The incidence of cardiac conduction defects in 1-year of follow-up in patients started on HCQ is 0.84.Conclusion: This study highlights need for periodic cardiac evaluation of patients receiving long-term antimalarials. Reversibility of antimalarial toxicity is also highlighted in this study. Conduction disorders observed were similar to that expected in general population thus adding further evidence on safety of HCQ

Stroke frequency, associated factors, and clinical features in primary systemic vasculitis: A multicentric observational study

Objectives: The cerebral vessels may be affected in primary systemic vasculitis (PSV), but little is known about cerebrovascular events (CVEs) in this population. This study aimed to determine the frequency of CVEs at the time of diagnosis of PSV, to identify factors associated with CVEs in PSV, and to explore features and outcomes of stroke in patients with PSV. Methods: Data from adults newly diagnosed with PSV within the Diagnostic and Classification Criteria in VASculitis (DCVAS) study were analysed. Demographics, risk factors for vascular disease, and clinical features were compared between patients with PSV with and without CVE. Stroke subtypes and cumulative incidence of recurrent CVE during a prospective 6-month follow-up were also assessed. Results: The analysis included 4828 PSV patients, and a CVE was reported in 169 (3.50%, 95% CI 3.00–4.06): 102 (2.13% 95% CI 1.73–2.56) with stroke and 81 (1.68% 95% CI 1.33–2.08) with transient ischemic attack (TIA). The frequency of CVE was highest in Behçet’s disease (9.5%, 95% CI 5.79–14.37), polyarteritis nodosa (6.2%, 95% CI 3.25–10.61), and Takayasu’s arteritis (6.0%, 95% CI 4.30–8.19), and lowest in microscopic polyangiitis (2.2%, 95% CI 1.09–3.86), granulomatosis with polyangiitis (2.0%, 95% CI 1.20–3.01), cryoglobulinaemic vasculitis (1.9%, 95% CI 0.05–9.89), and IgA-vasculitis (Henoch-Schönlein) (0.4%, 95% CI 0.01–2.05). PSV patients had a 11.9% cumulative incidence of recurrent CVE during a 6-month follow-up period. Conclusion: CVEs affect a significant proportion of patients at time of PSV diagnosis, and the frequency varies widely among different vasculitis, being higher in Behçet’s. Overall, CVE in PSV is not explained by traditional vascular risk factors and has a high risk of CVE recurrence

Fingerprint abnormalities in systemic sclerosis: Results of a single center pilot study

Background: Fingertip abnormalities in the form of digital ulcers and gangrene is well known in systemic sclerosis (SSc), but little has been described about the frequency and systemic associations of finger print (FP) abnormalities in these patients. Our objective was to study the FP abnormalities in SSc patients and find possible association with digital vasculopathy. Methods: Patients with SSc and SSc overlap with other connective tissue diseases were screened for FP abnormalities using a Standardization Testing and Quality Certification Directorate-certified biometric FP scanner. FP quality assessment was done by recording the National Institute of Standards and Technology FP Image Quality (NFIQ) scores. NFIQ's 5 levels of quality are intended to be predictive of fingerprint matching. NFIQ = 1 indicates high quality and NFIQ = 5 indicates poor quality FPs. Social difficulties due to fingerprint abnormalities were noted. Ten healthy controls were included for comparison. Results: Of 37 patients, 29 with SSc and 8 with overlap syndromes, 15 (40.5%) had FP abnormalities in the form of nonrecognition of at least one finger with a median of 2 fingers (range 1–6). The mean NFIQ score of these patients was 4.5 (poor) while mean NFIQ scores in SSc was 3.8. All FPs of 10 controls were recognized, and the mean NFIQ score was 2.2 indicating a better FPs quality. There was no association of FP abnormalities with digital vasculopathy. Conclusions: In this pilot study, we found that fingerprint abnormalities occur frequently in SSc patients. Documentation of this abnormality should allow the use of other biometric tools for personal identification

Pentraxin 3 is better than conventional inflammatory markers for disease activity assessment in takayasu arteritis

Objective: The objective of this study is to measure plasma pentraxin 3 (PTX3) levels in Takayasu arteritis (TA) patients and to compare the accuracy of PTX3, high-sensitive C-reactive protein (hsCRP), and erythrocyte sedimentation rate (ESR) in distinguishing active disease from the inactive disease. Methods: In a prospective, cross-sectional study, TA patients fulfilling 1990 American College of Rheumatology criteria and healthy controls were enrolled in this study. The Indian Takayasu Clinical Activity Score (ITAS 2010) and ITAS ESR were recorded. Patients were divided into active, grumbling and inactive disease using physician global assessment. Plasma PTX3, hsCRP, and ESR were measured. Receiver operating curves for PTX3 (pg/ml), hsCRP (mg/L), and ESR (mm at 1 h) were constructed to differentiate active from the inactive disease. Inter-group comparisons were made using Mann–Whitney test. Results: Forty patients and 20 controls with median age of 26 and 24 years, respectively, were enrolled in this study. Median disease duration was 2 years. Fourteen patients had active, 8 grumbling, and 18 inactive disease. ITAS 2010 and ITAS ESR in active disease (5 [3–8.5], 7.5 [5–11.5]) were significantly higher than grumbling (0.6 (0–1.5], 2.5 [1–4.5]) or inactive disease (0.5 [0–1.3], 2 [1.7–3]) (P = 0.001). PTX3 (pg/mL) was higher in cases (505 [261–1358]) as compared to that of controls (317 [135–450]) (P 46 mm), hsCRP (17.1 mg/L), PTX3 (>745 pg/ml) was (55, 89, and 0.72), (46, 89, and 0.75), and (64, 95, and 0.82), respectively. Conclusion: Elevated PTX3 in TA demonstrates more accuracy than hsCRP and ESR in differentiating active from the inactive disease. These biomarkers may differentiate grumbling from inactive disease better than ITAS2010 or ITAS-ESR

Outcome of therapy in biopsy proven lupus nephritis with cyclophosphamide or mycophenolate: Registry data from a South Indian tertiary care center

Background: Cyclophosphamide and mycophenolate are the currently proposed first-line agents for induction in lupus nephritis (LN). In this study, we analysed the response rates with the three different induction regimens currently available for LN. Methods: Patients with biopsy-proven LN with data available at least till completion of induction regimen was included. Data on demography, clinical, laboratory measures, disease activity, and treatment received at baseline, at the end of induction, and until the last follow-up were retrieved. Response at the end of induction was noted. Differences between groups were analyzed using Chi-square test. Results: Eighty-three patients (75 females) with the mean age of 25 ± 8.9 years were included. The median duration of follow-up was 18 months (range: 6–153). Forty-one patients had Class IV, 19 Class III, 11 Class V, 7 Class III/IV + V, and 5 Class II LN. Forty received high-dose cyclophosphamide (HD CyC), 14 Euro-Lupus Nephritis Trial cyclophosphamide (ELNT CyC), 20 mycophenolate mofetil (MMF) for induction, while two received azathioprine, one cyclosporine, one modified ponticelli, and five with Class II nephritis received no induction. Baseline characteristics were comparable between three groups. The response rate was similar between the three groups: 30/40 in the HD CyC group, 12/14 in the ELNT CyC group, and 15/20 in the MMF group responded at the end of induction (P = 0.69). Complete response rate was higher in the individuals who received cyclophosphamide (HD CyC + ELNT CyC) as compared to MMF (17/34 vs. 2/13, P = 0.05). Univariate analysis of factors predicting response revealed only class of nephritis as a significant factor predicting response (complete or partial) at the end of induction therapy. Conclusion: In this South Indian lupus registry a complete response at 6 months in biopsy-proven LN was better with cyclophosphamide than mycophenolate

Association of genetic variants of xenobiotic metabolic pathway with systemic lupus erythematosus

447-452In view of documented evidence that catechol estrogen-DNA adducts serve as epitopes for binding of anti-nuclear antibodies, genetic polymorphisms of the xenobiotic metabolic pathway involved in estrogen metabolism might contribute towards pathophysiology of systemic lupus erythematosus (SLE). To test this hypothesis, a case-control study was conducted. Cytochrome P 450 1A1 (CYP1A1) m4 (OR: 4.93, 95% CI: 1.31-18.49), catecholamine-o-methyl transferase (COMT) H108L (OR: 1.39, 95% CI: 1.03-1.88) and glutathione-S-transferase (GST) T1 null (OR: 1.83, 95% CI: 1.11- 3.01) variants showed association with SLE risk. SHEsis web-based platform analysis showed mild to moderate linkage disequilibrium between the CYP1A1 m1, m2 and m4 variants (D’: 0.19-0.37). Among the different haplotypes of CYP1A1, CAC-haplotype harboring CYP1A1 m1 variant showed association with SLE risk (OR: 1.46, 95% CI: 1.11-1.92). Multifactor dimensionality reduction analysis (MDR) showed potential gene-gene interactions between the phase II variants i.e. COMT H108L × GSTT1 null × GSTM1 null (p<0.0001) and also between the phase II and I variants i.e. COMT H108L × GSTT1 null × CYP1A1 m1 × CYP1A1 m2 in inflating the risk of SLE by 3.33-folds (95% CI: 2.30-4.82) and 4.00-folds (95% CI: 2.77-5.78), respectively. To conclude, hyperinducibility of CYP1A1 due to m1 and m4 variants and defective phase-II detoxification due to COMT H108L and GSTT1 null variants increase the susceptibility to SLE

Serum interferon-alpha predicts in-hospital mortality in patients hospitalised with acute severe lupus

Objectives Dysregulation of interferon-alpha (IFN-α) is considered central to the immunological abnormalities observed in SLE. Short-term mortality during high disease activity in lupus is up to 30%. Adenovirus vector-introduced IFN-α into a lupus-prone mouse causes the development of glomerulonephritis and death within weeks. We studied serum IFN-α as a biomarker of in-hospital mortality in patients of SLE with high disease activity.Methods Serum IFN-α (ELISA) was measured in patients hospitalised for acute severe lupus in a tertiary care rheumatology unit in India and the levels were compared between survivors and non-survivors. Serum IFN-α was compared with traditional clinical and serological markers associated with disease activity to assess which better prognosticates survival.Results In a cohort of 90 patients with a mean Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) of 19.3 (±5.5), the mean serum IFN-α was 88±144 pg/dL. Levels were undetectable in patients with inactive disease. SLEDAI, anti double stranded DNA (dsDNA) antibody titres and serum IFN-α levels were higher and serum complement (C3) lower in non-survivors (p=0.003, p=0.017, p<0.001, p=0.029, respectively). Serum IFN-α level of 140 pg/mL had a sensitivity of 86.7%, specificity of 94.6%, positive predictive value of 76% and negative predictive value of 83.3% (p<0.001) in predicting mortality. The area under the curve for predicting in-hospital mortality was 0.25 for C3, 0.72 for dsDNA, 0.77 for SLEDAI and 0.92 for serum IFN-α.Conclusions Serum IFN-α was better in predicting in-hospital mortality compared with conventional measures of disease activity such as anti-dsDNA, complements and SLEDAI

Anti-neutrophil cytoplasmic autoantibodies associated vasculitis – Clinical profile and outcomes

Background: Studies on antineutrophil cytoplasmic autoantibodies-associated vasculitis (AAV) from India are scarce. The aim of the present study was to characterize the profile of AAV and experience with rituximab in ocular granulomatous with polyangiitis (GPA) in our cohort. Methods: Clinical, laboratory, and treatment details of AAV from January 2010 to May 2017 were noted. Continuous variables were reported as mean and standard deviation (SD). In GPA, clinical variables between survivors and nonsurvivors were compared using independent sample t-test and Fisher's exact test. Cox regression analysis was done to estimate the hazard ratios. Our cohort of GPA was compared with other large single-center cohorts from India, USA, Germany, and France. Results: Thirty-one patients were diagnosed to have AAV. Seventeen were females. GPA was most common phenotype (23/31). Mean (SD) age at onset was 39.8 (15.7) years. Median (IQ) time to diagnosis was 6 (22) months. The most common manifestations in GPA were ocular (n = 20) and lower respiratory tract (n = 13). Mean (SD) Birmingham Vasculitis Activity Score (BVAS) at disease onset was 9.4 (6.9). Pulse methylprednisolone with cyclophosphamide was used as induction regime followed by maintenance with azathioprine. Rituximab was given to four patients with refractory GPA. Six patients succumbed to illness. Remission was achieved in 19/25 survivors. Mean (SD) BVAS at disease onset was significantly higher in nonsurvivors (17.6 ± 10.2) compared to survivors (9.4 ± 4.9) (P = 0.018). Higher proportion of renal involvement was seen in nonsurvivors (P = 0.03). There was three-fold increased mortality with renal and lung involvement. In addition, the risk of death increases by 1.13 fold with each point increase in BVAS score. Conclusion: Ocular involvement was higher in our GPA cohort. Baseline BVAS, renal, and lung involvement predicts poor prognosis in GPA. Sustained remission with rituximab was seen in all patients with refractory ocular disease

<span style="font-size:11.0pt;mso-bidi-font-size: 10.0pt;font-family:"Times New Roman";mso-fareast-font-family:"Times New Roman"; mso-bidi-font-family:"Times New Roman";mso-ansi-language:EN-GB;mso-fareast-language: EN-US;mso-bidi-language:AR-SA" lang="EN-GB">Association of estrogen receptor 1 (<i style="mso-bidi-font-style:normal">ESR1</i>) haplotypes with risk for systemic lupus erythematosus among South Indians</span>

714-718Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving genetic, epigenetic and environmental factors and has higher incidence in women. In this study, we explored the association of estrogen receptor 1 (ESR1) rs2234693 (PvuII) and rs9340799 (XbaI) polymorphisms with susceptibility to SLE. PCR-RFLP and ELISA were used for genetic analysis and determination of specific autoantibodies, respectively. The univariate analysis showed no independent association of rs2234693 (OR: 1.14, 95% CI: 0.87 - 1.49, p = 0.36) and rs9340799 (OR: 0.87, 95% CI: 0.66-1.14, p = 0.34). The haplotype analysis using SHEsis platform revealed strong linkage disequilibrium between these two polymorphisms (D': 0.81, r2: 0.55). Among the four haplotype groups, the C-A haplotype (rs2234693-rs9340799) was strongly associated with the risk for SLE (OR: 2.10, 95% CI: 1.32 - 3.34, p = 0.001). The homozygous variant genotype of rs2234693 exhibited elevated TNF-α and depleted IFN-α, while the effects of rs9340799 were contradictory. The wild genotype of rs2234693 exhibited lower levels of IL-12 with number of rs9340799 variant alleles pronouncing this effect. From this study, it is concluded that the ESR1 haplotypes may influence the Th2 cytokine profile and susceptibility to SLE among the South Indians

Necrotizing autoimmune myopathy: Clinicopathologic study from a single tertiary care centre

Background: Idiopathic inflammatory myopathies (IIMs) are a group of chronic, autoimmune disorders which include a new entity, necrotizing autoimmune myopathy (NAM). NAM lacks inflammation and presents with markedly elevated creatinine phosphokinase (CPK) levels. It is associated with connective tissue diseases (CTDs), statin use, malignancies, and most cases are idiopathic. Objectives: The objectives of this study are to describe the clinicopathologic features in muscle biopsy-proven cases of NAM. To emphasize the role of laboratory parameters such as CPK levels and myositis profile in the diagnosis of NAM. Materials and Methods: This is a retrospective study including 15 patients of NAM diagnosed on muscle biopsy over a period of 2 years. The slides of the biopsies were reviewed, and clinical data, electromyography findings, and CPK levels were obtained. Myositis profile was done. Results: Necrotizing myopathy accounted for 13.63% (15 cases) of total inflammatory myopathies (110 cases) in the study. These were grouped into CTD-associated NAM, statin-associated NAM, paraneoplastic NAM and idiopathic NAM which was the common type. All cases presented with progressive proximal muscle weakness and had markedly elevated CPK levels. Anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and antisignal recognition particle antibodies were seen to be positive in six patients. Muscle biopsies showed predominant fiber necrosis with significant fiber degeneration and regeneration in the absence of inflammation. All patients received immunotherapy with significant improvement was seen in six patients with two mortalities. Conclusion: Necrotizing myopathy is a new addition to the spectrum of IIM. Clinicopathologic correlation is important for appropriate diagnosis. It is found to be refractory to corticosteroids monotherapy. The course of illness is not uniform, and in some patients, there can be rapid worsening with mortality