Semi-quantitative thigh magnetic resonance imaging scores in assessing disease activity and determining long-term clinical outcome in idiopathic inflammatory myopathies: a causal mediation analysis.

OBJECTIVES: To evaluate the relationship of thigh MRI (t-MRI) with manual muscle testing-8 (MMT-8), muscle enzymes and autoantibodies. To determine the causal and mediating factors resulting in poor recovery of MMT-8 in inflammatory myositis (IIM). METHODS: This was a single-centre retrospective study in IIM patients. t-MRI was semi-quantitatively scored for muscle oedema, fascial oedema, muscle atrophy and fatty infiltration. Spearman correlation of t-MRI scores was done with muscle enzymes at baseline, and MMT-8 at baseline and on follow-up. Causal mediation analysis was performed with age, sex, symptom duration, autoantibodies, diabetes and BMI as independent variables, follow-up MMT-8 as dependent and t-MRI scores as mediating variables. RESULTS: Baseline evaluation was done on 59 and follow-up on 38 patients. Median follow-up of the cohort was 31 (10-57) months. Baseline MMT-8 negatively correlated with muscle oedema (r = -0755), fascial oedema (r = -0.443) and muscle atrophy (r = -0.343). Creatinine kinase (r = 0.422) and aspartate transaminase (r = 0.480) positively correlated with muscle oedema. Follow-up MMT-8 correlated negatively with baseline atrophy (r = -0.497) and fatty infiltration (r = -0.531). On follow-up, MMT-8 males had positive total effect (estimate (95%CI)) via atrophy [2.93 (0.44, 4.89)] and fatty infiltration [2.08 (0.54, 3.71)]. Antisynthetase antibody had a positive total effect via fatty infiltration [4.50 (0.37, 7.59)]. Age had a negative total effect via atrophy [-0.09 (0.19, -0.01)] and fatty infiltration [-0.07 (-0.15, -0.01)]. Disease duration had a negative total effect via fatty infiltration [-0.18 (-0.27, -0.02)]. CONCLUSION: Baseline fatty infiltration and muscle atrophy resulting from older age, female sex, longer disease duration and absent anti-synthetase antibodies, partly mediate muscle recovery in IIM.

Clusters based on demography, disease phenotype, and autoantibody status predicts mortality in lupus: data from Indian lupus cohort (INSPIRE).

OBJECTIVES: SLE is associated with significant mortality, and data from South Asia is limited. Thus, we analysed the causes and predictors of mortality and hierarchical cluster-based survival in the Indian SLE Inception cohort for Research (INSPIRE). METHODS: Data for patients with SLE was extracted from the INSPIRE database. Univariate analyses of associations between mortality and a number of disease variables were conducted. Agglomerative unsupervised hierarchical cluster analysis was undertaken using 25 variables defining the SLE phenotype. Survival rates across clusters were assessed using non-adjusted and adjusted Cox proportional-hazards models. RESULTS: Among 2072 patients (with a median follow-up of 18 months), there were 170 deaths (49.2 deaths per 1000 patient-years) of which cause could be determined in 155 patients. 47.1% occurred in the first 6 months. Most of the mortality (n = 87) were due to SLE disease activity followed by coexisting disease activity and infection (n = 24), infections (n = 23), and 21 to other causes. Among the deaths in which infection played a role, 24 had pneumonia. Clustering identified four clusters, and the mean survival estimates were 39.26, 39.78, 37.69 and 35.86 months in clusters 1, 2, 3 and 4, respectively (P < 0.001). The adjusted hazard ratios (HRs) (95% CI) were significant for cluster 4 [2.19 (1.44, 3.31)], low socio-economic-status [1.69 (1.22, 2.35)], number of BILAG-A [1.5 (1.29, 1.73)] and BILAG-B [1.15 (1.01, 1.3)], and need for haemodialysis [4.63 (1.87,11.48)]. CONCLUSION: SLE in India has high early mortality, and the majority of deaths occur outside the health-care setting. Clustering using the clinically relevant variables at baseline may help identify individuals at high risk of mortality in SLE, even after adjusting for high disease activity.

Kidney histopathology in predicting flares following drug withdrawal in proliferative lupus nephritis in clinical remission.

Residual renal histopathological activity at clinical remission in Proliferative Lupus Nephritis (PLN) can predict renal flare upon immunosuppression withdrawal. Data on the role of histological renal remission in predicting extra-renal flares is lacking. We assessed renal histopathology prior to drug withdrawal and the occurrence of renal and extra-renal flares over 52 weeks after drug withdrawal in PLN patients in long-term clinical remission. This is a subgroup analysis of a non-inferiority, open-label randomized (1:1) controlled trial. Patients with biopsy-proven Class III/IV LN in the past (biopsy 1), on immunosuppressants (IS) ≥ 3 years, in clinical remission for ≥ 1 year, on stable prednisolone dose (≤ 7.5 mg/day) plus a maintenance IS and hydroxychloroquine (HCQ) were subjected to a repeat renal biopsy (biopsy 2). Individuals with biopsy 2 having activity index (AI) < 4/24 were randomised to either prednisolone or IS withdrawal. Primary end-point was the proportion experiencing a flare [SELENA-SLEDAI flare index (SFI)] at week 52. Twenty-eight eligible patients underwent biopsy 2 and randomized to prednisolone (n = 15) and IS (n = 13) withdrawal. At biopsy 1, 12 (43%) had class III, 15 (53.5%) had class IV, and 1 (3.5%) had class III + V. At biopsy 2, PLN persisted in 4 (14.2%) while 18 (64.2%) were in histological remission (AI = 0) with 6 (21.4%) in class II. Following drug withdrawal, 9/28 (32%) had flares especially musculoskeletal (55.5%), mucocutaneous (44.4%), and renal (33.3%). Among the four persistent PLN patients, one of the two (50%) with AI = 1 had extra-renal flare while both the two with AI = 2 (100%) had renal and extra-renal flares. In those with histological remission (biopsy 2), 6/18 (66.6%) experienced extra-renal flare of whom one also had renal flare. Upon drug withdrawal, renal histopathology findings with any activity index can predict renal flare while histological remission is not enough to predict extra-renal flare, thus making it an unsuitable marker for deep SLE remission.

Performance of timed function tests as outcome measures in idiopathic inflammatory myopathy-results from a single-centre cohort.

OBJECTIVE: To evaluate performance of timed function tests (TFTs) in assessing muscle strength and endurance as determined by Manual Muscle Testing 8 (MMT-8) and Functional Index 2 (FI-2), respectively, in idiopathic inflammatory myopathies (IIM). METHODS: This cohort study included 42 IIM patients satisfying 2017 EULAR/ACR criteria. Patients were classified as active (n = 18) or inactive disease (n = 24) based on clinical status at baseline. MMT-8, FI-2, 30 s rise from chair test, 30 s 1 kg arm rise test and 2-min walking distance (2MWD) were administered at baseline, 3 months and 6 months. Pearson rank correlation analysis and receiver operating curves were performed to assess the performance of timed function tests. RESULTS: All patients were followed up at 3 months and 39 completed 6 months' follow-up. All the three TFTs had excellent convergent (r > 0.7, P < 0.05) and divergent validity (P < 0.05). Only 2MWD had moderate to strong correlation with ΔMMT-8 at 3 and 6 months among those with active disease (P = 0.001). All the TFTs correlated with ΔFI-2 in active disease but only Δ2MWD correlated with ΔFI-2 in inactive disease at 6 months (r = 0.506, P = 0.036). At a cut-off of 5% improvement in MMT-8, 2MWD had an area under the curve (AUC) of 0.868 with 95% sensitivity with 2% improvement at 3 months. To detect a 10% ΔMMT-8, Δ2MWD at a cut of 8% and 7% had an AUC of 0.909 and 0.893 with a sensitivity of 92% at 3 and 6 months, respectively (P < 0.05). CONCLUSION: 2MWD is a reliable indicator of muscle strength, endurance and treatment response. The 2MWD can be self-administered by patients, making it a potential patient-reported outcome measure.

Comparison between leflunomide and sulfasalazine based triple therapy in methotrexate refractory rheumatoid arthritis: an open-label, non-inferiority randomized controlled trial.

To compare efficacy and safety of two different combination csDMARD therapy in Methotrexate-failed Rheumatoid arthritis patients. In this 24-week open-label, parallel-group non-inferiority, single-center clinical trial, Methotrexate-failed Rheumatoid arthritis patients with disease duration < 2 years, were randomized to either of the two treatment regimens-Methotrexate + Leflunomide + Hydroxychloroquine or Methotrexate + Sulfasalazine + Hydroxychloroquine. Primary endpoint was proportion of patients achieving EULAR good response at 12 weeks. Non-inferiority of Leflunomide based therapy was confirmed if the upper limit of the 2-sided 95% confidence interval of treatment difference between the 2 groups was lower than the selected non-inferiority margin of (- 20%) in primary endpoint at 12 weeks. Secondary endpoints were improvement in DAS28, functional outcome and adverse events at 24 weeks. 136 eligible patients were randomized to either Leflunomide or Sulfasalazine group (68 in each group).63 and 59 patients in Leflunomide and 66 and 61 patients in Sulfasalazine group completed 12 and 24 weeks of trial, respectively. In Intension-to-treat analysis, EULAR good response was achieved by 58.8% and 54.4% patients (p = 0.7) at the end of 12 weeks, and 61.7% and 64.7% patients (p = 0.8) at the end of 24 weeks-in Leflunomide and Sulfasalazine group respectively. At 12 weeks, the difference in EULAR good response with 2-sided 95% confidence interval between 2 groups was 4.4% (- 12%, 20%) in intention-to-treat and 5.8% (- 11%, 23%) in perprotocol analysis.15 and 21 adverse events were recorded in Leflunomide and Sulfasalazine group respectively. Parenteral Methotrexate was required more in Sulfasalazine group due to gastrointestinal intolerance. Leflunomide based csDMARD therapy is non-inferior to Sulfasalazine based csDMARD therapy in Methotrexate-failed Rheumatoid arthritis patients with comparable safety profile. Trial registered at clinicaltrials.gov (NCT02930343) dated 10.09.2016.

Disease characteristics and clinical outcomes of adults and children with anti-MDA-5 antibody-associated myositis: a prospective observational bicentric study.

To study the demographic, clinical and serologic characteristics of anti-MDA5-positive DM from two geographically and ethnically disparate inception cohorts in India. To identify the clinical and serological parameters at inception that could predict mortality among these individuals. Individuals with anti-MDA5 antibody-positive DM diagnosed between 2017 and 2020 from two centres in India were prospectively followed up. The clinical and serological characteristics at baseline and the treatment outcome at follow-up were assessed for this study. Anti-MDA5 antibody was positive in 25 (7.5%) out of the 330 individuals with myositis. These 25 (21 adults, 4 juvenile) patients were followed up for a median duration of 14 months. Among adults, a majority had cutaneous manifestations 21 (84%) followed by, arthritis 17 (80%), and interstitial lung disease 12 (ILD, 57.1%). Four (19%) had rapidly progressive ILD (RP-ILD). Eight (38%) presented as clinically amyopathic DM. Among cutaneous manifestations, majority (62%) had classic features (gottron's papules/sign, heliotrope rash) while 8 (38%) had cutaneous ulceration and 2 each had periorbital edema and tendon rupture. Eight (38%) were positive for anti-Ro-52 antibody. Out of 21 adults, 8 (38%) succumbed to the diseases. RP-ILD (n = 4; 19%), ulcerative gottron's (n = 5) and anti-Ro-52 (n = 8) were significantly associated with mortality (p < 0.05). Upon binary logistic regression, positive anti-Ro-52 antibody predicted mortality [HR 17.3 (95%CI 1.4-210, p = 0.025)]. All juvenile anti-MDA5-positive DMs had classic cutaneous features with 2 of them having ulcerative gottron's. None of the juvenile patients had ILD and everyone survived till the last follow-up. Indian adults with anti-MDA5 DM have high mortality. Rarer atypical features like tendon rupture or periorbital edema could assist in diagnosis. Ulcerative gottron's, positive anti-Ro 52 antibodies, and RP-ILD are valuable clinical-serological markers that portend poor prognosis.

Factors associated with high cardiovascular risk in psoriatic arthritis and non-psoriatic spondyloarthritis.

To identify the association between traditional cardiovascular risk factors, diseases related factors, body composition and adipokines with high cardiovascular risk (HCVR) in psoriatic arthritis and non-psoriatic spondyloarthritis. This was a cross-sectional study involving age and BMI matched adults with psoriatic arthritis (PsA) (n = 56) and non-psoriatic spondyloarthritis (nPsA-SpA) (n = 58). Body composition using whole-body dual energy X-ray absorptiometry, adipokines and disease characteristics along with cardiovascular risk scoring QRISK3 and carotid intimal medial thickness (CIMT) was collected. Individuals with a QRISK3 ≥ 10% or CIMT of ≥ 75 percentile of the general population were categorised as HCVR. Predictors of HCVR were determined by logistic regression. HCVR was detected in 39 (34.2%) of the patients. After adjusting for all the factors, sarcopenia (aOR-15.83; 95% CI 1.16-215.48; p = 0.038) and presence of any traditional CV comorbidity (aOR: 18.97; 95% CI 1.63-221.29; p = 0.019) were associated with HCVR. nPsA-SpA had a 97% lesser chance of having HCVR as compared to PsA. The ROC curve analysis for the multiple logistic regression model which estimated the AUC as 0.787 (95% CI 0.701-0.874) and a P value < 0.001. Adipokine levels correlated well with body composition, but not with HCVR. PsA has a higher CV risk and the mechanisms for the same are poorly understood. Sarcopenia is an important determinant of HCVR and may be due to ectopic adipose tissue deposition in skeletal muscles. Focused physical therapy to prevent sarcopenia, optimum treatment of traditional CV risk factors and adequate disease control may help in preventing atherosclerosis in SpA.

Tele-rheumatology for overcoming socioeconomic barriers to healthcare in resource constrained settings: lessons from COVID-19 pandemic.

OBJECTIVES: To assess acceptability of teleconsultation among the socioeconomically marginalized sections of patients with rheumatic and musculoskeletal diseases (RMDs), to identify the socioeconomic barriers in continuing rheumatology care during the COVID-19 crisis and to identify patients who could benefit by shifting to tele-rheumatology consultations. METHODS: This was a cross sectional analytical study done at a tertiary care teaching hospital in India including patients with RMDs who were not on biological diseases modifying agents. Assessment of disease status, socioeconomic status and economic impact of COVID-19 was done via tele-consultation. RESULTS: Out of the 680 patients satisfying inclusion criteria, 373 completed the study. The format was found easy by 334 (89.6%) of them and 284 (76.1%) considered tele-rheumatology better than in-person consultation. During the pre-COVID months, the median monthly per capita income of the families of our patients and cost of illness was Indian rupees (INR) 2000 (US$ 26) and INR 1685 (US$ 21.91), respectively. Families whose financial needs were met (OR = 0.38, 95% CI: 0.239, 0.598) or those with schooling upto at least secondary school (OR = 0.442, 95% CI: 0.260, 0.752) (P =0.002) were less likely to stop prescription drugs. In a hypothetical model, 289 (77.4%) could be successfully switched to tele-rheumatology follow-up. CONCLUSION: The acceptability of tele-rheumatology among socioeconomically marginalized patients with RMDs is good. During times of crisis, patients from poorer strata of society and lower educational background are likely to abruptly stop medications. Switching to a telemedicine-based hybrid model is likely to improve drug adherence with substantial savings on loss of pay and out of pocket expenditure.

Impact of the COVID-19 pandemic on patients with systemic lupus erythematosus: Observations from an Indian inception cohort.

INTRODUCTION: The ongoing pandemic of COVID-19 has led to severe disruption of healthcare services worldwide. We conducted this study to assess the impact of COVID-19 pandemic on the management of Systemic Lupus Erythematosus (SLE) patients who were enrolled in the nation-wide inception cohort. METHODS: A questionnaire was administered to the SLE patients enrolled in the inception cohort. Questions related to the effect on disease activity, preventive measures adopted against COVID-19, the incidence of COVID-19, hardships faced in getting access to health care professionals and availability of medicines, adherence, fear of COVID-19 and the potential benefits of being part of the registry. RESULTS: A total of 1040 (90% females) patients completed the questionnaire. The mean age was 27.5 ± 19.1 years and the mean disease duration was 1.25 years. Twenty-Four (2.3%) patients had developed fever (>1 day) during this period, including one patient with additional symptoms of diarrhoea and anosmia, however, none of the patients developed COVID-19 infection. 262 patients (25.2%) reported financial difficulty during this period and patients reported an average excess expenditure of at least 2255.45 INR ($30) per month. 378 patients (36%) reported problems in getting their prescribed medicines due to lockdown. Of these, 167 (40%) patients needed to change their medication schedule due to this non-availability. Almost 54% of patients missed their scheduled follow up visits during the lockdown period and 37% of patients were unable to get their investigations done due to closure of laboratories and hospitals. 266 patients (25.5%) reported worsening of various symptoms of SLE during this period. Almost 61% patients felt confident that being associated with the inception cohort had helped them in managing their disease better during this period of lockdown as they received help in the form of timely and frequent telephonic consults, assistance in making the medicines available, and regular counselling resulting in abetment of their fears and anxieties. CONCLUSION: The current COVID-19 pandemic has made a huge impact on our SLE patients. Patients faced difficulty in the availability of medicines, missed the doses of medicines, had financial constraints, and spent more money on health during the pandemic.

Early-onset subclinical cardiovascular damage assessed by non-invasive methods in children with Juvenile Idiopathic Arthritis: analytical cross-sectional study.

Chronic inflammation starting early in life and continuing into adulthood may predispose children with Juvenile Idiopathic Arthritis (JIA) to cardiovascular (CV) complications. To compare non-invasive CV risk markers- left ventricular mass index (LVMi), brachial artery flow mediated dilatation (FMD) and carotid artery intima-media thickness (CIMT) between patients with JIA and healthy controls. Measurements of LVMi, CIMT and FMD and lipid profile were compared between 4 and 18 year old 81 patients with JIA and 78 age and sex matched healthy controls. Among 81, 20 had systemic onset, 19 enthesitis related arthritis, 9 polyarticular rheumatoid factor (RF) + ve, 19 polyarticular RF -ve, 11 oligo-articular, and 3 un-differentiated JIA. FMD was significantly lower (p < 0.001), CIMT and LVMi significantly higher in patients (p ≤ 0.001). CIMT showed positive correlation with blood pressure (p = 0.001), disease duration (p ≤ 0.001) and negative correlation with high density lipoprotein (HDL) (p ≤ 0.001). FMD correlated positively with HDL (p = 0.006) and negatively with disease duration (p ≤ 0.001). CIMT (p = 0.017) and FMD (p = 0.04) were significantly worse in active than inactive disease. Children with JIA have worse lipid profile, increased LVMi, CIMT, and reduced brachial artery FMD, suggestive of early cardiovascular dysfunction.

Indian SLE Inception cohort for Research (INSPIRE): the design of a multi-institutional cohort.

Systemic lupus erythematosus (SLE) cohorts across the world have allowed better understanding of SLE, including its bimodal mortality, and the impact of social factors and ethnicity on outcomes. The representation of patients from South Asia has been poor in the existing SLE cohorts across the world. Hence, we planned to initiate an inception cohort to understand the diversity of lupus in India. Indian SLE Inception cohort for REsearch (INSPIRE), planned over 5 years is a multi-centric cohort of adult and childhood lupus patients of Indian origin, fulfilling the SLICC-2012 classification criteria, with an aim to provide cross-sectional information on demography, ethnicity, socio-economic status, standard disease variables, quality of life, and prospective information on new events like hospitalization, infections, pregnancies, changes in disease activity, and damage. One of the other deliverables of this project is the establishment of a biorepository. The instruments to be used for each variable and outcome were finalized, and a web-enabled case report form was prepared to encompass SLEDAI, BILAG, SLICC damage scores, and Lupus quality-of-life index.Ten centers located in different geographic areas of India would enroll patients who are seen for the first time after the start of the study. In the first 8 months, 476 patients (63 children, 36 males) have been enrolled with a median disease duration of 10 (IQR 4-17) months and mucocutaneous features being the most prevalent clinical manifestations. INSPIRE is the first prospective Indian SLE cohort to study the diversity of Indian patients.

Association of Oxidative Stress with Disease Activity and Damage in Systemic Lupus Erythematosus: A Cross Sectional Study from a Tertiary Care Centre in Southern India.

To study oxidative stress in systemic lupus erythematosus (SLE) by estimating serum oxidised LDL (OxLDL), 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA), and total anti-oxidant status and to correlate with SLE disease activity and disease damage. Eighty SLE patients satisfying the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) 2012 criteria and 80 healthy controls were studied. Exclusion criteria were infections, renal insufficiency, other connective tissue diseases, drug-induced lupus, smoking, alcohol consumption. Disease activity was measured by SLE disease activity index-2 K (SLEDAI), disease damage was quantified by SLICC-Damage Index (SDI). Sera was tested for OxLDL, 8-OHdG, and total antioxidant status (TAS) by double-antibody sandwich ELISA; MDA measured by Colorimetric assay. Oxidative stress markers were compared between group1- controls, group 2-mildly active SLE (SLEDAI ≤ 5), group 3- moderate to highly active SLE (SLEDAI ≥ 6). SLE patients had significantly higher MDA, 8-OHdG and lower TAS when compared to healthy controls, while OxLDL was similar in the three groups. MDA, 8-OHdG were significantly higher, TAS lower in group 3 compared to group 2. MDA had positive correlation with SLEDAI, TAS negatively correlated with SLEDAI. SLE with neuropsychiatric manifestations, vasculitis, anti-sdDNA antibodies had higher MDA, MDA/TAS ratio. SLE patients with thrombocytopenia, and vasculitis had higher OxLDL. Only OxLDL was significantly higher in those patients who have SDI > 1. SLE patients have increased oxidative stress measured by increases in MDA, 8-OHdG, and lower total antioxidant status that was associated with disease activity and some disease manifestations. However only OxLDL was associated with damage.

Passive Serum Therapy to Immunomodulation by IVIG: A Fascinating Journey of Antibodies.

The immunoregulatory and anti-infective properties of normal circulating polyclonal Abs have been exploited for the therapeutic purposes in the form of IVIG as well as several hyperimmune globulins. Current knowledge on the therapeutic use of normal Igs is based on the discoveries made by several pioneers of the field. In this paper, we review the evolution of IVIG over the years. More importantly, the process started as an s.c. replacement in γ globulin-deficient patients, underwent metamorphosis into i.m. Ig, was followed by IVIG, and is now back to s.c. forms. Following successful use of IVIG in immune thrombocytopenic purpura, there has been an explosion in the therapeutic applications of IVIG in diverse autoimmune and inflammatory conditions. In addition to clinically approved pathological conditions, IVIG has been used as an off-label drug in more than 100 different indications. The current worldwide consumption of IVIG is over 100 tons per year.

Autoimmune and rheumatic musculoskeletal diseases as a consequence of SARS-CoV-2 infection and its treatment.

The coronavirus disease-2019 (COVID-19) pandemic is likely to pose new challenges to the rheumatology community in the near and distant future. Some of the challenges, like the severity of COVID-19 among patients on immunosuppressive agents, are predictable and are being evaluated with great care and effort across the globe. A few others, such as atypical manifestations of COVID-19 mimicking rheumatic musculoskeletal diseases (RMDs) are being reported. Like in many other viral infections, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can potentially lead to an array of rheumatological and autoimmune manifestations by molecular mimicry (cross-reacting epitope between the virus and the host), bystander killing (virus-specific CD8 + T cells migrating to the target tissues and exerting cytotoxicity), epitope spreading, viral persistence (polyclonal activation due to the constant presence of viral antigens driving immune-mediated injury) and formation of neutrophil extracellular traps. In addition, the myriad of antiviral drugs presently being tried in the treatment of COVID-19 can result in several rheumatic musculoskeletal adverse effects. In this review, we have addressed the possible spectrum and mechanisms of various autoimmune and rheumatic musculoskeletal manifestations that can be precipitated by COVID-19 infection, its therapy, and the preventive strategies to contain the infection.

Persistent eosinophilia in rheumatoid arthritis: a prospective observational study.

Eosinophilia is an uncommon manifestation in Rheumatoid arthritis (RA), and there is a paucity of data regarding the relationship of eosinophilia with disease-related factors. We prospectively evaluated the clinical and disease-specific characteristics of RA patients with eosinophilia. Consecutive patients with RA with an absolute eosinophil count ≥ 500/mm3 without an apparent cause for eosinophilia, were investigated for parasitic infestation. Patients with a definite parasitic infestation received targeted therapy, and the rest were treated with albendazole empirically. The RA disease-specific characteristics of the patients with persistent eosinophilia were compared with the patients without eosinophilia. Of the 160 patients with eosinophilia, 30 patients (19%) had allergic diseases, six patients had bronchiectasis, and one patient had hypereosinophilia of undetermined significance. Intestinal helminthiasis was found in 34 patients (21%). Eosinophilia was unexplained in 89 patients (56%) and it resolved after empirical albendazole therapy in about two-thirds (58 patients). Thirty-one patients had persistent eosinophilia. Nonsteroidal anti-inflammatory drug and disease-modifying antirheumatic drug modification did not show any effect on eosinophilia. The disease-related characteristics were similar between patients with persistent eosinophilia and those without eosinophilia. Eosinophilia is due to secondary causes in the majority of RA patients, and the most common cause in our setting is an intestinal helminthic infection. Persistent eosinophilia in our cohort of RA did not indicate a more severe disease phenotype.

Characterization of cell-derived microparticles in synovial fluid and plasma of patients with rheumatoid arthritis.

Microparticles (MP) are proposed to play a role in the pathogenesis of rheumatoid arthritis (RA). This study aimed to profile cell lineage-specific MP in patients with RA, osteoarthritis (OA), and healthy controls (HC) in synovial fluid and circulation. Patients with RA (n = 40), OA (n = 30) and HC (n = 33) were included. Cell-free synovial fluid (SF) and platelet-poor plasma samples were stained with annexin V APC and antibodies against CD45, CD20, CD14, CD4, CD8, CD66b, and CD61 for multicolor flow cytometry. Mann-Whitney U test/unpaired T test was used to assess intergroup differences among RA and OA SF and clinical, serological phenotypes of RA based on normality distribution; Kruskal-Wallis test with Dunn's multiple comparisons for comparing plasma MPs among RA, OA, and HC. Correlation between MP proportions and disease parameters was assessed by Spearman's correlation. The proportion of annexin V+ MP in SF of patients with RA [5 (6.35)] [median (IQR)] was higher compared to OA [1.8 (1.35), p < 0.001] and plasma of patients with RA [3.45 (5.63)] compared to OA [1.85 (1.4)] and HC [0.9 (1.1), p < 0.001]. Leukocyte-derived [0.85 (1.17)], granulocyte-derived [0.4 (2.05)], monocyte-derived [0.4 (0.4)], and T cell-derived MP [CD4+ - 0.1 (0.1); CD8+ - 0.1(0.1)] were higher in RA SF (p < 0.001). Platelet-derived MP (PMP) were the major fraction [1.5 (4.23), p < 0.001] in RA plasma. Leukocyte-derived MP were higher in RA plasma [0.1 (0.2); p < 0.001) than OA and HC. Annexin V+ MP and PMP were higher in the SF of RA with extra-articular manifestations (n = 15), as compared to those without (n = 25) (p = 0.02; p < 0.01, respectively). High SF granulocyte-derived MP were observed in patients with established RA (n = 24), ACPA-positive RA (n = 32) compared to their negative counterparts (p = 0.03; p = 0.02, respectively). Our observations of higher proportions of cell-derived MP in the plasma and synovial fluid of DMARD-naïve RA patients, their clinical and serological phenotypes suggest their role in dynamic cross talk between the joint and systemic circulation, disease pathology, and progression.

Physicians Perception of Rheumatology Practice and Training in India.

OBJECTIVE: To assess physicians' perception and their felt competence in dealing with patients with rheumatic complaints. METHODS: We assessed the quantum of rheumatological disorders seen by physicians in India, their felt competency in dealing with such patients, and their perceived adequacy of undergraduate and postgraduate medical training in Rheumatology by means of an anonymized questionnaire conducted at the annual national conference of internal medicine specialists. RESULTS: Our analysis of 333 respondents revealed that while they saw an average of 10 patients with rheumatic complaints every month, the felt competence in dealing with such cases was only a median of 6/10 (interquartile range 5-7). About 75% professed little or no exposure to Rheumatology as undergraduates, whereas only 20% perceived adequacy of training during internal medicine residency to treat such diseases confidently. 78.37% and 67.7% perceived an inadequacy of rheumatology training at undergraduate and postgraduate level respectively, and 83% felt the need for further training or sensitization in Rheumatology. CONCLUSION: There remains an unmet need to enhance existing undergraduate and postgraduate internal medicine curricula in India to impart greater skills in the diagnosis and management of rheumatic diseases. Initiatives and government funding to establish short-term training courses in Rheumatology for established internal medicine faculty, to enable them to provide basic Rheumatology services at their respective hospitals, are urgently needed.

The HLA-G Genetic Contribution to Bipolar Disorder: A Trans-Ethnic Replication.

Bipolar disorder (BD) is frequently associated with immune dysfunctions. Studying the genetic diversity of the immuno-modulatory human leukocyte antigen (HLA)-G locus in a French BD cohort, we previously reported an association between a functionally relevant 14 bp Ins/Del polymorphism and BD risk. The present study investigated the genetic and expression diversities of HLA-G in a geographically distinct South Indian population-group BD patients, as well as the influence of exposure to the neurotropic Toxoplasma gondii pathogen. Three functionally relevant HLA-G polymorphisms, i.e. HLA-G 14 bp Ins/Del (rs66554220), +3142G>C (rs1063320) and +3187A>G (rs9380142) were genotyped by polymerase chain reaction (PCR) and real-time PCR. Sub-samples of BD patients and healthy controls (HC) were investigated for plasma levels of soluble HLA-G (sHLA-G) isoforms, as well as circulating stigma of T. gondii infection. Findings indicate: (i) the frequency of the HLA-G 14 bp Del/Del genotype was higher in BD cases, as compared to HC; (ii) the HLA-G + 3142 C allele and CC genotype were more prevalent in BD patients than in HC; (iii) sHLA-G levels were significantly higher in BD cases, especially in females and in the early onset sub-group; and (iv) the InsGA haplotype was more prevalent in HC. Our findings further support the genetic contribution of HLA-G to BD risk, as well as indicate relevant expression profiles. Such data may also indicate a potential developmental role in BD etiology, given that HLA-G is an important immune regulator from the intrauterine period and across development.

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.