Critical peripheral ischemia: Higher prevalence in Indian systemic lupus erythematosus inception cohort for research (INSPIRE).

INTRODUCTION: There is limited literature on digital ischemia in systemic Lupus erythematosus (SLE). We report the prevalence, associations and outcome of digital infarcts and gangrene from the Indian SLE inception cohort (INSPIRE). METHODS: From the web-based database of INSPIRE, we extracted information for patients with 'Digital Infarct' and 'Digital gangrene' at enrolment into cohort, together considered as critical peripheral ischemia (CPI); all others were controls. We describe the associations of CPI with SLE clinical phenotype, autoantibodies, and disease activity at enrolment. We also report short term outcomes viz. Digital tissue loss and early mortality up to 6 months and recurrence of digital ischemic events in cases till date. RESULTS: Of 2503 SLE patients enrolled into the INSPIRE cohort, we identified 75 (2.9%) patients with CPI, 72 (96%) women and 6 (8%) children. Of them, 55 (73.3%) had digital gangrene and 21 (28%) patients had digital infarcts. Majority of digital gangrene resulted in amputation distal to terminal phalanx (63.6%). Multivariable analysis showed that pulmonary hypertension AOR [6.34 (1.99, 20.2)], coexistent thrombosis AOR [27.8 (15.7, 48.7)], triple antiphospholipid antibody positivity AOR [5.36 (1.67, 16.9)] and the presence of anti-Scl-70-antibody AOR [5.59 (1.86, 16.7)] were more likely while patients with class 3 or 4 lupus nephritis AOR [0.37 (0.15, 0.95)] and anti-nucleosome antibodies AOR [0.47 (0.23, 0.99)] were less likely to be associated with CPI. SLEDAI and short-term mortality were similar between cases and controls. CONCLUSIONS: CPI occurred in a higher proportion (2.9%) of SLE patients in the INSPIRE cohort as compared to earlier reports. Both prothrombotic state and vasculopathy contribute to its occurrence.

Pattern of disease expression in SLE patients with antiphospholipid antibodies: data from Indian Systemic Lupus Erythematosus Inception cohort (INSPIRE).

Antiphospholipid antibodies (APLA) are present in one-third of systemic lupus erythematosus (SLE) patients, and they are associated with both criteria and non-criteria manifestations. We studied the prevalence, clinical associations, and impact on mortality of APLA in SLE patients from India. Among the Indian SLE inception cohort (INSPIRE), patients who had data on all five routinely performed APLAs [lupus anticoagulant (LA), IgG and IgM anticardiolipin antibody (aCL) and anti-ß2-glycoprotein I(ß2GPI)] at enrolment were selected. Patients were divided into four categories based on the presence/absence of APLA associated manifestations and presence/absence of the APLA viz SLE-APS, SLE-APLA, SLE: events but no APLA, and SLE: no events, no APLA (reference group). 1035 SLE patients at least 1 APLA antibody was detected in 372 (35.9%). LA was present in 206 (19.9%), aCL in 126 (12.2%) and ß2-GPI in 178 (17.2%). There were 88 thrombotic events in 83 patients (8.0%); 73 (82.9%) being arterial; APLA positivity was present in 37 (44.6%) [AOR 1.70 (1.054, 2.76)]. SLE-APS patients were younger and had higher mortality [AOR 4.11 (1.51, 11.3)], neuropsychiatric and hematologic disease. SLE-APLA also had a higher mortality rate [AOR 2.94 (1.06, 8.22)] than the reference group. The mortality was highest in the subset of patients with thrombotic events in the presence of APLA [AOR 7.67 (1.25, 46.9)]. The mere presence of APLA also conferred higher mortality even in the absence of thrombotic events [AOR 3.51 (1.43, 8.63)]. Hematologic manifestations (36.1%) were the most common non-criteria-manifestation. One-third of SLE patients have APLA and its presence is associated with non-criteria hematologic manifestations, arterial thrombosis and higher mortality rate.

A novel cost-effective methodology for the screening of nanocellulose producing micro-organisms.

In this paper, the work has been done to develop a cost-effective methodology, for the isolation of the potential producer of bacterial nanocellulose. No report is available in the literature, on the use of gram flour and table sugar for the screening of nanocellulose-producing isolates. Since commercially used, Hestrin-Schramm medium is expensive for the isolation of nanocellulose-producing micro-organisms, the possibility of using gram flour-table sugar medium was investigated in this work. Qualitative screening of micro-organisms was done using cost-effective medium, i.e., gram flour-table sugar medium. Qualitative analysis of various nanocellulose-producing bacteria depicted that cellulose layer production occurred on both HS medium and gram flour-table sugar medium. The yield of nanocellulose was also better on air-liquid surface in case of gram flour-table sugar medium as compared to HS medium. 16S rRNA was used for molecular characterization of bacterial strain and the best nanocellulose producer was identified as Novacetimonas hansenii BMK-3_NC240423 (isolated from rotten banana). FTIR and FE-SEM studies of nanocellulose pellicle produced on HS medium and gram flour-table sugar medium demonstrated equivalent structural, morphological, and chemical properties. The cost of newly designed medium (0.01967 $/L) is nearly 90 times lower than the Hestrin-Schramm medium (1.748 $/L), which makes the screening of nanocellulose producers very cost-effective. A strategy of using gram flour extract-table sugar medium for the screening of nanocellulose-producing micro-organisms is a novel approach, which will drastically reduce the screening associated cost of cellulose-producing micro-organisms and also motivate the researchers/industries for comprehensive screening programme for getting high cellulose-producing microbes.

Infrared thermogram image guided discontinuous appearances of hyaluronic acid for classification of arthritic knee joints.

The liveliness of a human potentially depends on his/her smooth movability. To accomplish the work of daily life, the joints of the body need to be healthy. However, the occurrence of Rheumatoid arthritis and Osteoarthritis has a significant prevalence towards the immovability of humankind. Rheumatoid arthritis (RA) and Osteoarthritis (OA) mostly affect the joints of the hand and knee which result in lifelong pain, inability to climb, walk, etc. In the early stages, these diseases attack the synovial membrane and synovial fluid, and further it destroys the soft tissues and bone structure. By early diagnosis, we can start the treatment in the early stage which may cure these diseases with such extreme consequences. As per clinical studies of previous literature, it is observed that synovial fluid imbalance appears in the early stage of such diseases and Hyaluronic Acid (HA) concentration also decreases for that. Therefore, estimation of HA is a significant key to arthritis disease classification and grading. In this paper, we proposed a hybrid framework for classification of arthritic knee joints based on the analysis of the discontinuous appearances of the HA concentration using infrared imaging technology. To meet up the specific necessities, firstly we have proposed a modified K-Means clustering algorithm for extraction of the region of interest (ROI) i.e., the knee joint surface. Secondly, a mathematical formulation is proposed to calculate the concentration of HA from the segmented ROIs. This experimental process was implemented on the publicly available IR (Infrared) Knee Joint Dataset and for further evaluation of the novelty of mathematical formulation, we have extended the proposed work to the classification of healthy and arthritis affected knee joints depending on significant discriminative characteristics of the HA concentration with respect to the existing significant imaging features. Experimental results and analysis demonstrates that concentration of HA has the dominant potential for classifying healthy and arthritic knee joints using infrared holistic images. Our experimental analysis reveals that estimation and combination of the HA concentration features with conventional handcrafted and deep features increases the classification performance with an average accuracy of 91% and 97.22% respectively as compared to the each individual feature sets.

Negative impact of Interleukin-9 on synovial regulatory T cells in rheumatoid arthritis.

In Rheumatoid Arthritis (RA), regulatory T cells (Tregs) have been found to be enriched in the synovial fluid. Despite their accumulation, they are unable to suppress synovial inflammation. Recently, we showed the synovial enrichment of interleukin-9 (IL-9) producing helper T cells and its positive correlation with disease activity. Therefore, we investigated the impact of IL-9 on synovial Tregs in RA. Here, we confirmed high synovial Tregs in RA patients, however these cells were functionally impaired in terms of suppressive cytokine production (IL-10 and TGF-ß). Abrogating IL-9/ IL-9 receptor interaction could restore the suppressive cytokine production of synovial Tregs and reduce the synovial inflammatory T cells producing IFN-γ, TNF-α, IL-17. However, blocking these inflammatory cytokines failed to show any effect on IL-9 producing T cells, highlighting IL-9's hierarchy in the inflammatory network. Thus, we propose that blocking IL-9 might dampen synovial inflammation by restoring Tregs function and inhibiting inflammatory T cells.

Gastrointestinal Manifestations in Systemic Lupus Erythematosus: Data from an Indian Multi-institutional Inception (INSPIRE) Cohort.

OBJECTIVES: To study the prevalence, correlates, and outcomes of GI manifestations in a prospectively enrolled nationwide cohort of SLE in India (INSPIRE). METHODS: It is an observational cohort study with analysis of the baseline database of the INSPIRE cohort with early outcomes assessed till April 10, 2023. Cases with GI manifestations as per the BILAG index were selected, pertinent clinical and laboratory data were retrieved for analysis. Patients with GI manifestations were compared with the rest of the cohort and factors associated with death were determined. RESULTS: Of the 2503 patients with SLE enrolled in the INSPIRE cohort, 243(9.7%) had GI manifestations observed early in the disease course(1,0-3 months). Ascites(162,6.5%), followed by enteritis(41,1.6%), pancreatitis(35,1.4%) and hepatitis(24,0.9%) were the most prevalent manifestations.All patients received immunosuppressive therapy, and four patients required surgery. Twenty-nine patients died(11.9%), with uncontrolled disease activity(17,58.6%) and infection(6,20.7%) accounting for the majority of deaths. Low socioeconomic class[lower(Hazard Ratio (95% Confidence intervals- CI) 2.8(1.1-7.9); upper lower 7.5(2-27.7); reference as upper class] and SLEDAI 2K[1.06(1.02-1.11)] were associated with death in the GI group.GI manifestations were significantly associated with age[Odds Ratio & 95% CI 0.97(0.96-0.99)], pleural effusion[4.9(3.6-6.7)], thrombocytopenia[1.7(1.2-2.4)], myositis[1.7(1.1-2.7)], albumin[0.7(0.5-0.8)], alkaline phosphatase(ALP)[1.01(1.0-1.002)], low C3[1.9(1.3-2.5)], total bilirubin[1.2(1.03-1.3)], alopecia[0.62(0.5-0.96], elevated anti-dsDNA[0.5(0.4-0.8)], and anti-U1RNP antibody[0.8(0.5-0.7)] in model one; and age[0.97(0.96-0.99)], creatinine[1.2(1.03-1.4)], total bilirubin[1.2(1.03-1.3)], ALP[1.01(1.0-1.002)], albumin[0.6(0.5-0.7)], andanti-U1RNP antibody[0.6(0.5-0.8)] in model two in multivariate analysis compared with patients without GI features. The mortality was higher in the GI group(11.9% and 6.6%, p= 0.01) as compared with controls. CONCLUSION: GI manifestations were observed in 9.7% of the cohort and were always associated with systemic disease activity and had higher mortality.

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.

Association of glutathione-S-transferase polymorphism with genetic damage in paint workers.

BACKGROUND: Occupational exposure to toluene causes serious health problems ranging from drowsiness to lethal diseases such as cancer. Paint workers are exposed to toluene through inhalation or the dermal route, which can induce genetcic damage. The increased DNA damage could be linked to genetic polymorphism. Therefore, we evaluated the association of glutathione-S-transferase polymorphism with DNA damage in paint workers. METHODS: First, we included skilled paint workers (n = 30) as exposed and healthy individuals (n = 30) as control belonging to the same socio-economic strata. The genotoxicity biomarkers, Cytokinesis-block micronucleus (CBMN), and single-cell gel electrophoresis (SCGE)/Comet assay were used to assess genotoxicity while Multiplex-PCR and PCR-RFLP were used to assess polymorphism in glutathione-s-transferase (GST) genes. Using linear curve regression analysis, we assessed the association between genetic damage and polymorphism in the glutathione-s-transferase (GST) gene in the exposed and control subjects. RESULTS: A significantly higher frequency of CBMN (4.43 ± 1.50) and tail moment (TM) (11.23 ± 1.0) respectively in paint workers as compared to the control(1.50 ± 0.86 and (0.54 ± 0.37) underlined significantly high genetic damage in paint workers.Regression curve analysis reveals that polymorphism in the GST gene is significantly associated with higher MN and TM in paint workers. CONCLUSION: Overall, our study provides a strong rationale for identifying a clear association between glutathione-S-transferase polymorphism and genetic damage in paint workers.

Bacterial cellulose: Nature's greener tool for industries.

Bacteria are considered mini chemical factories that help us in providing a wide range of products for various purposes. These days, bacterial cellulose (BC) is getting attention by researchers due to its quality, eco-friendly nature, and excellent physical-mechanical qualities. It is being used in the fabrication of nanocomposites. Its nanocomposites can be used in various industries, including medicine, food, leather, textiles, environment, electronics, and cosmetics. This area of research is emerging and still in its infancy stage, as new applications are still coming up. Most of the work on BC has been done during the last two decades and serious inputs are required in this direction in order to make the production process commercially viable and ultimately the application part. Biowastes, such as fruits and vegetables wastes, can be used as a cost-effective medium to minimize the cost for large-scale production of BC-based nanocomposites thus will valorize the biowaste material into a valuable product. Using biowaste as media will also aid in better waste management along with reduction in detrimental environmental effects. This review will help the readers to understand the potential applications of BC and its nanocomposites as well as their vital role in our daily lives.

Association study of PCSK9 SNPs (rs505151 & rs562556) and their haplotypes with CVDs in Indian population.

BACKGROUND: Cardiovascular disease (CVD) has emerged as the most prevalent cause of death in India. Pro-protein Convertase Subtilisin/Kexin Type 9 (PCSK9) gene has been found to be associated with lipid levels and a biomarker for susceptibility of CVD. AIM: To study the association of PCSK9 SNPs rs505151 & rs562556 and their haplotypes with CVDs in the Indian population. SUBJECTS & METHODS: The present study comprised of 102 angiographically proven CVD patients & 100 healthy subjects. To study polymorphism, Polymerase Chain Reaction and Restriction Fragment Length Polymorphism (PCR-RFLP) method was used. Biochemical parameters were analysed by enzymatic methods or automated analysers. Haplotype analysis was done using SHEsis software. RESULTS: The dominant genetic model with an odds ratio (confidence interval) of 4.71 (2.59 - 8.5), (p value = .0001), shows the risk of CVDs. However, rs562556 (I474V) variant was not found to be associated with clinical parameters and risk of CVDs (p value >.05). Out of four haplotypes, H3 (G-A) was found to be associated with the CVDs (OR- 3.137, p value = .0001). CONCLUSION: This study concludes that G allele of rs505151 SNP (PCSK9) and the H3 (G-A) haplotype of rs505151 & rs562556 were found to be risk factors for CVDs in the Indian population.

Surgeon-specific factors have a larger impact on decision-making for the management of proximal humerus fractures than patient-specific factors: a prospective cohort study.

BACKGROUND: There is significant variability both in how proximal humerus fractures (PHFs) are treated and the ensuing patient outcomes. The purpose of this study was to investigate which surgeon- and patient-specific factors contribute to decision-making in the treatment of adult PHFs. We hypothesized that orthopedic sub-specialty training creates inherent bias and plays an important role in management algorithms for PHFs. METHODS: We performed a prospective cohort investigation in 2 groups of surgeons-traumatologists (N = 25) and shoulder & elbow/sports surgeons (SES) (N = 26)-and asked them to provide treatment recommendations for 30 distinct clinical cases with standardized radiographic and clinical data. This is a population-based sample of surgeons who take trauma call and treat PHFs with different sub-specializations and practice settings including academic, hospital-employed, and private. Surgeons characterized based on subspecialty (trauma vs. SES), experience level (>10 vs. ≤10-years), and employment type (hospital- vs. non-hospital-employed). Chi-square analyses, logistic mixed-effects modeling, and relative importance analysis were used to evaluate the data. RESULTS: Of the patient-specific factors, we found that the management of PHFs is largely dependent on initial radiographs obtained. Traumatologists were more likely to offer open reduction internal fixation (ORIF) and less likely to offer arthroplasty: 69% ORIF (traumatologists) vs. 51% ORIF (SES, P < .001), 8% arthroplasty (traumatologists) vs. 17% (SES, P < .001). Traumatologists were less likely to change from operative (either ORIF or arthroplasty) to non-operative management compared to SES surgeons when presented with additional patient demographic data. Surgeon-specific factors contributed to more than one-half of the variability in decision-making of PHF management while patient-specific factors contributed to about one-third of the variability in decision-making. CONCLUSIONS: As physicians strive to advance the treatment for PHFs and optimize patient outcomes, our findings highlight the complex overlap between surgeon-, fracture-, and patient-specific factors in the final decision-making process.

Long-term implications of COVID-19 on bone health: pathophysiology and therapeutics.

BACKGROUND: SARS-CoV-2 is a highly infectious respiratory virus associated with coronavirus disease (COVID-19). Discoveries in the field revealed that inflammatory conditions exert a negative impact on bone metabolism; however, only limited studies reported the consequences of SARS-CoV-2 infection on skeletal homeostasis. Inflammatory immune cells (T helper-Th17 cells and macrophages) and their signature cytokines such as interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha (TNF-α) are the major contributors to the cytokine storm observed in COVID-19 disease. Our group along with others has proven that an enhanced population of both inflammatory innate (Dendritic cells-DCs, macrophages, etc.) and adaptive (Th1, Th17, etc.) immune cells, along with their signature cytokines (IL-17, TNF-α, IFN-γ, IL-6, etc.), are associated with various inflammatory bone loss conditions. Moreover, several pieces of evidence suggest that SARS-CoV-2 infects various organs of the body via angiotensin-converting enzyme 2 (ACE2) receptors including bone cells (osteoblasts-OBs and osteoclasts-OCs). This evidence thus clearly highlights both the direct and indirect impact of SARS-CoV-2 on the physiological bone remodeling process. Moreover, data from the previous SARS-CoV outbreak in 2002-2004 revealed the long-term negative impact (decreased bone mineral density-BMDs) of these infections on bone health. METHODOLOGY: We used the keywords "immunopathogenesis of SARS-CoV-2," "SARS-CoV-2 and bone cells," "factors influencing bone health and COVID-19," "GUT microbiota," and "COVID-19 and Bone health" to integrate the topics for making this review article by searching the following electronic databases: PubMed, Google Scholar, and Scopus. CONCLUSION: Current evidence and reports indicate the direct relation between SARS-CoV-2 infection and bone health and thus warrant future research in this field. It would be imperative to assess the post-COVID-19 fracture risk of SARS-CoV-2-infected individuals by simultaneously monitoring them for bone metabolism/biochemical markers. Importantly, several emerging research suggest that dysbiosis of the gut microbiota-GM (established role in inflammatory bone loss conditions) is further involved in the severity of COVID-19 disease. In the present review, we thus also highlight the importance of dietary interventions including probiotics (modulating dysbiotic GM) as an adjunct therapeutic alternative in the treatment and management of long-term consequences of COVID-19 on bone health.

Genetic polymorphism impact superoxide dismutase and glutathione peroxidase activity in charcoal workers.

BACKGROUND: Incomplete combustion of wood releases toxic chemicals. Exposure to these chemicals during charcoal production can modulate redox status of cellular system which may further lead to genomic instability and of antioxidant enzymes. Genetic polymorphism may alter the functioning properties of these enzymes and modulate the response to oxidative stress. METHODS: In this study, we analyzed the link between genetic polymorphism and enzyme activity for antioxidant enzymes: MnSOD and GPx-1 in charcoal workers and control population. This study included 77 charcoal workers and 79 demographically matched healthy control subjects. This association was studied using multiple linear regression, adjusted for confounding factors viz. age, consumption habits and exposure duration. RESULTS: SOD activity was lower for TT genotype (3.47 ± 0.66; 5.92 ± 1.08) versus CC genotype (3.47 ± 0.66; 6.67 ± 1.60) in control and charcoal workers respectively. Significant lower GPx-1 activity was found in leu/leu genotype (7.25 ± 0.38; 3.59 ± 0.57) when compared to pro/pro genotype (7.78 ± 0.59; 4.28 ± 0.71) and pro/leu genotype (8.48 ± 0.34; 4.30 ± 0.76) in control population and charcoal workers respectively. A significant difference in the levels of 1-Hydroxypyrene (biomarker of exposure) and SOD and GPx-1 activity (biomarkers of oxidative stress) was evident in exposed group in comparison to the control one. CONCLUSION: Collectively, our findings suggested that PAH influenced the mode of action of SOD and GPx-1 which were impacted by polymorphism in SOD and GPx-1 gene. Hence, polymorphism of MnSOD and GPx-1 genes were found to play a modulatory role in human susceptibility to oxidative damage induced by wood smoke in charcoal workers.

Ameliorative role of naringenin against lead-induced genetic damage and oxidative stress in cultured human lymphocytes.

Lead (Pb) is a ubiquitous toxic heavy metal that is known to induce damage to major macromolecules (lipids, proteins, and nucleic acids) by enhancing the level of reactive oxygen species (ROS). Naringenin, a predominant flavonoid primarily found in citrus fruits has attained increasing attention due to its various pharmacological properties. Thus, the present investigation aimed to explore the ameliorative role of naringenin against Pb-induced toxicity in human peripheral blood lymphocytes (PBLs) under in vitro conditions. For this purpose, PBLs were exposed to Pb (350 µg/ml) alone as well in combination with naringenin (10 and 30 µg/ml). Sister chromatid exchange (SCE) and alkaline comet assay were used as genotoxic indices to evaluate the genotoxic and antigenotoxic activity of Pb and naringenin, respectively. Lipid peroxidation (LPO), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH) assays were used as oxidative damage markers. The results revealed that Pb induced a significant (p < 0.05) increase in genetic and oxidative damage as compared with the untreated sample whereas the treatment of cells along with naringenin (10 and 30 µg/ml) and Pb (350 µg/ml) caused a significant reduction in genetic damage and elevation in SOD, GPx, and CAT activities and GSH level, accompanied by a significant reduction in LPO level as compared with Pb alone treated sample. So, the present investigation revealed that naringenin might be used as a protective agent against Pb-induced toxicity due to its antigenotoxic and antioxidative properties.

Comparison of two dose escalation strategies of methotrexate in active rheumatoid arthritis: a multicentre, parallel group, randomised controlled trial.

OBJECTIVES: There are no head-to-head trials of different dose escalation strategies of methotrexate (MTX) in RA. We compared the efficacy, safety and tolerability of 'usual' (5 mg every 4 weeks) versus 'fast' (5 mg every 2 weeks) escalation of oral MTX. METHODS: This multicentre, open-label (assessor blinded) RCT included patients 18-55 years of age having active RA with disease duration <5 years, and not on DMARDs. Patients were randomized 1:1 into usual or fast escalation groups, both groups starting MTX at 15 mg/week till a maximum of 25 mg/week. Primary outcome was EULAR good response at 16 weeks, secondary outcomes were ΔDAS28 and adverse effects (AE). Analyses were intention-to-treat. RESULTS: 178 patients with mean DAS28-CRP of 5.4(1.1) were randomized to usual (n=89) or fast escalation groups (n=89). At 16 weeks, there was no difference in good EULAR response in the usual (28.1%) or fast escalation (22.5%) groups (p=0.8). There was no difference in mean ΔDAS28-CRP at 8 weeks (-0.9, -0.8, p=0.72) or 16 weeks (-1.3, -1.3, p=0.98). Even at 24 weeks (extended follow-up), responses were similar. There were no inter-group differences in ΔHAQ, or MTX-polyglutamates 1-3 levels at 8 or 16 weeks. Gastrointestinal AE were higher in the fast escalation group over initial 8 weeks (27%, 40%, p=0.048), but not over 16 weeks. There was no difference in cytopenias, transaminitis, or drug discontinuation/dose reduction between the groups. No serious AE were seen. CONCLUSION: A faster MTX escalation strategy in RA was not more efficacious over 16-24 weeks, and did not significantly increase AE, except higher gastrointestinal AE initially. TRIAL REGISTRATION NUMBER: CTRI/2018/12/016549.

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.

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.

Interleukin-9 Facilitates Osteoclastogenesis in Rheumatoid Arthritis.

In rheumatoid arthritis (RA), inflammatory cytokines play a pivotal role in triggering abnormal osteoclastogenesis leading to articular destruction. Recent studies have demonstrated enhanced levels of interleukin-9 (IL-9) in the serum and synovial fluid of patients with RA. In RA, strong correlation has been observed between tissue inflammation and IL-9 expression in synovial tissue. Therefore, we investigated whether IL-9 influences osteoclastogenesis in patients with RA. We conducted the study in active RA patients. For inducing osteoclast differentiation, mononuclear cells were stimulated with soluble receptor activator of NF-kB ligand (sRANKL) and macrophage-colony-stimulating factor (M-CSF) in the presence or absence of recombinant (r) IL-9. IL-9 stimulation significantly enhanced M-CSF/sRANKL-mediated osteoclast formation and function. Transcriptome analysis revealed differential gene expression induced with IL-9 stimulation in the process of osteoclast differentiation. IL-9 mainly modulates the expression of genes, which are involved in the metabolic pathway. Moreover, we observed that IL-9 modulates the expression of matrix metalloproteinases (MMPs), which are critical players in bone degradation. Our results indicate that IL-9 has the potential to influence the structural damage in the RA by promoting osteoclastogenesis and modulating the expression of MMPs. Thus, blocking IL-9 pathways might be an attractive immunotherapeutic target for preventing bone degradation in RA.

Examination of the human motor endplate after brachial plexus injury with two-photon microscopy.

INTRODUCTION: After traumatic nerve injury, neuromuscular junction remodeling plays a key role in determining functional outcomes. Immunohistochemical analyses of denervated muscle biopsies may provide valuable prognostic data regarding clinical outcomes to supplement electrodiagnostic studies. METHODS: We performed biopsies on nonfunctioning deltoid muscles in two patients after gunshot wounds and visualized the neuromuscular junctions using two-photon microscopy with immunohistochemistry. RESULTS: Although the nerves in both patients showed evidence of acute Wallerian degeneration, some of the motor endplates were intact but exhibited significantly decreased surface area and volume. Both patients exhibited substantial recovery of motor function over several weeks postinjury. DISCUSSION: Two-photon microscopic assessment of neuromuscular junction integrity and motor endplate morphometry in muscle biopsies provided evidence of partial sparing of muscle innervation. This finding supported the clinical judgment that eventual recovery would occur. With further study, this technique may help to guide operative decisionmaking after traumatic nerve injuries.

Urinary C3d is elevated in patients with active Lupus nephritis and a fall in its level after 3 months predicts response at 6 months on follow up.

INTRODUCTION: Complement activation is central to the pathogenesis of lupus nephritis (LN). Low serum complement C3 and C4, are traditionally used as markers of lupus disease activity in general and LN in particular. In this study we prospectively measured plasma and urine C3d and C4d, degradation products of C3 and C4 corrected to creatinine in a cohort of biopsy proven LN in a longitudinal fashion for its correlation with disease activity. METHODS: Twenty eight biopsy proven active lupus nephritis (AN) were recruited along with four inactive nephritis (IN) and 10 healthy controls (HC). Plasma and urine were collected at baseline, prior to induction treatment and 3 months later. Clinical measures of disease activity, Systemic lupus erythematosus disease activity index 2000 (SLEDAI 2K), renal SLEDAI, serum C3, C4 and antibodies to ds DNA, urine protein and creatinine excretion (UP/UC) were collected. Plasma and urine C3d and C4d were measured using ELISA and normalized to spot urine creatinine value. RESULTS: Twenty eight AN of median age of 26.5 (20-31.50) years and disease duration of 3 (0.7-5) years were enrolled. The median urinary C3d/creatinine before treatment was 388.20 (48.98-1296) ng/mg which fell significantly to 62.69 (28.04-502.4) ng/mg at 3 months followup (p-0.01). The baseline values for the active renal disease was significantly different from IN group (9.9 (4.5-46.53 ng/mg) p-0.00). Treatment responders (partial and complete) at 6 months showed a significant fall in urinary C3d at 3 months whereas non responders had a non significant change in value. There was a significant correlation of urine C3d/creatinine with SLEDAI2K (r-0.433, p-0.00), renal SLEDAI (r-0.356, p-0.00), UP/UC ratio (r-0.489, p-<0.0001) but no significant correlation with C3 or C4. There was a significant fall in the median values of plasma C3d from 791.1 (516.0.00-1550.43) µg/ml to 338.52 (211.35-525.82) (p-0.00) µg/ml at the end of 3 months. The values showed a significant correlation with SLEDAI 2K, renal SLEDAI, UP/UC along with a significant negative correlation with C3 and C4. CONCLUSION: Urinary C3d/creatinine levels and plasma C3d levels can be used as biomarker of disease activity and treatment response.