Immune-related adverse events after immune check point inhibitors: Understanding the intersection with autoimmunity.

Immune checkpoint inhibitor therapies act through blockade of inhibitory molecules involved in the regulation of T cells, thus releasing tumor specific T cells to destroy their tumor targets. However, immune checkpoint inhibitors (ICI) can also lead to a breach in self-tolerance resulting in immune-related adverse events (irAEs) that include tissue-specific autoimmunity. This review addresses the question of whether the mechanisms that drive ICI-induced irAEs are shared or distinct with those driving spontaneous autoimmunity, focusing on ICI-induced diabetes, ICI-induced arthritis, and ICI-induced thyroiditis due to the wealth of knowledge about the development of autoimmunity in type 1 diabetes, rheumatoid arthritis, and Hashimoto's thyroiditis. It reviews current knowledge about role of genetics and autoantibodies in the development of ICI-induced irAEs and presents new studies utilizing single-cell omics approaches to identify T-cell signatures associated with ICI-induced irAEs. Collectively, these studies indicate that there are similarities and differences between ICI-induced irAEs and autoimmune disease and that studying them in parallel will provide important insight into the mechanisms critical for maintaining immune tolerance.

Serine hydroxymethyltransferase6 is involved in growth and resistance against pathogens via ethylene and lignin production in Arabidopsis.

Photorespiratory serine hydroxymethyltransferases (SHMTs) are important enzymes of cellular one-carbon metabolism. In this study, we investigated the potential role of SHMT6 in Arabidopsis thaliana. We found that SHMT6 is localized in the nucleus and expressed in different tissues during development. Interestingly SHMT6 is inducible in response to avirulent, virulent Pseudomonas syringae and to Fusarium oxysporum infection. Overexpression of SHMT6 leads to larger flowers, siliques, seeds, roots, and consequently an enhanced overall biomass. This enhanced growth was accompanied by increased stomatal conductance and photosynthetic capacity as well as ATP, protein, and chlorophyll levels. By contrast, a shmt6 knockout mutant displayed reduced growth. When challenged with Pseudomonas syringae pv tomato (Pst) DC3000 expressing AvrRpm1, SHMT6 overexpression lines displayed a clear hypersensitive response which was characterized by enhanced electrolyte leakage and reduced bacterial growth. In response to virulent Pst DC3000, the shmt6 mutant developed severe disease symptoms and becomes very susceptible, whereas SHMT6 overexpression lines showed enhanced resistance with increased expression of defense pathway associated genes. In response to Fusarium oxysporum, overexpression lines showed a reduction in symptoms. Moreover, SHMT6 overexpression lead to enhanced production of ethylene and lignin, which are important components of the defense response. Collectively, our data revealed that SHMT6 plays an important role in development and defense against pathogens.

p53 amyloid pathology is correlated with higher cancer grade irrespective of the mutant or wild-type form.

p53 (also known as TP53) mutation and amyloid formation are long associated with cancer pathogenesis; however, the direct demonstration of the link between p53 amyloid load and cancer progression is lacking. Using multi-disciplinary techniques and 59 tissues (53 oral and stomach cancer tumor tissue samples from Indian individuals with cancer and six non-cancer oral and stomach tissue samples), we showed that p53 amyloid load and cancer grades are highly correlated. Furthermore, next-generation sequencing (NGS) data suggest that not only mutant p53 (e.g. single-nucleotide variants, deletions, and insertions) but wild-type p53 also formed amyloids either in the nucleus (50%) and/or in the cytoplasm in most cancer tissues. Interestingly, in all these cancer tissues, p53 displays a loss of DNA-binding and transcriptional activities, suggesting that the level of amyloid load correlates with the degree of loss and an increase in cancer grades. The p53 amyloids also sequester higher amounts of the related p63 and p73 (also known as TP63 and TP73, respectively) protein in higher-grade tumor tissues. The data suggest p53 misfolding and/or aggregation, and subsequent amyloid formation, lead to loss of the tumor-suppressive function and the gain of oncogenic function, aggravation of which might determine the cancer grade.

Long-term safety of biologic and targeted synthetic disease modifying drugs in rheumatology.

PURPOSE OF REVIEW: The landscape for treatment of rheumatic diseases is ever evolving, with several new drugs recently approved across diseases and more in the pipeline. This timely review aims to highlight the latest literature on long-term safety profiles of salient established and emerging biologic (b) and targeted synthetic (ts) disease modifying antirheumatic drugs (DMARDs). RECENT FINDINGS: The risk of infection remains elevated with the use of most b and tsDMARDs, with specifically risk of hepatitis B reactivation with rituximab and zoster infection with JAK inhibitors (JAKi). The results of the ORAL surveillance trial led to new black box warnings for JAKi and evoked critical risk-benefit discussions surrounding JAKi and DMARDs overall. SUMMARY: Such well conducted trials are needed to gather long term comparative safety data of DMARDs. In the interim, real world observational studies also have a role to play in our understanding of long-term drug safety, provided that detailed attention is paid to minimize biases inherent in observational studies.

Development and validation of a tool for assessing adherence to gluten free diet in patients with Celiac disease (Celiac Disease: Compliance Assessment Test; CD-CAT).

OBJECTIVE: Life-long adherence to gluten-free diet (GFD) and its assessment is essential for celiac disease (CeD) patients. We have developed and validated a tool for assessing adherence to GFD which can be used by both physicians and dietitians. DESIGN: Phase-I: Development, content validation and assessment of reliability of tool. Phase-II: Validation of tool against standard dietary evaluation (SDE) (gold standard), IgA anti-tissue transglutaminase antibody (IgA-anti-tTG Ab) and gluten immunogenic peptides in urine (Urine-GIP). Overall, 380 biopsy-confirmed CeD patients [Derivation-cohort: n=100(Phase:I), n=210(Phase:II) and Independent validation cohort, n=70)were recruited. RESULTS: Of initial 90-point questionnaire, 84-items (CD-CAT.v1) were retained after content validation and pilot testing. In Phase:I, upon administering CD-CAT.v1on 100 patients, a comprehensive 35-items tool (CD-CAT.v2;α=0.86) was obtained after removing items with low test-retest reliability and item-rest correlation values. In Phase:II, upon administering CD-CAT.v2 on 210patients,22 items were removed having low correlation values (R<0.4) with SDE. Finally, a 13-item tool (CD-CAT.v3;α=0.84) was obtained with high criterion validity with SDE (r=0.806, p<0.001), moderate convergent validity with CDAT (r=0.602, p=0.007) and moderate to weak correlation with urine GIP (r=0.46, p=0.001) and IgA anti-tTG Ab (r=0.39, p=0.008), respectively. The final 13-item tool also strongly correlated with SDE (r=0.78, p<0.001) in an independent validation cohort of 70 CeD patients. Principal component analysis identified three relevant sub-scales with a cumulative-variance of 62%. The sensitivity and specificity of CD-CAT.v3 were 80% and 91%, respectively, with an area under curve of 0.905 with SDE. The obtained cut-off score of <19 from ROC-curve was further categorized as: 13=excellent,14-18=very good, 19-28=average and >28=poor adherence to GFD. CONCLUSION: CD-CAT is a new and rapid tool for monitoring dietary adherence to GFD with high sensitivity and specificity which can be administered by both physicians and dietitians.

Integrated morphometric and molecular approaches to screen hybrid from wild Labeo rohita and Labeo catla parent populations.

BACKGROUND: Interspecific hybrids of rohu (Labeo rohita) and catla (Labeo catla) are common, especially in India due to constrained breeding. These hybrids must segregate from their wild parents as part of conservational strategies. This study intended to screen the hybrids from wild rohu and catla parents using both morphometric and molecular approaches. METHODS & RESULTS: The carp samples were collected from Jharkhand and West Bengal, India. The correlation and regression analysis of morphometric features are considered superficial but could be protracted statistically by clustering analysis and further consolidated by nucleotide variations of one mitochondrial and one nuclear gene to differentiate hybrids from their parents. Out of 21 morphometric features, 6 were used for clustering analysis that exhibited discrete separation among rohu, catla, and their hybrids when the data points were plotted in a low-dimensional 2-D plane using the first 2 principal components. Out of 40 selected single nucleotide polymorphism (SNP) positions of the COX1 gene, hybrid showed 100% similarity with catla. Concerning SNP similarity of the 18S rRNA nuclear gene, the hybrid showed 100% similarity with rohu but not with catla; exhibiting its probable parental inheritance. CONCLUSIONS: Along with morphometric analysis, the SNP comparison study together points towards strong evidence of interspecific hybridization between rohu and catla, as these hybrids share both morphological and molecular differences with either parent. However, this study will help screen the hybrids from their wild parents, as a strategy for conservational management.

Direct evidence of cellular transformation by prion-like p53 amyloid infection.

Tumor suppressor p53 mutations are associated with more than 50% of cancers. Aggregation and amyloid formation of p53 is also implicated in cancer pathogenesis, but direct evidence for aggregated p53 amyloids acting as an oncogene is lacking. Here, we conclusively demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to non-cancerous cells. p53 amyloid aggregates were transferred through cell generations, contributing to enhanced survival, apoptotic resistance with increased proliferation and migration. The tumorigenic potential of p53 amyloid-transformed cells was further confirmed in mouse xenografts, wherein the tumors showed p53 amyloids. p53 disaggregation rescued the cellular transformation and inhibited tumor development in mice. We propose that wild-type p53 amyloid formation contributes to tumorigenesis and can be a potential target for therapeutic intervention. This article has an associated First Person interview with the first author of the paper.

Utility of Fecal Elastase-1 to diagnose severe exocrine insufficiency in chronic pancreatitis: Real world experience.

INTRODUCTION: Quantitative fecal fat estimation is the gold standard test to diagnose steatorrhea (fecal fat >7 g/day) in chronic pancreatitis (CP), but cumbersome and inconvenient. So, fecal elastase-1 (FE) is proposed as a good alternative but the data on the diagnostic utility of FE to diagnose steatorrhea is variable. METHODS: This retrospective study included adult CP patients evaluated with both 24-h fecal-fat and FE tests within a 3-month period. The objective was to evaluate the diagnostic performance of FE to diagnose steatorrhea and to evaluate the FE progression over 9-month period. RESULTS: Among the 147 included patients, the frequency of steatorrhea (fecal fat >7 g/day) was 34%. The sensitivity, specificity, and negative likelihood ratio (LR) of FE was 90%, 28.9% and 0.35 at cut-off of <100 µg/g stool to diagnose steatorrhea; and 96%, 11.3% and 0.35 at cut-off of <200 µg/g stool, respectively. The optimal cut-off of FE was <20 on receiver operating characteristic curve (sensitivity 66%; specificity 69%; positive LR 2.14). There was no statistically significant variation in FE levels over 9 months interval among a hundred patients. CONCLUSION: Compared to FE ≥ 200 µg/g stool, FE ≥ 100 can used to exclude steatorrhea (better specificity and negative LR). FE < 20 alone cannot replace fecal fat estimation to confirm steatorrhea but to be interpreted with clinical features. Repeat FE testing for exocrine insufficiency progression can be done at least a year later.

Acute pancreatitis is characterized by generalized intestinal barrier dysfunction in early stage.

BACKGROUND AND AIMS: The role of intestinal-barrier in acute pancreatitis(AP) is poorly understood. We aimed to assess structural and functional changes in the intestinal-barrier in patients with early AP (time from onset<2 weeks) and the effect of enteral nutrition on them. METHODS: In this prospective observational study, patients with early AP not on enteral nutrition were compared with controls for baseline intestinal-permeability(lactulose: mannitol ratio(L:M)), endotoxinemia(serum IgM/IgG anti-endotoxin antibodies), bacterial-translocation(serum bacterial 16S rRNA) and duodenal epithelial tight-junction structure by immunohistochemistry(IHC) for tight-junction proteins(claudin-2,-3,-4, zonula occludens-1(ZO1), junctional adhesion molecule(JAM) and occludin) and electron microscopy. These parameters were reassessed after 2 weeks enteral feeding in a AP patients subset. RESULTS: 96 patients with AP(age: 38.0 ± 14.5 years; etiology: biliary[46.8%]/alcohol[39.6%]; severe:53.2%, mortality:11.4%) and 40 matched controls were recruited. Patients with AP had higher baseline intestinal permeability(median L:M 0.176(IQR 0.073-0.376) vs 0.049(0.024-0.075) in controls; p < 0.001) and more frequent bacteraemia(positive bacterial 16S rRNA in 24/48 AP vs 0/21 controls; p < 0.001) with trend towards higher serum endotoxinemia(median IgG anti-endotoxin 78(51.2-171.6) GMU/ml vs 51.2(26.16-79.2) in controls; p = 0.061). Claudin-2, claudin-3, ZO1 were downregulated in both duodenal crypts and villi while claudin-4 and JAM were downregulated in duodenal villi and crypts respectively. 22 AP patients reassessed after initiation of enteral nutrition showed trend towards improving intestinal permeability, serum endotoxinemia and bacteraemia, with significant improvement in claudin-2,-3 in duodenal villi. CONCLUSION: Patients with AP have significant disturbances in intestinal barrier structure and function in first 2 weeks from onset that persist despite institution of enteral nutrition.

Molecular spectrum of inherited FVII deficiency in North India revealed a recurrent variant with a founder effect.

INTRODUCTION: Inherited Factor VII (FVII) deficiency is commonest among the rare bleeding disorders. A small number of patients present in infancy with severe bleeding, and many may remain asymptomatic but detected before surgery/invasive procedures. Genetic testing may be helpful in predictive testing/prenatal diagnosis in severe cases. AIM: Characterisation of clinical and genotypic spectrum of patients with inherited FVII deficiency. METHODS: Retro-prospectively, 35 cases with prolonged prothrombin time and FVII activity (FVII:C) <50 IU/dl were subjected to targeted resequencing. After in-silico analysis, variant/s were validated by Sanger sequencing in index cases and family members. Haplotype analysis was done for F7 polymorphisms. RESULTS: Severe FVII deficiency was found in 50% of patients (FVII:C ≤1 IU/dl), and 42.9% were asymptomatic. Clinical severity assessment revealed 17% severe, 17% moderate and 22.9% patients with mild bleeds. FVII levels ranged from .3 to 38 IU/dl. Molecular analysis revealed variants in 30/35 cases, of which 17 were homozygous, 10 were compound heterozygous and 3 were heterozygous. Twelve genetic variants were identified, one promoter variant c.-30A>C; seven missense (c.215C>G, c.244T>C, c.253G>C, c.904G>A, c.961C>T, c.1109G>T, c.1211G>A), two deletions (c.21delG, c.868_870delATC), and one each of nonsense c.634C>T and splice-site variant c.316+1G>A. Recurrent variants c.1109G>T and c.215C>G were found in 17 and 8 cases, 12 of the former cases were homozygous. They had the same haplotype, indicating the founder effect in North Indians. CONCLUSION: This is the largest cohort of FVII genotyping from India, confirming heterogeneity in terms of clinical manifestations, FVII activity and zygosity of the variants with a limited genotypic phenotypic correlation.

Chronic Pancreatitis in Females is Not Associated With Adverse Pregnancy Outcomes: A Retrospective Analysis.

BACKGROUND: The effects of chronic pancreatitis (CP) on pregnancy and vice versa have not been studied well. We aimed to study the impact of CP on pregnancy-related outcomes and the effect of pregnancy on clinical profile of CP. STUDY AND GOALS: We did a retrospective analysis of all female patients of CP of child-bearing age (above 18 y). The pregnancy-related outcomes of patients with CP were compared with the age-matched 115 controls from the low-risk pregnancy group identified using a simplified antepartum high-risk pregnancy scoring form. The clinical course of CP during pregnancy was compared with the pre-pregnancy course. RESULTS: Among the 338 eligible patients, 46 patients were included after exclusions. All these 46 patients had at least 1 conception and 41 had at least 1 completed pregnancy with a total of 117 conceptions and 96 completed pregnancies. The pregnancy-related outcomes in patients with CP like abortions (21.7% vs. 11.3%; P =0.087), preterm deliveries (14.6% vs. 10.4%; P =0.47), antepartum course (82.7% vs. 82.6%; P =0.58), stillbirths (4.9% vs. 4.3%; P =0.88), cesarean section (36.6% vs. 34%; P =0.849) were comparable with controls. There was overall improvement in the severity and frequency of pain during pregnancy as compared with the pre-pregnancy symptoms ( P =0.001). CONCLUSION: CP is not associated with adverse pregnancy outcomes. Also, there is trend toward improvement in the clinical symptoms because of CP during the pregnancy.

Design and development of benzyl piperazine linked 5-phenyl-1,2,4-triazole-3-thione conjugates as potential agents to combat Alzheimer's disease.

Our present work demonstrates the molecular hybridization-assisted design, synthesis, and biological evaluation of 22 benzylpiperazine-linked 1,2,4-triazole compounds (PD1-22) as AD modifying agents. All the compounds were tested for their in vitro hChEs, hBACE-1, and Aß-aggregation inhibition properties. Among them, compound PD-08 and PD-22 demonstrated good hChE and hBACE-1 inhibition as compared to standards donepezil and rivastigmine. Both compounds displaced PI from PAS at 50 µM concentration which was comparable to donepezil and also demonstrated anti-Aß aggregation properties in self- and AChE-induced thioflavin T assay. Both compounds have shown excellent BBB permeation via PAMPA-BBB assay and were found to be non-neurotoxic at 80 µM concentration against differentiated SH-SY5Y cell lines. Compound PD-22 demonstrated an increase in rescued eye phenotype in Aß-phenotypic drosophila AD model and amelioration of behavioral deficits in the Aß-induced rat model of AD. The in-silico docking studies of compound PD-22 revealed a good binding profile towards CAS and PAS residues of AChE and the catalytic dyad of the BACE-1. The 100 ns molecular dynamics simulation studies of compound PD-22 complexed with AChE and BACE-1 enzymes suggested stable ligand-protein complex throughout the simulation run. Based on our findings compound PD-22 could further be utilized as a lead to design a promising candidate for AD therapy.

Vitamin D status & bone health in patients with liver cirrhosis.

Background & objectives: Vitamin D plays an important role in bone metabolism, and liver is the intermediary site of vitamin D metabolism. The purpose of this study was to study the prevalence of vitamin D deficiency and bone health in patients with cirrhosis. Methods: Prospectively, serum 25-hydroxy vitamin D [25(OH)D] level were assessed in cirrhotics by chemiluminescence method. Endocrine Society Clinical practice guideline was used to define deficiency and insufficiency of vitamin D. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry and the World Health Organization criteria was used to define osteoporosis and osteopenia. The lowest T score at the left hip neck or lumbar spine was taken as osteoporosis or osteopenia. The Child-Turcotte-Pugh score was used to assess the severity of cirrhosis. Results: Cirrhotics (n=350, male: 278, compensated: 210) were included. Mean serum 25(OH)D level was 8.75 ng/ml. The prevalence of vitamin D deficiency (VDD) and low-BMD (osteopenia and osteoporosis) was 89.4 and 86 per cent, respectively. VDD, insufficiency and osteoporosis was found in 86.7, 11.9 and 33.8 per cent, respectively, in patients with compensated cirrhosis; and 93.6, 3.6 and 40 per cent, respectively, in patients with decompensated cirrhosis. Body mass index of >25 kg/m2 was protective for bone health. Interpretation & conclusions: VDD and low-BMD is prevalent in Indian patients with cirrhosis and should be looked for in patients with cirrhosis for its prevention.

Antioxidant and Prooxidant Nanozymes: From Cellular Redox Regulation to Next-Generation Therapeutics.

Nanozymes, nanomaterials with enzyme-mimicking activity, have attracted tremendous interest in recent years owing to their ability to replace natural enzymes in various biomedical applications, such as biosensing, therapeutics, drug delivery, and bioimaging. In particular, the nanozymes capable of regulating the cellular redox status by mimicking the antioxidant enzymes in mammalian cells are of great therapeutic significance in oxidative-stress-mediated disorders. As the distinction of physiological oxidative stress (oxidative eustress) and pathological oxidative stress (oxidative distress) occurs at a fine borderline, it is a great challenge to design nanozymes that can differentially sense the two extremes in cells, tissues and organs and mediate appropriate redox chemical reactions. In this Review, we summarize the advances in the development of redox-active nanozymes and their biomedical applications. We primarily highlight the therapeutic significance of the antioxidant and prooxidant nanozymes in various disease model systems, such as cancer, neurodegeneration, and cardiovascular diseases. The future perspectives of this emerging area of research and the challenges associated with the biomedical applications of nanozymes are described.

The impact of disease severity measures on survival in U.S. veterans with rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: To determine whether RA and interstitial lung disease (ILD) severity measures are associated with survival in patients with RA-ILD. METHODS: We studied US veterans with RA-ILD participating in a multicentre, prospective RA cohort study. RA disease activity (28-joint DAS [DAS28-ESR]) and functional status (multidimensional HAQ [MDHAQ]) were collected longitudinally while pulmonary function tests (forced vital capacity [FVC], diffusing capacity for carbon monoxide) were obtained from medical records. Vital status and cause of death were determined from the National Death Index and administrative data. Predictors of death were assessed using multivariable Cox regression models adjusting for age, sex, smoking status, ILD duration, comorbidity burden and medications. RESULTS: We followed 227 RA-ILD participants (93% male and mean age of 69 years) over 1073 person-years. Median survival after RA-ILD diagnosis was 8.5 years. Respiratory diseases (28%) were the leading cause of death, with ILD accounting for 58% of respiratory deaths. Time-varying DAS28-ESR (adjusted hazard ratio [aHR] 1.21; 95% CI: 1.03, 1.41) and MDHAQ (aHR 1.85; 95% CI: 1.29, 2.65) were separately associated with mortality independent of FVC and other confounders. Modelled together, the presence of either uncontrolled disease activity (moderate/high DAS28-ESR) or FVC impairment (<80% predicted) was significantly associated with mortality risk. Those with a combination of moderate/high disease activity and FVC <80% predicted had the highest risk of death (aHR 4.43; 95% CI: 1.70, 11.55). CONCLUSION: Both RA and ILD disease severity measures are independent predictors of survival in RA-ILD. These findings demonstrate the prognostic value of monitoring the systemic features of RA-ILD.

Malnutrition by GLIM criteria in chronic pancreatitis: Prevalence, predictors, and its impact on quality of life.

INTRODUCTION: Malnutrition in chronic pancreatitis (CP) has prognostic value and there is limited data on the prevalence, predictors of malnutrition in CP and its effect on Quality of life (QoL). METHODS: A retrospective study was conducted in patients with CP to assess the prevalence of malnutrition as per the Global Leadership Initiative on Malnutrition (GLIM) criteria. Multivariable-adjusted regression was used to identify independent predictors of both malnutrition and global QoL. RESULTS: A total of 297 patients were included and the most common etiology of CP was idiopathic (75%) and alcohol (25%). The prevalence of malnutrition was 46.4% as per GLIM criteria. On univariate analysis, the risk of malnutrition was significantly higher in alcoholic etiology (p = 0.001), current alcohol consumption (p = 0.001), smokers (p < 0.001), those having higher cumulative days of pain in last 6 months (p < 0.001) and lower daily calorie intake (p = 0.019). On multivariate analysis, malnutrition was independently associated with current alcohol consumption (Odds ratio: 3.22, p = 0.017), current smokers (OR: 2.23, p = 0.042) and those having higher cumulative days of abdominal pain (OR: 1.01, p < 0.001), while higher daily calorie intake (per 100 kcal) (OR:0.94, p = 0.023) has reduced risk of malnutrition. Malnutrition (p = 0.015) and higher cumulative days of abdominal pain (p < 0.001) were independently associated with lower global QoL in patients with CP. CONCLUSION: Malnutrition is frequent in patients with CP; and current alcohol consumption, smoking and higher cumulative days of abdominal pain independently predicts risk of developing malnutrition. Patients with malnutrition and higher cumulative days of pain has poorer quality of life.

Comparison of overall efficacy and safety of oral versus subcutaneous methotrexate in severe psoriasis.

Subcutaneous (SC) methotrexate (MTX) is considered to be associated with a higher and predictable linear bioavailability as compared to oral MTX. Although various studies have reported SC MTX to be safe and effective in psoriasis, prospective head-to-head comparative trials on oral versus SC MTX are limited. To compare the efficacy and safety of SC versus oral MTX in severe psoriasis. It was a prospective, single-blinded, randomized controlled trial, in 100 eligible, adult patients of severe psoriasis randomized into two groups. Group-A (n = 50) patients were started on oral MTX at a full dose of 0.3 mg/kg/week (maximum 25 mg/week) given for 12 weeks or till achieving PASI90 [90% reduction in Psoriasis Area Severity Index (PASI) from baseline], whichever was earlier and group-B (n = 50) patients received SC MTX in the same dose and duration. MTX was then tapered gradually at 5 mg every 2 weeks and stopped. All patients were followed-up for 24 weeks post-treatment with monthly assessment of PASI and Dermatology Life Quality Index (DLQI) scores. Baseline demographic profiles of patients in both the groups were comparable. The mean ± SD baseline PASI scores were group-A: 15.1 ± 3.2 versus group-B:15.7 ± 3.3 (p = 0.35). The number of patients that achieved PASI90 at or before 12 weeks of treatment was numerically higher in group-B (39/50, 78%) versus group-A (31/50, 62%; p = 0.08) and the time to achieve PASI90 was significantly lesser (p < 0.001).Also, the percentage(%) decline in DLQI was significantly higher in group-B(p = 0.003). The overall side-effect profile was comparable between groups (p = 0.31), but the frequency of gastrointestinal side-effects was significantly less in group-B (p = 0.04). Among those patients who achieved a PASI90 response by week12, relapse rates were comparable during the subsequent 24-week follow-up period [group-A: 12/31 (39%), group-B: 11/39 (28%), and p-value = 0.33]. SC MTX results in a significantly faster achievement of PASI90 and greater reduction in DLQI as compared to oral MTX in patients who are candidates for systemic therapy with a comparable safety profile. CTRI/2018/01/011373, date of registration: 15 January, 2018; trial registered prospectively.

Comparison of the efficacy and cost-effectiveness of an immunologically targeted low-dose rituximab protocol with the conventional rheumatoid arthritis protocol in severe pemphigus.

BACKGROUND: Various dosing protocols of rituximab have been used in pemphigus. B-cell repopulation following rituximab treatment can be considered a forerunner of clinical relapse. Immunologically guided dosing may remove the need for fixed timepoint maintenance dosing, hence being more cost-effective and perhaps safer. AIM: To compare the overall efficacy and cost-effectiveness of a low-dose rituximab regimen (500 mg, 2 weeks apart) with immunologically guided, ultralow-dose (200 mg) top-up infusions on immunological relapse vs. the use of a rheumatoid arthritis (RA) protocol with rituximab 500 mg repeat infusion to treat clinical relapse in severe pemphigus, over a 1-year period, METHODS: In total, 23 patients with severe pemphigus were randomized into Group A (RA protocol: 1000 mg given as two doses, 2 weeks apart) and Group B (low-dose rituximab 500 mg given as two doses, 2 weeks apart). Both groups also received short-term oral corticosteroids, and underwent clinical and immunological (3-monthly flow cytometry assessments of B-cell subtypes) monitoring. Group A received a top-up dose of rituximab 500 mg upon clinical relapse, while Group B received an ultralow top-up dose (200 mg) following detection of B-cell repopulation, which was intended to prevent clinical relapse. Outcome parameters [complete remission off treatment (CROT), relapse (clinical and immunological), total corticosteroid dose and direct cost of therapy] were compared. RESULTS: The mean ± SD time to CROT (Group A, 27.1 ± 1.6 weeks; Group B, 26 ± 1.2 weeks, P = 0.09) and the cumulative prednisolone dose (P = 0.28) were comparable between the two groups. In Group A, 3 of 9 (33.3%) patients had clinical relapse (mean ± SD time of 9.3 ± 0.4 months). In Group B, B-cell repopulation was seen in 10 of 11 (90.9%) patients within a mean time of 8.4 ± 2.4 months, and a single top-up dose of 200 mg successfully prevented clinical relapse. The overall cost of therapy was 37.4% cheaper in Group B. CONCLUSION: An immunologically guided low-dose rituximab regimen can be an equally effective but more affordable alternative to conventional rituximab regimens in pemphigus.

Benzimidazole-based fluorophores for the detection of amyloid fibrils with higher sensitivity than Thioflavin-T.

Protein aggregation into amyloid fibrils is a key feature of a multitude of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Prion disease. To detect amyloid fibrils, fluorophores with high sensitivity and better efficiency coupled with the low toxicity are in high demand even to date. In this pursuit, we have unveiled two benzimidazole-based fluorescence sensors ([C15 H15 N3 ] (C1) and [C16 H16 N3 O2 ] (C2), which possess exceptional affinity toward different amyloid fibrils in its submicromolar concentration (8 × 10-9  M), whereas under a similar concentration, the gold standard Thioflavin-T (ThT) fails to bind with amyloid fibrils. These fluorescent markers bind to α-Syn amyloid fibrils as well as amyloid fibrils forming other proteins/peptides including Aß42 amyloid fibrils. The 1 H-15 N heteronuclear quantum correlation spectroscopy nuclear magnetic resonance data collected on wild-type α-Syn monomer with and without the fluorophores (C1 and C2) reveal that there is weak or no interactions between C1 or C2 with residues in α-Syn monomer, which indirectly reflects the specific binding ability of C1 and C2 to the α-Syn amyloid fibrils. Detailed studies further suggest that C1 and C2 can detect/bind with the α-Syn amyloid fibril as low as 100 × 10-9  M. Extremely low or no cytotoxicity is observed for C1 and C2 and they do not interfere with α-Syn fibrillation kinetics, unlike ThT. Both C1/C2 not only shows selective binding with amyloid fibrils forming various proteins/peptides but also displays excellent affinity and selectivity toward α-Syn amyloid aggregates in SH-SY5Y cells and Aß42 amyloid plaques in animal brain tissues. Overall, our data show that the developed dyes could be used for the detection of amyloid fibrils including α-Syn and Aß42 amyloids with higher sensitivity as compared to currently used ThT.

Impact of rheumatoid arthritis and biologic and targeted synthetic disease modifying antirheumatic agents on cancer risk and recurrence.

PURPOSE OF REVIEW: Several new therapeutic drugs are now available for the management of rheumatoid arthritis (RA). Given that RA has been associated with an increased risk of certain cancers like lymphoma and lung cancer, concern remains about the safety of (newer) immunosuppressants used in RA management as it relates to the risk of cancer. RECENT FINDINGS: Most meta-analyses of randomized clinical trials of tumor necrosis factor inhibitors (TNFi) have not observed an association between TNFi and risk of incident cancer. Studies of non-TNFi biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs and cancer are also reassuring but limited and of short-term follow-up. Regarding the use of DMARDs in patients with RA and a prior malignancy, retrospective studies have shown that TNFi use is not associated with recurrence. SUMMARY: There is a need for ongoing studies on the safety of non-TNFi bDMARDs and targeted synthetic disease modifying anti-rheumatic drugs and recurrent cancer. Further research is also needed to guide the patients, rheumatologists, and oncologists regarding the safest DMARDs to choose for patients with RA and a recent diagnosis of cancer.