Efficacy and safety of an early response-based tapering regimen of tocilizumab in children with systemic juvenile idiopathic arthritis.

INTRODUCTION: Systemic juvenile idiopathic arthritis (sJIA) is a distinct disease subset, with a poorer prognosis compared with other JIA subsets. Tocilizumab has an important role in the management of sJIA refractory to standard initial therapy. However, no specific guidelines exist for the tapering of tocilizumab therapy in sJIA, which could have implications on the overall cost and side effects of treatment. METHODS: This was an observational study which included 21 children with refractory sJIA, who were initially put on injection tocilizumab every 2 weekly, with subsequent dosing tapered to 4 weekly and 6 weekly intervals based on JIA ACR 70 responses at 12 and 24 weeks, respectively. The primary outcome at week 36 included JIA ACR 30, 50, 70, and 90 response rates with other efficacy and safety measures as secondary outcomes. RESULTS: At 36 weeks, JIA ACR 30, 50, 70, and 90 responses were observed in 90.5%, 90.5%, 71.4%, and 52.4% patients respectively along with significant improvement in hematological and inflammatory parameters. The mean prednisolone dose could be reduced from 0.54 to 0.13 mg/kg/day and around 29% patients were able to discontinue steroids altogether. No serious adverse events were recorded. With drug tapering, we could curtail on 26% of the total tocilizumab dose that would have been otherwise required on the continuous 2 weekly protocol. CONCLUSIONS: Tocilizumab, used in an early response-based tapering regimen, was both safe and efficacious in children with sJIA refractory to standard therapy. Larger and longer duration studies are required to further validate our observations.

SARS-CoV-2 seroprevalence in patients with autoimmune rheumatic diseases versus family controls: a multi-city cross-sectional survey.

There is uncertainty regarding the effect of the SARS-CoV-2 infection on patients with autoimmune rheumatic diseases (AIRD) who are on immunosuppressive drugs. We did a multicity cross-sectional seroprevalence study conducted in five different cities in India before COVID-19 immunization. Patients with a diagnosis of AIRD and DMARDs were included. Relatives of the patients, preferably staying in the same household with no known rheumatic diseases served as controls. Serum IgG antibodies to SARS-CoV-2 Receptor Binding Domain (RBD) of the spike protein and nucleoprotein (NP) were assayed in eight hundred and eighty nine sera (subjects with disease = 379 and in subjects without disease = 510). IgG antibodies to either RBD and/or NP were positive in 135 (36%) subjects with AIRD as compared to 196 (38%) controls. The seroprevalence of anti-RBD and anti-NP varied between different cities but was not significantly different between subjects with and without disease in Mumbai, Ahmedabad, Bengaluru and Bhubaneswar. However, the occurrence of IgG antibodies to RBD was significantly (p < 0.05) lower in subjects with disease (28/65;43%) as compared to subjects without disease (42/65;65%) in Kolkata, where the positivity rate was lower in connective tissue disease group than in inflammatory arthritis group. Overall, patients with rheumatic diseases on DMARDs have IgG antibodies to RBD and NP of SARSCoV-2 at a comparable level with that of subjects without disease, but the level of antibodies to RBD is lower in patients with connective tissue disease on immunosuppressive drugs in one centre.

Microscopic Polyangiitis with Pulmonary-renal Involvement in a Patient with Polyarticular Juvenile Idiopathic Arthritis: A Case Report.

The association of polyarticular juvenile idiopathic arthritis (p-JIA) and microscopic polyangiitis (MPA) is extremely rare. Very few case reports described the coexistence of these two diseases to date. Here we report a 26-year-old female, a diagnosed patient of rheumatoid factor positive p-JIA for 15 years who developed MPA with renal and pulmonary involvement at the age of 26 years. She was successfully treated with intravenous corticosteroid and injection rituximab. This case report is unique as an association between MPA and p-JIA is very rare.

Does post-COVID reactive arthritis exist? Experience of a tertiary care centre with a review of the literature.

BACKGROUND: Rheumatological manifestations following COVID-19 are various, including Reactive Arthritis (ReA), which is a form of asymmetric oligoarthritis mainly involving the lower limbs, with or without extra-articular features. The current case series describes the clinical profile and treatment outcome of 23 patients with post-COVID-19 ReA. METHODS: A retrospective, observational study of patients with post-COVID-19 arthritis over one year was conducted at a tertiary care centre in India. Patients (n=23) with either a positive polymerase chain reaction test for SARS-CoV2 or an anti-COVID-19 antibody test were included. Available demographic details, musculoskeletal symptoms, inflammatory markers, and treatment given were documented. RESULTS: Sixteen out of 23 patients were female. The mean age of the patients was 42.8 years. Nineteen patients had had symptomatic COVID-19 infection in the past. The duration between onset of COVID-19 symptoms and arthritis ranged from 5 to 52 days with a mean of 25.9 days. The knee was the most involved joint (16 out of 23 cases). Seven patients had inflammatory lower back pain and nine had enthesitis. Most patients were treated with non-steroidal anti-inflammatory drugs (NSAIDs) and steroids - either depot injection or a short oral course. Three patients required treatment with hydroxychloroquine and methotrexate which were eventually stopped. No relapse was reported in any of the patients. CONCLUSION: On combining our data with 21 other case reports of ReA, a lower limb predominant, oligoarticular, asymmetric pattern of arthritis was seen with a female preponderance. The mean number of joints involved was 2.8. Axial symptoms and enthesitis were often coexistent. Treatment with NSAIDs and intra-articular steroids was effective. However, whether COVID-19 was the definitive aetiology of the arthritis is yet to be proven.

Does post-COVID reactive arthritis exist? Experience of a tertiary care centre with a review of the literature.

Background: Rheumatological manifestations following COVID-19 are various, including Reactive Arthritis (ReA), which is a form of asymmetric oligoarthritis mainly involving the lower limbs, with or without extra-articular features. The current case series describes the clinical profile and treatment outcome of 23 patients with post-COVID-19 ReA. Methods: A retrospective, observational study of patients with post-COVID-19 arthritis over one year was conducted at a tertiary care centre in India. Patients (n = 23) with either a positive polymerase chain reaction test for SARS-CoV2 or an anti-COVID-19 antibody test were included. Available demographic details, musculoskeletal symptoms, inflammatory markers, and treatment given were documented. Results: Sixteen out of 23 patients were female. The mean age of the patients was 42.8 years. Nineteen patients had had symptomatic COVID-19 infection in the past. The duration between onset of COVID-19 symptoms and arthritis ranged from 5 to 52 days with a mean of 25.9 days. The knee was the most involved joint (16 out of 23 cases). Seven patients had inflammatory lower back pain and nine had enthesitis. Most patients were treated with non-steroidal anti-inflammatory drugs (NSAIDs) and steroids - either depot injection or a short oral course. Three patients required treatment with hydroxychloroquine and methotrexate which were eventually stopped. No relapse was reported in any of the patients. Conclusion: On combining our data with 21 other case reports of ReA, a lower limb predominant, oligoarticular, asymmetric pattern of arthritis was seen with a female preponderance. The mean number of joints involved was 2.8. Axial symptoms and enthesitis were often coexistent. Treatment with NSAIDs and intra-articular steroids was effective. However, whether COVID-19 was the definitive aetiology of the arthritis is yet to be proven.

Antecedentes: Las manifestaciones reumatológicas posteriores al COVID-19 son diversas, entre ellas, la artritis reactiva, que es una forma de oligoartritis asimétrica que afecta principalmente a los miembros inferiores, con o sin características extraarticulares. La serie de casos actual describe el perfil clínico y el resultado del tratamiento de 23 pacientes con artritis reactiva posterior a COVID-19. Métodos: Se realizó un estudio observacional retrospectivo de pacientes con artritis post-COVID-19 durante un año en un centro de atención terciaria en India. Se incluyeron pacientes (n = 23) con una prueba de reacción en cadena de la polimerasa positiva para SARS-CoV-2 o una prueba de anticuerpos anti-COVID-19. Se documentaron los detalles demográficos disponibles, los síntomas musculoesqueléticos, los marcadores inflamatorios y el tratamiento administrado. Resultados: Dieciséis de los 23 pacientes eran mujeres. La edad media de los pacientes fue de 42,8 años. Diecinueve pacientes habían tenido infección sintomática por COVID-19 en el pasado. La duración entre el inicio de los síntomas de COVID-19 y la artritis osciló entre 5 y 52 días, con una media de 25,9 días. La rodilla fue la articulación más comúnmente involucrada (16 de 23 casos). Siete pacientes tenían dolor lumbar inflamatorio y 9 tenían entesitis. La mayoría de los pacientes fueron tratados con medicamentos antiinflamatorios no esteroideos y esteroides, ya fuera una inyección de depósito o un ciclo oral corto. Tres pacientes requirieron tratamiento con hidroxicloroquina y metotrexato, que finalmente se suspendieron. No se reportaron recaídas en ninguno de los pacientes. Conclusión: Al combinar nuestros datos con otros 21 informes de casos de artritis reactiva, se observó un patrón de artritis oligoarticular asimétrico predominante en las extremidades inferiores con predominio femenino. El número medio de articulaciones afectadas fue de 2,8. A menudo coexistían síntomas axiales y entesitis. El tratamiento con antiinflamatorios no esteroideos y esteroides intraarticulares fue eficaz. Sin embargo, aún no se ha demostrado si el COVID-19 fue la etiología definitiva de la artritis.

Effect of vasodilator and immunosuppressive therapy on the endothelial dysfunction in patients with systemic sclerosis.

A comparative analysis of flow-mediated vasodilation (FMD), vasoactive angiogenic, and fibrogenic mediators between treatment-naive and treated systemic sclerosis (SSc) patients is an unmet need. (1)To assess the FMD and different pathogenic mediators in SSc patients about endothelial dysfunction. (2) To assess the proportion of circulating endothelial cells (CECs) in treatment-naïve patients. SSc patients were grouped into treatment-naïve (Group-I, n = 24) on vasodilator (Group-II, n = 10), on vasodilator + immunosuppressive (Group-III, n = 22)]. Age-sex matched healthy controls (n = 20) were included. Endothelial dysfunction (ED) was measured radiologically using FMD. Serum levels of NO, ET1, NO/ET1, sVCAM, sICAM, TGF, IL-6, and VEGF, as well as gene expressions of eNOS, iNOS, ET-1, and TGF, were measured to assess the status of ED in various study groups. CEC was measured in Group-I and HC. CEC was used as a marker to identify a key regulator of ED in SSc. FMD was significantly decreased in all SSc patients through receiving treatment. Upregulation of serum NO and ET concentrations was noted post-treatment with an unaltered NO/ET1 ratio. NO was positively correlated with FMD (r = 0.6) and negatively with TGFß (r = - 0.5). ET-1 showed a negative correlation with TGFß (r = - 0.5) but no significant correlation with FMD. Circulating endothelial cell (CEC) was significantly higher in Group-I (3.2%) than HC (0.8%) (p = 0.002), and it showed a good correlation with NO (r = - 0.7, p = 0.0001) and NO/ET1 (r = - 0.6, p = 0.007). Persistent ED was observed in all SSc patients irrespective of treatment. Dysbalance in NO/ET1 ratio might be the considering factor for the underlying progression of ED. Based on our findings, it may be hypothesized that reduced NO may be a contributing factor in the pathogenesis of endothelial dysfunction in SSc.

Validation of antioxidant, antiproliferative, and in vitro anti-rheumatoid arthritis activities of epigallo-catechin-rich bioactive fraction from Camellia sinensis var. assamica, Assam variety white tea, and its comparative evaluation with green tea fraction.

The epigallocatechin-rich polyphenolic fraction of Assam variety white tea, traditionally used for the management of diverse inflammatory ailments and health drink, was investigated through eco-friendly green aqueous extraction, TLC, and HPLC characterization, phytochemical screening, in vitro DPPH assay, anti-proteinase, MTT assay on synovial fibroblast and colon cancer cells, apoptotic FACS analysis, cytokine ELISA, p-STAT3 western blotting, and in silico docking analysis. HPLC-TLC standardized white tea fraction (WT-F) rendered higher extractive-yield (21%, w/w), than green tea fraction(GT-F) (12%, w/w). WT-F containing flavonoids and non-hydrolysable polyphenols showed better antioxidant activity, rather than equivalent GT-F. WT-F demonstrated remarkable anti-rheumatoid-arthritis activity via killing of synovial fibroblast cells (66.1%), downregulation of TNF-α (93.33%), IL-6 (87.97%), and p-STAT3 inhibition (77.75%). Furthermore, WT-F demonstrated better anti-proliferative activity against colon cancer cells (HCT-116). Collectively, our study revealed that the white tea fraction has boundless potential as anti-rheumatoid arthritis and anti-proliferative agent coupled with apoptotic, antioxidant anti-proteinase, and anti-inflammatory properties. PRACTICAL APPLICATIONS: Our eco-friendly extracted bioactive aqueous fraction of white tea, characterized by TLC-HPLC study and phytochemical screening have demonstrated remarkable anti-rheumatoid arthritis property and anti-proliferative action on colon cancer cells including potential anti-oxidant, anti-inflammatory, and anti-proteinase efficacy. The test WT-F sample has shown impressive safety on normal mammalian cells. WT-F has demonstrated better efficacy against rheumatoid arthritis and cancer model compared to equivalent green tea fraction. Traditionally, it is extensively used for boosting immunity, and energy, with cosmetic, and agricultural applications by the native inhabitants. So, the aqueous fraction of WT is suggested to be used as a prophylactic nutraceutical supplement and or therapeutic agent in commercial polyherbal formulation to attenuate and management of auto-inflammatory rheumatoid arthritis and carcinogenesis of colon. It is additionally suggested to establish in vivo rheumatoid arthritis animal and clinical study to validate their pharmacokinetic stability and dose optimization coupled with anti-inflammatory, cytotoxicity, and anti-oxidant property.

Recurrent macrophage activation syndrome as the initial manifestation of paediatric systemic lupus erythematosus.

Introduction: Macrophage Activation Syndrome (MAS) is a rare but potentially fatal complication in rheumatic diseases. Here, we report the case of a 14-year-old girl with MAS as the primary manifestation of Systemic Lupus Erythematosus (SLE). She had three episodes of MAS during the course of her treatment. This case is unique as recurrent MAS in pediatric SLE is rare.Methods: Demographic, clinical, laboratory features and outcomes of our patient was noted. We also reviewed the two reported cases of recurrent MAS in pediatric SLE. Literature review was performed on PubMed search forum. Search items included Macrophage activation syndrome, pediatric systemic lupus erythematosus, recurrent MAS.Conclusion: The diagnosis and management of MAS are challenging as it can simulate an infectious complication or can be the exacerbation of the underlying disease. Early detection and prompt treatment can reduce morbidity in these patients.

Role of oxidative stress in induction of trans-differentiation of neutrophils in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder whose etiopathology involves an interplay between genetic and environmental factors, with oxidative stress being a key contributory factor. This study aimed to establish the impact, if any, of an oxidative, pro-inflammatory milieu upon trans-differentiation of neutrophils and disease progression. In the synovial fluid (SF) and peripheral blood sourced from patients with RA (n = 40) along with healthy controls (n = 25), the proportion of neutrophil-dendritic (N-DC) cell hybrids, i.e. CD66b+/CD83+ was characterized in terms of their antigen presentation (HLA-DR, CD80, andCD86) and cell adhesion and migration (ICAM-1, VCAM-1, and CD62L) properties, along with their ability to generate reactive oxygen species (ROS). In the SF of RA cases, the raised levels of circulating and intra-neutrophilic pro-inflammatory cytokines/chemokines were accompanied by an enhanced proportion of CD66b+ neutrophils, that co-expressed features of antigen presenting cells (APCs) namely CD83, HLA-DR, CD80, CD86, ICAM-1, VCAM-1, and decreased CD62L. These N-DCs as compared to canonical neutrophils demonstrated a higher generation of ROS, and their frequency positively correlated with disease activity score (DAS28). An ex-vivo functional assay validated that oxidative stress supported trans-differentiation and could be attenuated by a free radical scavenger. Taken together, the pro-inflammatory microenvironment in the SF of patients with RA coupled with a higher generation of ROS promoted the trans-differentiation of neutrophils into N-DCs, suggesting the inclusion of anti-oxidants as an add-on therapeutic strategy to limit trans-differentiation.

Interleukin-17 as a predictor of subclinical synovitis in the remission state of rheumatoid arthritis.

OBJECTIVES: To compare the level of pro and anti-inflammatory cytokines, and angiogenic mediators between Rheumatoid arthritis (RA) patients with and without subclinical synovitis (SS) in remission state, to find the correlation of these mediators with Greyscale synovitis (GSS) and power Doppler (PD) scores, and to find the probable predictor/s of SS. METHODS: 52 RA patients in remission state were recruited and subdivided into with and without SS group by Ultrasonography (USG) of 14 joints. Total GSS and PD scoring was done. The serum levels of the pro/anti-inflammatory cytokines and angiogenic mediators were compared between groups, and correlation and regression analysis were done with GSS and PD scores. RESULT: 63.46% patients had USG evidence of SS. Patients with SS had significantly higher levels of pro-inflammatory and angiogenic mediators [matrix-metalloproteinase -3 (p = 0.0001), Tumour necrosis factor-α (p = 0.0001), Interleukin (IL)-6 (p = 0.001), IL-1b (p = 0.0001), IL-17 (p = 0.0005), IL-33 (p = 0.0003), Tie-2 (p = 0.0001), vascular endothelial growth factor (VEGF (p = 0.03)], and lower anti-inflammatory cytokines [IL-27 (p = 0.0003), IL-10(p = 0.0001)]. A strong positive correlation of GSS score was noted with IL-17(r = 0.7), IL-6 (r = 0.7), IL-1b (r = 0.7), and IL-33 (r = 0.6). Multiple linear regression model identified IL-17 and IL-6 as predictors of GSS score, and TNF-α and VEGF as predictors of PD score. IL-17 level > 249 picogram/millilitre (pg/ml) could predict the SS with high specificity (89.5%). CONCLUSION: Patients with SS in the remission state of RA showed altered expression of some of the pro/anti-inflammatory/angiogenic markers compared to those not having SS. IL-17, IL-6, VEGF, and TNF-α could be the predictors of USG synovial scores.

Two flares of Still's disease after two doses of the ChAdOx1 vaccine.

We report the case of an 18-year-old male with Still's disease for the last 3 years, in remission, who developed two flares of his disease after receiving two doses of the ChAdOX1 nCoV-19 vaccine. While the first flare was mild requiring steroid initiation and resolved rapidly, the second flare after the second dose was much severe, requiring pulse steroid and tocilizumab. We also review three reported cases of flares of Still's disease after COVID-19 vaccination. The temporal association of the flares with both vaccine doses strengthens the association between the vaccine administration and the flare. The proposed mechanism may be due to activation of the innate immune system by the vaccine adjuvants. This review serves to inform the medical community regarding a possible role of the vaccine in producing a systemic inflammatory response. Early detection and treatment can help reduce morbidity in these cases.

Evaluation of Subclinical Hand Joint Synovitis by Ultrasonography in Patients with Psoriatic Arthritis and Cutaneous Psoriasis: A Case-Control Study.

Objectives: To find the frequency of subclinical hand joint synovitis (SS) in patients with psoriatic arthritis (PsA) and cutaneous psoriasis (PsC) compared to healthy controls (HC), and correlation of SS with disease activity. Methods: PsA patients (n= 52), without any past/current history of hand joint arthritis, PsC patients (n= 48), and 45 HC were recruited. Grey-scale and power Doppler Ultrasonography of bilateral hand joints were performed. The proportions of hand joints with SS were estimated in each group. A wrist-ray score was devised. Correlations were obtained between the number of joints with SS and disease activity parameters. Results: Higher proportion of PsA patients (55.8%) had SS than PsC (29.2%, p= 0.007), and HC (22.2%, p=0.001). Proportion of joints with SS was higher in PsA patients (5.38%) compared to PsC (2.92%, [p=0.0008]), and HC (1.11%, [p=0.0007]). Compared to HC, PsA patients had significantly higher bilateral ray 3 (p=0.002 and 0.01 for left and right ray 3, respectively), and right ray 4 involvement (p=0.037) and PsC patients had higher left ray 3 involvement (p=0.03). Wrist-ray score above 2.5 could distinguish patients of PsC with significant subclinical synovitis compared to controls (area under curve: 0.857, 95% confidence interval: 0.71-1.00). There was a significant correlation of SS with ESR in PsA group (p-value: 0.044), and with CRP in PsC group (p-value: 0.003), but not with other disease activity indices. Conclusion: SS was noted in approximately half of PsA and 1/3rd of PsC patients. Both PsA and PsC patients had a significantly higher number of hand joint SS than HC. Ray pattern of hand joint SS could be present in both PsA and PsC.

A combination of circulating microRNA-375-3p and chemokines CCL11, CXCL12, and G-CSF differentiate Crohn's disease and intestinal tuberculosis.

Differentiation of Crohn's disease (CD) from intestinal tuberculosis (ITB) is a big challenge to gastroenterologists because of their indistinguishable features and insensitive diagnostic tools. A non-invasive biomarker is urgently required to distinguish ITB/CD patients particularly in India, a TB endemic region, where CD frequency is increasing rapidly due to urbanization. Among the three differentially expressed miRNAs obtained from small RNA transcriptomic profiling of ileocaecal/terminal ileal tissue of ITB/CD patients (n = 3), only two down-regulated miRNAs, miR-31-5p, and miR-215-5p showed comparable data in qRT-PCR. Out of which, only miR-215-5p was detectable in the patient's plasma, but there was no significant difference in expression between ITB/CD. On the other hand, miR-375-3p, the pulmonary TB specific marker was found in higher amount in the plasma of ITB patients than CD while reverse expression was observed in the ileocaecal/terminal ileal tissues of the same patients. Next, using Bioplex pro-human cytokine 48-plex screening panel, only three chemokines, Eotaxin-1/CCL11, SDF-1α/CXCL12, and G-CSF have noted significantly different levels in the serum of ITB/CD patients. ROC analysis has revealed that compared to a single molecule, a combination of miR-375-3p + Eotaxin-1/CCL11 + SDF-1α /CXCL12 + G-CSF showed a better AUC of 0.83, 95% CI (0.69-0.96) with 100% specificity and positive predictive value while sensitivity, negative predictive value, and accuracy were 56%, 69%, and 78% respectively in distinguishing ITB from CD. This study suggests that a combination of plasma markers shows better potential in differentiating ITB from CD than a single marker and this panel of markers may be used for clinical management of ITB/CD patients.

Methotrexate and theaflavin-3, 3'-digallate synergistically restore the balance between apoptosis and autophagy in synovial fibroblast of RA: an ex vivo approach with cultured human RA FLS.

BACKGROUND: Imbalance between apoptosis and autophagy in fibroblast-like synoviocytes (FLS) is one of the pathogenic mechanisms responsible for their abnormal proliferation in rheumatoid arthritis (RA). Methotrexate (MTX) demonstrated limited efficacy in amending this imbalance in fluid-derived (fd)-FLS. The active compound of black tea Theaflavin 3,3'-digallate (TF3) may be effective in restoring apoptosis-autophagy imbalance in (fd)-FLS. The combined effect of MTX + TF3 upon the same is yet to be elucidated. OBJECTIVE: To evaluate the effect of MTX + TF3 on fd-FLS to induce apoptosis and inhibit autophagy through Endoplasmic Reticulum (ER) stress-mediated pathways. METHODS: FLS from synovial fluid of 11 RA and 10 osteoarthritis patients were cultured after treatment with MTX/TF3 or a combination of MTX (125 nM) and TF3(10 µM) and the following parameters were evaluated. C-reactive protein, cytokines (TNF-α, IL-6), angiogenic markers were quantified by ELISA. fd-FLS viability was determined by MTT assay and apoptosis by flow cytometry. ER stress markers were estimated by RT-PCR (IRE1A, spliced-XBP-1) and immunoblotting (Grp78, Hsp70, CHOP, HIF-1α). Immunoblot studies were done to evaluate apoptotic (Bcl-2, Bax, Caspases) and autophagic (Beclin1, LC3b, p62) proteins. RESULTS: MTX (IC25) and TF3 (IC50) both in single doses could down-regulate the levels of pro-inflammatory and angiogenic markers. Combinatorial treatment modulated autophagosomal proteins in fd-FLS and induced apoptosis by regulating ER stress response. CONCLUSION: Disruption in homeostasis between apoptosis and autophagy in fd-FLS might be an underlying phenomenon in the progression of pathophysiology in RA. Co-administration of MTX + TF3 successfully restored the homeostasis by inducing apoptosis.