Severe Arthritis Research Articles

The dual role of body mass index on Juvenile Idiopathic Arthritis course: a pediatric experience.

Despite the well-known role of obesity as risk factor for Juvenile Idiopathic Arthritis (JIA) severity, emerging but limited evidence suggested a similar role for underweight. We investigated the role of body mass index (BMI) across its full spectrum in a cohort of children with JIA.We retrospectively studied 113 children with JIA classified according to the International League of Association for Rheumatology (ILAR) criteria attending our Rheumatology Clinic. The patients underwent a comprehensive evaluation including both clinical and biochemical assessments. According to BMI Z-score, the cohort was divided into five groups as underweight, normal weight, overweight (OW), obesity (OB), and severe OB. Disease activity was calculated by Juvenile Arthritis Disease Activity Score 10 (JADAS-10) joint reduced count and relapses were defined according to Wallace criteria.The mean age of the cohort was 7.43 ± 4.03years. The prevalence of underweight, normal weight, OW, OB, and severe OB was 7.2%, 54.1%, 10.8%, 17.1%, and 10.8%, respectively. Significant higher ferritin levels and erythrocyte sedimentation rate values were found in patients with severe OB and underweight compared to subjects belonging to normal weight, OW, and OB groups. A greater JADAS-10 score was observed in underweight patients and in those with severe OB than other groups. The relapse rate was higher in patients with severe OB and underweight compared to other groups. Conclusions: Both underweight and OB might negatively affect JIA course. Weight control is fundamental in children with JIA to avoid a more unfavourable course of the disease. What is Known: • Obesity represents a well-known risk factor for JIA severity. • The role of underweight in children with JIA is still poorly explored. What is New: • As observed in children with obesity, underweight young patients with JIA seem to experience a more severe JIA course. • Healthy lifestyle promotion in children with JIA is a crucial step in the management of the disease.

ALKBH5-Mediated RNA m6 A Methylation Regulates the Migration, Invasion, and Proliferation of Rheumatoid Fibroblast-Like Synoviocytes.

Fibroblast-like synoviocytes (FLSs) are critical for promoting joint damage in rheumatoid arthritis (RA). N6 -methyladenosine (m6 A) modification plays key roles in various diseases, but its role in the pathogenesis of RA is largely unknown. Here, we investigate increased demethylase ALKBH5 promotion of proliferation, migration, and invasion of RA FLSs via regulating JARID2 expression. ALKBH5 expression in FLSs was evaluated using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. 5-ethynyl-2'-deoxyuridine, scratch wound healing, and transwell assays were implemented to determine the role of ALKBH5 on RA FLS proliferation, mobility, and migration. Then, m6 A sequencing combined with RNA sequencing was performed to identify the potential targets of ALKBH5. RNA immunoprecipitation and RNA pulldown were then used to validate the interaction between the protein and messenger RNA (mRNA). Collagen-induced arthritis (CIA) and delayed-type hypersensitivity arthritis (DTHA) models were further established to assess the therapeutic potency of ALKBH5 in vivo. We demonstrated that ALKBH5 expression was increased in FLSs and synovium from RA. Functionally, ALKBH5 knockdown inhibited the proliferation, migration, and invasion of RA FLSs, whereas overexpression of ALKBH5 displayed the opposite effect. Mechanistically, ALKBH5 mediated m6 A modification in the JARID2 mRNA and enhanced its mRNA stability in cooperation with IGF2BP3. Intriguingly, the severity of arthritis was attenuated in mice with DTHA and ALKBH5 knockout or rats with CIA and intra-articular injection of ALKBH5 short hairpin RNA. Our findings suggest that ALKBH5-mediated m6 A modification is crucial for synovial hyperplasia and invasion in RA. ALKBH5 might be a potential therapeutic target for RA and even for dysregulated fibroblasts in a wide range of diseases.

Anti-Citrullinated Protein Antibodies With Multiple Specificities Ameliorate Collagen Antibody-Induced Arthritis in a Time-Dependent Manner.

Anti-citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA) and have long been regarded as pathogenic. Despite substantial in vitro evidence supporting this claim, reports investigating the proinflammatory effects of ACPAs in animal models of arthritis are rare and include mixed results. Here, we sequenced the plasmablast antibody repertoire of a patient with RA and functionally characterized the encoded ACPAs. We expressed ACPAs from the antibody repertoire of a patient with RA and characterized their autoantigen specificities on antigen arrays and enzyme-linked immunosorbent assays. Binding affinities were estimated by bio-layer interferometry. Select ACPAs (n=9) were tested in the collagen antibody-induced arthritis (CAIA) mouse model to evaluate their effects on joint inflammation. Recombinant ACPAs bound preferentially and with high affinity (nanomolar range) to citrullinated (cit) autoantigens (primarily histones and fibrinogen) and to auto-cit peptidylarginine deiminase 4 (PAD4). ACPAs were grouped for in vivo testing based on their predominant cit-antigen specificities. Unexpectedly, injections of recombinant ACPAs significantly reduced paw thickness and arthritis severity in CAIA mice as compared with isotype-matched control antibodies (P ≤ 0.001). Bone erosion, synovitis, and cartilage damage were also significantly reduced (P ≤ 0.01). This amelioration of CAIA was observed for all the ACPAs tested and was independent of cit-PAD4 and cit-fibrinogen specificities. Furthermore, disease amelioration was more prominent when ACPAs were injected at earlier stages of CAIA than at later phases of the model. Recombinant patient-derived ACPAs ameliorated CAIA. Their antiinflammatory effects were more preventive than therapeutic. This study highlights a potential protective role for ACPAs in arthritis.

Complications of total elbow arthroplasty

The indications for total elbow arthroplasty have been expanded beyond severe arthritis to include acute comminuted fractures. Advances in implant manufacturing and surgical techniques in recent decades have led to increasingly better results. Semiconstrained implants are most commonly used, followed by conversion-type and unlinked implants. However, the results are still worse than those of arthroplasty in the knee or hip joint, and various complications such as aseptic loosening, infection, bushing wear, and periprosthetic fractures still occur. As aging adults are increasingly indicated for surgery, we inevitably face complications that are not easy to control. In this review, we discuss intraoperative and late complications, their prevention, and treatment options.

Functional Outcome of Mechanical Alignment in Total Knee Arthroplasty Surgery: A Short-Term Cohort Study at an Indian Tertiary Care Hospital.

In severe arthritis cases, goal of total knee arthroplasty (TKA) management is to attain pain-free joint and restore the overall limb alignment. There are limitedshort-term studies publishedfrom Indian hospitals that investigated the importance of neutral mechanical component alignment in TKA patients. Retrospective and prospective study was conducted at the Department of orthopaedics, Sancheti Institute for Orthopaedics and Rehabilitation, Pune from June 2020 to September 2022. Enrolled patients were assessed preoperatively and postoperatively using clinical examination, radiological assessment and functional outcomes through the Oxford knee score, Knee society score and VAS score. 204 patients enrolled, and 267 knees were evaluated for the study. Osteoarthritis was the commonest diagnosis (254 knees, 95.13%). Pre-operatively, 92.13% knees were varus, 4.87% valgus and 3% neutral while post-operatively, 51.69% were varus, 16.1% were valgus, and 32.32% were with neutral axis. Majority of patients with a pre-operative neutral axis converted to varus axis (62.5%), while most valgus axis cases preoperatively converted to a neutral axis (53.84%). For pre-operative varus subgroup, the majority patients with < 10° pre-operative axis converted to neutral (41.28%). Majority patients with 10°-20° pre-operative axis remained varus (60.53%) and with > 20° pre-operative axis remained varus (78.26%). Functional outcome parameters were significantly improved at follow-up (P < 0.05). Short-term postoperative functional scores were significantly improved in postoperative cases, with the postoperative alignment of 0° ± 3° relative to the mechanical axis was achieved. Thus, postoperative neutral mechanical alignment of 0° ± 3° can be the standard of care for patients undergoing TKA.

A novel single domain bispecific antibody targeting VEGF and TNF-α ameliorates rheumatoid arthritis

Anti-TNF-α therapy fails in 30% of patients, where TNF-α may not be the key causative factor in these patients. We developed a bispecific single-domain antibody block TNF-α and VEGF (V5-3).The experiments showed that V5-3 effectively activated proliferation and migration of RA-FLS and HUVEC, tube-forming role of HUVEC, and expression of inflammatory factors in vitro. Besides, the experiments indicated that the anti-RA activity of V5-3 was superior to Anbainuo in vivo. Application of V5-3 reduced the expression of inflammatory factors, extent of synovial inflammation and angiogenesis and attenuated the severity of autoimmune arthritis in collagen-induced arthritis (CIA) mice. Mechanistically, V5-3 suppressed p65, AKT and VEGFR2 phosphorylation, as well as production of TNF-α and VEGF in joint tissues. These results demonstrated that V5-3 displayed a superior effect of anti-RA, may be a new therapy to overcome the limitations of anti-TNF-α monoclonal antibody.

Staged Extra-Articular Deformity Correction in the Setting of Total Knee Arthroplasty

BackgroundExtra-articular lower-leg deformities mandate unique considerations when planning total knee arthroplasty (TKA). Poor limb alignment may increase perioperative complications and cause early implant failure. This study reports on the safety and efficacy of staged, extra-articular deformity correction about the knee in the setting of osteoarthritis and TKA. MethodsA retrospective review was conducted from December 2007 to December 2019 identifying 30 deformities in 27 patients (average age: 52.7 years; range 31-74) who underwent staged surgical correction of extra-articular deformity in preparation for TKA. Patient demographics, surgical details, clinical and radiographic measurements, severity of knee arthritis, and complications were collected. ResultsThere were 17 femur and 12 tibia deformities. There was an average improvement of 14.7° of deformity measured in the coronal plane and 12.7° of deformity in the sagittal plane in the femur and 13.5° in the coronal plane and 10.3° in the sagittal plane in the tibia. Leg length discrepancies improved by 26 mm on average (1-100 mm). After an average 3.1-year follow-up, 12 out of 27 patients proceeded with primary or revision TKA. There were no cases of blood transfusion, nerve palsy, or compartment syndrome, and all patients achieved bony union. ConclusionsStaged, extra-articular deformity correction is a safe and effective approach to improve limb alignment in the setting of knee osteoarthritis and TKA.

A Crossed Screw Patellar Reconstruction Technique for the Treatment of the Severely Deficient Scaphoid Shaped Patella in Total Knee Arthroplasty

One of the contraindications to patella resurfacing in total knee arthroplasty is a thin and severely eroded ‘deficient’ patella. However, such patients often present with severe patellofemoral joint arthritis, patellar lateral subluxation, and patella maltracking, which can only be treated effectively with resurfacing. While various treatments have been proposed, options remain limited.Here we introduce a method of patella reconstruction using four 2.7-mm titanium cortical screws crossing each other into the inner shell of the patella. This provides a scaffold onto which bone cement and any standard polyethylene patellar component can be fixed. Postoperatively, the patient had no anterior knee pain, no patella maltracking, and no component loosening.Advantages of this technique include minimization of extensor disruption, low costs, easy accessibility, reproducibility, and improved mechanical strength.

Tofacitinib Efficacy in Patients with Rheumatoid Arthritis and Probable Depression/Anxiety: Post Hoc Analysis of Phase 3 and 3b/4 Randomized Controlled Trials.

The aim of our work is to assess the prevalence of probable major depressive disorder and/or probable generalized anxiety disorder (pMDD/pGAD) in patients with moderate to severe rheumatoid arthritis (RA), and to evaluate the efficacy of tofacitinib on RA symptoms stratified by baseline pMDD/pGAD status. Data were pooled from five phase 3 randomized controlled trials (RCTs) and one phase 3b/4 RCT, assessing tofacitinib 5 or 10mg twice daily (BID), adalimumab (two RCTs), or placebo. pMDD/pGAD was defined as Short Form-36 Health Survey (SF-36) Mental Component Summary (MCS) score ≤ 38. Efficacy outcomes over 12months included least squares mean change from baseline in SF-36 MCS score and Health Assessment Questionnaire-Disability Index, proportions of patients with pMDD/pGAD in those with baseline pMDD/pGAD, and American College of Rheumatology 20/50/70 response, and Disease Activity Score in 28 joints, erythrocyte sedimentation rate remission (< 2.6) rates. A total of 4404 patients with non-missing baseline values were included. Baseline pMDD/pGAD was reported by 44.5%, 39.8%, 45.4%, and 39.1% of patients receiving tofacitinib 5mg BID, tofacitinib 10mg BID, adalimumab, and placebo, respectively. SF-36 MCS improvements were greater for tofacitinib versus adalimumab/placebo through month 6, with numerical improvements for tofacitinib versus adalimumab sustained through month 12, when the proportions of patients with baseline pMDD/pGAD who continued to have pMDD/pGAD were reduced. RA efficacy outcomes were generally similar in patients with/without baseline pMDD/pGAD. The percentage of patients with pMDD/pGAD reduced from baseline over 1year of treatment with tofacitinib or adalimumab. Effective treatment of underlying RA may lead to improvements in depression and anxiety, based on the SF-36 MCS. Specially designed studies using gold-standard diagnostic tools would be warranted to investigate this further. Video Abstract available for this article. NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT02187055. Video Abstract (MP4 204475 KB).

Phytochemical characterization and anti-arthritic potential of Croton bonplandianus leaves extract: In-vivo and in-silico approach

Croton bonplandianus, a natural source traditionally used for treating various illnesses, including rheumatoid arthritis, was evaluated in this study. The effects of ethanolic extracts (CBEE) and aqueous fractions (CBAF) of C. bonplandianus leaves on arthritis-induced inflammation were studied using an albino rat model of inflammation induced by Freund's complete adjuvant. Eight test groups (n = 5 per group) and one vehicle control were used to evaluate the antiarthritic effects of different doses of CBEE and CBAF (125 mg.kg−1, 250 mg.kg−1, and 500 mg.kg−1) on days 5, 10, 15, and 20 compared to arthritic and vehicle controls. Arthritis severity was assessed using macroscopic arthritis grading, histological analysis, body weights, and paw thickness. CBEE and CBAF were found to reduce the prevalence of arthritis, increase body weight, and decrease paw inflammation compared to the vehicle control group by the 23rd day. In addition, they showed no effect on biochemical parameters, but a significant difference (p < 0.05) in hematological parameters compared to the arthritic control group. The study identified Hentriacontane compound as a potential contributor to the anti-inflammatory effect of C. bonplandianus, as it showed the lowest dock score for IL-1β and IL-6. Palmitoylethanol amide was identified as a potential contributor to the anti-inflammatory effect of TNF-α. Gene expression of IL-6, IL-1β, and TNF-α was down-regulated significantly (p < 0.05) in a dose-dependent manner in all treatment groups compared to the arthritic control group. In conclusion, this study validated the anti-arthritic and anti-inflammatory properties of CBEE and CBAF in a time and dose-dependent manner.

A US Retrospective Observational Study of Rituximab Use in Cold Agglutinin Disease

Background Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia (AIHA). Rituximab is approved for treatment of B-cell lymphoma and severe rheumatoid arthritis and used off-label as a treatment for AIHA, including CAD. There is limited real-world evidence on patterns of rituximab use, safety, response rate and duration of response among patients with CAD. Objectives The key objectives were: 1) to characterize patients who initiated rituximab and examine their treatment patterns; 2) to describe the incidence of serious infections (SIs) prior and post rituximab treatment; 3) to assess the rate and duration of response to rituximab using hemolytic markers. Methods This retrospective, cohort study included adult (aged ≥18 years) patients with CAD from Optum's de-identified Market Clarity Data (2007-2021). Patients with CAD (Cohort 1) were indexed on their CAD diagnosis date. Cohort 1 patients who had ≥1 rituximab infusion (Cohort 2) were indexed on their 1 st rituximab infusion date ( Figure 1). Patients with cold agglutinin syndrome associated comorbidities on or before their index date were excluded. For each cohort, demographics, and clinical characteristics at index date, and for Cohort 2, clinical characteristics during 1 year before index date were described. Data for rituximab treatment patterns included number of courses, treatment type (monotherapy or combination therapy), complete or incomplete course, and the use of blood transfusion (BT) as rescue therapy. In Cohort 2, the incidence rates of SIs per 1000 patient-years before and after treatment (within 6 months of 1 st infusion) were assessed. Response to treatment was assessed using hemolytic markers (hemoglobin [Hb], bilirubin, and lactate dehydrogenase [LDH]). From baseline, a change of ≥2 g/dL was considered a Hb response, while a decrease of 50% was assessed as proxy for a bilirubin or LDH response. Relapse was defined as the reversal of biomarker levels below the minimum response threshold. Response duration was the period from the date of response to that of relapse. Results A total of 611 CAD patients were identified (Cohort 1); 94 of them received rituximab (Cohort 2). Median time from CAD diagnosis to rituximab initiation was 43.5 (Interquartile range [IQR]: 13.0-308.3) days. Overall, Cohort 2 had a more severe disease status at treatment initiation than all patients with CAD (Cohort 1) at diagnosis (higher comorbidity scores, rates of health care resource utilization, lower Hb, and more severely elevated hemolytic markers; Table 1). In Cohort 2, the mean (SD) number of rituximab courses per patient was 1.45 (1.16); 24 (25.5%) of patients had ≥1 incomplete course; 37 (39.4%) required BT rescue therapy, and the median time from rituximab initiation to 1 st BT was 31 (IQR: 1.5-110.5) days. Combination therapy was rarely used (3/94; 0.03%); only 1 patient completed. The incidence rate (95% CI) of SIs (per 1000 patient-years) post CAD diagnosis in Cohort 2 was ~3 times higher in the 4 to 6 months after rituximab initiation (637.1 [242.2-1032.0]) than before (245.4 [125.1-365.6]). Proportion of corticosteroid use was the same during 1 year prior to rituximab initiation and concomitantly with rituximab (54/94; 57.4%, both). For patients in Cohort 2 with available data, 69.5% (41/59) had a Hb response, 59.6% (28/47) had a bilirubin response, and 31.3% (10/32) had a LDH response to the 1 st course of rituximab (median [IQR] time to response: 48.0 [33.5-85.0], 68.0 [33.3-199.8], and 67.5 [45.3-211.3] days, respectively). Among patients who responded to the 1 st course, Hb relapse occurred in 68.3% (28/41), bilirubin relapse in 53.6% (15/28), and LDH relapse in 80.0% (8/10) of patients (median [IQR] time from response to relapse: 44.0 [13.3-90.8], 98.00 [29.0-257.0], and 93.00 [21.3-161.8] days, respectively). Conclusions The findings highlight outcomes of rituximab use for treatment of CAD in a real-world setting. Patients who initiated rituximab had more severe disease compared to all patients with CAD. Rituximab was predominantly given as monotherapy, with an average of 1.45 courses per patient. About 25% of patients had ≥1 incomplete rituximab course, and rescue therapy with BTs was often required. Patients receiving rituximab experienced 3 times more SIs after initiating rituximab than before treatment. Although responses to rituximab were commonly observed, duration of response was short, and the rate of relapse was high.

New animal model of chronic gout reproduces pathological features of the disease in humans

ObjectivesGout, as the most prevalent form of inflammatory arthritis, necessitates the use of animal models to investigate the molecular mechanisms involved in its development. Therefore, our objective was to develop...

Blood Cytokines in Psoriasis: Association with Clinical Scores of the Disease Severity and Psoriatic Arthritis

Blood Cytokines in Psoriasis: Association with Clinical Scores of the Disease Severity and Psoriatic Arthritis

Association of mutations in hemochromatosis genes with clinical severity of calcium pyrophosphate arthritis

Aims: To study factors associated with the development of calcium pyrophosphate (CPP) arthritis and the severity phenotype. Methods: Transversal case-control study. Cases had to be confirmed by both X-ray chondrocalcinosis and CPP crystals in synovial fluid. Controls had neither chondrocalcinosis nor CPP crystals in synovial fluid. Patients and controls with hemochromatosis or primary hyperparathyroidism were not included. Mutations of hemochromatosis genes (HFE), magnesium (Mg), calcium (Ca), phosphate, iron (Fe), transferrin saturation, ferritin, parathyroid hormone (PTH), and calcifediol levels were studied. Results: Three hundred patients and 300 sex and age matched controls were compared. Lower serum Mg (sMg) and higher ferritin levels were found among patients. Hypomagnesemia (HypoMg) and HFE mutations were more frequent among patients. Involvement of over one joint was observed in 199 (66.4%) patients whereas persistent joint inflammation was retrieved in 154 (51.4%) of the patients. Initial analysis showed that the frequency of polyarticular and inflammatory phenotypes seemed to be progressively overrepresented in patients with HFE mutations. Further bivariate and multivariate analysis adjusted for the time from onset disclosed that the presence of genotypes with C282Y mutations was associated with polyarticular disease (hazard risk 3.501, 95% confidence interval 1.862–6.581, P &lt; 0.001). Although C282Y mutations also seemed to be associated with inflammatory patterns, the association did not reach statistical significance (P = 0.173). Conclusions: Low sMg and high ferritin levels are associated with CPP arthritis (CPPA). In patients without hemochromatosis, HFE mutations, and specifically C282Y mutations seem to associate with the polyarticular disease phenotype, and plausibly with the chronic inflammatory phenotype.

Red Cell Distribution Width and Neutrophil Lymphocyte Ratio as A New Biomarker for Severity in Rheumatoid Arthritis and its Comparison with DAS 28 ESR Score

Objective: To determine the association of red cell distribution width (RDW)and neutrophil-lymphocyte ratio (NLR)with the severity of rheumatoid arthritis by using DAS28 ESR. Additionally, toxic granulations were assessed as an indicator of disease severity. Study Design: Cross-sectional study. Place and Duration of Study: Rheumatology Outpatient Department, Federal Government Polyclinic Hospital, IslamabadPakistan, from Dec 2020 to Jun 2021. Methodology: Two hundred ninety rheumatoid arthritis patients were included. DAS 28 ESR was calculated using the DAS 28 ESR calculator, and RDW and NLR were extracted from the complete blood picture and peripheral smears. Results: There were 238(82.1%) female and 52 17.9%) male study participants. The mean age of patients was 45.2±12.8. The mean RDW, NLR and DAS 28 ESR in the study were 45.67±4.25, 2.93±1.35 and 4.29±1.25, respectively. Toxic granulations on peripheral smears were also found in 188(64.8%) patients. A significant positive association was found using the Spearman rho correlation between the DAS28 ESR score, RDW and NLR (p-value 0.024 and &lt;0.001, respectively). Conclusion: Red cell distribution width and neutrophil-lymphocyte ratio, along with toxic granulations, can be used as reliable biomarkers of inflammation in rheumatoid arthritis patients. Values higher than the reference range indicate higher disease severity.

Low-dose ethanol consumption inhibits neutrophil extracellular traps formation to alleviate rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Ethanol consumption has been reported to reduce morbidity in RA patients, but the mechanism behind it remains unclear. Our results showed that Muribaculaceae was predominant in the gut microbiota of mice after ethanol treatment, and the levels of microbiota metabolite acetate were increased. Acetate reduced arthritis severity in collagen-induced arthritis (CIA) mice, which was associated with a decrease in the articular neutrophils and the myeloperoxidase-deoxyribonucleic acid complex in serum. Meanwhile, in vitro experiments confirmed that acetate affected neutrophil activity by acting on G-protein-coupled receptor 43, which reduced endoplasmic reticulum stress in neutrophils and inhibited neutrophil extracellular traps formation. Furthermore, exogenous acetate reversed CIA mice with exacerbated gut microbial disruption, further confirming that the effect of gut microbial metabolite acetate on neutrophils in vivo is crucial for the immune regulation. Our findings illuminate the metabolic and cellular mechanisms of the gut-joint axis in the regulation of autoimmune arthritis, and may offer alternative avenues to replicate or induce the joint-protective benefits of ethanol without associated detrimental effects.

Enzyme targeted delivery of sivelestat loaded nanomicelle inhibits arthritic severity in experimental arthritis

AimsRheumatoid arthritis (RA) is chronic inflammatory disorder mainly affects the lining of articular cartilage of synovial joints characterized by severe inflammation and joint damage. The expression of proteolytic enzymes like MMP-2 and Neutrophil Elastase (NE) worsens the RA condition. To address this concern, we have synthesized dual enzyme targeted chlorotoxin conjugated nanomicelles loaded with sivelestat as broad spectrum treatment for RA. Materials and methodsConjugation of the chlorotoxin over nanomicelle and incorporation of sivelestat in nanomicelle provide it dual targeting potential. The sivelestat loaded nanomicelle (SLM) evaluated for the drug release and in-vitro cytocompatibility. Further, investigated its in-vivo anti-arthritic potential on collagen-induced arthritis in wistar rats. Key findingsThe microscopic observation of SLM showed spherical ball like appearance with size ranging from 190 to 230 nm. SLM showed good drug loading and encapsulation efficiency along with no cytotoxicity against healthy cell lines. In-vivo therapeutic assessment on collagen induced arthritis rat model showed potential chondroprotection. The microscopic visualization of articular cartilage by staining showed that it restores the cartilage integrity and lowers the expression of pro-inflammatory enzymes showed by Immunohistochemistry and Immunofluorescence. We observed that, it restrain the mediators of synovial inflammation by simultaneous inhibition of the proteolytic enzymes involved in swelling, cartilage destruction and joint damage which provides strong chondroprotection. SignificanceWe report that significant alleviation of inflammation and inhibition of proteolytic enzymes together might provide enhanced potential for the treatment and management of RA.

Ixekizumab Efficacy in Patients with Severe Peripheral Psoriatic Arthritis: A Post Hoc Analysis of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (SPIRIT-P1).

The efficacy and safety of ixekizumab, an anti-interleukin-17A antibody, in patients with severe symptoms of psoriatic arthritis are largely unexplored. We report the efficacy and safety of ixekizumab in a post hoc analysis of the SPIRIT-P1 trial. Patients were treated with placebo, ixekizumab 80mg every 2weeks (Q2W) or 4weeks (Q4W), or adalimumab 40mg Q2W for 24weeks. In this subgroup analysis of SPIRIT-P1, the population with severe psoriatic arthritis was defined using the modified composite psoriatic activity index total score > 7 and peripheral arthritis score = 3 (> 4 tender or swollen joint count and ≥ 0.5 Health Assessment Questionnaire-Disability Index). Efficacy was measured by joint and skin endpoints including disease progression. In the severe population, significantly more patients (p ≤ 0.001) treated with ixekizumab than placebo achieved 20% improvement according to the American College of Rheumatology criteria (ACR 20): 63.3% for ixekizumab Q4W, 60.4% for ixekizumab Q2W, and 24.5% for placebo. Statistically greater responses compared with placebo were observed in the severe population for ACR 50, ACR 70, ACR core set, disease activity index for psoriatic arthritis (DAPSA) low disease activity and DAPSA remission, and 28-joint disease activity score using C-reactive protein, as well as Psoriasis Area and Severity Index (PASI) 75, PASI 90, and PASI 100 (p ≤ 0.001). Efficacy findings and the safety profile of ixekizumab in the severe population were consistent with those of the overall population, with no new safety concerns identified. In patients with severe psoriatic arthritis, 24weeks of treatment with ixekizumab resulted in improvements in both joint and skin symptoms. The safety profile in the severe population was consistent with the established safety profile of ixekizumab. ClinicalTrials.gov identifier, NCT01695239.

Neutralizing anti-IFN-γ IgG was increased in patients with systemic lupus erythematosus and associated with susceptibility to infection

ObjectivesSystemic lupus erythematosus (SLE) is a complicated autoimmune disease, in which infection is a leading cause of death. Some SLE patients clinically presented with recurrent and refractory infections, which manifested as adult-onset immunodeficiency syndrome due to the production of anti-interferon-γ (anti-IFN-γ) autoantibodies. This study aimed to investigate the role of anti-IFN-γ autoantibodies concerning severe infections in SLE patients.MethodsWe detected serum levels of anti-IFN-γ IgG/IgM isotypes in SLE patients with severe infections (n = 55), SLE patients without severe infections (n = 120), rheumatoid arthritis (n = 24), ankylosing spondylitis (n = 24), and healthy controls (n = 60). The relationship between anti-IFN-γ autoantibodies and clinical characteristics and laboratory parameters were analyzed. We further evaluated the neutralizing ability of anti-IFN-γ IgG.ResultsThe level of anti-IFN-γ IgG was significantly elevated in SLE patients with severe infections compared with the other groups (all p < 0.01), and the positive rates of anti-IFN-γ IgG in SLE patients with and without severe infections were 29.1% and 10.8%, respectively. Further analysis indicated that the levels of anti-IFN-γ IgG were positively associated with the SLEDAI score (r = 0.6420, p < 0.001), and it could predict the susceptibility to severe infections in SLE patients. Moreover, the inhibition and function assay showed that purified IgG from anti-IFN-γ IgG-positive SLE patients could neutralize IFN-γ, and further impair IFN-γ-induced STAT1 phosphorylation.ConclusionsThe neutralizing anti-IFN-γ IgG might increase the susceptibility to infection in SLE patients, which has important implications for the treatment.Key Points• The role of anti-IFN-γ autoantibodies concerning severe infections in SLE patients remains unknown.• The results of this study reveals that anti-IFN-γ IgG levels were significantly elevated in SLE patients with severe infections.• This study suggests that neutralizing anti-IFN-γ IgG might increase the susceptibility to infection in SLE patients.

Asymmetric Post-Traumatic Knee Arthritis Is Closely Correlated With Both Severity and Time for Lower Limb Coronal Plane Malalignment.

Mechanical alignment of the lower limbs has been suggested to cause abnormal uneven loading across the compartments at the knee, but its contribution to the initiation and progression of arthritis remains controversial. This study aimed to establish whether malalignment of the lower limb after trauma is associated with worsened arthritis scores in the theoretically overloaded compartment, and if arthritis scores continuously correlate with the degree of malalignment and time with deformity. After screening 1160 X-rays, 60 patients were identified with long-leg radiographs > 2 years after fracture. Measurement of mechanical axis deviation (MAD) divided into groups of varus malalignment (n = 16, >16 mm), valgus (n = 25, <0 mm), and normal alignment (n = 19). Alignment and bilateral knee compartmental arthritis scores were recorded by three clinicians, compared via analysis of variance and assessed with linear regression against time since injury using MAD as a covariate. In varus and valgus malalignment, there was a greater mean arthritis score in the "overloaded" compartment compared to the contralateral side, with varus medial Osteoarthritis Research Society International (OARSI) scores 5.17 ± 2.91 vs 3.50 ± 2.72 (P = 0.006) and Kellegren-Lawrence scores 2.65 ± 1.19 vs 1.79 ± 1.24 (P ≤ 0.001). In a linear regression model, OARSI arthritis score was significantly associated with absolute MAD (0.6/10 mm MAD, P < 0.001) and time (0.7/decade, P ≤ 0.001). Malalignment consistently results in more advanced arthritis scores in the overloaded compartment, most likely related to abnormal loading across the knee. Severity of arthritis using OARSI grading continuously correlates with degree of malalignment and time with deformity after post-traumatic malunion.