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Juanfang Gu,1,2 Mingfeng Yang,1,2 Bin Zhang,1,2 Hongzhi Wang1,2 1Department of Rheumatology and Immunology, The Affiliated Hospital of Jiaxing University (The First Hospital of Jiaxing), Jiaxing, Zhejiang, 314300, People’s Republic of China; 2Jiaxing Key Laboratory of Osteoporosis and Bone Metabolism, Jiaxing, Zhejiang, 314300, People’s Republic of ChinaCorrespondence: Hongzhi Wang; Bin Zhang, Email 1975129622@qq.com; zbwzmc@163.comObjective: This retrospective analysis was to assess the role of Janus kinases (JAK) inhibitors compared with conventional disease modifying anti-rheumatic drugs (DMRADs) in the treatment of polymyalgia rheumatica (PMR) with glucocorticoids (GCs) reduction.Methods: Clinical information was collected from PMR patients in the JAK inhibitor group and the DMARDs group from January 2020 to August 2021 at Jiaxing first Hospital. Serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), hemoglobin (Hb), albumin and dose of GCs before and after treatment were compared between two groups.Results: Thirty female patients with PMR were included into this study. The dose of GCs in the JAK inhibitor group was significantly lower than in the DMARDs group at baseline and at 3 and 6 months after treatment. There were no significant differences in various laboratory parameters (including CRP, ESR, Hb and albumin) between two groups (P > 0.05) except that Hb in the DMARDs group was significantly higher than in the JAK inhibitor group at 3 and 6 months after treatment (P< 0.05). One patient in the JAK inhibitor group developed herpes zoster, and received tofacitinib treatment after herpes zoster was relieved.Conclusion: Our study indicates that JAK inhibitors in the treatment of PMR are as effective as DMRADs and are also helpful for the reduction of GCs dose.Keywords: JAK inhibitors, polymyalgia rheumatica, glucocorticoids, disease modifying anti-rheumatic drug

ObjectivesOur goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: tocilizumab, rituximab, methotrexate, and adalimumab.MethodsSynovial tissue was obtained using ultrasound-guided biopsy from affected joints of 14 patients, before and 16 weeks after treatment with subcutaneous abatacept 125 mg weekly. Paraffin-sections were stained and scored for CD3+, CD20+, and CD68+ cell infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix) and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape, and EnrichR.ResultsGene expression analysis identified 304 transcripts modulated by abatacept in synovial tissue. Downregulated genes were significantly enriched for immune processes, strongly overlapping with our findings on other therapies. Data were pooled across these studies, revealing that genes downregulated by DMARDs are significantly enriched for both T-cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have coordinate effects on the two pathways, with a stronger impact in good responders to therapy as compared to moderate and non-responders.ConclusionWe provide evidence that the effects of five DMARDs on the RA synovium culminate in the same pathways. This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets.

Objectives: Our goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: tocilizumab, rituximab, methotrexate, and adalimumab. Methods: Synovial tissue was obtained using ultrasound-guided biopsy from affected joints of 14 patients, before and 16 weeks after treatment with subcutaneous abatacept 125 mg weekly. Paraffin-sections were stained and scored for CD3+, CD20+, and CD68+ cell infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix) and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape, and EnrichR. Results: Gene expression analysis identified 304 transcripts modulated by abatacept in synovial tissue. Downregulated genes were significantly enriched for immune processes, strongly overlapping with our findings on other therapies. Data were pooled across these studies, revealing that genes downregulated by DMARDs are significantly enriched for both T-cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have coordinate effects on the two pathways, with a stronger impact in good responders to therapy as compared to moderate and non-responders. Conclusion: We provide evidence that the effects of five DMARDs on the RA synovium culminate in the same pathways. This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a condition caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Severe cases of COVID-19 result in acute respiratory distress syndrome and death. A detrimental, hyper-inflammatory immune response with excess release of cytokines is the main driver of disease development and of tissue damage in these patients. Thus, repurposing of biologic agents and other pharmacological inhibitors of cytokines used for the treatment of various inflammatory conditions emerged as a logical therapeutic strategy to quench inflammation and improve the clinical outcome of COVID-19 patients. Evaluated agents include the interleukin one receptor blocker anakinra, monoclonal antibodies inhibiting IL-6 tocilizumab and sarilumab, monoclonal antibodies inhibiting granulocyte-monocyte colony stimulating factor and tumor necrosis factor, and Janus kinase inhibitors. In this review, we discuss the efficacy and safety of these therapeutic options based on direct personal experience and on published evidence from observational studies and randomized clinical trials.

OBJECTIVE: New treatments in rheumatoid arthritis (RA) have been developed to improve patient outcomes, raise their quality of life, and reduce joint damage, but long-term responses and remission remain low. This study aimed to analyse the Spanish prescribing patterns and the effectiveness of biological (b) disease-modifying anti-rheumatic drugs (DMARDs) available for RA in clinical practice. PATIENTS AND METHODS: An observational retrospective study was performed in a teaching hospital, analysing the different combinations of drugs prescribed, real-life effectiveness and reasons for withdrawal. RESULTS: In total, 210 patients were included, with 19 different patterns (pharmacological groups alone or in combination) of treatment prescribed. Most patients started their treatment with a conventional synthetic (cs) DMARD alone or in combination with a glucocorticosteroid. Among the initial patterns, treatment with only one csDMARD showed a longer duration. The time to first bDMARD was 6 years. TNF-α inhibitors are the most commonly prescribed drugs as initial biological treatments. The highest percentages of good responses and remissions were achieved with tocilizumab, etanercept and infliximab. The time to remission was also lower with tocilizumab. Lack of response, adverse effects and remission were the main causes of bDMARD withdrawal. The duration of treatments until withdrawal was similar among bDMARDs, except for rituximab, for which the duration was slightly shorter. CONCLUSIONS: Prescribing pattern analysis showed the highest responses and remission rates with tocilizumab and TNF-α inhibitors. The main reasons for withdrawal were lack of response and adverse effects. Further research is needed to improve pharmacological RA management in real-life settings. [ABSTRACT FROM AUTHOR]

Importance: Paediatric uveitis is a severe sight‐threatening uveitis due to disease progression and treatment failure. Biological agents are a promising new treatment. This study provides real‐world data on their use from Sydney, Australia. Background: Traditionally corticosteroids and non‐biological immunosuppressive agents were used to treat paediatric uveitis, often with poor outcomes. Design: Retrospective, chart review over an 8‐year period at a tertiary referral eye hospital. Participants: A total of 27 paediatric uveitis patients treated with biological agents. Methods: Chart review of demographic data and treatment outcomes. Main Outcome Measures: Treatment efficacy (corticosteroid‐sparing effect, topical steroid cessation/reduction, reduction in systemic‐steroid sparing agents, change in intraocular inflammation, visual acuity and central macular thickness); treatment failure; and adverse events. Data were collected at biological initiation, 6 weeks, 6 months and 12 months. Results: Biological therapy over 1 year was effective with prednisolone dose reduced to <5 mg/day in five of six patients (83%), number of systemic steroid‐sparing agents was reduced to ≤1 in two of four patients (50%) and cessation of topical steroid achieved in 12/41 of eyes (29%). Improvement of anterior chamber cells by two grades occurred in 20/25 eyes (80%), improvement of logMAR to ≤0.3 occurred in 12/18 eyes (67%) and macular oedema decreased in 4/5 eyes (80%). Treatment failure occurred in six eyes (13.01%) and five patients (18.5%) developed an adverse reaction. Conclusions and Relevance: Biological therapy was effective in paediatric patients with uveitis. Intraocular inflammation improved with maintained visual acuity, systemic corticosteroid dose decreased and there was a low frequency of adverse events. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to explore current disease activity status and simultaneous pharmacological therapies in patients with established rheumatoid arthritis (RA) to determine the extent to which treatment targets are achieved. Patients and methods: One hundred patients (7 males, 93 females: median age 57 years; range 31 to 76 years) with established RA receiving any conventional synthetic disease modifying anti-rheumatic drug (DMARD) and/or biological DMARD for at least three months were enrolled. Disease activity was determined by using the Simplified Disease Activity Index. First, patients were categorized into four groups as remission, low disease activity, moderate disease activity, and high disease activity. Then, they were divided into two subgroups, namely a remission/low disease activity subgroup and moderate disease activity/high disease activity subgroup. Results: Fifty-one percent of the patients had remission or low disease activity. The most frequently used conventional synthetic DMARDs were methotrexate (50%) and leflunomide (34%). Forty-five percent of patients were receiving glucocorticoid therapy. In patients receiving only conventional synthetic DMARDs, the proportion of remission and low disease activity was 54% (42/78). Forty-two percent (8/19) of the patients receiving biological DMARDs were in remission or had low disease activity. A comparison of subgroups revealed that median age and sulfasalazine use were significantly higher in the moderate disease activity/high disease activity subgroup. Conclusion: The results of this study demonstrated that half of patients with established RA had moderate or high disease activity in our local outpatient clinic. Some barriers might be responsible for the difficulties in controlling disease activity. Determining such barriers might result in a better clinical response during the management of patients with established RA in real-life practice. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is a chronic inflammatory arthritis, with significant impact on quality of life and functional status. Whilst biologic disease modifying anti-rheumatic drugs (bDMARD) such as tumour necrosis factor-inhibitor (TNFi) agents have revolutionised outcomes in RA, early diagnosis with immediate conventional therapy, titrated in a treat to target approach is also associated with high remission rates. The main aim of the VEDERA study (Very Early versus Delayed Etanercept in Rheumatoid Arthritis) is to assess the depth of remission, sustainability of remission and immunological normalisation induced by very early TNFi with etanercept (ETN) or standard of care +/- delayed ETN.Methods/design: VEDERA is a pragmatic, phase IV single-centre open-label randomised superiority trial of 120 patients with early, treatment-naive RA. Patients will be randomised 1:1 to first-line ETN and methotrexate (MTX) or MTX with additional synthetic disease modifying anti-rheumatic drugs (sDMARDs) according to a treat to target (TT) protocol with further step up to ETN and MTX after 24 weeks if remission is not achieved. Participants will have regular disease activity assessments and imaging evaluation including musculoskeletal ultrasound and MRI. The main objective of this study is to assess the proportion of patients with early RA that achieve clinical remission at 48 weeks, following either treatment strategy. In addition, the participants are invited to take part in a cardio-vascular sub-study (Coronary Artery Disease in RA, CADERA), which aims to identify the incidence of cardiovascular abnormalities in early RA.Discussion: The hypothesis underlining this study is that very early treatment with first-line ETN increases the proportion of patients with rheumatoid arthritis achieving clinical remission, in comparison to conventional therapy.Trial Registration: NCT02433184 , 23/04/2015. [ABSTRACT FROM AUTHOR]

Risk for amyloidosis in rheumatic diseases is associated with a long-lasting inflammation. To assess possible changes in the incidence of terminal uraemia due to amyloidosis associated with rheumatic diseases on a nationwide basis, we scrutinised the files of the Finnish Registry for Kidney Diseases for patients suffering from amyloidosis associated with rheumatoid arthritis (RA), ankylosing spondylitis (AS) or juvenile idiopathic arthritis (JIA) over the period 1995--2008. The registry has an estimated 97--99%% coverage of all patients accepted for renal replacement therapy (RRT) in the country. Data on the consumption of antirheumatic drugs were collected from two sources: the Social Insurance Institution's Drug Reimbursement Register, and the Sales Register of the National Agency for Medicines from the above period. Altogether 264 cases were identified. Two hundred twenty-nine of them had RA, 15 AS and 20 JIA. When the total annual number of new admissions to RRT varied between 20 and 37 at the end of 1990s, it was under half of that from 2002 onwards. Over this period, the number of users of low-dose methotrexate (MTX) has increased 3.6-fold, the drug being the most frequently used disease modifying anti-rheumatic drug in Finland. The present nationwide series is the first to show that the incidence of end-stage renal disease due to amyloidosis associated with rheumatic diseases is decreasing. An obvious reason for this is intensive anti-rheumatic drug therapy. [ABSTRACT FROM AUTHOR]

We investigated trends in life expectancy in rheumatoid arthritis (RA) patients, reviewing records for 286 patients (204 female, 82 male) who had died over the past 20 years. The average age at death was 68.8 years before 1990, increasing to 72.1 years after 2001. Trends in disease modifying anti-rheumatic drugs (DMARDs) saw gold preparations (45.2%) predominate before 1990, sulphydryl donor agents (53.6%) from 1991 to 2000, then methotrexate (43.0%) after 2001. The most common causes of death were infectious diseases up to 1995, rheumatic disease 1996–2000, and cardiovascular events and malignancies after 2001. Major advances in surgical interventions, such as joint replacement surgery, occurred after 1990. Surgical intervention followed by a period of rehabilitation maintained a favourable level of activities of daily living (ADLs), The requirements for favourable life expectancy are control of RA inflammation and maintenance of a favourable level of ADLs. Although recently developed DMARDs and biological agents show promise, caution is required to avoid serious adverse reactions. Optimum care of patients with RA will require preventive measures and early intervention for infections and rheumatic diseases, as well as for lifestyle diseases, osteoporosis and malignancies. [ABSTRACT FROM AUTHOR]

In 37 patients with active rheumatoid arthritis (RA) responding insufficiently to a diseasemodifying anti-rheumatic drug (DMARD), we compared the safety and efficacy of methotrexate (MTX) used alone (MTX-only group) with MTX used in combination (combined-treatment group). Patients were assigned randomly to 5 years of treatment with MTX alone (initial dose, 7.5 mg/week) or with MTX (initial dose, 5 mg/week) plus their previous DMARD continued at half dosage. After 3 years of therapy, the combined-treatment group showed significantly better sustained response of the Lansbury index, erythrocyte sedimentation rate and C-reactive protein than the MTX-only group. Ten patients withdrew because of adverse drug effects, with a somewhat higher frequency in the combined-treatment group (six of 19, 32%) than in the MTX-only group (four of 18,22%) difference not significant). One patient in each group withdrew because of insufficient response to therapy. We found that combining the original drug with MTX in previously intractable RA cases resulted in at least additive efficacy. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a condition caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Severe cases of COVID-19 result in acute respiratory distress syndrome and death. A detrimental, hyper-inflammatory immune response with excess release of cytokines is the main driver of disease development and of tissue damage in these patients. Thus, repurposing of biologic agents and other pharmacological inhibitors of cytokines used for the treatment of various inflammatory conditions emerged as a logical therapeutic strategy to quench inflammation and improve the clinical outcome of COVID-19 patients. Evaluated agents include the interleukin one receptor blocker anakinra, monoclonal antibodies inhibiting IL-6 tocilizumab and sarilumab, monoclonal antibodies inhibiting granulocyte-monocyte colony stimulating factor and tumor necrosis factor, and Janus kinase inhibitors. In this review, we discuss the efficacy and safety of these therapeutic options based on direct personal experience and on published evidence from observational studies and randomized clinical trials. [ABSTRACT FROM AUTHOR]

Methotrexate, a structural analogue of folic acid, is one of the most effective and extensively used drugs for treating many kinds of cancer or severe and resistant forms of autoimmune diseases. In this paper, we take an overview of the present state of knowledge with regards to complex mechanisms of methotrexate action and its applications as immunosuppressive drug or chemotherapeutic agent in oncological combination therapy. In addition, the issue of the potential benefits of methotrexate in the development of neurological disorders in Alzheimer's disease or myasthenia gravis will be discussed. [ABSTRACT FROM AUTHOR]