Treatment Of Refractory Rheumatoid Arthritis Research Articles

Severe myocarditis as a cause of the formation of cardiorenal syndrome in a patient with refractory rheumatoid arthritis

According to modern concepts, myocarditis is an inflammatory disease of the myocardium, diagnosed on the basis of generally accepted histological, immunological, immunohistochemical criteria. Previously, most researchers believed that the most common cardiac extra-articular manifestation of rheumatoid arthritis (RA) is pericarditis. In the last decade, using magnetic resonance imaging (MRI) of the heart, it turned out that myocarditis in patients with rheumatoid arthritis is not a rare manifestation of the disease. Recently, there is increasing evidence that inflammatory cytokines in RA can also directly cause chronic myocardial damage, further contributing to the development of chronic heart failure (CHF). In our clinical case, myocarditis developed in a patient with active refractory rheumatoid arthritis. The myocardial lesion in the patient was characterized by pronounced echocardiographic signs of restrictive cardiomyopathy, a significant decrease in the ejection fraction with the development of heart failure, various rhythm disturbances in combination with acute renal dysfunction, which led to the formation of cardiorenal syndrome (CRS). Complete regression of myocarditis and cattle occurred precisely against the background of effective treatment of refractory rheumatoid arthritis (RA) with basic antirheumatic drugs and the successful use of biological therapy.

Real-world treatment patterns for repository corticotropin injection in patients with rheumatoid arthritis

IntroductionRepository corticotropin injection (RCI, Acthar® Gel) is a naturally sourced mixture of adrenocorticotropic hormone analogues and other pituitary peptides with anti-inflammatory and immunomodulatory effects. In a recent clinical trial, RCI was safe and effective for the treatment of refractory rheumatoid arthritis (RA). This study aims to describe real-world use and outcomes of patients with RA who were prescribed RCI in clinical practice through retrospective analysis of an electronic medical record database.MethodsPatients with RA who were prescribed RCI were identified through the ColumbusTM electronic medical record repository, representing approximately 100 rheumatology practices. Demographics, medications, comorbidities, disease histories, laboratory evaluations, clinical outcomes and patient-reported outcomes were evaluated from 12 months pre-RCI to 12 months post-RCI initiation.ResultsThe RCI cohort (n=63) comprised predominantly white women, aged 54 years on average, at 6 years from RA diagnosis, with high disease activity at baseline according to Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) scores. Within the 12 months pre-RCI initiation, 87% of patients were prescribed disease-modifying antirheumatic drugs and 67% were prescribed glucocorticoids. Twelve months post-RCI initiation, glucocorticoid, opioid and non-steroidal anti-inflammatory drug prescriptions decreased; disease-modifying antirheumatic drug prescriptions remained stable. Reductions in CDAI, RAPID3, physician global assessment, tender joint count, swollen joint count, and pain visual analogue scale scores were observed 12 months post-RCI initiation. Few discontinuations were due to side effects. Study limitations included small sample size and incomplete electronic medical record data.ConclusionThese findings support the safety and effectiveness of RCI for short-term adjunctive treatment of refractory RA and provide patient-management insights from routine clinical practice.

Therapeutic Role of Tocilizumab in SARS-CoV-2-Induced Cytokine Storm: Rationale and Current Evidence.

Among patients suffering from coronavirus disease 2019 (COVID-19) syndrome, one of the worst possible scenarios is represented by the critical lung damage caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced cytokine storm, responsible for a potentially very dangerous hyperinflammatory condition. Within such a context, interleukin-6 (IL-6) plays a key pathogenic role, thus being a suitable therapeutic target. Indeed, the IL-6-receptor antagonist tocilizumab, already approved for treatment of refractory rheumatoid arthritis, is often used to treat patients with severe COVID-19 symptoms and lung involvement. Therefore, the aim of this review article is to focus on the rationale of tocilizumab utilization in the SARS-CoV-2-triggered cytokine storm, as well as to discuss current evidence and future perspectives, especially with regard to ongoing trials referring to the evaluation of tocilizumab’s therapeutic effects in patients with life-threatening SARS-CoV-2 infection.

Janus kinase inhibitors for the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory destructive disorder that affects the joints, muscles, and tendons accompanying various extra-articular manifestations. Traditional disease-modifying anti-rheumatic drugs (DMARDs) represent the basic treatment for rheumatoid arthritis. Over the last 20 years, biologic DMARDs (tumor necrosis factor inhibitors, interleukin-1 inhibitors, interleukin-6 inhibitors, T cell inhibitors, and B cell inhibitors) have been widely used as a novel class of DMARDs that have efficacy and efficiency. Discovery of the underlying pathogenesis of autoimmune disease enables us to develop new target therapies such as a Janus kinase (JAK) inhibitor. Activated JAK is known to activate signal transducers as well as activators of transcription (STAT) signaling. A JAK inhibitor is a type of medication that functions by inhibiting the JAK-STAT signaling pathway. In addition, it is easy to take a JAK inhibitor orally. In Korea, several JAK inhibitors have been approved. This review describes the types of JAK inhibitors, recommended doses, side effects, and updated European Alliance of Associations for Rheumatology guidelines. Clinicians should more often consider JAK inhibitors in the treatment of refractory rheumatoid arthritis in current rheumatology clinics

Rituximab for rheumatoid arthritis.

Rituximab for rheumatoid arthritis.

Refrakter Romatoid Artrit Tedavisinde Terapotik Aferez Uygulamaları

Rheumatoid arthritis is a chronic and progressive autoimmune disease of unknown cause. It is usually symmetrical, peripheral joint involvement and inflammatory synovitis. The goal of treatment, pain relief, reduction of inflammation, joint structures ensuring, functions protection and control of systemic involvement. Despite the new treatment in the last decade, especially in late or have not been well treated cases, the disease causes joint destruction proceeding permanent. In this situation treatment of pain control and other methods can be used in order to restore joint motion. Therapeutic apheresis applications could be suggested alternative methods or supporting therapy in the treatment of refractory rheumatoid arthritis.

Reactivation of occult hepatitis B virus infection, following treatment of refractory rheumatoid arthritis with abatacept

Reactivation of occult hepatitis B virus infection, following treatment of refractory rheumatoid arthritis with abatacept

TG20, a Transgenically-Derived Anti-CD20 Monoclonal Antibody, Exhibits Enhanced Cytotoxicity Against Cells with Low Levels of CD20

Abstract 2730CD20 is a cell-surface glycoprotein that is highly expressed on most B-cells, tightly restricted to the B-cell lineage, and not expressed on either precursor lymphoid cells or the majority of plasma cells. These characteristics make CD20 an appealing target for mAb therapy of B-cell malignancies and B-cell dependent autoimmune conditions, because antibody production is maintained during therapy and B-cell regeneration post-CD20 mAb treatment is facilitated. Among several marketed anti-CD20 mAbs, rituximab is the prototype; a chimeric human–mouse type-1 antibody that has proven efficacy in a wide variety of mature B-cell malignancies, including CD20+ B-cell lymphoma, and has also been approved for the treatment of refractory rheumatoid arthritis. However, patients do not always respond to this therapy, and it has been reported that close to 60% of follicular lymphoma patients previously treated with chemotherapy, while initially responsive, become resistant upon repeat treatment with rituximab monotherapy. Furthermore, the high cost of treatment with rituximab and other anti-CD20 mAbs severely curtails their availability to patients in emerging economies, as well as their use post treatment for maintenance therapy.Transgenic production offers an easily scalable system for the cost-effective manufacturing of large amounts of complex therapeutic proteins. The regulatory approvals of ATryn® (recombinant antithrombin), first by the EMA (August 2006) and by the FDA (February 2009) have provided a strong regulatory validation of this production platform. Produced in the milk of transgenic goats, TG20, a novel chimeric IgG1 strongly binding a specific discontinuous epitope on CD20 (KD = 1–2 × 10−8 M), is being developed as a second-generation anti-CD20 mAb with enhanced cytotoxic activity. Using regulatory sequences from the caprine beta-casein gene to target expression of the TG20 heavy- and light-chains to the lactating mammary gland, 7 independent lines of transgenic goats were generated by somatic cell nuclear transfer. Induced lactation studies indicated that these lines expressed TG20 in their milk at levels varying from 2 g/liter up to ∼ 10 g/liter. Following genetic characterization (Southern blotting, FISH analysis) and expression analysis (protein and peptide mapping, glycosylation profiling, amino-acid sequence analysis), one line was selected for expansion and further development.In-vitro studies comparing TG20 to rituximab showed a significantly increased ability to activate effector cells expressing the FcgRIIIa receptor (CD16a). Not surprisingly, this translates to a significantly increased ability to activate NK cells and to induce target lysis. This increased ADCC has been demonstrated both with CD20+ Raji cells and with primary B-cells isolated from patients with B-CLL (TG20 EC50 = 3.6 ng/ml vs. rituximab EC50 = 59.4 ng/ml). The ability of TG20 to activate the complement system was assessed using human serum as complement and WIL2-S cells as target exhibiting a > 50% increase in CDC activity vs. rituximab (TG20 = 170% CDC activity vs. rituximab = 100%). Finally, studies conducted in Cynomolgus monkeys were performed to assess pharmacokinetics and in-vivo depletion activities of TG20.In conclusion, TG20 is a highly active anti-CD20 mAb showing interesting characteristics in terms of cytotoxicity that makes it a promising agent for indications in which rituximab is poorly active. Furthermore, the use of the cost-efficient transgenic production platform for the large-scale production of this antibody drug candidate may allow expanded access of anti-CD20 therapy to those who currently cannot afford these expensive treatments, especially in emerging market countries. Disclosures:Echelard:GTC Biotherapeutics, Inc.: Employment. Pollock:GTC Biotherapeutics, Inc.: Employment. De Coupade:LFB Biotechnologies: Employment. Groseil Olivier:LFB Biotechnologies: Employment. Brune:LFB Biotechnologies: Employment. Chen:GTC Biotherapeutics, Inc.: Employment. Masiello:GTC Biotherapeutics, Inc.: Employment. Williams:GTC Biotherapeutics, Inc.: Employment. Gavin:GTC Biotherapeutics, Inc.: Employment. Chtourou:LFB Biotechnologies: Employment. Meade:GTC Biotherapeutics, Inc.: Employment.

Application of blood purification technique in autoimmune disease

The improvement of blood purification technologies in the recent years brings new methods of treating autoimmune diseases. Blood purification therapy mainly includes plasma exchange, immune adsorption and cell purification etc. It can rapidly remove a great amount of circulating pathological elements like autoantibodies,or remove the immune cells. It is effective for the treatment of refractory rheumatoid arthritis,severe systemic lupus erythematosus, acute autoimmune hemolytic, myasthenia gravis and other autoimmune diseases. But this is only a symptomatic treatment. Long-term steroid and immunosuppressive therapy are still needed to consolidate the curative effect. Key words: Blood purification; Autoimmune diseases

Rituximab for Rheumatoid Arthritis: A Meta-Analysis and Systematic Review

Background Rituximab (RTX) is a biological agent used for the treatment of refractory rheumatoid arthritis (RA). The present systematic review and meta-analysis update the safety and efficacy of RTX for the treatment of RA in data published since 2006. Methods We searched PubMed from January 2000 to March 2010, and recent ACR Annual meeting abstracts for randomized (RCT) and non-randomized, controlled clinical trials (CCT) investigating the effects of RTX in RA. Included studies were at least six months, included participants who were ≥16 years of age meeting ACR revised criteria for RA, and compared RTX in combination with any DMARD or RTX alone versus placebo or other DMARDs or any biologic. Studies were excluded if they included patients previously exposed to RTX. Two reviewers independently extracted the data, and disagreement was resolved by discussion and consensus. The primary outcome was the Disease Activity Score (DAS28). The secondary outcome was American College of Rheumatology (ACR50) response. The efficacy results were combined in a meta-analysis. The primary endpoint was analyzed as a continuous variable using a random-effects analysis model to account for the fact that intervention effects were not uniform across all the studies. The secondary endpoint was analyzed as an odds ratio using the Mantel-Haenszel estimator under a random effects model to account for heterogenity in intervention effects across the studies. Descriptive statistics were used to compare adverse event (AE) rates and included both randomized and observational trials. Results For the meta-analysis of efficacy, we initially examined 45 studies, devolving to 6 studies after applying inclusion/exclusion criteria. 5 were RCTs and 1 was a controlled clinical trial. Improvements in DAS28 and ACR50 statistically favored RTX ( Figure 1 ). For the safety evaluation, 22 studies (5 RCTs and 17 observational studies) were examined. Infusion-related reactions were higher in the RTX group (mean: 28%) vs. placebo (18%). Overall infection incidence was similar for both groups (RTX: 39 vs. placebo: 40%). Conclusions Our updated review supports RTX as a safe and efficacious therapy for treatment-naïve and methotrexate and/or TNF-alpha refractory patients with RA. AE's revealed no more frequent infections than control. Future trials need to assess the longer-term efficacy and safety of RTX for RA, as well as the optimal time of re-administration of this agent.

A Bayesian Approach to Therapy Selection in the Treatment of Refractory Rheumatoid Arthritis

Bayesian hierarchical modeling is a general strategy for synthesizing disparate sources of evidence about medical treatments. This kind of data synthesis can be useful in drawing comprehensive inferences about treatment effects and addressing therapeutic questions that have yet to be experimentally tested. We apply this methodology to construct a quantitative guideline for the individualized treatment choice of combinatorial therapy in the treatment of refractory rheumatoid arthritis (RRA). The mean predictive probability of ACR20 response at 1–2 years is the basis for treatment selection. We show how this choice can be made patient-specific when individual-level experimental outcomes are available.

Efficacy and safety of leflunomide alone and in combination with methotrexate in the treatment of refractory rheumatoid arthritis

Rheumatoid arthritis patients who develop refractoriness are left with no alternatives other than leflunomide and costly biological response modifiers. Leflunomide, though effective, was associated with adverse events and has not been extensively studied in the Indian population. Determination of safety and efficacy of leflunomide alone and if not useful, in combination with methotrexate in patients refractory to conventional disease-modifying agents. Open labeled clinical trial with leflunomide [100 mg, OD x 3 days followed by 20 mg, OD x 6 months], if no improvement at three months, combined with methotrexate [5-7.5 mg, OD x 3 months] at a tertiary care hospital. The primary endpoint in the improvement in EULAR criteria and secondary endpoints were patient and physician global evaluation, incidence of remission and biochemical and clinical adverse events. Chi square test or Fisher's exact test and parametric and non-parametric repeat measure ANOVA were used for analysis. Among 84 patients who were included in the study, leflunomide showed improvement and remission in 52 [62%] and 6 [7%] in six months, by intention to treat analysis. Adverse events were observed in 15, discontinuation in 5 and 24 dropped out. With combination in 11 patients, there was improvement and remission in nine [91%] and one [9%] after three months. Adverse events were observed in six and one discontinued. If regular monitoring of hepatic function and hematological parameters are performed, leflunomide is an effective and safe drug in the Indian population in resistant rheumatoid arthritis patients, especially if used alone.

Rituximab Treatment of Refractory Rheumatoid Arthritis

To review published literature using rituximab for treatment of refractory rheumatoid arthritis (RA). An English-language literature search was conducted using MEDLINE (1966-May 2005) and EMBASE (1980-May 2005). References of identified articles were subsequently reviewed for additional data. Evidence suggests that B lymphocyte depletion in patients suffering from refractory RA may be a key component in the interruption of the disease pathogenesis. Successful depletion of B lymphocytes with rituximab in patients with RA has been reported in case reports, open-label pilot studies, and a randomized, double-blind, placebo-controlled trial. Based on the limited published data, rituximab, when used in combination with other agents (ie, cyclophosphamide or methotrexate), appears to be a reasonable treatment option for refractory RA. However, additional controlled trials need to be conducted to further define optimal dosing, response rates, comparative long-term efficacy, and RA treatment algorithm placement of rituximab in this patient population.

Successful Therapy of Rheumatoid Arthritis With Rituximab

Rheumatoid arthritis (RA) is often considered a T cell-mediated disease, yet recent studies describe benefit with rituximab, a monoclonal antibody directed against the B cell antigen CD20. We report our experience using rituximab for 5 patients with severe, disease-modifying antirheumatic drug (DMARD)-refractory RA. Five patients with seropositive, erosive RA received rituximab as 4 weekly doses of 375 mg/m. Four subjects experienced remission lasting 5 to 12 months after noting lack of efficacy with antitumor necrosis factor (TNF) therapy. All patients have relapsed, with signs and symptoms of RA returning a mean of 8 months after therapy. Rituximab appears to be a safe and potentially helpful treatment of refractory RA and, until U.S. Food and Drug Administration approval, could be considered for compassionate use in people who have failed multiple DMARDs. Individuals who do not respond to anti-TNF therapy could experience arthritis that is perpetuated by B cell more than T cell function; these patients could be most likely to respond to rituximab. Further studies are needed to clarify the optimal dose and frequency of rituximab therapy, and its role in combination therapy for individuals with RA.

Weekly dose of leflunomide for the treatment of refractory rheumatoid arthritis: an open pilot comparative study

Aims. To assess the therapeutic effect of leflunomide in weekly dose of 100 mg in patients with refractory rheumatoid arthritis. Material and Methods. Sixteen patients were included (18-72 years, disease duration 2-32 years). Eight patients received a weekly dose of 100 mg of leflunomide and 8 the conventional dose. Current treatment was not modified. All patients underwent a monthly evaluation for one year, applying the 1995 ACR preliminary definition of improvement in rheumatoid arthritis. Results. After 2 months, the group treated with the conventional leflunomide dose evidenced a remarkable improvement (7/8 patients achieving ACR 20), while the group receiving the weekly dose, the improvement was not as clearly evident (3/8 patients achieving ACR 20). By the fourth to sixth month, the response was comparable on both groups (6/6 and 6/8 patients achieving ACR 50 in the daily and weekly dose, respectively) and prevailed through the end of the study. There were no statistical differences between groups at any evaluation. Side effects made itself clear in 6 patients in the daily leflunomide group, and 2 patients withdrawn leflunomide because severe gastrointestinal symptoms and hepatotoxicity, respectively. In the group of weekly leflunomide 2 patients presented side effects which disappeared spontaneously. Conclusion. The use of leflunomide in a weekly dose of 100 mg proved to have similar therapeutic benefit as that of the conventional scheme and might represent a new option for the treatment of refractory rheumatoid arthritis patients.

Treatment of rheumatoid arthritis: new therapeutic approaches with biological agents.

Rheumatoid arthritis is a chronic polyarthritis leading to joint destruction and remarkable disability. Current therapies have various degrees of efficacy, but toxicity frequently limits their long-term use. Furthermore, treatment of refractory rheumatoid arthritis includes increasing disease-modifying antirheumatic drugs dosage, using combination therapy, and adding or increasing the posology of corticosteroids. Although the etiology of the disease remains unknown, our increasing knowledge of the mechanisms underlying pathogenic events in rheumatoid synovitis, has provided opportunities to specifically target cell surface markers or cytokines involved in the inflammatory response. The objective of this review is to describe the different therapeutic approaches with biological agents that are either being utilized or are under development. Some of these products reflect the evolving capacity for the biotechnology industry to synthesize and humanize therapeutic agents: anti-tumor necrosis factor (TNF) alpha monoclonal antibodies (MoAb) and recombinant TNF-receptor construct appear to be validated tools. These treatments alone, or in combination with methotrexate are very effective in rheumatoid patients. Data from clinical trials and issues related to mechanisms of action, potential toxicity, and future perspectives for these novel therapeutic options are considered in this review. Anti-cytokine treatment include other interesting approaches to interfere with on-going inflammatory processes, such as the use of recombinant human interleukin (IL)1 receptor antagonist, or recombinant human IL10. T cell constimulatory blockade, induction of apoptosis in the synovial tissue, and gene therapy could represent future strategies in rheumatoid disease.

A Randomized Double‐Blind Sham‐Controlled Trial of the Prosorba Column for Treatment of Refractory Rheumatoid Arthritis

The Prosorba column has been studied as a novel therapy for rheumatoid arthritis in several clinical settings over the last 5 years. In this article, we summarize the pivotal clinical trial study supporting the safety and efficacy of the Prosorba column as it is applied to treatment of rheumatoid arthritis. The Prosorba column is a medical device that contains purified staphylococcal protein A covalently bound to a silica matrix. This device is used to treat patient plasma in conjunction with a plasmapheresis machine. In this ex vivo treatment, blood is withdrawn from the patient, cells are separated from plasma in the machine, and the plasma is passed through the Prosorba column. The plasma then is recombined with the cells and returned to the patient. The Prosorba column was approved for the treatment of idiopathic thrombocytopenic purpura in 1987 and, in 2 open-label trials (1,2), showed promising evidence of efficacy in rheumatoid arthritis. A subsequent Phase 3 pivotal trial demonstrated statistical superiority of Prosorba treatments to sham column apheresis (3). Analysis of the pivotal trial of patients who completed all treatments indicated that 41.7% of the Prosorba treated patients met American College of Rheumatology defined response criteria as compared to 15.6% of the sham treated patients. This difference was significant at a level of p < or = 0.02.

Samarium-153-EDTMP in the treatment of refractory rheumatoid arthritis

We examined the preliminary safety and efficacy of intravenous samarium-153-EDTMP (Sm-153) in the treatment of refractory rheumatoid arthritis (RA). In an open-label sequential group comparison of 0.5, 1.0, and 2.0 mCi/kg, Sm-153 was administered as a single intravenous infusion to 24 patients with refractory disease. Across treatment doses, the frequency of American College of Rheumatology (ACR) 20% responses was 25%, 29%, 25%, and 33% at 2, 4, 8, and 12 weeks, respectively. Expected significant declines in absolute neutrophil count, hemoglobin, and platelet counts were observed with nadirs seen between 2&4 weeks. Sm-153, at doses of 0.5 and 1.0 mCi/kg, is well tolerated but minimally effective in the treatment of refractory RA as measured using ACR response criteria.

Additive combination of actarit and methotrexate in the treatment of refractory rheumatoid arthritis

Additive combination of actarit and methotrexate in the treatment of refractory rheumatoid arthritis

Additive combination of actarit and methotrexate in the treatment of refractory rheumatoid arthritis

The objective of this study was to evaluate the efficacy and safety of an additive combination of a disease-modifying antirheumatic drug (DMARD) actarit and low-dose methotrexate (MTX) in patients with active rheumatoid arthritis (RA) unresponsive to MTX. Thirty-four patients with active RA, who had been unsuccessfully treated with MTX for at least 3 months were enrolled on a 24-week course of actarit (300 mg/day) and MTX (2.5–10 mg/week). Disease activity was evaluated by physical global assessments using conventional measures (Japan Rheumatism Association), and the American College of Rheumatology (ACR) criteria of improvements in RA. Thirty-two patients completed this study. No severe adverse drug reactions were seen. Patients whose RA did not respond to MTX alone responded to the combination therapy, with a significant improvement in the duration of morning stiffness, grip strength, swollen joint counts, patient's articular pain score, modified health assessment questionnaire (M-HAQ) score, score of both patient's and physician's global assessments, and C-reactive proteins (CRP). Sixteen patients (50.0%) and 9 patients (31.0%) showed a significant improvement in overall conventional measures, and ACR response criteria, respectively, and 60.0% of RA patients who received MTX for more than 1 year showed improvement in ACR definition. Patients who responded to the combination treatment within the first 12 weeks showed persistent improvement for the remaining part of the 24 week period. Our results indicate that the additive combination of actarit and MTX is safe, and without serious adverse effects, and has an excellent efficacy in patients with active and refractory RA.