Refractory Rheumatoid Arthritis Research Articles

Circulating Biomarkers for Predicting Infliximab Response in Rheumatoid Arthritis: A Systematic Bioinformatics Analysis.

BackgroundInfliximab shows good efficacy in treating refractory rheumatoid arthritis (RA). However, many patients responded poorly and related studies were inconsistent in predictive biomarkers. This study aimed to identify circulating biomarkers for predicting infliximab response in RA.Material/MethodsPublic databases of Gene Expression Omnibus (GEO) and ArrayExpress were searched for related microarray datasets, focused on the response to infliximab in RA. All peripheral blood samples were collected before infliximab treatment and gene expression profiles were measured using microarray. Differential genes associated with infliximab efficacy were analyzed. The genes recognized by half of the datasets were regarded as candidate biomarkers and validated by prospective datasets.ResultsEight microarray datasets were identified with 374 blood samples of RA patients, among which 191 (51.1%) were diagnosed as non-responders in the subsequent infliximab treatment. Five genes (FKBP1A, FGF12, ANO1, LRRC31, and AKR1D1) were associated with the efficacy and recognized by half of the datasets. The 5-gene model showed a good predictive power in random- and prospective-designed studies, with AUC (area under receiver operating characteristic [ROC] curve)=0.963 and 1.000, and it was also applicable at the early phase of treatment (at week 2) for predicting the response at week 14 (AUC=1.000). In the placebo group, the model failed to predict the response (AUC=0.697), indicating the model’s specificity in infliximab treatment.ConclusionsThe model of FKBP1A, FGF12, ANO1, LRRC31, and AKR1D1 in peripheral blood is useful for efficiently predicting the response to infliximab treatment in rheumatoid arthritis.

Fungal periprosthetic joint infection following total elbow arthroplasty: a case report and review of the literature

BackgroundWith improving surgical techniques for total elbow arthroplasty clinical outcomes have improved and its utilization continues to increase. Despite these advances, complication rates remain as high as 24%. Of these complications periprosthetic joint infection is one of the most common and morbid. The rheumatoid elbow remains a leading indication for total elbow arthroplasty. Patients with this condition frequently require immunosuppressive therapy, which places them at higher risk of both typical and atypical infections.Case presentationWe present the case of a persistent, late-onset periprosthetic joint infection in a total elbow arthroplasty of a 64-year-old Caucasian woman with severe refractory rheumatoid arthritis. The offending pathogen, Aspergillus terreus, is previously unreported in the arthroplasty literature and grew concurrently with coagulase-negative staphylococcus. Eradication of the fungal and bacterial agents involved resection arthroplasty, serial debridement, and multiple courses of intravenous and oral antimicrobial therapy. Two attempts at reimplantation arthroplasty failed to eliminate the infection and our patient ultimately required definitive resection arthroplasty.ConclusionsArthroplasty in the rheumatoid elbow confers with it a high complication rate. Inflammatory disease and immunosuppressive drugs combined with the subcutaneous anatomy of the elbow contribute to the risk of infection. Fungal periprosthetic joint infection in the rheumatoid patient presents both diagnostic and therapeutic challenges. Fungal growth should always be treated and requires organism-specific antimicrobials in conjunction with surgical debridement. More literature is needed to determine the optimal treatment regimen for this devastating complication.

The effectiveness of new triple combination therapy using synthetic disease-modifying anti-rheumatic drugs with different pharmacological function against rheumatoid arthritis: the verification by an in vitro and clinical study.

The study aims to confirm the feasibility of new oral triple combination therapy using methotrexate (MTX), mizoribine (MZR), and tacrolimus (TAC) in patients with rheumatoid arthritis (RA) by in vitro and clinical analyses. Triple therapy with a combination of MTX, MZR, and TAC was used for an in vitro study with osteoclasts and a prospective clinical study in order to show the efficacy of these agents against refractory RA. In particular, low-dose TAC or MZR was added to treat 14 patients with RA that was resistant to MTX+MZR or MTX+TAC dual therapy. The combination of three pharmacological agents showed statistically significant differences to reduce differentiation induction and activity of osteoclasts compared with single and double agents. In clinical use, triple therapy showed a statistically significant difference in the improvement of Disease Activity Score-28-erythrocyte sedimentation rate and the Simple Disease Activity Index score at around 8months. Additionally, the serum matrix metalloproteinase-3 level significantly decreased. No patients dropped out because of adverse effects. Based on this in vitro and prospective clinical study, oral triple therapy might be effective against refractory RA. Furthermore, this therapy might be safe and economical for clinical practice.

Combination leflunomide and methotrexate in refractory rheumatoid arthritis: a biologic sparing approach.

In resource-constrained settings where biologic agents are not widely available, there are limited therapeutic options for patients with rheumatoid arthritis (RA) refractory to other synthetic disease modifying antirheumatic (DMARD) therapies. The aim of this study is to evaluate the effectiveness and safety of leflunomide (LEF) with methotrexate (MTX) in refractory RA. A retrospective record review of adult RA patients treated with LEF/MTX. Demographic details, adverse reactions, and the 3-variable 28 joint disease activity score (DAS28-3) were recorded at initiation of LEF/MTX therapy, and after 4 and 12 months of treatment. Of 194 patients, most were middle-aged seropositive Black African females, with established disease [mean (standard deviation, SD) disease duration 9.4 (8.2) years] and time on previous DMARDs of 7.0 (5.5) years. Before adding LEF, the mean (SD) dose of MTX was 21.7 (3.5) mg/week, and 87.6% of patients used low dose oral corticosteroids. A good or moderate EULAR response was achieved by 44% and 42% of patients, and the retention rate was 71%. Major infections were seen in 6 patients: comprising 2 deaths, 3 cases of leucopaenia and septicaemia and 1 case of tuberculosis. Hepatotoxicity (n = 3), intolerable gastrointestinal symptoms (n = 3), and hypertension (n = 17) were the most common problems. Predictors of remission or low disease activity at 12 months was a baseline DAS28-3 ⩽ 5.5 [odds ratio (OR) = 2.7; 95% confidence interval (CI) 1.1-5.6; p = 0.01]. LEF/MTX was effective in the majority of patients in this cohort of mainly Black African women who failed other combination synthetic DMARDs, particularly in those with moderate disease activity at the time of addition of LEF. Infections and hypertension were important complications. In a setting where biologic DMARDs are not readily accessible, the combination of LEF/MTX is a cost-effective approach.

Safety and efficacy of the leukocytapheresis procedure in eighty-five patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory disease in which the predominant symptom is polyarthritis that follows a chronic and progressive clinical course characterized by destructive synovitis and various immune disorders. Striking progress in RA treatment was achieved with the emergence of monoclonal antibodies to target cytokines. However, drug choices are limited for many patients due to resistance to multidrug antirheumatic therapy, concomitant disease, and infection. We evaluated the efficacy of treatment in 85 patients with RA for whom leukocytapheresis (LCAP) was initiated at our hospital between 2006 and 2015. All patients continued drug therapy and were treated with LCAP once a week for up to 5 weeks. The clinical response was evaluated at the completion of LCAP series and 4 weeks later using the American College of Rheumatology (ACR) criteria and the 28-joint disease activity score (DAS28) of European League Against Rheumatism (EULAR). The tender joint counts, swollen joint counts, and C-reactive protein (CRP) levels decreased remarkably. DAS28-CRP was significantly improved by LCAP. And furthermore, the efficacy lasted at least 4 weeks after the completion of LCAP. These results suggest that LCAP is a beneficial and are consistent with several trials' reported effect of LCAP. This treatment can contribute to improvements in activities of daily living (ADLs) and long-term outcome by improving swollen and tender joint counts and CRP levels even in refractory patients for whom the use of conventional disease-modifying antirheumatic drugs (DMARDs) and biopharmaceuticals is problematic. LCAP might be a promise therapy to refractory RA.

Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial

ObjectivesTo evaluate the safety and tolerability of the intravenous administration of Cx611, a preparation of allogeneic expanded adipose-derived stem cells (eASCs), in patients with refractory rheumatoid arthritis (RA), as well...

Rituximab as first choice for patients with refractory rheumatoid arthritis: cost-effectiveness analysis in Iran based on a systematic review and meta-analysis.

The aim of this study was to evaluate the effectiveness and cost-effectiveness of using rituximab as first line for patients with refractory rheumatoid arthritis in comparison with continuing conventional DMARDs, from a perspective of health service governors. A systematic review was implemented through searching PubMed, Scopus and Cochrane Library. Quality assessment was performed by Jadad scale. After meta-analysis of ACR index results, QALY gain was calculated through mapping ACR index to HAQ and utility index. To measure the direct and indirect medical costs, a set of interviews with patients were applied. Thirty-two patients were selected from three referral rheumatology clinics in Tehran with definite diagnosis of refractory rheumatoid arthritis in the year before and treatment regimen of either rituximab or DMARDs within last year. Incremental cost-effectiveness ratio was calculated for base case and scenario of generic rituximab. Threefold of GDP per capita was considered as threshold of cost-effectiveness. Four studies were eligible to be considered in this systematic review. Total risk differences of 0.3 for achieving ACR20 criteria, 0.21 for ACR50 and 0.1 for ACR70 were calculated. Also mean of total medical costs of patients for 24weeks were $3985 in rituximab group and $932 for DMARDs group. Thus, the incremental cost per QALY ratio will be $45,900-$70,223 in base case and $32,386-$49,550 for generic scenario. Rituximab for treatment of patients with refractory rheumatoid arthritis is not considered as cost-effective in Iran in none of the scenarios.

Tocilizumab in refractory rheumatoid arthritis: long-term efficacy, safety, and tolerability beyond 2 years.

ObjectivesTo evaluate the long-term efficacy and safety of tocilizumab (TCZ) in clinical patients with rheumatoid arthritis (RA) refractory to synthetic disease-modifying antirheumatic drugs, anti-tumor necrosis factor agents, and B-cell depletion therapy with rituximab (RTX).MethodsWe conducted a single-center retrospective study of 22 patients with RA treated with TCZ. We collected data including demographics and medication histories. We recorded clinical parameters including tender joint counts and swollen joint counts, and laboratory parameters including inflammatory makers and lipid profiles over regular intervals of TCZ treatment.ResultsIn all, 22 patients with RA were included, 20 of whom were female. The median age at the first dose of TCZ was 62 years (range: 35–75 years). The mean duration of the disease from diagnosis with RA to May 2015 was 15.7 years (range: 6–30 years). A total of 15 out of 22 patients remained on TCZ at the end of the study, and in all, there was an improvement in markers of disease activity following initiating TCZ. The effect was sustained for a mean of 35 months (SD±15.5 months, range: 9–72 months). Of the 17 patients who failed to respond to RTX previously, 12 patients remained on TCZ. In all, eight out of 22 patients developed adverse events, five of whom discontinued TCZ. In contrast to previously documented short-term data, TCZ did not result in a statistically significant (P<0.05) long-term deterioration in lipid profile for any of the lipid parameters measured in our cohort (mean ± SD at initiation of TCZ to most recent follow-up: total cholesterol 5.25±1.05 to 5.28±0.77 mmol/L, high-density lipoprotein 1.72±0.54 to 1.67±0.43 mmol/L, low-density lipoprotein 3.05±0.98 to 2.98±0.81 mmol/L, and cholesterol to high-density lipoprotein ratio 3.41±1.23 to 3.40±1.22).ConclusionThe efficacy of TCZ in patients with RA refractory to disease-modifying drugs, including anti-tumor necrosis factor blockade and RTX, is sustained over 3 years. TCZ confers a good safety profile in the long term even in patients who previously developed adverse events to other rheumatic drugs. In the long run, there is no statistically significant deterioration in lipid profile during treatment with TCZ.

Overexpression of P-glycoprotein on fibroblast-like synoviocytes in refractory rheumatoid arthritis patients: a potential mechanism for multidrug resistance in rheumatoid arthritis treatment.

This study aims to investigate the role of P-glycoprotein (P-gp) expression level in drug resistance to disease-modifying anti-rheumatic drugs in refractory rheumatoid arthritis (RRA). We evaluated and compared the expression levels of P-gp in fibroblast-like synoviocyte (FLS) cells in patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and investigated the potential mechanism of P-gp-induced multidrug resistance in RRA. Ten patients were enrolled and divided into two groups: six in the RA group and four in the OA group. The expression level of P-gp in FLS cells was detected by western blotting following cell culture. A linear correlation algorithm was used to assess the association between the level of P-gp and disease activity (using DAS28 scoring), as well as the duration of methotrexate (MTX) treatment in the RRA patients. The level of P-gp in the RRA patients was markedly higher than that in the OA patients (P < 0.05, t = -4.179). There was a positive linear correlation between the P-gp level in FLS cells and the duration of MTX treatment in the RRA group (Г = 0.733, P < 0.05), whereas there was no significant correlation between the P-gp level and DAS28 scoring (Г = 0.206, P > 0.05). P-gp might be upregulated during the progression of RRA, which possibly correlates with the development of resistance to MTX.

New small molecule drug shows promise in refractory rheumatoid arthritis

New small molecule drug shows promise in refractory rheumatoid arthritis

Protection against Methotrexate Induced Hepato-Renal Toxicity in Rats by Zinc and its Combination with Vitamin C and Vitamin E

Methotrexate, a well-known cytotoxic chemotherapy, anti-folate, immunosuppressant and effectively treats all major disorders like cancer, psoriasis, refractory rheumatoid arthritis, etc. It is widely and mostly used drug having multitherapy properties and well tolerated, however, its cytotoxic nature leads to many serious side effects, including hepato-renal toxicity, so it is necessary to reduce its side effect and get its benefit. Among all hypothesis, oxidative stress and toxic metabolite are the noticeable cause of toxicity. The present study investigated the protective effects of Zinc alone and its combination with vitamin C and vitamin E against the methotrexate induced hepato-renal toxicity in male albino rats. Zinc is a well-known potent anti-oxidant that scavenges the free radical in tissues. Vitamin C and vitamin E are water soluble and insoluble antioxidant, respectively. In conclusion, the rats treated with zinc alone and its combination with vitamin C and vitamin E had a significant decrease in the level of creatinine, urea, total bilirubin, SGOT, SGPT in blood serum when compared with methotrexate treated rats. Similarly the activity of catalase and reduced glutathione were enhanced and lipid peroxidase was decreased. Histopathology report confirmed the hepato-renal protectivity of Zinc and its combination with vitamin C and vitamin E by restoring the normal architecture of liver and kidney.

Low pre-treatment B-cell counts are not a risk factor of infection in patients treated with rituximab for autoimmune diseases: An observational study

ObjectivesRituximab (RTX) is increasingly used in patients with refractory rheumatoid arthritis (RA) and other severe autoimmune diseases (AID). In practice, many clinicians are reluctant to prescribe RTX in patients with low B-cell counts because of the presumed risk of infection. The aim of this study was therefore to investigate whether B-cell counts before treatment or retreatment with RTX predict the occurrence of infections. MethodsObservational, single-centre study of 161 patients treated with RTX for RA and other AID at a tertiary hospital. CD19+ B-cell counts were assessed by flow cytometry and multivariate statistical analysis adjusted for various potential predictors was performed. ResultsThe rate of severe infection was 5.9/100 patient-years in RA patients and 24.9 in non-RA AID (P<0.001). Low B-cell counts at the time of RTX infusion were not associated with subsequent severe (HR=0.55, P=0.60) or overall infection (HR=0.85, P=0.58). Significant pre-treatment predictors of severe infection were a diagnosis other than RA (HR=4.68, P<0.001), immunoglobulin (Ig) G levels <7g/L (HR=2.36, P=0.01), age (HR=1.03, P=0.01), and diabetes (HR=3.61, P=0.01). ConclusionsLow B-cell counts before RTX infusion did not predict subsequent infections in this population treated with RTX for RA and other AID, therefore not supporting the practice of pre-treatment assessment of B-cells. Nevertheless, a higher risk of severe infection was confirmed for low pre-treatment IgG levels, older age, diabetes, and AID other than RA.

Adrenocorticotropic hormone gel in patients with refractory rheumatoid arthritis: a case series

While many patients with rheumatoid arthritis respond to treatment with disease-modifying antirheumatic drugs, some patients have refractory disease. The mechanism of action of adrenocorticotropic hormone (ACTH) gel and its direct action on melanocortin receptors is thought to result in steroid-independent anti-inflammatory and immunomodulatory effects, in addition to steroidogenic effects. ACTH gel may provide efficacy for patients who previously failed treatment with prednisone or disease-modifying antirheumatic drugs. In this case series, we report five patients with refractory rheumatoid arthritis on ACTH gel who have failed up to five previous treatments. In these patients, ACTH gel provided improvements in inflammatory markers and/or patient-reported symptoms in each case.

Predictors of European League Against Rheumatism (EULAR) good response, DAS-28 remission and sustained responses to TNF-inhibitors in rheumatoid arthritis: a prospective study in refractory disease.

The aim of this study was to survey factors related to EULAR good response, the DAS-28 definition of remission, ACR 50 response, sustained response to tumor necrosis factor inhibitors (TNF-I) therapy in biologic naïve patients with refractory rheumatoid arthritis. This was a single center observational clinical prospective 2 years’ study, EULAR response criteria, DAS 28, HAQ and radiographic changes were recorded. Eighty patients included (64 females and 16 males, mean age was 48.4 + −17.9 years, mean disease duration 7.3 + −5.9 years). At 6 months 70% achieved EULAR good response, 51.8% achieved DAS-28 remission. Good response/sustained responses inversely correlated with baseline DAS-28 and radiographic erosions P <0.05. EULAR good response/remission by 6 months, sustained response at 2 years positively correlated with the decline in RF titers (r = 0.33, P < 0.05 & r = 0.30, P < 0.03 respectively), negatively correlated with the baseline HAQ. Regression analysis identified higher serum hemoglobin concentration, lower baseline HAQ scores, and the absence of radiographic erosions as significant predictors of good as well as sustained responses after adjustment for potential covariates. Methotrexate was associated with favorable responses and remission at 6 months (ORs = 1.13, 1.30 respectively). The study concluded that a lower baseline DAS-28 and HAQ scores, the lack of radiographic erosions favored EULAR good response and were significant predictors of sustained response to TNF-I.

Rituximab for rheumatoid arthritis.

Rituximab for rheumatoid arthritis.

The Synovial Signature and Response to Biologics-A step towards Personalized Medicine in Refractory Rheumatoid Arthritis

Rheumatoid Arthritis is a multi-system autoimmune disease in which symmetrical joint inflammation, hyperplasia of the synovium, and formation of invasive granulation tissue (pannus) stand out as distinctive disease features. The advancing disease process eventually proceeds to joint destruction with deformity and persistent disability [1-3]. Through-out its’ history the disease have displayed a complex heterogeneity in both disease course and patient response to therapy. Clinical response depends on disease state and disease characteristics indeed there are different subtypes of RA with different genetic backgrounds that interpret into benign or destructive, seropositive versus seronegative RA.

PMS53 - Rituximab as First Choice for Patients With Refractory Rheumatoid Arthritis: Cost-Effectiveness Analysis in Iran Based on A Systematic Review and Meta-Analysis

The aim of this study was to evaluate the effectiveness and cost-effectiveness of using rituximab as first line for patients with refractory rheumatoid arthritis in comparison with continuing conventional DMARDs, from a perspective of health service governors. A systematic review was implemented through searching PubMed, Scopus and Cochrane Library. Quality assessment was performed by Jadad scale. After meta-analysis of ACR index results, QALY gain was calculated through mapping ACR index to HAQ and utility index. To measure the direct and indirect medical costs, a set of interviews with patients were applied. Thirty-two patients were selected from three referral rheumatology clinics in Tehran with definite diagnosis of refractory rheumatoid arthritis in the year before and treatment regimen of either rituximab or DMARDs within last year. Incremental cost-effectiveness ratio was calculated for base case and scenario of generic rituximab. Threefold of GDP per capita was considered as threshold of cost-effectiveness. Four studies were eligible to be considered in this systematic review. Total risk differences of 0.3 for achieving ACR20 criteria, 0.21 for ACR50 and 0.1 for ACR70 were calculated. Also mean of total medical costs of patients for 24 weeks were $3985 in rituximab group and $932 for DMARDs group. Thus, the incremental cost per QALY ratio will be $45,900–$70,223 in base case and $32,386–$49,550 for generic scenario. Rituximab for treatment of patients with refractory rheumatoid arthritis is not considered as cost-effective in Iran in none of the scenarios.

Expression of Survivin in Patients With Refractory Rheumatoid Arthritis in a Chinese Population

Results: The survivin level was significantly higher in the refractory group than healthy controls (270.04±23.03 pg/ml vs. 116.68±19.07 pg/ml, p<0.05) and treatment-responsive group (270.04±23.03 pg/ml vs. 127.37±11.42 pg/ml, p<0.05). The survivin level in refractory RA patients was positively correlated with the Disease Activity Score 28. Immunohistochemical analysis revealed that survivin expression was significantly higher in the synovial tissues of refractory RA patients compared to treatment-responsive patients and healthy controls. Conclusion: The results of this study showed that survivin is overexpressed in refractory RA patients and the serum survivin level is correlated with disease activity.

FRI0323 Prospective Follow-Up of Tocilizumab Treatment in 1503 Patients with Refractory Rheumatoid Arthritis: Tolerance Data at 1 Year from the French Registry Regate (Registry – Roactemra)

ObjectivesTo assess tolerance and safety of rheumatoid arthritis (RA) treatment by tocilizumab (TCZ) in real lifeMethodsThe French Society of Rheumatology set up the REGATE registry to prospectively collect, at 3...

The Role of Anti-TNFα Therapy in the Amelioration of Disease Burden in Patients with Refractory Rheumatoid Arthritis

To evaluate the changes in anti cyclic citrullinated peptide (Anti-CCP) antibodies,rheumatoid factor (RF), interleukins 17 and 10 (IL-17 and IL-10), high sensitivity C- reactiveprotein (hs CRP) and T regulatory cells (Treg) count following an anti TNF-α biological agent(etanercept) therapy in patients with rheumatoid arthritis.Refractory rheumatoid arthritis patients who failed treatment with DMARDs (diseasemodifying anti rheumatic drugs) were treated with etanercept for three months. Serum and bloodsamples were tested before and after therapy for six markers including ACCP, RF, IL- 10, IL 17,hs CRP, and Treg cell. A significant dropping down in the serum level of ACCP, RF and hs CRPwas documented 3 months after etanercept therapy. On the other hand a non- significant elevationin IL-10 serum level and peripheral blood Treg cell count, as well as a non significant droppingdown in the serum level of IL-17 were also reported. Etanercept is a successful anti-TNF-αtherapy in refractory RA patients for the first three months of the course therapy as indicated byclinical improvement and amelioration in 6 disease activity markers.