Secondary failure to treatment with recombinant human IL-1 receptor antagonist in Chinese patients with rheumatoid arthritis

The aim of this study is to assess the efficacy of anakinra, a recombinant human interleukin 1 receptor antagonist, plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) refractory to MTX therapy. A total of 54 patients with active RA, who were taking MTX at a stable dosage, were randomized to receive daily subcutaneous injections of anakinra (80 mg) or placebo. Clinical outcomes were assessed every 4 weeks for 24 weeks by using the criteria of the American College of Rheumatology. After 24 weeks, more patients achieved clinical benefits as determined by the ACR20 improvement treated with anakinra plus MTX compared with MTX alone (64% vs. 17%, P = 0.004). In the anakinra group, an ACR50 response was observed in 38% and an ACR70 response in 17%. None of the patients treated with MTX alone achieved ACR50 or ACR 70 improvement. However, nine of 42 (21.4%) patients in the anakinra group, who showed therapeutic response initially, had secondary drug failure to anakinra therapy thereafter. A significant increase in mean DAS28 from baseline was found in the non-responders to anakinra compared with placebo (0.83 ± 1.38 vs. −1.28 ± 0.78, P < 0.001). Anakinra is effective in the treatment of patients with active RA by blocking IL-1. However, the efficacy of anakinra is soon lost in about one fifth of patients in spite of initial good response.     

Randomized double blind trial of an ayurvedic plant derived formulation for treatment of rheumatoid arthritis

OBJECTIVE: To evaluate RA-1, a standardized plant extract formulation, traditionally considered a safe, effective antiarthritic in the Asian-Indian Ayurvedic medicinal system. METHODS: One hundred eighty-two patients with active-on-chronic rheumatoid arthritis (RA) participated in a 16 week randomized, double blind, placebo controlled, parallel efficacy clinical drug trial in Pune, India. Tenderness, pain, swelling, and several other efficacy measures were assessed by (1) ACR core set 20% and 50% improvement; (2) ACR 20% improvement response. An intent-to-treat analysis was performed; p<0.05 considered significant. RESULTS: Seventeen patients withdrew (active = 9; placebo = 8); none withdrew due to drug toxicity. An unprecedented placebo response (often p<0.001 in within-group change) was observed. The active RA-1 group remained numerically superior at all evaluation timepoints. RA-1 demonstrated few significant differences: (1) increased proportion with 50% reduction in swollen joint count (95% CI approximately 1.52, 29.90) and swollen joint score (95% CI approximately 0.91, 28.73); (2) reduced rheumatoid factor (95% CI approximately -303.7, -2.72); 39% in the RA-1 group versus 30% placebo showed ACR 20% improvement (95% CI approximately -5.48, 24.59). Only minor side effects were seen, with no significant differences by treatment group. CONCLUSION: In a trial with sufficient power, RA-1 revealed efficacy that was not significantly superior to the strong placebo response, except for improvement in joint swelling. Further, the effect on RF and good safety profile led to an open label phase.     

A randomized,double‐blind,placebo‐controlled,phase III study of the human anti‐tumor necrosis factor antibody adalimumab administered as subcutaneous injections in Korean rheumatoid arthritis patients treated with methotrexate

Objective: Adalimumab is a fully human, monoclonal, antitumour necrosis factor antibody approved for the treatment of rheumatoid arthritis (RA) in more than 60 countries. We investigated the efficacy and safety of 40 mg every‐other‐week (eow) subcutaneous injections of adalimumab with methotrexate (MTX) versus placebo with MTX in Korean patients with RA with insufficient responses to MTX. Methods: This was a 24‐week, randomized, double‐blind, placebo‐controlled, phase III study conducted at six sites in Korea. The primary efficacy endpoint was a 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Secondary endpoints included ACR50, ACR70, and individual ACR components. Beginning at week 18, non‐responders (< 20% reduction in swollen and tender joint counts) could switch to rescue therapy with open‐label adalimumab 40 mg eow. Results: Of the 128 patients enrolled, 65 received adalimumab and 63 received placebo. An ACR20 response at week 24 was achieved by 61.5% of patients receiving adalimumab versus 36.5% receiving placebo (P < 0.01). ACR50 and ACR70 responses were achieved by 43.1% and 21.5% of adalimumab patients versus 14.3% and 7.9% of placebo patients (P < 0.001 and P < 0.05, respectively). Adalimumab significantly improved all seven ACR core components. Statistically significant improvements in ACR20 were observed with adalimumab as early as week 2. Adalimumab was generally well tolerated; there were no significant differences in incidences of adverse events between groups. Conclusions: In Korean patients with RA with insufficient responses to MTX, combination therapy with adalimumab and MTX was more efficacious than placebo and MTX in reducing RA signs and symptoms.     

The efficacy and safety of rituximab for the treatment of active rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials

The aims of this study were to assess the efficacy and safety of rituximab in patients with active rheumatoid arthritis (RA). The authors surveyed randomized controlled trials (RCTs) that examined the efficacy of rituximab in disease modifying anti-rheumatic drug (DMARD) (including methotrexate [MTX]) or tumor necrosis factor (TNF)-blocker-resistant or intolerant patients with active RA using Medline, the Cochrane Controlled Trials Register, and manual searches. Meta-analysis of RCTs was performed to determine the treatment efficacy and safety outcomes of rituximab (1 course, consisting of two infusions of 1,000 mg each) concomitant with MTX. The three RCTs included 938 DMARD or TNF-blocker-resistant or intolerant RA patients. Follow-up periods ranged from 24 to 48 weeks. American College of Rheumatology response (ACR) 20, ACR50, and ACR70 response rates were significantly higher for the rituximab plus MTX than for placebo controls (primary efficacy outcome, ACR50; risk ratio [RR] 3.648, 95% confidence interval [CI] 2.478–5.369, P < 0.001). For those treated with rituximab, the incidence adverse events of all systems were not higher than in those treated with placebo (RR 1.062, 95% CI 0.912–1.236, P = 0.438). With respect to the number of patients that experienced at least one serious adverse event, no significant difference was observed between patients treated with rituximab and placebo (RR 0.855, 95% CI 0.622–1.174, P = 0.333). A single course of rituximab with concomitant MTX therapy was found to be effective in DMARD or TNF-blocker-resistant or intolerant patients with active RA.     

Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study

Abstract

This multicenter, double-blind study evaluated the effects of three doses of adalimumab in Japanese patients with rheumatoid arthritis (RA). Patients were randomized to placebo (n = 87) or adalimumab 20 mg (n = 87), 40 mg (n = 91), or 80 mg (n = 87) every other week for 24 weeks. The primary efficacy endpoint was the American College of Rheumatology criteria for 20% improvement (ACR20) at Week 24. At Week 24, all adalimumab treatment groups achieved statistically significantly better ACR20 response rates (20 mg: 28.7%, P < 0.05; 40 mg: 44.0%, P < 0.001; and 80 mg: 50.6%, P < 0.001) versus placebo (13.8%), as well as statistically significantly greater ACR50 and ACR70 responses for the two higher adalimumab doses versus placebo. Rates of adverse events were comparable between the adalimumab groups and the placebo group, except for injection-site reactions, which occurred in more adalimumab-treated patients. Adalimumab 20, 40, and 80 mg were safe and effective in Japanese patients; however, the greatest responses occurred with the 40 and 80 mg doses. These results and comparable ACR20 responses in Western patients support adalimumab 40 mg every other week as the appropriate dosage to treat RA in Japanese patients.     

Association of tri-nucleotide (CAG and GGC) repeat polymorphism of androgen receptor gene in Taiwanese women with refractory or remission rheumatoid arthritis

We investigated the relationship between CAG and GGC repeat polymorphism of the androgen receptor (AR) gene and rheumatoid arthritis (RA) in female patients with different disease subtypes. This case-control study enrolled 215 women in three groups: RA patients refractory to standardized therapy (n = 51); RA patients at complete remission phase (n = 60); and healthy controls (n = 104). CAG and GGC repeat lengths were determined by automated fluorescence-based DNA fragment-sizing method. Demographic data, allele lengths, allele distribution, and zygosity status of CAG/GGC repeats were assessed for the three groups. Refractory RA patients tend to have a significantly younger onset age of RA and more elevated erythrocyte sedimentation rates than do remission RA patients. Mean and median values of CAG and GGC repeat lengths are similar in both RA and control patients. However, RA patients harboring any long CAG alleles with more than 23 repeats had an increased risk of a refractory course, whereas differences in risk were not observed between these patients and RA subtypes harboring any long GGC alleles with more than 16 repeats. In addition, the homozygous frequency of CAG but not GGC alleles was lower in refractory RA than in remission RA patients or in controls (p = 0.042). Neither CAG nor GGC repeat lengths had a significant relationship with rheumatoid factor reactivity. Our observations indicate that short CAG repeats of the AR gene with higher transactivation activity may have protective effects against refractory course of RA development and that homozygous frequency of CAG alleles may be involved in the disease remission subtype. In contrast, lack of association of GGC polymorphism and RA was also observed. Together, these data imply that CAG but not GGC alleles in the AR polymorphism may play an important role in modulating the disease pattern of RA among Taiwanese women.     

Treatment of rheumatoid arthritis with ornidazole: a randomized, double-blind, placebo-controlled study

The aim of our study was to evaluate the clinical efficacy, safety, and tolerability of ornidazole in patients with rheumatoid arthritis (RA). This was 3 months, randomized, double-blind,placebo-controlled study. A total of 160 patients with active RA were randomly assigned to receive 1,000 mg ornidazole (n = 53), 500 mg ornidazole (n = 55), or placebo (n = 52). A significantly greater percentage of patients treated with 1,000 mg ornidazole met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at 3 months compared with patients who received placebo (62.0 vs. 32.4%; P < 0.001). Greater percentages of patients treated with 1,000 mg ornidazole also achieved ACR50 responses (38.3 vs. 10.9%; P < 0.001) and ACR70 responses (19.6 vs. 1.2%; P < 0.001) compared with patients who received placebo. Ornidazole treatment was also associated with significant reductions in pain and duration of morning stiffness, significant improvement in the quality of life and both the physician’s and patient’s global assessments, and significant reductions in disease activity as assessed by objective laboratory measures (erythrocyte sedimentation rate and C-reactive protein level). Ornidazole was well tolerated. There were no dose-limiting toxic effects. In this 3-month-trial ornidazole was safe, well tolerated, and associated with improvement in the inflammatory symptoms of RA.     

A pilot study of acupuncture as adjunctive treatment of rheumatoid arthritis

We evaluated the efficacy of acupuncture as a useful adjuvant treatment in the management of rheumatoid arthritis (RA). A pilot, randomized, double-blind, and controlled clinical trial was conducted. Forty RA patients with active disease despite stable therapy for at least the preceding 1 month were randomized to receive a standard protocol of acupuncture (AC) or superficial acupuncture at non-acupuncture points (controlAC) for 9 weeks. The primary outcome was achievement of 20% improvement according to the American College of Rheumatology (ACR) 20 criteria after five and ten treatment sessions and after 1 month of follow-up. Secondary measures included Disease Assessment Scale (DAS), tender and swollen joint count, morning stiffness, Health Assessment Questionnaire (HAQ), visual analogue scale (VAS) of pain, physician global assessment of activity disease, physician and patient global assessment of treatment, and inflammatory markers (erythrocyte sedimentation rate and C-reactive protein). There was not significant difference between the groups regarding the number of patients that reached ACR20 at the end of the treatment (p = 0.479). However, after 1 month of follow-up, there was a trend in favor of the AC group, with p = 0,068. Compared with the controlAC, the AC group also demonstrated significant improvement in the patient and physician global assessment of treatment and physician global assessment of disease activity, but there was no difference on other clinical and laboratorial measures. On the other hand, only the AC patients had within group improvement on the variables DAS, HAQ, morning stiffness, patient and physician global assessment of treatment, and physician global assessment of disease activity in comparison to baseline visit. Despite the improvement of some studied variables, there was no significant difference in the proportion of patients that reached ACR20 between the AC and controlAC groups. This negative result can be related to the small sample size, selection of patients, type of acupuncture protocol applied, and difficulties in establishing an innocuous and trustworthy placebo group to studies involving acupuncture.     

Randomized double‐blind clinical drug trials of meloxicam in rheumatoid arthritis and osteoarthritis knees: an Indian experience

Background: Indian data from controlled drug trials on the use of meloxicam (a new preferential COX‐2 inhibitor) and other non‐steroidal anti‐inflammatory drugs (NSAIDs) in arthritis is sparse. Aim: To evaluate the clinical efficacy and safety of meloxicam. Patients and methods: One hundred and twenty‐one patients with rheumatoid arthritis (RA) and 133 patients with osteoarthritis (OA) knees were randomized into two different multicentric, double‐blind, drug trials of four‐weeks duration each. Meloxicam 7.5 mg (OA study) and 15 mg (RA study) was compared to diclofenac 100 mg and piroxicam 20 mg in daily dosages, respectively. Strict eligibility criteria ensured active symptomatic disease. Standard ACR efficacy measures of pain and function (including validated Indian versions of HAQ & WOMAC) were used. Protocol‐driven evaluations were carried out throughout the study. An intent‐to‐treat efficacy analysis (significance at P < 0.05) was carried out to test the hypothesis of equal efficacy between meloxicam and comparator. Results: (i) There were no significant differences between meloxicam and piroxicam in the RA study. (ii) While joint count for pain/tenderness was improved (P < 0.05) by both meloxicam and piroxicam, only meloxicam showed significant improvement (95% CI ≈ 0.7,5.6) in swollen joint count. (iii) In the OA study, though painVAS reduction was marginally better (95% CI ≈ ?15,?0.6) with diclofenac, both meloxicam and diclofenac were equally effective (95% CI ≈ ?10,2.0) in improving WOMAC‐physical function. (iv) Overall, meloxicam demonstrated a superior safety and gut tolerability profile as compared to piroxicam (maximum adverse events, 29.3%) and diclofenac. (iv) Maximum dyspepsia (6.2%) was reported by the diclofenac group. (v) Overall, the drug toxicity seen in the trials was mild, and only one patient (on diclofenac) was withdrawn due to haematuria. (vi) All treatment groups consumed paracetamol (P > 0.05) as a rescue analgesic. Conclusions: When compared to piroxicam and diclofenac, meloxicam has equal clinical efficacy and a better safety profile. Multicentric control drug trials are feasible in our population.     

Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study

This multicenter, double-blind study evaluated the effects of three doses of adalimumab in Japanese patients with rheumatoid arthritis (RA). Patients were randomized to placebo (n = 87) or adalimumab 20 mg (n = 87), 40 mg (n = 91), or 80 mg (n = 87) every other week for 24 weeks. The primary efficacy endpoint was the American College of Rheumatology criteria for 20% improvement (ACR20) at Week 24. At Week 24, all adalimumab treatment groups achieved statistically significantly better ACR20 response rates (20 mg: 28.7%, P < 0.05; 40 mg: 44.0%, P < 0.001; and 80 mg: 50.6%, P < 0.001) versus placebo (13.8%), as well as statistically significantly greater ACR50 and ACR70 responses for the two higher adalimumab doses versus placebo. Rates of adverse events were comparable between the adalimumab groups and the placebo group, except for injection-site reactions, which occurred in more adalimumab-treated patients. Adalimumab 20, 40, and 80 mg were safe and effective in Japanese patients; however, the greatest responses occurred with the 40 and 80 mg doses. These results and comparable ACR20 responses in Western patients support adalimumab 40 mg every other week as the appropriate dosage to treat RA in Japanese patients.     

Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study

Disease-modifying antirheumatic drug (DMARD) combination therapies are used widely, but there have been few reports clearly demonstrating that combination therapy is more effective than DMARD monotherapy. We conducted a multicenter, double-blind controlled trial in order to clarify that the combination of methotrexate and bucillamine is more effective than either alone. The subjects of this study were 71 patients with active rheumatoid arthritis within 2 years of onset. Dosages were 8 mg methotrexate with 5 mg folic acid per week (MTX group), 200 mg bucillamine per day (BUC group), or both MTX and BUC (combination group). Clinical effects and adverse reactions were observed for 96 weeks. The ACR 20 response rate was 79.2% in the combination group, significantly higher than the rates of 43.5% for the MTX group (P = 0.008) and 45.8% for the BUC group (P = 0.0178). The cumulative survival curve of maintaining the ACR 20 response was significantly higher in the combination group than in the MTX and BUC groups (P = 0.0123 and P = 0.0088, respectively). The mean increase in the total Sharp score over 96 weeks was 12.6 ± 9.0 in the combination group, significantly lower (P = 0.0468) than the value of 28.0 ± 28.3 for the single DMARD (combined MTX and BUC) group. The incidence of adverse reactions did not differ significantly between the three groups. It was concluded that the combination therapy with MTX and BUC showed significantly higher clinical efficacy than either of the single DMARD therapies.     

A cross-sectional and longitudinal comparison of the rome criteria for active rheumatoid arthritis (equivalent to the american college of rheumatology 1958 criteria) and the american college of rheumatology 1987 criteria for rheumatoid arthritis

Objective. To compare the diagnostic properties of the Rome 1961 criteria for active rheumatoid arthritis (RA) and the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) 1987 criteria for RA with regard to their ability to classify, diagnose, and predict outcome in RA. Methods. Analysis of cross-sectional and longitudinal data from repeated health examinations and review of clinical records of 3,509 Pima Indians followed up from January 1966 to December 1990. Results. The ACR 1987 criteria identified ˜50% of the cases identified by the Rome 1961 criteria, in both cross-sectional and longitudinal analyses. The ACR 1987 criteria were better predictors of subsequent development of a clinically supported diagnosis and treatment with slow-acting antirheumatic drugs (both P < 0.001), but were less sensitive than the Rome 1961 criteria for detecting cases for which there already was a clinically supported diagnosis (P < 0.001). Conclusion. In a population-based analysis, the ACR 1987 criteria are less sensitive for detecting clinical disease, but predict a clinically more severe prognosis, compared with the Rome 1961 criteria. The sensitivity of both sets of criteria to identify clinical disease is improved if multiple examinations or inactive disease are taken into account.     

Etanercept can induce resolution of renal deterioration in patients with amyloid A amyloidosis secondary to rheumatoid arthritis

The benefit of biological therapies in rheumatoid arthritis (RA) treatment is well known, but their role in amyloid A (AA) amyloidosis secondary to RA is unclear. The aim of this study was to clarify the clinical benefit of etanercept in RA patients with AA amyloidosis. We treated 14 RA patients who had serum amyloid A protein (SAA) 1.3 allele, with biopsy-confirmed AA amyloidosis with etanercept and investigated the efficacy of etanercept treatment, focusing on renal function retrospectively. The AA amyloidosis improved and stabilized after 89.1 ± 27.2 weeks. Proteinuria decreased from 2.24 ± 0.81 to 0.57 ± 0.41 g/day (P < 0.01) and SAA fell from 250 ± 129 to 26 ± 15μg/ml (P < 0.01), respectively. Diarrhea secondary to gastrointestinal AA amyloidosis was less. Overall, the serum creatinine levels did not benefit with treatment, but in those with a creatinine values <2.0 mg/dl the creatinine level continued to fall (P = 0.021). Serum albumin increased following 96 weeks of etanercept treatment (P = 0.003). Etanercept treatment led to clinical improvement in proteinuria and serum albumin levels accompanied by a fall in SAA levels.     

Disability and patient’s appraisal of general health contribute to depressed mood in rheumatoid arthritis in a large clinical study in Japan

The aim of this study was to evaluate the factors responsible for depressed mood in rheumatoid arthritis (RA). Clinical and laboratory measures were collected from 4558 RA patients enrolled in a large clinical cohort study for RA conducted at the Institute of Rheumatology, Tokyo Women's Medical University (IORRA study). A two-question depressed screening included in the U.S. Preventive Services Task Force recommendation were utilized to identify “depressed patients.” A total of 1875 (41.1%) were identified as “depressed patients” who presented with symptoms suggestive of depression. Patient's Visual Analog Scale (VAS) for general health (43.3 mm vs 24.6 mm, P < 0.0001) and pain (40.9 mm vs 23.8 mm, P < 0.0001) and the disability index scores measured by the Health Association Questionnaire (HAQ) (0.986 vs 0.574, P < 0.0001) were significantly higher in depressed patients than in nondepressed patients. The presence of three or more comorbidities (odds ratio [OR] 2.157, P < 0.0001), infection (OR 1.754, P < 0.0001), and joint surgery (OR 1.878, P < 0.0001) were significantly correlated with depressed mood in RA. The results of the Generalized Linear Model analysis showed that HAQ disability index (P < 0.0001) and patient's VAS for general health (P < 0.0001) were also strongly and significantly associated to the response variable “probability of depressed patients.” Patient appraisal of poor general health and greater disability were associated with depressed mood in RA.     

Serological investigation of IgG levels and subclasses in rheumatoid arthritis patients following ingestion of bovine type II collagen: results of a double blind,randomised controlled trial

The purpose of this study was to investigate whether clinical improvement in patient with rheumatoid arthritis (RA) taking oral Bovine type II collagen (bCII) is associated with changes in levels of anti-bCII total IgG antibody and its subclasses. Four groups were given either 5, 0.5 or 0.05 mg of bCII or a placebo in a double-blind randomised control trial. The sera IgG anti-collagen type II and antibodies of the IgG subclasses, IgG1–4, were measured at the start and end of the trial by ELISA. Total IgG anti-collagen II antibodies in the pooled active treatment groups were statistically significantly reduced compared with the placebo group (p = 0.021). Decreasing total IgG titres were observed in the 0.5-mg group (p = 0.008), 0.05-mg group (p = 0.004) and 5-mg group (p = 0.078) before and after treatment. For IgG1, IgG2, IgG3 and IgG4 subclasses, in the 0.5-mg group in which the best clinical response was observed, there was statistically significant decreases observed in the IgG2 and IgG3 subclasses (p = 0.047, p = 0.046). Treatment with bCII in patients with RA led to a reduction in anti-collagen II antibody titre indicating an active biological effect as observed previously in animal model of RA. The largest decrease in total and subclasses of anti-collagen antibody titres occurred in the groups of patients with the best therapeutic response to bCII, supporting the conclusion of the clinical trial and suggests that immune regulation explains the therapeutic effect.     

Adalimumab response in patients with early versus established rheumatoid arthritis: DE019 randomized controlled trial subanalysis

In recent years, there has been a shift in the therapeutic approach to rheumatoid arthritis (RA), with emphasis on early therapy. The DE019 trial demonstrated adalimumab efficacy in patients with RA. This subanalysis compares response to adalimumab based on clinical, functional, and radiographic outcomes in patients with early versus established RA. Patients enrolled in the DE019 trial were divided into two groups based on disease duration (≤3 years = early RA; >3 years = established RA). Data from 407 patients with RA were included, with 78 early (41 adalimumab, 37 placebo) and 329 established (166 adalimumab, 163 placebo) patients. Patients with early disease achieved slightly greater American College of Rheumatology 20 (20% or more improvement or ACR20), 50, and 70 responses of 61%, 46.3%, and 24.4%, respectively, at 52 weeks, compared with those with established disease, with ACR20, 50, and 70 responses of 56%, 37.3%, and 19.9%, respectively. The Health Assessment Questionnaire score improvement between adalimumab and placebo in patients with early disease (0.44) was greater than that for those with established disease (0.25). With adalimumab treatment, there was a statistically significant mean reduction in total Sharp score progression relative to placebo (5.32) in early disease compared with established disease (2.06). While adalimumab is effective for RA of all disease durations, there is a trend toward superior clinical, functional, and radiographic outcomes in patients with early disease.     

Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: A double‐blind trial

Objective

To evaluate the efficacy and safety of tacrolimus as monotherapy in controlling the signs and symptoms of patients with rheumatoid arthritis (RA).

Methods

This was a 6‐month, phase III, double‐blind, multicenter study. Patients with active RA who had discontinued all disease‐modifying antirheumatic drugs (DMARDs) for an appropriate washout period (at least 1 month) and who, after the washout period, had a stable joint count (at least 10 tender/painful joints and 7 swollen joints) were stratified according to DMARD intolerance or DMARD resistance, and randomized to receive a single daily oral dose of placebo, tacrolimus 2 mg, or tacrolimus 3 mg.

Results

A total of 464 patients received at least 1 dose of study drug. Baseline characteristics were similar among the 3 treatment groups. American College of Rheumatology 20% improvement (ACR20) success (defined as completion of 6 months of treatment and an ACR20 response at the month 6 visit) for the placebo, tacrolimus 2 mg, and tacrolimus 3 mg groups was 10.2%, 18.8% (P < 0.05 versus placebo), and 26.8% (P < 0.0005 versus placebo), respectively. At the end of treatment, the ACR20 and ACR50 response rates in the 3‐mg group were 32.0% (P < 0.005 versus placebo) and 11.8% (P < 0.05 versus placebo), respectively. DMARD‐intolerant patients had better ACR response rates than did DMARD‐resistant patients. Although serum creatinine levels increased by ≥40% from baseline at some time during the trial in 20% and 29% of patients receiving tacrolimus 2 mg/day and 3 mg/day, respectively, the serum creatinine level remained within the normal range throughout the trial in ∼90% of patients.

Conclusion

Tacrolimus, at dosages of both 2 mg/day and 3 mg/day, is efficacious and safe as monotherapy for patients with active RA, but treatment with the 3‐mg dose of tacrolimus resulted in generally better ACR response rates.

     

Rare copresent rheumatoid arthritis and gout: comparison with pure rheumatoid arthritis and a literature review

Copresent rheumatoid arthritis (RA) and gout is seldom reported. This study summarizes the findings of eight cases of copresent RA and gout and compares them with 31 pure RA cases. Additional reported cases were retrieved from the current literature by Medline search. Patients with copresent RA and gout were older (p = 0.014) and predominantly male (p < 0.01). Synovial fluid, positive for urate crystals, was aspirated most frequently from the knee (five out of eight), followed by the first metatarsophalangeal joint (three out of eight). Serum creatinine and urate levels in the copresent group were significantly higher (p < 0.01, both), and serum hemoglobin was lower (p = 0.04) than those with pure RA. Copresent subjects had much lower percentage of positive rheumatoid factor (RF) tests than patients with pure RA (37.5 vs 80.6%). Only one copresent subject had both RF and anti-cyclic citrullinated peptide antibody. Of copresent subjects, 75% had gouty arthritis before diagnosis of RA, which is consistent with earlier reports. Seven copresent subjects had gout attacks under disease-modifying antirheumatic drug use. This study revealed that polyarthritis negative for RF in a previously gouty patient may be RA and vice versa. This combination occurs more frequently in males. Moreover, anti-CCP antibody examination is not helpful for this diagnosis. Therefore, physicians must obtain synovial fluid for analysis in joints with intense swelling, especially in old RA subjects with renal insufficiency or involvement of lower extremities. Conversely, RA must be considered in gouty patients with polyarticular involvement.     

The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized,double‐blind,placebo‐controlled,dose‐ranging trial

Objective

To examine the efficacy and safety of different rituximab doses plus methotrexate (MTX), with or without glucocorticoids, in patients with active rheumatoid arthritis (RA) resistant to disease‐modifying antirheumatic drugs (DMARDs), including biologic agents.

Methods

A total of 465 patients were randomized into 9 treatment groups: 3 rituximab groups (placebo [n = 149], 500 mg [n = 124], or 1,000 mg [n = 192] on days 1 and 15) each also taking either placebo glucocorticoids, intravenous methylprednisolone premedication, or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10–25 mg/week); no other DMARDs were permitted.

Results

Significantly more patients who received 2 500‐mg or 2 1,000‐mg infusions of rituximab met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 24 (55% and 54%, respectively) compared with placebo (28%; P < 0.0001). ACR50 responses were achieved by 33%, 34%, and 13% of patients, respectively (P < 0.001), and ACR70 responses were achieved by 13%, 20%, and 5% of patients (P < 0.05). Changes in the Disease Activity Score in 28 joints (−1.79, −2.05, −0.67; P < 0.0001) and moderate to good responses on the European League Against Rheumatism criteria (P < 0.0001) reflected the ACR criteria responses. Glucocorticoids did not contribute significantly to the primary efficacy end point, ACR20 response at 24 weeks. Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion–associated events; oral glucocorticoids conferred no additional safety benefit. Rituximab was well tolerated; the type and severity of infections was similar to those for placebo.

Conclusion

Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA. The primary end point (ACR20 response) was independent of glucocorticoids, although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion.

     

Foot pain in rheumatoid arthritis prevalence, risk factors and management: an epidemiological study

Foot involvement is a major feature of rheumatoid arthritis (RA). Most epidemiological studies of the RA foot report radiological changes and results of clinical examination. This study aimed to determine the prevalence of foot symptoms, frequency of foot assessment and access to foot care from the perspective of people with RA. A questionnaire was sent to 1,040 people with RA throughout the UK enquiring about foot symptoms, their anatomical distribution (via validated mannequins) availability of podiatry services and perceived usefulness of interventions for alleviating foot symptoms. Altogether 585 useable replies were received; 93.5% of respondents reported having experienced foot pain, and 35.4% reported current foot pain as the presenting symptom. Most (68.2%) reported moderate or severe foot pain daily. Pain was most prevalent in the forefoot and/or ankle. The main predictive factors for reporting current foot pain were longer disease duration (mean 13 vs 10.3 years, p = 0.009), higher BMI (25.6 vs 24.1 p = 0.001) and the prevalent foot symptoms foot stiffness and numbness (both p < 0.0001). Age, gender and current treatment were not significantly associated. Most (82%) had discussed foot symptoms with their rheumatologist, and only 64% had seen a podiatrist. Reported current adherence to prescribed orthoses was 55.8% and to prescribed shoes was 29.5%. Foot symptoms are ubiquitous in RA and frequently severe. Most patients had discussed their symptoms with their rheumatologist, and only 64% had specifically seen a podiatrist. Despite the remarkable progress in development of new treatment modalities for RA, foot pain remains a common and disabling symptom. Our findings support the need for wider access to specific foot care services and evidence-based, patient-centred interventions.