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ID PMID Title PublicationDate abstract
20877977 Oral events related to low-dose methotrexate in rheumatoid arthritis patients. 2010 Jul Low-dose methotrexate (MTX) is frequently used for patients with rheumatoid arthritis (RA). High doses of MTX frequently produce side effects. The aim of this study was to explore oral complications of low-dose MTX therapy in a population of RA patients. This is a cross-sectional study in which oral examination was performed on a population of RA patients. Patients undergoing MTX therapy (5-20 mg weekly) for at least six months were included in the study group, and RA patients being treated under another regimen were used as controls. The frequency of oral lesions was compared between groups. The chi-square test was used to compare frequencies. Relative risk (RR) and its confidence interval (CI) were established. Significance level was set at 0.05. Twenty-eight RA patients on a low-dose MTX regimen and 21 controls were enrolled in the study. Oral lesions were found in 22 patients (78.6%) undergoing MTX therapy, and in 5 patients (23.8%) undergoing other therapies (p < 0.001). There were no significant differences regarding age, gender or dosage. The most common oral events observed in patients in the MTX group were ulcerative/erosive lesions (60.7%) and candidiasis (10.7%). Patients in the control group presented lower prevalence of the same lesions (p < 0.001). The RR for developing oral lesions was 11.73 (CI 2.57 - 58.98), with low-dose MTX therapy. In conclusion, the prevalence of oral mucosa lesions in RA patients receiving low doses of MTX therapy is higher than in RA patients not receiving the drug.
18792423 Providing patients with information about disease-modifying anti-rheumatic drugs: Individu 2009 Jun BACKGROUND: Communicating information about disease-modifying anti-rheumatic drugs (DMARDs) before patients start treatment is a key role for some rheumatology clinical nurse specialists. This is done in our unit to promote understanding of the risks and benefits of drug therapy and encourage timely and reliable use of DMARDs. Information is routinely provided individually but this can lead to delays in starting treatment because of limited nursing resources. In this randomized trial we tested the feasibility of giving patients, who were about to start on a DMARD, information about the drug in groups and compared this with information given individually. METHODS: Adults with a clinical diagnosis of rheumatoid arthritis or psoriatic arthritis who were referred to the nursing team for counselling about starting on methotrexate, sulfasalazine or leflunomide were included. Patients who had previously taken a DMARD were not excluded and those consenting were randomized to receive drug information individually or in groups (of three to six patients). We provided all patients with written materials about the relevant drug and discussed the risks and benefits of drug use verbally. Patients allocated to group counselling received this intervention in a teaching room, with a slide presentation. The primary outcome was adherence with medication use, ascertained by pill counts, self-report diaries and prescription dispensation. Secondary outcomes included satisfaction with information about medicines (SIMS) by questionnaire; time taken to provide information; adherence to scheduled hospital appointments and blood monitoring schedules; and DMARD continuation rates at four and twelve months. RESULTS: Of 127 eligible patients referred for counselling about DMARDs, 62 consented to take part: 32 were randomized to receive drug information individually and 30 to receiving it in groups. Patients allocated to the two different interventions were comparable for age and diagnoses at baseline but more patients allocated individual counselling had not taken a DMARD previously: 56% (18/32) versus 20% (6/30). More patients counselled in groups were adherent (27/30; 90%) compared with patients counselled individually (22/32; 69%; p = 0.06) by pill counts. However, on self-report diaries, similar proportions were adherent (group counselling 97% (29/30) versus individual 94% (30/32); p = 1.0). All but two prescriptions were dispensed. More patients allocated to individual counselling missed at least one blood monitoring visit (25% versus 17%; p = 0.54) and at least one scheduled clinic visit (19% versus 3%; p = 0.10). SIMS scores indicated high levels of patient satisfaction and were similar for both groups. The time taken to run group and individual counselling sessions were similar (median of 35 minutes versus 33 minutes, respectively). Nursing time per individual patient in those allocated group counselling was 11.6 minutes. Drug continuation rates were higher for those counselled in groups compared with those counselled individually: at four months, 73% versus 63 %; p = 0.42; at twelve months, 47% versus 38%; p = 0.61). CONCLUSIONS: Our pilot study demonstrated the feasibility of providing counselling on DMARDs to groups of patients with important time savings for specialist nurses and while maintaining high levels of patient satisfaction. There was a trend for better outcomes in terms of adherence and drug continuation rates for patients counselled in groups, indicating potential benefits from group interactions. However, these findings need to be investigated further in a larger, fully powered trial.
19455337 The effect of infliximab on antiviral antibody profiles in patients with rheumatoid arthri 2010 Jan The duration of humoral immunity in patients treated with immunosuppressive drugs is poorly defined. The objective of the study was to investigate the effect of infliximab on the levels of antiviral antibodies against poliomyelitis, rubella and measles in rheumatoid arthritis (RA) patients. Fifty-two consecutive RA patients being treated with 3 mg/kg infliximab were prospectively studied. The antiviral antibody profiles for measles, rubella and three serotypes of poliomyelitis were tested on the day of the first infusion of infliximab and 6 months later. The study group comprised 36 women and 16 men (mean age 54 years, range 33-81) with a mean disease duration of 15 +/- 9 years. Forty-two (81%) patients were being treated with methotrexate and 22 (42%) were receiving prednisone. All patients had baseline protective levels of antibodies against measles and the three strains of polio, while 48 (92%) patients had protective antibodies against rubella. No significant change in the levels of antiviral antibodies was observed after 6 months of treatment with infliximab: from 3.67 at baseline to 3.87 IU/ml for measles, 169.50-197.0 IU/ml for rubella. No change was noticed for the geometric mean concentrations of antibodies against strains of poliomyelitis: 366-478 IU/ml for the Mahoney polio strain, 906-845 IU/ml for the MEF strain and 175-196 IU/ml for the Sauket strain. Patients with longstanding RA conserve long-term immunity to common viruses despite the use of immunosuppressive drugs. Levels of antiviral antibodies against measles, rubella and polio remain stable under treatment with infliximab.
20695769 Potent antirheumatic activity of a new DNA vaccine targeted to B7-2/CD28 costimulatory sig 2011 Jan Rheumatoid arthritis is a proinflammatory autoimmune disease attributed to failure of both CD4(+)CD25(+) regulatory T (Tr) and CD8(+)CD28(-) suppressor T (Ts) cells to control autoreactive CD4(+)CD28(+) Th1 (Th1) and autoantibody-producing B cells. Here we show a single intramuscular injection of our novel targeted DNA vaccine encoding Pseudomonas exotoxin A and costimulatory molecule B7-2 without autoantigens in a collagen-induced arthritis model simultaneously increased Tr and Ts cells and selectively decreased autoreactive Th1 cells. The vaccine induced a shift from Th1 to Th2 and Th3 cellular and cytokine profiles and a decrease in CD4(+)/CD8(+) cell ratios. Importantly, the vaccine showed potent antirheumatic activity by clinical and other examinations such as X-ray, histopathology, and anti-type II collagen IgG levels and was comparable to methotrexate, the current "gold standard" treatment. As an effective stimulator of both Tr and Ts cells and a specific suppressor of autoreactive Th1 cells, this vaccine is a promising therapeutic approach for rheumatoid arthritis.
19790066 Normalization of A2A and A3 adenosine receptor up-regulation in rheumatoid arthritis patie 2009 Oct OBJECTIVE: To investigate A(1), A(2A), A(2B), and A(3) adenosine receptors in lymphocytes and neutrophils from patients with early rheumatoid arthritis (ERA) as well as from RA patients treated with methotrexate (MTX) or anti-tumor necrosis factor alpha (anti-TNFalpha), as compared with those in age-matched healthy controls, and to examine correlations between the status and functionality of adenosine receptors and TNFalpha release and NF-kappaB activation. METHODS: Adenosine receptors were analyzed by saturation binding assays and Western blot analyses. We investigated the potency of typical A(2A) and A(3) agonists in the production of cAMP in control subjects, ERA patients, and RA patients treated with MTX or anti-TNFalpha. In a separate cohort of RA patients, TNFalpha release and NF-kappaB activation were evaluated in plasma and nuclear extracts, respectively. RESULTS: In ERA patients, we found a high density and altered functionality of A(2A) and A(3) receptors. The binding and functional parameters of A(2A) and A(3) receptors normalized after anti-TNFalpha, but not MTX, treatment. TNFalpha release was increased in ERA patients and in MTX-treated RA patients, whereas in anti-TNFalpha-treated RA patients, release was comparable to that in the controls. NF-kappaB activation was elevated in ERA patients and in MTX-treated RA patients. Anti-TNFalpha treatment mediated decreased levels of NF-kappaB activation. CONCLUSION: A(2A) and A(3) receptor up-regulation in ERA patients and in MTX-treated RA patients was associated with high levels of TNFalpha and NF-kappaB activation. Treatment with anti-TNFalpha normalized A(2A) and A(3) receptor expression and functionality. This new evidence of A(2A) and A(3) receptor involvement opens the possibility of exploiting their potential role in human diseases characterized by a marked inflammatory component.
21149498 Predictors of response to methotrexate in early DMARD naive rheumatoid arthritis: results 2011 Mar OBJECTIVE: To identify predictors of response to methotrexate (MTX) in early rheumatoid arthritis (RA). METHODS: In the SWEFOT trial, patients with RA with symptom duration <1 year started MTX monotherapy (20 mg/weekly) and 405/487 continued until the 3-4- month visit. The primary outcome measure was the DAS28-based European League against Rheumatism (EULAR) response criteria. Multivariate logistic regression was used to study the association between response and the following baseline characteristics: gender, age, symptom duration, cigarette smoking habits, autoantibody status, Health Assessment Questionnaire (HAQ) score, concurrent prednisolone and treatment with non-steroidal anti-inflammatory drugs. Secondary response and remission measures were the American College of Rheumatology and the Simple Disease Activity Index and Clinical Disease Activity Index (SDAI/CDAI)-derived criteria. RESULTS: After 3-4 months of MTX treatment, the frequency of EULAR good/moderate/no response was 34%/41%/25%, respectively. Parameters associated with a decreased likelihood of EULAR response were female gender (adjusted OR (adj OR) 0.50, 95% CI 0.31 to 0.81), symptom duration (adj OR per month increase 0.93, 95% CI 0.88 to 0.99), current smoking (adj OR 0.35, 95% CI 0.20 to 0.63) and higher HAQ (adj OR 0.56, 95% CI 0.40 to 0.80). Parameters associated with an increased likelihood of EULAR response were higher age (adj OR per 10-year increase 1.30, 95% CI 1.11 to 1.51) and prednisolone treatment (adj OR 2.84, 95% CI 1.43 to 5.63). The findings were similar when patients on prednisolone were excluded and other response criteria tested, although current smoking was the only significant predictor using all response criteria, while HAQ was the only significant predictor of all the remission criteria used. A matrix showed up to ninefold differences between subgroups stratified by the main predictors. CONCLUSION: Current smoking, female sex, longer symptom duration and younger age predict a worse response to MTX in patients with new-onset RA. TrialRegNo NCT00764725.
20614469 Tocilizumab for rheumatoid arthritis. 2010 Jul 7 BACKGROUND: Tocilizumab, a new biologic that inhibits interleukin-6, is approved for treatment of rheumatoid arthritis (RA) in Europe, Japan and the US. OBJECTIVES: To assess the efficacy and safety of tocilizumab in patients with RA using the data from published randomized or quasi-randomized controlled trials (RCTs). SEARCH STRATEGY: We performed a search of the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) up to issue 3, 2009; OVID MEDLINE(1966 to 1 October 2009); CINAHL(1982 to 2009); EMBASE (1980 to week 39, 2009); Science Citation Index (Web of Science) (1945 to 2009) and Current Controlled Trials. SELECTION CRITERIA: Tocilizumab alone or in combination with disease-modifying anti-rheumatic drugs (DMARDs) or biologics compared to placebo or other DMARDs or biologics. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data including major (ACR50, adverse events, serious adverse events, withdrawals, specific adverse events) and secondary outcomes. We calculated the risk ratio for dichotomous outcomes and mean difference for continuous outcomes. MAIN RESULTS: Eight RCTs were included in this systematic review with 3334 participants; 2233 treated with tocilizumab and 1101 controls. Of the 2233, 1561 were treated with tocilizumab 8 mg/kg every four weeks, which is the approved dose. In patients taking concomitant methotrexate, compared to placebo, tocilizumab-treated patients were four times more likely to achieve ACR50 (absolute %, 38.8% versus 9.6%), 11 times more likely to achieve Disease Activity Score (DAS) remission (absolute %, 30.5% versus 2.7%), 1.8 times more likely to achieve clinically meaningful decrease in Health Assessment Questionnaire (HAQ/mHAQ) scores (absolute %, 60.5% versus 34%), 1.2 times more likely to have any adverse event (absolute %, 74% versus 65%) and 0.6 times less likely to withdraw from therapy for any reason (absolute %, 8.1% versus 14.9%). With the limitation that none of the studies were powered for safety as primary outcome, there were no statistically significant differences in serious adverse effects, or withdrawals due to adverse events. A significant increase in total, HDL and LDL cholesterol and triglyceride level was seen in the tocilizumab treated patients. AUTHORS' CONCLUSIONS: Tocilizumab is beneficial in decreasing RA disease activity and improving function. Tocilizumab treatment was associated with significant increase in cholesterol levels and in total adverse events. Larger safety studies are needed to address these safety concerns.
20346242 Renal safety of initial combination versus single DMARD therapy in patients with early rhe 2010 Jan OBJECTIVE: To evaluate the renal safety of traditional disease-modifying antirheumatic drugs (DMARDs) in early rheumatoid arthritis (RA). METHODS: One hundred and ninety-five DMARD-naïve patients with recent-onset RA were randomised to receive combination DMARD therapy (n=97) starting with sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone (COMBI) or monotherapy (n=98), initially with sulfasalazine, with or without prednisolone (SINGLE). After two years, the choice and dosing of DMARDs and prednisolone were not restricted, but the treatment was still targeted to achieve or maintain remission. Urinalysis, serum creatinine and glomerular filtration rate (GFR; estimated according to the Cockcroft-Gault formula [eGFRCG]) were analysed at baseline and at months 6, 9, 12, 18, 24 and thereafter yearly up to 11 years. RESULTS: The cumulative incidence of repeated (>or=3 times) abnormal renal findings during the 11-year follow-up period were as follows (COMBI versus SINGLE; p-values adjusted for age and sex): proteinuria (dipstick positive) 4.8% (95%CI 1.8-12.2) vs. 5.3% (95%CI 2.0-13.7, p=0.93), haematuria (dipstick positive) 14.1% (95%CI 8.0-24.2) vs. 22.1 % (95%CI 14.5-33.0, p=0.14), raised serum creatinine (>or=100 micromol/l in females and >or=115 micromol/l in males) 4.4% (95%CI 1.7-11.4) vs. 6.7% (3.0-14.3, p=0.87) and eGFRGC<60 ml/min/1.73 m2 11.9% (95%CI 6.8-20.5) vs. 10.5% (95%CI 5.8-18.7, p=0.85). CONCLUSION: Initial remission targeted therapy with the FIN-RACo DMARD combination in early RA is safe for kidneys and does not induce more short- or long-term renal complications compared to traditional therapy with a single DMARD.
19489653 Golimumab: in the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing s 2009 Golimumab is a human anti-tumor necrosis factor (TNF) monoclonal antibody that acts principally by targeting and neutralizing TNF to prevent inflammation and destruction of cartilage and bone. Large, randomized, double-blind trials in patients with rheumatoid arthritis who were methotrexate-naïve (GO-BEFORE) or -experienced (GO-FORWARD) have shown that golimumab 50 or 100 mg every 4 weeks, in combination with methotrexate, was more effective than methotrexate alone for improving signs and symptoms of arthritis at weeks 14 and/or 24, according to American College of Rheumatology (ACR) criteria. In patients with active rheumatoid arthritis despite previous treatment with anti-TNF agents (GO-AFTER), golimumab 50 or 100 mg every 4 weeks was more effective than placebo for improving ACR responses at weeks 14 and 24; most patients in the study received concomitant methotrexate. In patients with psoriatic arthritis in the GO-REVEAL study, significantly more golimumab than placebo recipients achieved a >or=20% improvement in ACR criteria at week 14. Golimumab was also superior to placebo for improving the signs and symptoms of ankylosing spondylitis in the GO-RAISE study; significantly more golimumab than placebo recipients achieved a >or=20% improvement in the Assessment in Ankylosing Spondylitis (ASAS) criteria at week 14. In the five phase III trials in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis, there was no clear evidence of improved ACR or ASAS responses with the 100 mg dosage compared with the 50 mg dosage of golimumab. The tolerability profile of golimumab was generally consistent with that of other anti-TNF agents.
20849666 Strongyloides stercoralis hyperinfection in a patient with rheumatoid arthritis and bronch 2010 Sep 20 OBJECTIVE: Strongyloides stercoralis is a soil-transmitted intestinal nematode that has been estimated to infect at least 60 million people, especially in tropical and subtropical regions. Strongyloides infection has been described in immunosupressed patients with lymphoma, rheumatoid arthritis, diabetes mellitus etc. Our case who has rheumatoid arthritis (RA) and bronchial asthma was treated with low dose steroids and methotrexate. METHODS: A 68 year old woman has bronchial asthma for 55 years and also diagnosed RA 7 years ago. She received immunusupressive agents including methotrexate and steroids. On admission at hospital, she was on deflazacort 5 mg/day and methotrexate 15 mg/week. On her physical examination, she was afebrile, had rhonchi and mild epigastric tenderness. She had joint deformities at metacarpophalengeal joints and phalanges but no active arthritis finding. RESULTS: Oesophagogastroduodenoscopy was performed and it showed hemorrhagic focus at bulbus. Gastric biopsy obtained and showed evidence of S.Stercoralis infection. Stool and sputum parasitological examinations were also all positive for S.stercoralis larvae. Chest radiography result had no pathologic finding. Albendazole 400 mg/day was started for 23 days. After the ivermectin was retrieved, patient was treated with oral ivermectin 200 μg once a day for 3 days. On her outpatient control at 15th day, stool and sputum samples were all negative for parasites. CONCLUSION: S.stercoralis may cause mortal diseases in patients. Immunosupression frequently causes disseminated infections. Many infected patients are completely asymptomatic. Although it is important to detect latent S. stercoralis infections before administering chemotherapy or before the onset of immunosuppression in patients at risk, a specific and sensitive diagnostic test is lacking. In immunosupressed patients, to detect S.stercoralis might help to have the patient survived and constitute the exact therapy.
20879879 An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. 2010 Sep 30 BACKGROUND: Spleen tyrosine kinase (Syk) is an important modulator of immune signaling. The objective of this phase 2 study was to evaluate the efficacy and safety of R788, an oral inhibitor of Syk, in patients with active rheumatoid arthritis despite methotrexate therapy. METHODS: We enrolled 457 patients who had active rheumatoid arthritis despite long-term methotrexate therapy in a 6-month, double-blind, placebo-controlled trial. The primary outcome was the American College of Rheumatology (ACR) 20 response (which indicates at least a 20% reduction in the number of both tender and swollen joints and improvement in at least three of five other criteria) at month 6. RESULTS: R788, at a dose of 100 mg twice daily and at a dose of 150 mg once daily, was significantly superior to placebo at month 6 (ACR 20 response rates of 67% and 57%, respectively, vs. 35%; P<0.001 for the comparison of both doses with placebo). It was also significantly superior with respect to ACR 50, which indicates at least a 50% improvement (43% and 32% vs. 19%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.007 for the comparison of the 150-mg dose with placebo) and ACR 70 (28% and 14% vs. 10%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.34 for the comparison of the 150-mg dose with placebo). A clinically significant effect was noted by the end of the first week of treatment. Adverse effects included diarrhea (in 19% of subjects taking the 100-mg dose of R788 vs. 3% of those taking placebo), upper respiratory infections (14% vs. 7%), and neutropenia (6% vs. 1%). R788 was associated with an increase in systolic blood pressure of approximately 3 mm Hg between baseline and month 1, as compared with a decrease of 2 mm Hg with placebo; 23% of the patients taking R788 vs. 7% of the patients receiving placebo required the initiation of or a change in antihypertensive therapy. CONCLUSIONS: In this phase 2 study, a Syk inhibitor reduced disease activity in patients with rheumatoid arthritis; adverse events included diarrhea, hypertension, and neutropenia. Additional studies will be needed to further assess the safety and efficacy of Syk-inhibition therapy in patients with rheumatoid arthritis. (Funded by Rigel; ClinicalTrials.gov number, NCT00665925.)
19452100 Are glucocorticoids a consistent risk factor for infections in rheumatoid arthritis patien 2009 OBJECTIVE: To evaluate the incidence of infections in subjects with rheumatoid arthritis (RA), treated with an anti-TNFalpha blocker during one year follow-up. The aim of the study was focused to evaluate the number of infectious episodes in two groups of patients treated with etanercept (ETN) plus methotrexate (MTX) or ETN plus MTX and glucocorticoid drugs (GCs/prednisone) for a 12 months period. MATERIALS AND METHODS: Sixty-nine out of 122 RA patients treated with an anti-TNFalpha drug (ETN) were included in an outpatient control system within the Immunology Department Sapienza-University of Rome-II; School of Medicine. RA patients were studied during the first year after ETN introduction. Particularly 20 RA patients have been included in a subgroup. For these 20 patients infections have been monitored for 2 years: 12 months before and 12 months after ETN treatment starting. RESULTS: According to drugs administration protocols, after a careful screening aiming to exclude latent tuberculosis infection, 20 patients have been treated with ETN (10 of them received treatment in association to MTX, while 10 were given a GCs therapy plus MTX). During the one-year ETN treatment period, 7 infections have been described in the group treated with ETN, MTX and GCs and no infection in the group treated with ETN and MTX. After analysing the infection number in the two groups of patients, in the year preceding biological treatment no significant change arose. CONCLUSIONS: The risk of infections in subjects treated with the biological drug ETN is well known. Our data show that after one year therapy the [ETN+MTX+GCs] group is marked by a greater frequency of infectious episodes compared to the subjects treated with ETN plus MTX. Therefore, the additional infectious risk appears to be related to steroid therapy itself, though infections were not serious.
19915943 Etanercept overcomes P-glycoprotein-induced drug resistance in lymphocytes of patients wit 2010 Apr P-glycoprotein (P-gp) on activated lymphocytes is an adenosine triphosphate (ATP)-binding cassette transporter that causes drug resistance by exclusion of intracellular drugs in patients with active rheumatoid arthritis (RA). However, infliximab with methotrexate (MTX) can overcome P-gp-mediated drug resistance. We encounter patients who cannot continue infliximab or MTX. Here we tested how etanercept affected P-gp-mediated drug resistance in such intractable RA patients. Peripheral lymphocytes of 11 RA patients (3 switched from infliximab and 8 who could not be treated with MTX) were analyzed for P-gp expression by flow cytometry and for drug exclusion using radioisotope-labeled dexamethasone. Activated lymphocytes of RA patients overexpressed P-gp and coexpressed CD69. Incubation of these lymphocytes with dexamethasone in vitro reduced intracellular dexamethasone levels. Two-week etanercept therapy significantly reduced P-gp expression and eliminated such P-gp- and CD69-high-expressing subgroup. The reduction in P-gp resulted in recovery of intracellular dexamethasone levels in lymphocytes and improvement of disease activity, thus allowing tapering of corticosteroids. None of the patients experienced any severe adverse effects. Etanercept is useful for overcoming P-gp-mediated treatment resistance in intractable RA patients who have to discontinue infliximab or are intolerant to MTX.
20233177 Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in pa 2010 Feb AIMS: To investigate the effects of methotrexate (MTX) on the pharmacokinetics (PK) of CP-690,550, a novel Janus kinase (JAK) inhibitor in development as a therapy for rheumatoid arthritis (RA), to determine the effects of multiple doses of CP-690,550 on the PK of MTX, and to evaluate the short-term safety and tolerability of co-administration of CP-690,550 and MTX. METHODS: This was a fixed-dose drug-drug interaction study. Twelve patients diagnosed with RA for at least 6 months were enrolled in a Phase I, open-label study of the PK of multiple doses of CP-690,550 (30 mg b.i.d.) and single doses of MTX (15-25 mg per week). RESULTS: All patients completed the study and were evaluated for PK and safety. CP-690,550 exposure was not affected by co-administration with MTX; AUC(12) ratio (CP-690,550 + MTX/CP-690,550) was 103.06% [90% confidence interval (CI) 99.00, 107.29]. MTX exposure decreased by 10%; AUC(12) ratio (CP-690,550 + MTX/MTX) was 89.53% (90% CI 77.38, 103.57), which was not considered clinically significant. Co-administration of CP-690,550 and MTX was safe and well tolerated. There were no serious adverse events or withdrawals from the study and there was no trend in the incidence or severity of adverse events across treatments. CONCLUSIONS: Co-administration of CP-690,550 and MTX was safe and well tolerated. There was no clinically significant effect on the PK profile of either drug. Therefore, dose adjustments should not be required when co-administering CP-690,550 and MTX.
19368701 Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor ther 2009 Conventional disease-modifying antirheumatic drugs such as methotrexate are the mainstay of treatment for rheumatoid arthritis. More recently, biologic agents such as etanercept, infliximab and adalimumab, which act by inhibiting tumour necrosis factor (TNF), have become available. TNF inhibitors have proved to be very effective in patients not responding to conventional disease-modifying antirheumatic drugs. However, about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor. In this group of patients, therapeutic options were limited until recently and an established treatment approach was to switch from one TNF inhibitor to another. In recent years, therapeutic options in these patients have increased with the introduction of biologic agents with novel mechanisms of action, such as rituximab and abatacept. This review outlines the current evidence in support of the available treatment strategies in patients with an inadequate response or intolerance to an initial TNF inhibitor.
20511610 Are switches from oral to subcutaneous methotrexate or addition of ciclosporin to methotre 2010 Oct OBJECTIVE: To investigate the effects of a switch from oral methotrexate (MTX) to subcutaneous MTX (scMTX) or adding ciclosporin to oral MTX with a simultaneous reduction of the MTX dose, in case of adverse events (AE) or insufficient effect (IE) in rheumatoid arthritis (RA). METHODS: The tight control treatment arm of the Computer Assisted Management in Early RA (CAMERA) trial was evaluated. The change in 28-joint Disease Activity Score (DAS28) after taking scMTX (over 1 month) or adding ciclosporin (over 3 months) was compared to the average monthly change in the preceding 3 months. Analyses were performed separately for strategy steps because of AE or IE. RESULTS: Of 151 patients, 57 needed the scMTX strategy step (21 because of AE, 36 because of IE) and 40 the following ciclosporin strategy step (20 and 20, respectively). The decrease in DAS28 after taking the scMTX strategy step was 0.30 points (p<0.05); no significant change in DAS28 was seen after the ciclosporin strategy step. In both strategy steps for AE or IE, quite similar observations were made. Of the patients who took the scMTX strategy step, 63% showed improvement. CONCLUSION: scMTX seems a useful treatment step after oral MTX in a tight control strategy, whereas the ciclosporin step seems ineffective.
18718986 Inhibition of radiographic progression with combination etanercept and methotrexate in pat 2009 Jul OBJECTIVE: To determine the effect of changing from etanercept or methotrexate monotherapy to etanercept plus methotrexate combination therapy on radiographic progression in rheumatoid arthritis (RA) patients. METHODS: Patients enrolled in this 1-year open-label study previously completed a 3-year blinded study in which they received methotrexate or etanercept monotherapy or the combination of both. All patients received the combination of etanercept 25 mg subcutaneously twice weekly plus oral methotrexate up to 20 mg/week. The primary radiographic endpoint was a change in modified total Sharp score (TSS), as assessed by blinded readers. RESULTS: At baseline, patients previously receiving methotrexate monotherapy (etanercept-added, n = 52) or etanercept monotherapy (methotrexate-added, n = 68) had moderate disease activity levels (mean disease activity score (DAS) of 2.6 and 2.5, respectively), whereas patients previously receiving combination therapy (n = 90) had a low disease activity level (mean DAS of 2.0). The addition of etanercept to methotrexate monotherapy resulted in a significant reduction in radiographic progression (p<0.05). Mean TSS changes in the previous year versus the current year were +1.79 versus +0.25 for the etanercept-added group (p<0.05); +0.51 versus -0.18 for the methotrexate-added group (NS) and +0.42 versus +0.24 for the combination group (NS). CONCLUSION: In these RA patients with on average moderate disease activity despite previous methotrexate monotherapy, combination treatment with etanercept and methotrexate inhibited radiographic progression and improved radiographic outcomes. These data, in conjunction with the previously published clinical data, support the use of combination therapy in RA patients with moderate disease activity.
20472596 Long-term safety of anti-TNF treatment in patients with rheumatic diseases and chronic or 2010 Jul OBJECTIVES: The aim of this prospective study was to examine the safety of anti-tumour necrosis factor (TNF) therapy in patients with rheumatic disease and hepatitis B virus (HBV) infection. METHODS: 14 patients with chronic HBV infection, 19 HBV-vaccinated patients and 19 patients with resolved HBV infection were included in the study. All HBV-infected patients received combination therapy with oral antivirals and anti-TNF agents. During treatment the levels of hepatitis B surface antibodies (anti-HBs) in HBV-vaccinated patients and of serum HBV DNA in patients with chronic or resolved HBV infection were monitored. RESULTS: No viral reactivation was observed in patients with resolved HBV infection while anti-HBs titres decreased during anti-TNF treatment in vaccinated patients, similarly to patients treated with methotrexate alone. None of the HBV-infected patients developed liver decompensation or a significant increase in alanine aminotransferase levels. One patient (7%) treated with lamivudine and etanercept showed viral reactivation due to the emergence of a lamivudine-resistant mutant strain. CONCLUSIONS: Anti-TNF agents represent a safe option for patients with chronic HBV infection when combined with antiviral therapy, as well as in patients previously exposed to HBV receiving no HBV prophylaxis. Resistant HBV strains may arise in patients with chronic hepatitis B, necessitating the initial use of anti-HBV agents with a low risk of resistance.
18704426 A comparison study of a recombinant tumor necrosis factor receptor:Fc fusion protein (rhTN 2009 Jan The objective of this study is to evaluate the efficacy and safety of rhTNFR:Fc: a recombinant tumor necrosis factor receptor:Fc fusion protein compared with methotrexate (MTX) in patients with rheumatoid arthritis in China. We treated 238 patients with active rheumatoid arthritis with either twice weekly subcutaneous injection rhTNFR:Fc (25 mg) or weekly oral MTX (mean 15 mg per week) for 24 weeks (registration number: 2003L01264). Clinical responses were defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology (ACR-N). As compared with MTX-treated patients, more patients who received rhTNFR:Fc had ACR20 improvement in disease activity during the first 2 weeks (P < 0.05). Similarly, more patients treated with rhTNFR:Fc having ACR20, ACR50, ACR70 improvement in disease activity during 8 weeks (P < 0.05). At the end of 12-week treatment, patients received rhTNFR:Fc also had significant improvement at ACR20 (P < 0.05). Compared with oral MTX, patients received rhTNFR:Fc also had significant improvement at ACR70 at the end of 24 weeks treatment (P < 0.05). In conclusion, compared with oral MTX subcutaneous injection, rhTNFR:Fc acted more rapidly to release symptoms and signs of active RA in Chinese patients, and well tolerated in patients with rheumatoid arthritis in China.
19578932 Prediction of DAS28-ESR remission at 6 months by baseline variables in patients with rheum 2009 We tried to determine which baseline variables are responsible for remission induction at 6 months in unselected rheumatoid arthritis (RA) patients of Japanese population treated with etanercept. One hundred forty-one patients with RA who were administered etanercept were registered. Thirty-four patients were started on etanercept monotherapy, 60 patients on cotherapy with methotrexate (MTX) (MTX cotherapy), and 47 patients on cotherapy with other non-MTX nonbiologic disease-modifying antirheumatic drugs (DMARDs) (non-MTX cotherapy). None of the patients were treated with both MTX and non-MTX nonbiologic DMARDs at entry. Outcome was set as achievement of disease activity score 28 (DAS28)-ESR remission at 6 months. We examined association of gender, DAS at baseline, MTX cotherapy at baseline, non-MTX cotherapy at baseline, and prednisolone use at baseline with achievement of remission at 6 months by logistic regression analysis. All subjects were classified as having high (N = 109) or moderate disease activity (N = 32) at entry. One hundred twenty out of 141 patients (85.1%) continued treatment with etanercept at 6 months. Continuation rate was statistically higher in MTX cotherapy (93.3%) compared with etanercept monotherapy (73.5%), and tended to be higher than with non-MTX cotherapy (85.1%). Logistic regression analysis identified that MTX cotherapy at entry and moderate disease activity at entry were independent variables for remission induction at 6 months. Accordingly, DAS28-ESR at 6 months was significantly lower with MTX cotherapy as compared with etanercept monotherapy or non-MTX cotherapy. To a lesser extent, DAS28-ESR with non-MTX cotherapy at 6 months was lower than with etanercept monotherapy. In this study of unselected patients, use of MTX and moderate disease activity at entry were associated with higher likelihood of response to etanercept. Non-MTX nonbiologic DMARDs may be an alternative in RA patients administrated etanercept who are intolerant to MTX.