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ID PMID Title PublicationDate abstract
21083889 Association of serum markers with improvement in clinical response measures after treatmen 2010 INTRODUCTION: The goal of this study was to identify serum markers that are modulated by treatment with golimumab with or without methotrexate (MTX) and are associated with clinical response. METHODS: Sera were collected at weeks 0 and 4 from a total of 336 patients (training dataset, n = 100; test dataset, n = 236) from the GO-FORWARD study of patients with active rheumatoid arthritis despite MTX. Patients were randomly assigned to receive placebo plus MTX; golimumab, 100 mg plus placebo; golimumab, 50 mg plus MTX; or golimumab, 100 mg plus MTX. Subcutaneous injections were administered every 4 weeks. Samples were tested for select inflammatory, bone, and cartilage markers and for protein profiling using multianalyte profiles. RESULTS: Treatment with golimumab with or without MTX resulted in significant decreases in a variety of serum proteins at week 4 as compared with placebo plus MTX. The American College of Rheumatology (ACR) 20, ACR 50, and Disease Activity Score (DAS) 28 responders showed a distinct biomarker profile compared with nonresponding patients. CONCLUSIONS: ACR 20 and ACR 50 responders among the golimumab/golimumab + MTX-treated patients had a distinct change from baseline to week 4 in serum protein profile as compared with nonresponders. Some of these changed markers were also associated with multiple clinical response measures and improvement in outcome measures in golimumab/golimumab + MTX-treated patients. Although the positive and negative predictive values of the panel of markers were modest, they were stronger than C-reactive protein alone in predicting clinical response to golimumab. TRIAL REGISTRATION: http://ClinicalTrials.gov identification number: NCT00264550.
21044442 Perioperative use of methotrexate. 2010 Sep Methotrexate (MTX) is the disease modifying antirheumatic 'anchor' drug for the treatment of patients with rheumatoid arthritis (RA). Despite its widespread use and the frequent need of elective orthopaedic and other types of surgical procedures in patients with RA, some confusion exists concerning the use of MTX in the perioperative period. Currently available data do not suggest a need to discontinue MTX because of surgery. There is some evidence that treatment with MTX is safe prior to and after elective surgical procedures. Importantly, disease activity is better controlled when MTX is not interrupted from weekly administration.
19026580 Visceral leishmaniasis in a rheumatoid arthritis patient treated with methotrexate. 2009 Jul Visceral leishmaniasis (VL) is a relatively rare occurrence in rheumatoid arthritis (RA) patients treated with tumor necrosis factor-alpha (TNF-alpha) antagonists, corticosteroids and methotrexate, or methotrexate alone. A review of the literature revealed that only one case of VL in an RA patient treated with methotrexate has been previously published. We describe an additional case, that of a 65-year-old female with RA being treated with methotrexate, who presented with fever, abdominal discomfort, splenomegaly and pancytopenia. A diagnosis of VL was ultimately established, after a splenectomy was performed. Because RA is characterized by immune cell dysfunction and dysregulation, which potentially predisposes patients to infection, it is unclear whether this serious opportunistic infection can be solely attributable to the methotrexate, an immunosuppressive medication that also increases the risk of infection.
19858780 Gene-gene interactions in folate and adenosine biosynthesis pathways affect methotrexate e 2009 Dec OBJECTIVE: As no single nucleotide polymorphism has emerged as pivotal to predict the lack of efficacy and dose-limiting toxicities to methotrexate (MTX), we evaluated the contribution of gene-gene interactions to the effects of this prodrug in rheumatoid arthritis. METHODS: A total of 255 patients treated with MTX for at least 3 months were evaluated with efficacy assessed using the European League Against Rheumatism response criteria or a physician's assessment of patient's response to MTX visual analog scale. Gastrointestinal and neurological idiosyncrasies were recorded in 158 patients. Fourteen single nucleotide polymorphisms in folate and adenosine biosynthesis pathways were measured and detection of gene-gene interactions was performed using multifactor-dimensionality reduction, a method that reduces high-dimensional genetic data into a single dimension of predisposing or risk-genotype combinations. RESULTS: Efficacy to MTX (53% responders) was associated with high-order epistasis among variants in inosine-triphosphate pyrophosphatase, aminoimidazole-carboxamide ribonucleotide transformylase, and reduced folate carrier genes. In the absence of predisposing genotype combinations, a 3.8-fold lower likelihood of efficacy was observed (vs. in their presence, 95% confidence interval: 2.2-6.4; P<0.001). Increasing MTX polyglutamate concentrations tended to partially overcome this selective disadvantage. Idiosyncrasies occurred in 29% of patients. In the presence of risk-genotype combinations among variants in methylene tetrahydrofolate reductase, γ-glutamyl-hydrolase, thymidylate synthase, serine hydroxymethyltransferase, and inosine-triphosphate pyrophosphatase genes, an 8.9-fold higher likelihood to exhibit toxicities was observed (vs. in their absence, 95% confidence interval: 3.6-21.9; P<0.001). False-positive report probabilities were below 0.2, thereby indicating that true signals were likely detected in this cohort. CONCLUSION: These data indicate that gene-gene interactions impact MTX efficacy and tolerability in rheumatoid arthritis.
21059675 Improvements in patient-reported outcomes, symptoms of depression and anxiety, and their a 2011 Feb OBJECTIVES: To assess the association between clinical remission in RA and patient-reported outcomes (PROs), including depression/anxiety symptoms, in adults with moderate-to-severe active early RA. METHODS: Patients from the COmbination of Methotrexate and ETanercept in Active Early Rheumatoid Arthritis (COMET) trial (104 weeks) with measures on the Hospital Anxiety and Depression Scale at baseline and subsequent visits (n = 389) were included. PROs investigated were the HAQ disability index, pain and fatigue visual analogue scales (VASs), EuroQoL health status VAS and the Medical Outcomes Short Form-36 physical and mental component summaries. The impact of clinical remission as measured by 28-joint DAS (DAS-28) on depression/anxiety symptoms at Week 104 was assessed using logistic regression. Least square means for PRO improvements from baseline were estimated by analysis of covariance. Missing data were imputed using the last observation carried forward method. RESULTS: When depression/anxiety symptoms were absent at baseline, significantly more patients achieved clinical remission, low disease activity and normal functioning at Week 104. Reciprocally, patients who achieved clinical remission were less likely to maintain symptoms of depression or anxiety compared with non-remitters [depression odds ratio (OR): 0.35, P = 0.0233; anxiety OR: 0.48, P = 0.0371]. Fatigue and pain had a significant impact on changes in depression status, but did not influence anxiety status. Finally, clinical remission was significantly associated with improvements in all PRO measures (P < 0.001); conversely, depression/anxiety symptoms reduced PRO improvements. CONCLUSIONS: Among moderate-to-severe active early RA patients, clinical remission reduces symptoms of depression/anxiety, and independently improves PROs, thereby suppressing the negative impact of depression/anxiety on these measures.
19424068 Denosumab update. 2009 Jul PURPOSE OF REVIEW: Denosumab is an investigational fully human monoclonal antibody to receptor activator of nuclear factor kappaB ligand, an essential mediator of osteoclastic bone resorption. Receptor activator of nuclear factor kappaB ligand plays a major role in the pathogenesis of postmenopausal osteoporosis, structural damage in rheumatoid arthritis, and bone loss associated with other skeletal disorders. This is a review of recent clinical data on the efficacy and safety of denosumab for the treatment of postmenopausal osteoporosis and rheumatoid arthritis. RECENT FINDINGS: Denosumab reduces bone turnover markers and increases bone mineral density in postmenopausal women with low bone mineral density, reduces fracture risk in women with postmenopausal osteoporosis, and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment. In postmenopausal women with low bone mineral density, denosumab is associated with a greater increase in bone mineral density and greater reduction in bone turnover markers compared with alendronate; when women treated with alendronate are switched to denosumab, there is an increase in bone mineral density that is greater than in those continuing alendronate. Adverse events and serious adverse events, including infections and malignancy, are generally similar in patients treated with denosumab compared with those receiving placebo or alendronate. SUMMARY: Denosumab is a promising therapeutic agent for the management of postmenopausal osteoporosis and rheumatoid arthritis.
20211020 Circulating surfactant protein -D is low and correlates negatively with systemic inflammat 2010 INTRODUCTION: Surfactant protein D (SP-D) is a collectin with immuno-regulatory functions, which may depend on oligomerization. Anti-microbial and anti-inflammatory properties have been attributed to multimeric SP-D variants, while trimeric subunits per se have been suggested to enhance inflammation. Previously, we reported low circulating SP-D in early rheumatoid arthritis (RA), and the present investigation aims to extend these data by serial SP-D serum measurements, studies on synovial fluid, SP-D size distribution and genotyping in patients with early RA. METHODS: One-hundred-and-sixty disease-modifying antirheumatic drug (DMARD) naïve RA patients with disease duration less than six months were studied prospectively for four years (CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) trial) including disease activity measures (C-reactive protein, joint counts and Health Assessment Questionnaire (HAQ) score), autoantibodies, x-ray findings and SP-D. SP-D was quantified by enzyme-linked immunosorbent assay (ELISA) and molecular size distribution was assessed by gel filtration chromatography. Further, SP-D Met11Thr single nucleotide polymorphism (SNP) analysis was performed. RESULTS: Serum SP-D was significantly lower in RA patients at baseline compared with healthy controls (P < 0.001). SP-D increased slightly during follow-up (P < 0.001), but was still subnormal at four years after adjustment for confounders (P < 0.001). SP-D in synovial fluid was up to 2.5-fold lower than in serum. While multimeric variants were detected in serum, SP-D in synovial fluid comprised trimeric subunits only. There were no significant associations between genotype distribution and SP-D. Baseline SP-D was inversely associated to CRP and HAQ score. A similar relationship was observed regarding temporal changes in SP-D and CRP (zero to four years). SP-D was not associated to x-ray findings. CONCLUSIONS: This study confirms that circulating SP-D is persistently subnormal in early and untreated RA despite a favourable therapeutic response obtained during four years of follow-up. SP-D correlated negatively to disease activity measures, but was not correlated with x-ray progression or SP-D genotype. These observations suggest that SP-D is implicated in RA pathogenesis at the protein level. The exclusive presence of trimeric SP-D in affected joints may contribute to the maintenance of joint inflammation. TRIAL REGISTRATION: (j.nr NCT00209859).
20618765 Golimumab therapy of rheumatoid arthritis: an overview. 2010 Aug Golimumab is a new approved humanized antibody for the treatment of rheumatoid arthritis (RA). This antibody belonging to biologic agents is raised against the pro-inflammatory cytokine tumour necrosis factor-alpha playing an essential role in the initiation of RA. To date, Golimumab administration for patients with RA, as indicated by USA Food and Drug Administration, is subcutaneous combined with methotrexate (MTX). Here, we have reviewed current literature with a focus on characteristics of Golimumab and also have exposed the clinical trials either using MTX or not using MTX. We have also highlighted the incoming clinical trials on Golimumab and have proposed some indications for the future studies based on a setting of clinical data and post-marketing observational studies. These studies will advance rheumatologists' decisions in the beginning of RA therapeutic interventions to insure the best outcomes for patients with RA and to improve their quality of life.
20401724 Pulmonary non-Hodgkin's lymphoma developed during long-term methotrexate therapy for rheum 2012 Nov Methotrexate is effective in treating rheumatoid arthritis (RA). Some reports have discussed the possible association between methotrexate and lymphoma. Here, we report a case of pulmonary non-Hodgkin's lymphoma (NHL) developed after 11 years' methotrexate therapy for RA. Biopsy of the pulmonary mass demonstrated a diffuse large B-cell lymphoma. After withdrawal of methotrexate without any other intervention for 4 weeks, a significant reduction in the size of the lymphoma was observed. The causative relationship between methotrexate and pulmonary lymphoma is suggested by the persistent remission after stopping methotrexate therapy.
19843471 Ten years of infliximab: insights from clinical trials in rheumatoid arthritis. 2009 Nov 25 Early animal and open label human studies suggested a pivotal role for tumor necrosis factor (TNF) inhibition in the treatment of rheumatoid arthritis (RA). Subsequent randomized controlled trials with infliximab showed a rapid reduction of signs and symptoms as well as fast normalization of C reactive protein (CRP) in patients responding to treatment. In addition, a synergistic effect of methotrexate (MTX) in combination with infliximab was evident. Infliximab treatment can inhibit progression of structural joint damage, a newly reported outcome of TNF inhibition in rheumatoid arthritis shown to be largely independent of clinical response to infliximab treatment. Early treatment with infliximab in combination with methotrexate in methotrexate-naive patients showed similar inhibition of x-ray progression, and change of the natural course of disease thus became an achievable treatment goal in rheumatoid arthritis. Current clinical practice in rheumatology aims at obtaining low disease activity and remission state. Application of new treatment strategies with tight control of disease activity allows to reach these new treatment goals in many patients. The extended research programs of infliximab have added significant knowledge to our current clinical management of rheumatoid arthritis patients. We also learned, however, that anti-TNF treatment is not without risk, and that careful patient selection, screening, and monitoring are vital to achieve these outcomes in every day clinical practice.
19838716 [Methotrexate in rheumatology]. 2009 Nov Methotrexate (MTX) is a folate inhibitor which has gained a major role in the treatment of rheumatoid arthritis (RA). MTX is not only the disease modifying anti-rheumatic drug of first choice, a large number of clinical trials moreover show that biologic drugs should be combined with MTX in order to obtain optimal therapeutic efficacy. Therefore, MTX is an anchor drug for the treatment of RA. Large studies show the general safety of the drug for long term treatment. The mechanisms of action of MTX in inflammation are complex but increasingly better understood. Current publications show that first steps have been done towards prediction of therapeutic response and toxicity of MTX by analysis of gene polymorphism. Conjugates of MTX which use endogenous albumin as a drug carrier to synovitis as well as new receptor-specific folate inhibitors are currently tested in pre-clinic investigations. The goal to further develop the most successful principle of folate inhibition for the treatment of rheumatic diseases seems to be feasible.
18930988 Clinical and radiological efficacy of initial vs delayed treatment with infliximab plus me 2009 Jul OBJECTIVES: To compare the clinical and radiological efficacy of initial vs delayed treatment with methotrexate (MTX) and infliximab (IFX) in patients with recent onset rheumatoid arthritis (RA). METHODS: In a post hoc analysis of the BeSt study (for Behandel Stratagieen, Dutch for treatment strategies), 117 patients who started initial MTX+IFX were compared with 67 patients who started MTX+IFX treatment after failing (disease activity score (DAS)>2.4; median delay to IFX: 13 months) on > or =3 traditional DMARDs. If the DAS remained >2.4, the protocol dictated IFX dose increases to 6, 7.5 and 10 mg/kg. In case of a DAS < or =2.4 for > or =6 months, IFX was tapered and finally stopped. We aimed to correct for allocation bias using propensity scores. Functional ability was measured by the Health Assessment Questionnaire (HAQ), radiological progression by Sharp/van der Heijde scoring (SHS). RESULTS: Baseline differences between the initial and delayed groups were no longer significant after propensity score adjustment. At 3 years after baseline, patients treated with initial MTX+IFX experienced more improvement in HAQ over time and were less likely to have SHS progression than patients treated with delayed MTX+IFX (p = 0.034). At 2 years after IFX initiation, more patients in the initial group compared with the delayed group could discontinue IFX after a good response (56% vs 29%, p = 0.008). CONCLUSIONS: The results of this post hoc analysis suggest that using MTX+IFX as initial treatment for patients with recent onset RA is more effective than reserving MTX+IFX for patients who failed on traditional DMARDs, with more HAQ improvement over time, more IFX discontinuation and less progression of joint damage.
19327235 The proteasome inhibitor bortezomib inhibits the release of NFkappaB-inducible cytokines a 2009 Jan OBJECTIVE: The proteasome is a multicatalytic proteinase complex regulating the intracellular breakdown of many proteins, including those mediating the activation of pro-inflammatory signaling pathways (e.g. NFkappaB), cell proliferation and survival. Conceptually, proteasome inhibitors may therefore elicit potential anti-inflammatory properties by inhibiting these processes and thereby impair the cellular release of pro-inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-alpha) in RA patients. METHODS: Whole-blood from 19 RA patients (including methotrexate-responsive and non-responsive patients) and 7 healthy volunteers was incubated ex-vivo with the proteasome inhibitor bortezomib after T-cell stimulation with alphaCD3/CD28. Inhibition of cytokine production by bortezomib was measured after 24 and 72 hours by ELISA. Effects of bortezomib on apoptosis and T-cell activation (CD25 expression) were measured by FACS-analysis. RESULTS: Bortezomib proved to be a rapid (<24 hour) and potent inhibitor of the release of several NFkappaB-inducible cytokines (including TNF-alpha, IL-1Beta, IL-6 and IL-10) by activated T-cells from healthy volunteers and RA patients, regardless of their clinical responsiveness to methotrexate. Median concentrations of bortezomib required to inhibit TNF-alpha production by 50% (mIC-50) were 12 nM (range: 8-50 nM) for healthy volunteers and 46 nM (range: 18-60 nM) for RA patients. A reduction of T cell activation and a marked induction of T-cell apoptosis were revealed as late effects after bortezomib incubations beyond 24 hours. CONCLUSION: Proteasome inhibitors represented by bortezomib may elicit potential anti-inflammatory properties that deserve further exploration in experimental therapies for RA.
19303802 Prevalence of subclinical amyloidosis in Tunisian patients with rheumatoid arthritis. 2009 May INTRODUCTION: Secondary amyloidosis is a serious complication of rheumatoid arthritis (RA). Symptoms are late to occur, so that screening is in order, most notably in patients with long-standing RA. The objectives of our study were to determine the prevalence of subclinical amyloidosis in RA patients by abdominal fat aspiration biopsy (AFAB) and minor salivary gland biopsy (MSGB) and to identify factors associated with subclinical amyloidosis. METHODS: We prospectively studied 107 consecutive patients with RA (94 women and 13 men) recruited between March 2005 and January 2006. Clinical and laboratory findings, imaging study results, and treatment were recorded for each patient. AFAB and MSGB were performed routinely. Amyloid deposits were identified by polarized light microscopy after Congo red staining. RESULTS: The prevalence of subclinical amyloidosis was 21.5% by AFAB and 3.7% by MSGB. Factors associated with subclinical amyloidosis were a longer time to diagnosis (P=0.03), extraarticular manifestations (P=0.019), proteinuria >0.3 g/24 h (P=0.024), and absence of methotrexate therapy (P=0.046). Subclinical amyloidosis was not associated with age, sex, RA duration, joint deformities, DAS28 score, Health Assessment Questionnaire score, Steinbrocker radiological stage, rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, creatinine, or hemoglobin. CONCLUSION: The prevalence of subclinical amyloidosis by AFAB is high (21.5%). AFAB is more sensitive than MSGB for detecting subclinical amyloidosis. A simple screening tool such as AFAB should be used, particularly in patients with risk factors. Subclinical amyloidosis requires close monitoring to ensure the early detection and treatment of symptomatic amyloidosis.
19852747 Can RAPID3, an index without formal joint counts or laboratory tests, serve to guide rheum 2009 Tight control of rheumatoid arthritis (RA) may be guided by RAPID3 (routine assessment of patient index data), an index without formal joint counts or laboratory tests, which can be scored on a multidimensional health assessment questionnaire (MDHAQ) in 5 seconds, compared to 42 seconds to score a standard HAQ, 90 seconds to perform a 28-joint count, 114 seconds to score a disease activity score 28 (DAS28), and 106 seconds to score a clinical disease activity index (CDAI). RAPID3 scores are correlated significantly with DAS28 and CDAI (rho > 0.65, p < 0.001), and distinguish active from control treatment similarly to DAS28 and CDAI in clinical trials of methotrexate, lefunomide, adalimumab, abatacept, certolizumab, and infiximab. RAPID3 scores can be used to classify patient disease activity status as high (> 12), moderate (6.1-12), low (3.1-6), and remission (
20230993 Effect of light emitting diodes in the photodynamic therapy of rheumatoid arthritis. 2010 Mar BACKGROUND: Complex and painful surgical removal of synovium was replaced by arthroscopic synovectomy as an early treatment of rheumatoid arthritis (RA), which being limited to bigger joints, was replaced by laser synovectomy. Having been more time consuming, laser photodynamic therapy (PDT) replaced this method. Due to thermal side effects of laser PDT, an alternative source of light has been sought. Therefore, to make RA treatment cheaper, less hazardous and suitable according to anatomical geometry, light emitting diodes (LEDs) were used in this study as a potential source of light. METHODS: Red, white, yellow and infra-red (IR) LEDs were tested to measure the optical penetration for soft tissue and their scattering. In vitro study of the cellular response of normal and inflamed lymphocytes from healthy and RA patients was conducted respectively. Methotrexate was injected as photosensitizer to achieve cell-specific precision. RESULTS: IR LEDs showed the maximum penetration and least scattering of all LEDs used. Specimen with drug administration and with subsequent exposure to IR LEDs exhibited massive suppression of inflamed activated lymphocytes in comparison to other controls. CONCLUSION: The properly selected wavelength and intensity of light beam were incident with great precision so that they would not affect unwanted cells, but inflamed activated cells were suppressed due to intense light energy following Methotrexate injection. Without invasion, IR LED PDT showed an effective and cheaper treatment solution for RA.
19644849 Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutan 2009 Aug OBJECTIVE: To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis (RA). METHODS: MTX-naive patients with RA (n = 637) were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Subcutaneous injections of golimumab or placebo were administered every 4 weeks. The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week. The primary end point, the proportion of patients meeting the American College of Rheumatology 50% improvement criteria (achieving an ACR50 response) at week 24, required significant differences between groups 3 and 4 combined (combined group) versus group 1 and significant differences in a pairwise comparison (group 3 or group 4 versus group 1). RESULTS: An intent-to-treat (ITT) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 (38.4% and 29.4%, respectively; P=0.053), while a post hoc modified ITT analysis (excluding 3 untreated patients) of the ACR50 response showed statistically significant differences between the combined group and group 1 (38.5% versus 29.4%; P=0.049) and between group 3 (40.5%; P=0.038) but not group 4 (36.5%; P=0.177) and group 1. Group 2 was noninferior to group 1 for the ACR50 response at week 24 (33.1%; 95% confidence interval lower bound -5.2%; predefined delta value for noninferiority -10%). The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters, including response/remission according to the Disease Activity Score in 28 joints. Serious adverse events occurred in 7%, 3%, 6%, and 6% of patients in groups 1, 2, 3, and 4, respectively. CONCLUSION: Although the primary end point was not met, the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than, and the efficacy of golimumab alone is similar to, the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients, with no unexpected safety concerns.
19585118 Successful treatment of refractory cardiac tamponade due to rheumatoid arthritis using per 2010 Jun Rheumatoid pericarditis occurs in patients with rheumatoid arthritis (RA). However, cardiac tamponade due to rheumatoid pericarditis is rare; we describe a case of a 72-year-old man with a 6-year history of rheumatoid arthritis who developed rheumatoid pericarditis with recurrent cardiac tamponade. The patient experienced relapse of the cardiac tamponade despite treatment with pericardiocentesis. Therefore, the patient underwent surgical pericardial drainage. The patient was also subsequently treated with increasing doses of corticosteroid, methotrexate and leukocytapheresis. These treatments resulted in a successful outcome without any complication. This case suggests that in addition to immunosuppressive therapy, pericardial drainage should be considered in the treatment of life-threatening refractory cardiac tamponade caused by rheumatoid arthritis.
19180516 Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a doubl 2009 Feb OBJECTIVE: To determine the efficacy and safety of pamapimod (a selective inhibitor of the alpha-isoform of p38 MAP kinase) as monotherapy in comparison with methotrexate (MTX) treatment in adult patients with active rheumatoid arthritis (RA). METHODS: Patients were randomly assigned to 1 of 4 treatment groups and received 12 weeks of double-blind treatment. One group received MTX (7.5 mg/week with planned escalation to 20 mg/week), and 3 groups received pamapimod (50, 150, or 300 mg) once daily. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at 12 weeks. Secondary end points included ACR50 and ACR70 responses, change from baseline in the Disease Activity Score in 28 joints (DAS28), categorical analyses of DAS28/European League Against Rheumatism response, and change from baseline in each parameter of the ACR core set of measures. Safety monitoring included recording of adverse events (AEs), laboratory testing, immunology assessments, administration of electrocardiograms, and assessment of vital signs. RESULTS: Patients assigned to receive MTX and pamapimod had similar demographics and baseline characteristics. At week 12, fewer patients taking pamapimod had an ACR20 response (23%, 18%, and 31% in the 50-, 150-, and 300-mg groups, respectively) compared with patients taking MTX (45%). Secondary efficacy end points showed a similar pattern. AEs were typically characterized as mild and included infections, skin disorders, and dizziness. Pamapimod was generally well tolerated, but the 300-mg dose appeared to be more toxic than either the 2 lower doses or MTX. CONCLUSION: The present results showed that pamapimod was not as effective as MTX in the treatment of active RA.
20476861 Expression of full-length and splice forms of FoxP3 in rheumatoid arthritis. 2010 Aug OBJECTIVE: The aim of our study was to compare the presence of full-length and alternative splice forms of FoxP3 mRNA in CD4 cells from rheumatoid arthritis (RA) patients and healthy controls. METHODS: A quantitative real-time polymerase chain reaction (QRT-PCR) method was used to measure the amount of FoxP3 mRNA full-length and splice forms. CD4-positive T cells were isolated from peripheral blood from 50 RA patients by immunomagnetic separation, and the FoxP3 mRNA expression was compared with the results from 10 healthy controls. RESULTS: We observed an increased expression of full-length FoxP3 mRNA in RA patients when compared to healthy controls, as well as an increase in CD25 mRNA expression, but no corresponding increase in CTLA-4 mRNA expression. The presence of an alternative splice form of FoxP3 lacking exon 2 was confirmed in both RA patients and healthy controls, but with no significant difference in expression between the two groups. There was a positive correlation between the amount of FoxP3 mRNA and the clinical inflammation parameters C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and a negative correlation between FoxP3 mRNA and the dose of methotrexate (MTX) given to the patients. CONCLUSION: RA patients express more full-length FoxP3 than healthy controls in peripheral blood CD4-positive cells, suggesting an increased number of regulatory T cells (Tregs). However, no concomitant increase in CTLA-4 expression was seen. We therefore propose that the Tregs are left unable to suppress the ongoing inflammation due to a deficiency in CTLA-4 needed for cell contact-dependent suppression.