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ID PMID Title PublicationDate abstract
15519494 Methotrexate enhances prostaglandin D2-stimulated heat shock protein 27 induction in osteo 2004 Dec As for the pathogenesis of rheumatoid arthritis (RA), prostaglandins (PGs) act as important mediators of inflammation and joint destruction. Among them, PGD2 is well recognized as a potent regulator of osteoblastic functions. We previously showed that PGD2 stimulates the induction of heat shock protein 27 (HSP27) via protein kinase C (PKC)-dependent p38 mitogen-activated protein (MAP) kinase and p44/p42 MAP kinase in osteoblast-like MC3T3-E1 cells. Therefore, it is a current topic to clarify how HSP27 plays a role for regulating osteoblastic functions in the lesion of RA. On the other hand, methotrexate (MTX) is one of the most effective medicines for the treatment of RA. Here, we examined the effect of MTX on PGD2-stimulated HSP27 induction in MC3T3-E1 cells. The cells were pretreated with various doses of MTX including therapeutic dosage for RA, and then stimulated by PGD2. MTX significantly enhanced the PGD2- increased levels of HSP27 in a dose-dependent manner, although MTX alone had no effect on the levels of HSP27. In addition, MTX amplified the PGD2-increased levels of HSP27 mRNA. On the contrary, MTX had little effect on PGD2-induced formation of inositol phosphates, PKC activation and phosphorylations of MAP kinases. Our results strongly suggest that MTX enhances PGD2-stimulated HSP27 induction at a point downstream from MAP kinases in osteoblasts.
14648712 Lymphoproliferative disorders in autoimmune diseases in Japan: analysis of clinicopatholog 2004 Jan 20 Lymphoproliferative disorders (LPD) occasionally develop in individuals with immune deficiencies such as immunosuppressive conditions and autoimmune diseases (AID). In our study, the clinicopathologic features and virus status were analyzed in 53 cases with LPD developing in rheumatoid arthritis (RA) and other AID. AID in only 4 of 53 patients had been treated with some sort of immunosuppressive therapy, including methotrexate. Median age at the diagnosis of LPD in AID was 60 years old with marked female predominance (M/F = 0.4). The median interval between the onset of AID and LPD development was 45 months, and longer in RA patients than in other AID (p < 0.01). The primary site of lymphoma was nodal in 21 cases and extra-nodal in 24, with clinical Stage I in 17, II in 5, III in 13, and IV in 13. Immunohistochemistry showed that 39 cases were B cell type, 10 were T cell type and 4 were Hodgkin lymphoma (HL). Then majority of B cell cases were diffuse large B cell lymphomas, and 2 were diffuse polymorphic type. EBER-1 in situ hybridization for Epstein-Barr virus (EBV) showed positive signals in tumor cells in 16 of 53 (30.2%) cases. The EBV-positive rate in T cell LPD (70%) was much higher than that in B cell LPD (12.8%) (p < 0.01). All 4 cases of HL were EBV-positive. Immunohistochemistry showed a latency II pattern of EBV infection (LMP-1(+) and EBNA-2(-)). Five-year overall survival rate was 33%. Multivariate analysis showed that only type of AID was an independent factor for survival of patients, i.e., LPD in RA showed the most favorable prognosis. In conclusion, LPD in AID generally shared common features with sporadic LPD except for a much higher EBV-positive rate in T cell LPD.
14679295 The health assessment questionnaire (HAQ) is strongly predictive of good outcome in early 2004 Apr OBJECTIVE: Scoring poorly on the health assessment questionnaire (HAQ) has recently been shown to be a strong predictor of morbidity and mortality in rheumatoid arthritis (RA), while a good HAQ score is predictive of a better outcome. In patients presenting with early diffuse scleroderma prognosis is variable. Our goal was to determine possible baseline predictors of future good outcomes. METHODS: We used the raw data from two randomized controlled trials (RCTs) in early diffuse scleroderma: methotrexate (Pope et al.) and D-penicillamine (Clements et al.). Subjects in the methotrexate trial were divided into the following groups: (1) those with at least 20% improvement in the primary outcome measurements [patient global assessment, physician global assessment, UCLA skin tethering score, modified Rodnan skin score (MRSS), DLCO as % predicted and HAQ disability] at 1 yr vs (2) the others. Baseline factors (including age, gender, skin scores, physician and patient global assessments, HAQ disability and pain scores, DLCO and physical parameters) were analysed to find baseline variables strongly correlated with later improvement. These variables were explored in the D-penicillamine trial to determine if (in a separate trial) they were still predictive of improved outcome at 1 and 2 yr. Adjusted models were used to find baseline predictors of good outcome. The median HAQ-DI was 1.3 (methotrexate) and 1.0 (D-penicillamine). RESULTS: A baseline HAQ disability score of less than the median was predictive of at least a 20% improvement at 1 and 2 yr with odds ratios of 1.77 to 5.05, in four of the five outcome measurements (in both groups); with strongly significant P values for 3 of 5 outcomes (UCLA skin score, MRSS, patient global skin score; P<0.02) from the methotrexate study group. These three outcomes were strongly correlated with improvement (r between 0.25 and 0.35). Although data from the D-penicillamine trial were less convincing, in both trials the less than median HAQ-DI and HAQ pain scores showed a stronger association with improved outcome, more so than age, gender, skin score and baseline global assessment. CONCLUSION: A low baseline HAQ (defined as less than the median HAQ score) is predictive of improved outcome in diffuse scleroderma at 1 and 2 yr.
15007115 Idiopathic hypertrophic pachymeningitis. 2004 Mar 9 BACKGROUND: Hypertrophic pachymeningitis is an uncommon disorder that causes a localized or diffuse thickening of the dura mater and has been associated with rheumatoid arthritis, syphilis, Wegener's granulomatosis, tuberculosis, and cancer. Few series of the idiopathic variety have been described, particularly with respect to MRI correlation to clinical outcome and treatment. OBJECTIVE: To investigate the clinical and laboratory evaluation, course, and treatment of patients with idiopathic hypertrophic pachymeningitis (IHP), to correlate the MRI findings with the clinical course, and to review the literature on IHP. METHODS: Retrospective case series of 12 patients (9 men, 3 women), with a mean age of 55 years (range 39 to 88 years), who had IHP by imaging studies, meningeal or orbital biopsy, or both. The clinical features, laboratory evaluation, contrast-enhanced MRI, treatment, and clinical outcome were documented for each case. The mean duration of follow-up was 3.5 years (range 3 months to 16 years). RESULTS: The main clinical features at presentation were headache (11 cases), loss of vision (7 cases), diplopia (4 cases), papilledema (2 cases), other cranial nerve involvement (3 cases), ataxia (2 cases), and seizures (1 case). On the initial MRI, the location of abnormal enhancement of the dura mater correlated with the clinical findings and the sphenoid wing area was affected in all patients. The sedimentation rate was elevated in five cases. The CSF had increased protein in six cases and lymphocytosis in four cases. Biopsy of the dura mater in five cases and the orbital soft tissue in one case showed infiltrates of small mature lymphocytes, plasma cells, and epithelioid histiocytes, but no neoplasia, vasculitis, or infectious agents. Cultures of the CSF and biopsy material remained sterile. Corticosteroid therapy improved the vision in 7 of 8 cases and controlled headache in 10 of 11 cases. Five cases had partial improvement of other neurologic symptoms and signs. Recurrence developed with steroid tapering in six cases. One case had progressive deterioration and died. In four cases methotrexate or azathioprine was added with reduction of the steroid dose. Follow-up MRI performed in 11 patients correlated 80% with the clinical state (p = 0.01). CONCLUSION: IHP can be suspected on MRI and defined pathologically on biopsy. Untreated, the clinical course is usually marked by severe headache and progressive neurologic deterioration and vision loss. Although initially steroid-responsive, clinical manifestations frequently recur with corticosteroid taper, requiring the addition of immunosuppressive agents in some cases.
12114277 Antiproliferative-antiinflammatory effects of methotrexate and sex hormones on cultured di 2002 Jun Methotrexate (MTX) is believed to exert both antiproliferative and antiinflammatory effects in a dose-related manner in a majority of rheumatoid arthritis (RA) patients along with an abrupt flare of the disease after drug discontinuation. To investigate the antiproliferative and antiinflammatory actions of MTX and the combined action of sex hormones, we evaluated these effects in differentiated monocytic myeloid cells (THP-1) prestimulated with testosterone (T) or 17-beta estradiol (E2). The effects of MTX and T combined treatment (T/MTX) on THP-1 cells showed a significant inhibition of cell proliferation when compared with E2/MTX- treated cells or controls: 53% at 72 h versus E2-treated cells; 58% at 96 h versus E2-treated cells; and 41% versus controls, respectively. Bax and Fas CD95 expression was found increased in T-treated cells: 14% T at 48 h vs. E(2)-treated cells and controls; 45% T at 72 h versus E2-treated cells and controls; 97% at 96 h versus E2-treated cells and 37% versus controls for Bax: 33%, 41%, and 42% T versus E2-treated cells for Fas. Moreover, a significant decrease of IL-12 levels in T/MTX treated cells was found at any time when compared to E2-treated cells. In summary, the association of testosterone and MTX compared to MTX alone suggests possible synergistic actions. Therefore, the enhancing antiinflammatory effects exerted by androgens might represent a further explanation for the reduced frequency of inflammatory diseases in male subjects.
12535475 Methotrexate for induction of remission in refractory Crohn's disease. 2003 BACKGROUND: Although corticosteroids are effective for induction of remission of Crohn's disease, approximately 20% of patients who respond relapse when steroids are withdrawn and become steroid dependent (Binder 1985). Furthermore, corticosteroids exhibit significant adverse effects. The success of methotrexate as a treatment for rheumatoid arthritis led to its evaluation in patients with refractory Crohn's disease. Methotrexate has been studied for induction of remission of refractory Crohn's disease and has become the principal alternative to azathioprine/6MP therapy. The evidence for its effectiveness has not been subjected to a systematic review. OBJECTIVES: To conduct a systematic review of the evidence for effectiveness of methotrexate for induction of remission in patients with active Crohn's disease in the presence and absence of concomitant steroid therapy. SEARCH STRATEGY: A computer-assisted search of MEDLINE and EMBASE for relevant studies published in English, French, Spanish, Italian and German between 1966 and June 2002. Manual searches of reference lists from potentially relevant papers were performed to identify additional studies. The Cochrane Controlled Trials Register and the IBD Review Group Specialized Trials Register were also searched. SELECTION CRITERIA: Randomized controlled trials involving patients of age > 17 years with refractory Crohn's disease defined by conventional clinical, radiological and endoscopic criteria, which was categorized as being active (Crohn's disease activity index >150). OUTCOME MEASURES: The outcome measure was the rate of induction of remission and complete withdrawal from steroids in the treatment and control groups after 16 weeks of treatment. A secondary outcome was induction of remission with reduction in steroid dose of at least 50%. Selection of trials: The results of the searches above were reviewed independently by two observers and relevant studies selected according to the predefined selection criteria. Any disagreement among reviewers was resolved by consensus. The same two reviewers assessed the methodological quality of each trial (details of randomization method, including whether intention-to-treat analysis was possible from the published data, number of patients lost to follow-up, and if a blinded outcome assessment was used). A standard data extraction form was used. Appropriateness of combining results: Trials were first reviewed to assess the clinical comparability of trial protocols and study populations. MAIN RESULTS: Three randomized placebo-controlled trials were identified. The three studies differed with respect to participants, intervention, and outcomes to the extent that it was considered to be inappropriate to combine the data statistically. Two studies which employed low doses of methotrexate orally showed no statistically significant difference between methotrexate and placebo treated patients, and one which employed a higher dose intramuscularly showed substantial benefit (number needed to treat, NNT=5). Adverse effects were more common with high dose intramuscular methotrexate therapy than with placebo. REVIEWER'S CONCLUSIONS: There is evidence from a single large randomized trial on which to recommend the use of methotrexate 25 mg intramuscularly weekly for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Although adverse effects are more common than with placebo, they were not severe. There is no evidence on which to base a recommendation for use of lower dose oral methotrexate.
15184196 Tumour necrosis factor alpha blocking agents in refractory adult Still's disease: an obser 2005 Feb BACKGROUND: Consensus is lacking on treatment for corticosteroid resistant adult onset Still's disease (ASD). OBJECTIVE: To assess anti-TNFalpha efficacy and tolerance in refractory ASD. METHODS: All departments of rheumatology and internal medicine in France were contacted by mail to identify cases of refractory ASD for which anti-TNFalpha had been used. Medical information was collected using a standardised questionnaire. RESULTS: Of 20 patients with mean age 40.7 years (range 18-74) at treatment start and mean disease duration 8.5 years (range 2-21), the clinical expression of ASD was predominantly systemic in five patients and polyarticular in 15. Response to corticosteroids and methotrexate had been considered inadequate in all patients. Infliximab was used to treat 15 patients, and etanercept used for 10; five had received both drugs consecutively. Steroids were concurrently used in 18 patients and an immunosuppressant in 17. At a mean (SD) follow up of 13 (14) months, complete remission had occurred in five cases (of 25 treatment sequences): one receiving etanercept and four infliximab. Partial response was observed in 16 cases (seven etanercept and nine infliximab). Treatment failed in four cases (two with each anti-TNFalpha). At the last visit, anti-TNFalpha therapy was discontinued in 17 cases, 11 times because of lack (or loss) of efficacy, four times because of a side effect, and twice for other reasons. CONCLUSION: Anti-TNFalpha therapy may be helpful for some patients with refractory ASD. However, most patients achieve only partial remission. Additional information is thus needed to evaluate more precisely the risk-benefit ratio of this treatment.
15103242 B cells as therapeutic targets for rheumatic diseases. 2004 May PURPOSE OF REVIEW: Trials treating human rheumatic diseases with biologic agents and drugs that selectively affect B cells will be reviewed. Rituximab, an anti-CD20 monoclonal mouse/human antibody, will be the primary focus of the review because it has been widely used in several autoimmune and rheumatic conditions, but the limited studies on other reagents such as anti-BlyS, anti-CD154, and B cell tolerogens will also be covered. RECENT FINDINGS: The single most important recent development was the completion of a randomized, double-blind, placebo-controlled trial of rituximab in methotrexate-resistant rheumatoid arthritis. In this trial, B cell depletion with rituximab led to a sustained clinical response with an impressive improvement in America College of Rheumatology 50% response (ACR 50) at both 24 and 48 weeks. Additional open studies of rituximab showing clinical benefit in systemic lupus erythematosus, cryoglobulinemia, antineutrophil cytoplasmic antibodies+ vasculitis, and dermatomyositis are noteworthy but must be interpreted with caution until randomized control trials are available. Two well-designed studies of anti-CD154 antibodies in systemic lupus erythematosus were reported. Unfortunately, one was halted because of unexpected vascular complications, and the other failed to show any beneficial clinical effect. A phase I study using anti-BlyS in SLE demonstrated a selective effect on B cells and no overt toxicity, but in this very short-term study no effect on serology or clinical activity was seen. Two B cell tolerogens have been used in human trials. The first tolerogen, directed at anti-dsDNA responses in SLE, did significantly decrease titers of high-affinity anti-dsDNA antibodies but had no clinically beneficial effect overall. A phase I trial of a tolerogen directed at anti-beta2-glycoprotein I antibodies demonstrated a decrease in antibody titers after a single injection. SUMMARY: Several therapeutic agents targeting B cells have now been tested or are being tested in human trials. The success of rituximab in a well-controlled trial confirms previous preliminary reports indicating that B cell depletion can treat established autoimmune disease.
15504755 Plant alkaloid tetrandrine downregulates IkappaBalpha kinases-IkappaBalpha-NF-kappaB signa 2004 Dec Plant alkaloid tetrandrine (Tet), purified from Chinese herb Han-Fang Chi, is a potent immunomodulator used to treat rheumatic disorders, silicosis and hypertension in mainland China. We previously demonstrated that Tet effectively suppresses cytokine production and proliferation of CD28-costimulated T cells. In the present study, we investigated the possible involvement of nuclear factor kappa B (NF-kappaB) transcription factors, critical in CD28 costimulation, in Tet-mediated immunosuppression in human peripheral blood T cells. We showed that Tet inhibited NF-kappaB DNA-binding activities induced by various stimuli, including CD28 costimulation. At equal molar concentrations, Tet was as strong as methotrexate in suppressing CD28-costimulated NF-kappaB activities. Since Tet itself did not affect NF-kappaB binding to its corresponding DNA sequence, the results suggested that Tet might regulate NF-kappaB upstream signaling molecules. Further studies demonstrated that Tet could prevent the degradation of IkappaBalpha and inhibit nuclear translocation of p65 by blocking IkappaBalpha kinases alpha and beta activities. In addition, the activation of mitogen-activated protein kinases such as c-jun N-terminal kinase, p38 and extracellular signal-regulated kinase and activator protein-1 DNA-binding activity were all downregulated by Tet. Transfection assays performed in purified human peripheral blood T cells also confirmed the inhibition of NF-kappaB transcriptional activity by Tet. When four Tet analogues were readily compared, dauricine appeared to preserve the most potent inhibition on CD28-costimulated but not on H(2)O(2)-induced NF-kappaB DNA-binding activities. Our results provide the molecular basis of immunomodulation of Tet for being a potential disease-modifying antirheumatic drug in the therapy of autoimmune disorders like rheumatoid arthritis.
14971796 Effect of methotrexate and folinic acid on skeletal growth in mice. 2003 Dec AIM: To investigate whether chronic administration of medium doses of methotrexate (MTX) causes suppression of skeletal growth in young mice and to determine whether folinic acid supplementation could reverse this effect. METHODS: Four equal groups of Balb/c young male mice (6 animals in each group; mean body weight 11.9 +/- 0.25 g, in their rapid growth phase) were subjected to the following drug treatment for a period of 3 wk. Group 1 was given intraperitoneal MTX (3.5 mg kg(-1) body weight) every second day. Group 2 received folinic acid (7.0 mg kg(-1) body weight) intraperitoneally every second day. Group 3 was given both drugs (MTX every second day and folinic acid 8 h post-MTX injection). Group 4 was injected with physiological saline every other day to serve as a control group. Total body weight of the animals in each group was monitored every second day for the entire study period. The animals were sacrificed, the bilateral femurs and tibias of each animal were harvested and X-rays of the bones were taken. The length of each femur and tibia was measured using a micrometer. Measurements from the radiographs were also recorded using image analysis software. The MTX concentrations in the plasma and the folate levels in erythrocytes were determined. The heights of the distal femoral and the proximal tibial growth plate for each animal were measured on histological tissue sections. RESULTS: Mean lengths of both the tibia and femur of animals were compared in the four treatment groups. A significant decrease in the mean lengths (one-way ANOVA, p < 0.005) was observed in the group receiving MTX alone. Similarly, there was a significant decrease (p < 0.001) in the height of the femoral and tibial growth plate in this group when compared with the other groups. The main effect of MTX seemed to be on the hypertrophic proliferative zone of chondrocytes in the growth plate. Furthermore, animals in this MTX-treated group also showed increased levels of MTX in plasma and low levels of erythrocyte folate. CONCLUSION: These data show that chronic administration of MTX induces suppression of skeletal growth in mice, possibly through the inhibition of the pathway of de novo DNA synthesis. Folinic acid treatment following MTX administration appears to reverse this growth inhibition. Based on these observations, children suffering from juvenile rheumatoid arthritis, osteosarcoma or acute lymphoblastic leukaemia and receiving MTX over long periods of time could be at risk of short-term suppression of skeletal growth. If this is the case, it is possible that they could benefit from dietary supplementation with folinic acid.
12209039 Inflammatory myositis associated with anti-U1-small nuclear ribonucleoprotein antibodies: 2002 Sep OBJECTIVES: Inflammatory myositides are rare chronic disorders which may be either isolated or associated with other conditions such as connective tissue diseases or neoplasia. A large variety of autoantibodies can be detected in patients with myositis, some of which have a diagnostic and/or a prognostic value. Myositis associated with anti-U1-small nuclear ribonucleoprotein antibodies (anti-U1-snRNP Abs) are usually considered as overlapping syndromes, mainly mixed connective tissue diseases (MCTD) in which muscle symptoms occur insidiously during the disease course and are characterized by a favourable outcome. METHODS: The clinical, biological, immunological and pathological findings as well as the outcome of five patients with anti-U1-snRNP-associated myositis were retrospectively analysed. RESULTS: Patients were mainly black females. In all five patients, myositis was the predominant manifestation at presentation. Associated conditions consisted of interstitial lung disease (ILD) (three), arthritis (three) and neurological symptoms (two). No patient presented Raynaud's phenomenon nor met criteria for MCTD. Biological inflammatory features, rheumatoid factor and polyclonal hypergammaglobulinaemia were present in all cases. Besides anti-U1-snRNP Abs, one patient had anti-Ro/SSA and anti-La/SSB Abs at presentation and one additional patient developed anti-double-stranded-DNA and anti-Sm Abs after a follow-up of more than 4 yr. No patient had anti-PM/sclerosis (Scl) nor anti-aminoacyl-tRNA synthetase Abs. All patients dramatically improved with steroids, and reached complete remission (CR) within 3 weeks. Two patients relapsed 18 months after CR. They both reached rapidly second CR using steroids associated or not with oral methotrexate. CONCLUSION: Our data suggest that anti-U1-snRNP Abs may define a subset of myositis characterized by a favourable outcome, though often associated with ILD and/or neurological manifestations.
16582693 Early rheumatoid arthritis. 2006 May PURPOSE OF REVIEW: This review provides novel and updated information on pathogenesis, referral, and clinical characteristics as well as therapeutic approaches in early rheumatoid arthritis. RECENT FINDINGS: Early referral is important, but new classification criteria for early rheumatoid arthritis need to be elaborated. Predictive markers for rheumatoid arthritis are still confined to autoantibodies; respective algorithms have been presented. Other biomarkers will still have to prove their usefulness. Magnetic resonance imaging and sonography do not appear to sufficiently distinguish between early rheumatoid and nonrheumatoid arthritis. Rheumatoid arthritis has become milder at presentation in recent years. In its very early stages, the cytokine profile reflects T-cell activation and switches to abundant proinflammatory cytokines thereafter. Disease-modifying antirheumatic drugs plus glucocorticoids are highly effective, as is early use of tumor necrosis factor blockers plus methotrexate. Tight control of disease activity and subsequent therapeutic adjustments are highly effective. Disease activity indices that are simple to calculate have been presented and validated. Early intensive therapy may lead to decrease in disability and cost reduction in rheumatoid arthritis. SUMMARY: Understanding of early arthritis is increasing, especially in prognostic and therapeutic respects, and new treatment strategies appear to improve the outcome in patients with early arthritis. Nevertheless, much remains to be studied to better address the issue of early rheumatoid arthritis.
17223742 Adalimumab for rheumatoid arthritis. 2006 Dec In the last few years significant advances have been made in our understanding of the molecular mechanisms underlying rheumatoid arthritis pathogenesis. Pro-inflammatory cytokines, such as TNF-alpha, play a pivotal role in its pathogenesis. Anti-TNF-alpha biological agents are considered a major advance in the treatment of rheumatoid arthritis. Adalimumab is a fully human monoclonal antibody that binds specifically to TNF-alpha, thereby neutralising its activity. It had significant efficacy in well-designed, placebo-controlled trials in patients suffering from rheumatoid arthritis, both as monotherapy and in combination with various disease-modifying antirheumatic drugs, including methotrexate. Adalimumab was generally well tolerated during both concomitant therapy with methotrexate or standard antirheumatic therapy and monotherapy. In addition, the radiographic progression of structural joint damage was significantly inhibited by adalimumab and improved quality of life. This review summarises the recent available data.
16864922 Pregnancy and rheumatoid arthritis. 2006 Aug Pregnancy in most cases, is associated with remission of rheumatoid arthritis (RA), but a quarter of patients continue to have active disease or even worsening of the disease and most patients who improve, relapse in the postpartum period. The pathophysiology of this improvement in disease activity during pregnancy remains unknown, but hormonal, cell-mediated immunological and humoral immunological changes during pregnancy, have been proposed responsible for this. Most of the pregnant women with RA have an uneventful course, with no significant complications. In general, no significant increase in maternal or fetal morbidity seems to be attributable to RA. Patients with RA do not have decreased fertility. A majority of patients with RA may go in remission and anti-rheumatic treatment may not be required as soon as women become pregnant. But other patients who continue with the disease activity require treatment. The preferred disease-modifying agents during pregnancy are sulfasalazine and hydroxychloroquine. Azathioprine and cyclosporine can be used if the benefits outweigh the risks. Paracetamol and low dose prednisone are preferred and considered safe, both for mother and fetus. Methotrexate and lefunomide are contraindicated and must be prophylactically withdrawn before a planned pregnancy. Biologics generally should be stopped when pregnancy is discovered. An overall rational approach is highly warranted to treat RA during pregnancy.
15951465 Rheumatoid arthritis: an overview of new and emerging therapies. 2005 Jul Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disorder characterized by symmetric inflammation of synovial joints leading to progressive erosion of cartilage and bone. The aim of treatment is to mitigate joint destruction, preserve function, and prevent disability. The American College of Rheumatology guidelines for the treatment of RA recommend that newly diagnosed patients with RA begin treatment with disease-modifying antirheumatic drugs (DMARDs) within 3 months of diagnosis. Methotrexate remains the most commonly prescribed DMARD and is the standard by which recent new and emerging therapies are measured. Increasing knowledge regarding the immunologic basis of RA and advances in biotechnology have resulted in new, targeted biological therapies against proinflammatory cytokines that have dramatically changed the treatment paradigm and outcomes of patients with RA. This article reviews the pharmacological rationale underlying RA therapy, with a focus on currently available biological therapies and new therapies in development.
15960819 Unmet needs in rheumatoid arthritis. 2005 Until the pathophysiology/etiology of rheumatoid arthritis (RA) is better understood, treatment strategies must focus on disease management. Early diagnosis and treatment with disease-modifying antirheumatic drugs (DMARDs) are necessary to reduce early joint damage, functional loss, and mortality. Several clinical trials have now clearly shown that administering appropriate DMARDs early yields better therapeutic outcomes. However, RA is a heterogeneous disease in which responses to treatment vary considerably for any given patient. Thus, choosing which patients receive combination DMARDs, and which combinations, remains one of our major challenges in treating RA patients. In many well controlled clinical trials methotrexate and other DMARDs, including the tumor necrosis factor-alpha inhibitors, have shown considerable efficacy in controlling the inflammatory process, but many patients continue to have active disease. Optimizing clinical response requires the use of a full spectrum of clinical agents with different therapeutic targets. Newer therapies, such as rituximab, that specifically target B cells have emerged as viable treatment options for patients with RA.
17133760 Rheumatoid arthritis: A review. 2006 Sep Rheumatoid arthritis (RA) is a systemic autoimmune disease with primary manifestations in the diarthrodial (movable) joints. Methotrexate in weekly doses is the most widely used disease modifying agent. The recent development of biologic agents designed to shut off disease activity can be of great benefit to individuals who fail methotrexate therapy. New treatments such as tumor necrosis factor suppressants are effective in up to 80% of patients. It is extremely important to diagnose RA in its earliest stages so that patients may benefit from antimetabolites and biologics before permanent joint damage takes place.
15914465 Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. 2005 Jun Methotrexate administered weekly in low doses is a mainstay in the therapy of rheumatoid arthritis. Although originally developed as a folate antagonist for the treatment of cancer, its mechanism of action in the therapy of rheumatoid arthritis remains less clear. Several mechanisms have been proposed including inhibition of T cell proliferation via its effects on purine and pyrimidine metabolism, inhibition of transmethylation reactions required for the prevention of T cell cytotoxicity, interference with glutathione metabolism leading to alterations in recruitment of monocytes and other cells to the inflamed joint, and promotion of the release of the endogenous anti-inflammatory mediator adenosine. These mechanisms of action and the role of methotrexate in the suppression of rheumatoid arthritis are reviewed.
15588977 Therapeutic strategies in early rheumatoid arthritis. 2005 Feb Rheumatoid arthritis (RA) therapy rests primarily on the use of disease-modifying antirheumatic drugs (DMARDs). It has been unequivocally shown that DMARD therapy early in the course of RA retards progression of damage and disability to a larger degree compared with delayed institution; the most effective DMARD is methotrexate (MTX). Moreover, combination therapy including intermediate to high doses of glucocorticoids and combinations of MTX with tumour necrosis factor blockers are more effective than monotherapies. However, early DMARD treatment requires early referral of patients and early diagnosis. This is hampered by the current lack of classification criteria for early RA, since the aim is to prevent destruction from occurring, while RA is typically characterized by the presence of erosions. Novel treatment strategies and therapeutic agents allow us to aim for remission rather than improvement of disease activity. Whether a 'window of opportunity' exists during which effective therapy might lead to cure is still an open issue and will be the focus of clinical trials in the near future.
15833077 Infliximab for the treatment of early rheumatoid arthritis. 2005 Mar Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease characterised predominately by polyarthritis with frequent progression to permanent joint damage and disability. Evidence shows that starting treatment with disease-modifying antirheumatic drug (DMARD) therapy early in the course of disease can slow radiographic progression of RA compared with a more delayed approach. Moreover, in the early stages of RA, treatment with a combination of methotrexate (MTX), a traditional DMARD, and a biologic with tumour necrosis factor (TNF)-alpha blocking activity has proven to be more effective than using MTX alone. Among the approved TNF-alpha inhibitors, infliximab is a chimeric monoclonal antibody with high affinity and specificity for its target cytokine. It binds to soluble TNF monomers and trimers, as well as membrane-bound TNF-alpha, forming a stable complex which prevents TNF-alpha from binding to its receptor and triggering a biological response. The combination of MTX and infliximab therapy has shown superior clinical outcomes compared with MTX monotherapy in early RA, as well as greater protection against joint damage and physical disability. Although infliximab therapy has been associated with side effects, including serious infections, this drug can be administered with an acceptable margin of safety for several years by appropriate selection of patients, screening for latent and active tuberculosis, and monitoring of patients for infection and other toxicities. The knowledge of the benefits of infliximab therapy for early RA affords groundwork for developing more effective treatment strategies that can minimise disease progression over the long term.