Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
ID | PMID | Title | PublicationDate | abstract |
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21786120 | Primary Sjögren's syndrome in Moroccan patients: characteristics, fatigue and quality of | 2012 Sep | Our aim was to evaluate fatigue and quality of life (QoL) in Moroccan patients with primary Sjögren's syndrome (PSS) and determine their correlates with disease-related parameters. Fifty-seven consecutive patients with PSS according to the American-European Consensus group (AEGG) criteria were included. Demographic, clinical, biological and immunological characteristics for all patients were collected. Xerostomia was demonstrated by histological grading of lower lip glandular biopsy. A Schirmer test was performed to measure lachrymal flow. Oral, ocular, skin, vaginal and tracheal dryness were evaluated by using a visual analogue scale (VAS). Fatigue was assessed by the Multidimensional assessment of fatigue (MAF) and the QoL by using the generic instrument: SF-36. 90% of our patients were women. The mean age of patients was 53.73 ± 7.69 years, and the mean disease duration was 5.38 ± 4.11 years. The mean oral dryness was 68.38 ± 20.29, and the mean ocular dryness was 51.91 ± 14.03. The mean total score of the MAF was 26.73 ± 8.33, and 87.5% of our patients experienced severe fatigue. Also, physical and mental domains of QoL were altered in a significant way, and the severity of fatigue had a negative impact on SF-36 scores. MAF and SF-36 scores were correlated with the delay of diagnosis, the intensity of xerostomia and the activity of joint involvement. A low socioeconomic and educational level had a negative impact on fatigue scores and QoL. Histological grading of lower lip glandular biopsy, immunological status and the severity of systemic involvement had no correlations with fatigue scores or the alteration of QoL. Patients receiving antidepressant have lesser fatigue and those receiving Methotrexate have better SF-36 scores. In our data, there was a high prevalence of fatigue in Moroccan patients with PSS associated with altered QoL. Severe fatigue and reduced QoL seem to be related to the severity of joint involvement, xerostomia and both educational and socioeconomic levels. Also, treatment with methotrexate and antidepressant seems to improve patients' living and QoL. An appropriate therapeutic intervention for depression and articular manifestations in PSS should be applied to improve patients' living. | |
20936538 | Attenuation of arthritis in rodents by a novel orally-available inhibitor of sphingosine k | 2011 Apr | Pro-inflammatory cytokines like TNF-α activate sphingosine kinase (SK). Therefore, inhibition of SK is a potential molecular target for the treatment of rheumatoid arthritis. AIMS: The primary goal of this study was to assess the efficacy of ABC249640 (a selective SK-2 inhibitor) in two models of rodent arthritis. A secondary goal was to evaluate the pharmacological profile of ABC294640, when given in combination with methotrexate. METHODS: The efficacy of ABC294640 was determined by paw diameter/volume measurements, histological evaluations, and micro-CT analyses. RESULTS: ABC294640 attenuated both collagen-induced arthritis in mice, as well as adjuvant-induced arthritis in rats. With the adjuvant arthritis model, the prophylactic efficacy profile of ABC294640 was similar to indomethacin. Of note, ABC294640 reduced the bone and cartilage degradation, associated with adjuvant-induced arthritis. Rats treated with a suboptimal dose of MTX (50 μg/kg/day) in combination with ABC249640 (100 mg/kg/day) had better anti-arthritis effects in the adjuvant model, than treatment with either agent alone. CONCLUSION: Our results suggest that ABC249640 is an orally available drug candidate with a good pre-clinical efficacy profile for the prevention and/or treatment of RA. | |
22745918 | Formulation and in vitro evaluation of ufasomes for dermal administration of methotrexate. | 2012 | Dermal drug delivery system that is required to localizes methotrexate (MTX) in the synovial joint is needed to treat inflammation in rheumatoid arthritis (RA). The present investigation aims at exploring the potential of fatty acid vesicles for the topical delivery of methotrexate. Vesicles were prepared by film hydration method using oleic acid as a fatty acid principal component. Developed vesicles were characterized for size, size distribution, shape, in vitro release, pH dependent, and storage stability. Interaction between MTX and oleic acid was investigated using differential scanning calorimetry. The MTX amount permeated through rat skin was three- to fourfold higher using oleic acid compared to those from plain drug solution or carbopol gel. At the end of the skin permeation assay using ufasomes, up to 50% of the administered dose was found in the skin. These results suggest that methotrexate encapsulated in oleic acid vesicles may be of value for the topical administration of MTX in the treatment of psoriasis. | |
22550565 | Methotrexate induced lung injury in a patient with primary CNS lymphoma: a case report. | 2012 | Methotrexate is an antimetabolite commonly used in clinical practice for a variety of indications ranging from rheumatoid arthritis and other connective tissue disorders to high dose regimens in many malignancies. This folate antagonist has got a spectrum of toxicities among which gastrointestinal effects predominate. Lung injury is a well described but rare event and has been reported most often in patients who have been on long term oral therapy for rheumatic disorders. Acute lung injury in a patient receiving a high dose regimen for haematological malignancies has not been reported previously. We present one such case of methotrexate related acute lung injury in a patient of primary CNS lymphoma receiving high dose methotrexate. | |
22161801 | Association between systemic antipsoriatic drugs and cardiovascular risk in patients with | 2012 Jun | OBJECTIVE: Psoriasis is associated with ischemic heart disease (IHD). Results of prior studies have suggested that methotrexate (MTX) may improve vascular disease in patients with psoriasis and rheumatoid arthritis. The aim of this study was to assess the risk of new-onset IHDs in psoriasis patients, comparing those taking MTX with those taking other nonbiologic antipsoriatic drugs. METHODS: In this retrospective cohort study, we utilized claims data from the National Health Insurance Research Database of Taiwan to identify 179,200 subjects who had received a diagnosis of psoriasis, with or without psoriatic arthritis, on at least 3 visits. The risk of hospitalization for new-onset IHD was compared between psoriasis patients taking MTX monotherapy (n = 6,578; MTX case cohort) and psoriasis patients taking other nonbiologic antipsoriatic drugs (n = 5,471; reference control cohort) between January 1996 and December 2008. Additional adjustments were made for cardiovascular risk factors, number of hospital visits, Charlson comorbidity score, and use of other antiinflammatory drugs. RESULTS: The incidence rates of IHD were 666 cases per 100,000 person-years in the MTX case cohort and 830 cases per 100,000 person-years in the reference control cohort (unadjusted P = 0.027). Increasing age, male sex, presence of hypertension, presence of diabetes, Charlson comorbidity score, and use of phototherapies were independent risk factors for hospitalization related to a new IHD in the study cohorts. However, the multivariate-adjusted hazard ratio for IHD-related hospitalizations among patients receiving MTX, in comparison with those receiving other nonbiologic antipsoriatic drugs, was 0.97 (95% confidence interval 0.79-1.19), after adjustment for age, sex, comorbidity score, number of hospital visits, and other antiinflammatory treatments for psoriasis. CONCLUSION: In patients with psoriasis with or without coexisting psoriatic arthritis, the adjusted risk of hospitalization for an IHD among individuals receiving MTX was comparable with that among individuals receiving other nonbiologic antipsoriatic drugs. | |
21619918 | An aqueous birch leaf extract of Betula pendula inhibits the growth and cell division of i | 2011 Jul 14 | ETHNOPHARMACOLOGICAL RELEVANCE: Leaf extracts of Betula pendula have been traditionally used for the treatment of patients with rheumatoid arthritis (RA) or osteoarthritis. AIM OF THE STUDY: We investigated the anti-proliferative capacity of an aqueous leaf extract of Betula pendula (BPE) on human primary lymphocytes in vitro, because activated lymphocytes play a major role in the initiation and maintenance of RA. MATERIALS AND METHODS: Lymphocyte proliferation and cell division was measured by the activity of mitochondrial dehydrogenases and by using the membrane-permeable dye carboxyfluorescein diacetate succinimidyl ester (CFSE), respectively. Apoptosis was analyzed by surface staining of phosphatidylserine and intracellular activation of effector caspases 3 and 7 in comparison to the drug methotrexate using flow cytometric and photometrical analysis. In addition, the impact of the extract on cell cycle distribution was investigated by propidium iodide staining of DNA. For the bioassays BPE concentrations of 10-160 μg/mL were investigated. A phytochemical analysis, using LC-MS and HPLC, was conducted to identify the polyphenolic constituents of the birch leaf extract. RESULTS: Leaf extracts of Betula pendula inhibited the growth and cell division (CD8(+): 40 μg/mL: 45%; 80 μg/mL: 60%; 160 μg/mL: 87%) (CD4(+): 40 μg/mL: 33%; 80 μg/mL: 54%; 160 μg/mL: 79%) of activated, but not of resting T lymphocytes in a significant dose-dependent manner. The inhibition of lymphocyte proliferation due to apoptosis induction (compared to untreated control: 40 μg/mL: 163%; 80 μg/mL: 240%; 160 μg/mL: 348%) and cell cycle arrest was comparable to that of methotrexate. LC-MS analyses showed that the extract contains different quercetin-glycosides. CONCLUSION: Our results give a rational basis for the use of Betula pendula leaf extract for the treatment of immune disorders, like rheumatoid arthritis, by diminishing proliferating inflammatory lymphocytes. | |
22085504 | Psoriasiform disorders with joint symptoms. | 2011 | We present a 49-year-old man seen at the dermatology outpatient department with a 3-year history of painful swollen digits of hands and feet. On enquiry he reported dysuria. On examination we saw extensive swelling of the digits, keratosis of the nails, and some psoriasiform skin lesions on the soles of the feet. The differential diagnosis included acrodermatitis continua suppurativa, reactive arthritis and psoriatic arthritis. Radiographic imaging revealed the presence of arthritis. Testing proved negative for rheumatoid factor and positive for HLA-B27 making spondyloarthropathy the most likely diagnosis, either in the form of reactive arthritis or psoriatic arthritis. The patient was treated with combination therapy of doxycycline, methotrexate and folic acid. Because of insufficient response to therapy, the methotrexate dose was raised and eventually etanercept was added. During the last visit to the outpatient clinic, the patient still showed insufficient response to therapy. | |
21463515 | Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic a | 2011 Apr 4 | INTRODUCTION: Folate receptor (FR)-expressing macrophages have been shown to accumulate at sites of inflammation, where they promote development of inflammatory symptoms. To target such a macrophage population, we designed and evaluated the biologic activity of EC0746, a novel folic acid conjugate of the highly potent antifolate, aminopterin. METHODS: Using a FR-positive subclone of murine macrophage-derived RAW264.7 cells and rat thioglycollate-elicited macrophages, we studied the effect of EC0746 on dihydrofolate reductase activity, cell proliferation, and cellular response towards bacterial lipopolysaccharide as well as IFNγ activation. The EC0746 anti-inflammatory activity, pharmacokinetics, and toxicity were also evaluated in normal rats or in rats with adjuvant-induced arthritis; that is, a FR-positive macrophage model that closely resembles rheumatoid arthritis in humans. RESULTS: EC0746 suppresses the proliferation of RAW264.7 cells and prevents the ability of nonproliferating rat macrophages to respond to inflammatory stimuli. In the macrophage-rich rat arthritis model, brief treatment with subcutaneously administered EC0746 is shown to mediate an FR-specific anti-inflammatory response that is more potent than either orally administered methotrexate or subcutaneously delivered etanercept. More importantly, EC0746 therapy is also shown to be ~40-fold less toxic than unmodified aminopterin, with fewer bone marrow and gastrointestinal problems. CONCLUSIONS: EC0746 is the first high FR-binding dihydrofolate reductase inhibitor that demonstrates FR-specific anti-inflammatory activities both in vitro and in vivo. Our data reveal that a relatively toxic anti-inflammatory drug, such as aminopterin, can be targeted with folic acid to inflammatory macrophages and thereby relieve inflammatory symptoms with greatly reduced toxicity. | |
21288455 | [Anti-angiogenic effects of genistein on synovium in a rat model of type II collagen-induc | 2011 Feb | OBJECTIVE: To explore the anti-angiogenic effects of genistein on synovium in a rat model of type II collagen-induced arthritis (CIA). METHODS: Forty SD rats were randomly divided into normal group, model group, genistein group, methotrexate (MTX) group and Gen plus MTX group with 8 rats in each group. Arthritis in rats was induced by subcutaneous injection of type II collagen combined with complete Freund's adjuvant (CFA). On the second day after the injection, 1 mL of suspension liquid of genistein (30 mg/kg body weight, once daily) and MTX (0.2 mg/kg body weight, once a week) were administered by oral gavage respectively. The rats in normal group and model group were administered with normal saline in the same volume. Synovium of knee joints and peripheral serum were collected from the CIA rats. Microvessel density in synovium (MVD) was detected by immunohistochemical method and serum vascular endothelial growth factor (VEGF) and matrix metallopeptidase (MMP)-1, 2 and 9 levels were detected by using Western blotting. RESULTS: Arthritis index score, paw volume of rats in the model group were significantly higher than those in the normal group (P<0.05), which suggested that a model of CIA induced by injection of type II collagen and CFA was successfully constructed. The arthritis index scores of rats in the treatment groups were decreased compared with the model group. The results of Western blotting showed that genistein obviously attenuate the levels of VEGF and MMP-1, 2 and 9 in serum (P<0.05). Immunohistochemical method showed that MVDs in the treatment groups were reduced as compared with the model group. CONCLUSION: The expressions of VEGF and MMP-1, 2 and 9 are related to the synovial pannus formation in CIA rats. The anti-angiogenic activity of genistein may correlate to its inhibitory effect on the expressions of VEGF and MMP-1, 2 and 9 in serum of CIA rats; genistein plus MTX are superior to single agents in treating rheumatoid arthritis. | |
22228807 | RN486, a selective Bruton's tyrosine kinase inhibitor, abrogates immune hypersensitivity r | 2012 Apr | Genetic mutation and pharmacological inhibition of Bruton's tyrosine kinase (Btk) both have been shown to prevent the development of collagen-induced arthritis (CIA) in mice, providing a rationale for the development of Btk inhibitors for treating rheumatoid arthritis (RA). In the present study, we characterized a novel Btk inhibitor, 6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one (RN486), in vitro and in rodent models of immune hypersensitivity and arthritis. We demonstrated that RN486 not only potently and selectively inhibited the Btk enzyme, but also displayed functional activities in human cell-based assays in multiple cell types, blocking Fcε receptor cross-linking-induced degranulation in mast cells (IC(50) = 2.9 nM), Fcγ receptor engagement-mediated tumor necrosis factor α production in monocytes (IC(50) = 7.0 nM), and B cell antigen receptor-induced expression of an activation marker, CD69, in B cells in whole blood (IC(50) = 21.0 nM). RN486 displayed similar functional activities in rodent models, effectively preventing type I and type III hypersensitivity responses. More importantly, RN486 produced robust anti-inflammatory and bone-protective effects in mouse CIA and rat adjuvant-induced arthritis (AIA) models. In the AIA model, RN486 inhibited both joint and systemic inflammation either alone or in combination with methotrexate, reducing both paw swelling and inflammatory markers in the blood. Together, our findings not only demonstrate that Btk plays an essential and conserved role in regulating immunoreceptor-mediated immune responses in both humans and rodents, but also provide evidence and mechanistic insights to support the development of selective Btk inhibitors as small-molecule disease-modifying drugs for RA and potentially other autoimmune diseases. | |
23117365 | [Sarcoidosis with right middle lobe atelectasis initially suspected of malignant lymphoma; | 2012 Nov | 60-year-old woman was admitted with an abnormal shadow on the chest roentgenogram. Computed tomography showed atelectasis of the right middle lobe and hilar and mediastinal lymphadenopathy. Bronchoscopic examination revealed an obstruction at the orifice of the right middle lobe bronchus and biopsy was performed. The biopsy suggested malignant lymphoma. A diagnosis of methotrexate-associated lymphoproliferative disorders was suspected because the patient was administered methotrexate to treat the rheumatoid arthritis. The video-assisted thoracoscopic surgery was performed. Histological examination showed no malignancy and sarcoidosis in the peribronchial lymph nodes. The compressed middle lobe bronchus by enlarged lymph nodes was consider to be the cause of the middle lobe atelectasis. | |
24280676 | Involvement of Multiple Transporters-mediated Transports in Mizoribine and Methotrexate Ph | 2012 Aug 10 | Mizoribine is administered orally and excreted into urine without being metabolized. Many research groups have reported a linear relationship between the dose and peak serum concentration, between the dose and AUC, and between AUC and cumulative urinary excretion of mizoribine. In contrast, a significant interindividual variability, with a small intraindividual variability, in oral bioavailability of mizoribine is also reported. The interindividual variability is mostly considered to be due to the polymophisms of transporter genes. Methotrexate (MTX) is administered orally and/or by parenteral routes, depending on the dose. Metabolic enzymes and multiple transporters are involved in the pharmacokinetics of MTX. The oral bioavailability of MTX exhibits a marked interindividual variability and saturation with increase in the dose of MTX, with a small intraindividual variability, where the contribution of gene polymophisms of transporters and enzymes is suggested. Therapeutic drug monitoring of both mizoribine and MTX is expected to improve their clinical efficacy in the treatment of rheumatoid arthritis. | |
22802024 | [Janus kinase inhibitors]. | 2012 Aug | Janus protein tyrosine kinase (JAK) inhibitors are new therapeutic targets in the treatment of rheumatoid arthritis. Tofacitinib has shown good clinical efficacy in phase II and III studies with American College of Rheumatology (ACR) 20 response rates over 50% for monotherapy and in combination with methotrexate (MTX). Also the safety profile shows similar infection rates as observed with known biologicals. The crude rate of serious infection events was 3/100 patient-years. Often reported adverse events are infections of the upper respiratory tract and urogenital infections. | |
21905970 | Further assessment of the clinically effective dose range of etoricoxib: a randomized, dou | 2011 Oct | OBJECTIVE: To further assess the clinically active dose range of etoricoxib, a COX-2 selective inhibitor, in rheumatoid arthritis (RA). METHODS: RA patients were randomized to etoricoxib 10, 30, 60, or 90 mg or placebo in a double-blind, 12-week study. DMARDs (methotrexate, biologics) or low-dose corticosteroids were allowed in stable doses. The primary endpoint was the proportion of patients completing the study and achieving an American College of Rheumatology 20% (ACR20) response. Secondary endpoints included individual components of the ACR index and Patient Global Assessment of Pain. Safety was assessed by physical exam and adverse experiences (AEs) occurrences. RESULTS: Etoricoxib 90 mg was the only dose to reach a statistically significant difference from placebo (p < 0.001) on the primary endpoint; etoricoxib 60 mg approached significance (p = 0.057). Significant pain improvement vs. placebo was observed with etoricoxib 90 mg (p < 0.001), 60 mg (p = 0.018), and 30 mg (p = 0.017). Despite the use of background biologics and corticosteroids, a dose response was still apparent. A higher proportion of etoricoxib 60 and 90 mg patients had renovascular AEs (i.e., edema and hypertension) compared with placebo, although discontinuations for renovascular AEs were rare. Etoricoxib 90 mg had a higher incidence of serious AEs (n = 5; 1 was considered drug-related) versus placebo (n = 0). LIMITATIONS: The present study was not powered to detect differences in cardiovascular or gastrointestinal safety by dose. Additionally, further research is needed to clarify the role of doses less than the etoricoxib 90 mg dose for pain management in RA patients. CONCLUSION: Etoricoxib 90 mg demonstrated statistically superior efficacy (ACR20) compared with placebo and numerical superiority over the other doses of etoricoxib studied. Etoricoxib 30 and 60 mg demonstrated significant pain improvement versus placebo, suggesting utility for some patients. | |
22942332 | Safety of nonsteroidal antiinflammatory drugs and/or paracetamol in people receiving metho | 2012 Sep | OBJECTIVE: To systematically review the literature on the safety of using nonsteroidal antiinflammatory drugs (NSAID) and/or paracetamol in people receiving methotrexate (MTX) for inflammatory arthritis (IA), as an evidence base for generating clinical practice recommendations. METHODS: A systematic literature review was performed using the Cochrane Library, Medline, Embase, and conference proceedings for the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) for 2008-2009. The search aimed to identify studies describing adverse events (AE) with the concurrent use of paracetamol and/or NSAID in people taking MTX for IA. Articles fulfilling our predefined inclusion criteria were systematically reviewed and quality appraised. RESULTS: Seventeen publications out of 8681 identified studies were included in the review, all of which included people with rheumatoid arthritis (RA) using various NSAID; there were no identified studies for other forms of IA or with paracetamol. Of the studies examining concurrent use of MTX and NSAID, there were no reported adverse effects on lung, liver, or renal function, and no increase in MTX withdrawal or in major toxic reactions. However, transient thrombocytopenia was demonstrated in 1 study. Looking at specific NSAID, there were no clinically significant AE with concomitant piroxicam or etodolac, and only mild AE with celecoxib or etoricoxib. Antiinflammatory dose aspirin was demonstrated to have an adverse effect on liver and renal function. CONCLUSION: In the management of RA, concurrent use of NSAID with MTX appears to be safe, provided appropriate monitoring is performed. The use of antiinflammatory doses of aspirin should be avoided. | |
21339747 | Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone de | 2011 May | Methotrexate (MTX) is widely utilized for the treatment of patients with rheumatoid arthritis (RA); however, recent observation of the MTX-resistant patients proposed some difficulty in MTX-dependent therapeutic approach for RA. To access cellular events related to MTX resistance in RA in respect to inflammatory bone destruction, we investigated on an involvement of the potent inflammatory mediator adenosine in the regulation of osteoclastogenesis and inflammatory bone destruction. In rats with adjuvant-induced arthritis (AA rats), MTX efficiently suppressed bone destruction when it was administrated within 3 days after adjuvant injection, while it could not suppress inflammatory bone destruction if MTX was injected at the time of onset of inflammation (at day 10 after adjuvant injection). Time-course change in the level of plasma adenosine of AA rats was estimated by use of high-performance liquid chromatography and elucidated that adenosine level was markedly elevated till 10 days after adjuvant injection. In vitro bone marrow culture system for evaluating osteoclastogenesis, MTX markedly suppressed osteoclastogenesis in a stromal cell-dependent manner. This MTX-induced suppression of osteoclastogenesis was abrogated by the addition of adenosine. MTX suppressed the expression of mRNA for the receptor activator NF-κB ligand (RANKL), but it did not suppress the expression of osteoprotegerin (OPG). The addition of MTX and adenosine together markedly suppressed the level of OPG expression. Abolishment of MTX action by adenosine was significantly blocked by MRS1754, a highly selective antagonist for the A(2b) adenosine receptor (A(2b)AR), but not by caffeine, an antagonist for Aâ‚, A(2a), A₃ AR (Aâ‚AR, A(2a)AR, and A₃AR), which suggests that adenosine acts through A(2b)AR. Immunohistochemical studies showed abundant expression of A(2b)AR in cells localized in the bone-bone marrow boundary of the distal tibia in AA rats but not in control rats. When adenosine was injected in the ankle joints of MTX-treated AA rats, the suppressive effects of MTX on bone destruction was abolished. The current data therefore suggest that upregulation of adenosine production abolished the suppressive effect of MTX on osteoclastic bone destruction. Involvement of the adenosine-A(2b)AR system may explain MTX resistance in RA. | |
21801113 | Leflunomide: dermatologic perspective. | 2013 Apr | Leflunomide, an isoxazole derivative, is a disease-modifying antirheumatic drug. It has successfully been used for the treatment of rheumatoid arthritis as a feasible alternative to methotrexate. Recently, leflunomide has been used in certain dermatologic conditions. Medline/PubMed search revealed only 201 articles of its application in dermatologic conditions, of which 21 were relevant for inclusion. Prime mode of action of leflunomide is through the inhibition of dihydroorotate dehydrogenase, a key enzyme in the de novo pyrimidine synthesis pathway used by lymphocytes for clonal expansion. The current level of evidence and strength of recommendation suggest its use in psoriasis and psoriatic arthritis. However, the use of leflunomide in severe atopic dermatitis, systemic lupus erythematosus, Wegener's granulomatosis, primary Sjögren's syndrome, bullous pemphigoid, dermatomyositis, sarcoidosis and systemic sclerosis still requires further evaluation. | |
21584942 | Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rhe | 2011 Aug | OBJECTIVE: To compare the efficacy, safety, and tolerability of 4 doses of oral tofacitinib (CP-690,550) with placebo in Japanese patients with active rheumatoid arthritis (RA) receiving stable background methotrexate (MTX) who had an inadequate response to MTX alone. METHODS: A total of 140 patients were randomized to receive tofacitinib 1, 3, 5, and 10 mg twice a day or placebo in this 12-week, phase II, double-blind study. All patients remained on background MTX. Efficacy and safety were assessed at weeks 1, 2, 4, 8, and 12. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. RESULTS: ACR20 response rates at week 12 were significant (P < 0.0001) for all tofacitinib treatment groups: 1 mg twice a day, 64.3%; 3 mg twice a day, 77.8%; 5 mg twice a day, 96.3%; and 10 mg twice a day, 80.8% versus placebo, 14.3%. A significant dose-response relationship for the ACR20 was observed (P < 0.0001). Low disease activity was achieved by 72.7% of patients with high baseline disease activity for tofacitinib 10 mg twice a day at week 12 (P < 0.0001). Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index, and Disease Activity Score 28-3 (C-reactive protein) were also reported. The most commonly reported adverse events (AEs) were nasopharyngitis (n = 13) and increased alanine aminotransferase (n = 12) and aspartate aminotransferase (n = 9) levels. These AEs were mild or moderate in severity. Serious AEs were reported by 5 patients. No deaths occurred. CONCLUSION: In Japanese patients with active RA with an inadequate response to MTX, tofacitinib in combination with MTX over 12 weeks was efficacious and had a manageable safety profile. | |
23237242 | Onset of polyarticular juvenile idiopathic arthritis with both anti-cyclic citrullinated p | 2012 Dec 13 | This report describes 3 year old girl with the unusual presentation of polyarticular juvenile idiopathic arthritis (JIA) with anti-cyclic citrullinated peptide (anti-CCP) antibodies and a positive rheumatoid factor (RF). She was initially treated with a nonsteroidal anti-inflammatory drug (NSAID; ibuprofen) followed by methotrexate (MTX, 10 mg/m2/week) and prednisolone (0.25 mg/kg/day), but these treatments were ineffective. Administration of tocilizumab, a humanized antihuman interleukin-6 receptor monoclonal antibody, promptly improved her clinical manifestations, and she has been in complete remission (DAS28 <2.6) without bone erosion and/or destruction. Positivity for both antibodies (anti-CCP and RF) can forecast the severity of JIA (radiographic bone destruction). In such cases the administration of biologic remissive therapy may be prudent early in the disease course. | |
23189211 | Human umbilical cord mesenchymal stem cells as treatment of adjuvant rheumatoid arthritis | 2012 Oct 26 | AIM: To investigate the effect of human umbilical cord stem cells, both mesenchymal and hematopoietic (CD34+), in the treatment of arthritis. METHODS: Mesenchymal stem cells (MSCs) and hematopoietic (CD34+) stem cells (HSC) were isolated from human umbilical cord blood obtained from the umbilical cord of healthy pregnant donors undergoing full-term normal vaginal delivery. MSC, HSC, methotrexate (MTX) and sterile saline were injected intra-articularly into the rat hindpaw with complete freunds adjuvant (CFA) induced arthritis after the onset of disease (day 34), when arthritis had become well established (arthritis score ≥ 2). Arthritic indices were evaluated and the levels of interleukin (IL)-1, tumor necrosis factor (TNF)-α and interferon (IFN)-γ and anti-inflammatory cytokine IL-10 in serum were determined using enzyme-linked immunosorbent assay. Animals of all groups were sacrificed 34 d after beginning treatment, except positive control (PC) which was sacrificed at 10, 21 and 34 d for microscopic observation of disease progression. We used hematoxylin, eosin and Masson's trichrome stains for histopathological examination of cartilage and synovium. RESULTS: The mean arthritis scores were similar in all groups at 12 and 34 d post immunization, with no statistical significant difference. Upon the injection of stem cells (hematopoietic and mesenchymal), the overall arthritis signs were significantly improved around 21 d after receiving the injection and totally disappeared at day 34 post treatment in MSC group. Mean hindpaw diameter (mm) in the MSC rats was about half that of the PC and MTX groups (P = 0.007 and P = 0.021, respectively) and 0.6 mm less than the HSC group (P = 0.047), as indicated by paw swelling. Associated with these findings, serum levels of TNF-α, IFN-γ and IL-1 decreased significantly in HSC and MSC groups compared to PC and MTX groups (P < 0.05), while the expression of IL-10 was increased. Histopathological examination with H and E stain revealed that the MTX treated group showed significant reduction of leucocytic infiltrate and hypertrophy of the synovial tissue with moderate obliteration of the joint cavity. Stem cells treated groups (both hematopoietic CD34+ and mesenchymal), showed significant reduction in leucocytic infiltrate and hypertrophy of the synovial tissue with mild obliteration of the joint cavity. With Masson's trichrome, stain sections from the PC group showed evidence of vascular edema of almost all vessels within the synovium in nearly all arthritic rats. Vacuoles were also visible in the outer vessel wall. The vessel became hemorrhagic and finally necrotic. In addition, there was extensive fibrosis completely obliterating the joint cavity. The mean color area percentage of collagen in this group was 0.324 ± 0.096, which was significantly increased when compared to the negative control group. The mean color area percentage of collagen in hematopoietic CD34+ and mesenchymal groups was 0.176 ± 0.0137 and 0.174 ± 0.0197 respectively, which showed a marked decrement compared to the PC group, denoting a mild increase in synovial tissue collagen fibers. CONCLUSION: MSC enhance the efficacy of CFA-induced arthritis treatment, most likely through the modulation of the expression of cytokines and amelioration of pathological changes in joints. |