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ID PMID Title PublicationDate abstract
16649186 The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite 2006 May OBJECTIVE: To examine the efficacy and safety of different rituximab doses plus methotrexate (MTX), with or without glucocorticoids, in patients with active rheumatoid arthritis (RA) resistant to disease-modifying antirheumatic drugs (DMARDs), including biologic agents. METHODS: A total of 465 patients were randomized into 9 treatment groups: 3 rituximab groups (placebo [n = 149], 500 mg [n = 124], or 1,000 mg [n = 192] on days 1 and 15) each also taking either placebo glucocorticoids, intravenous methylprednisolone premedication, or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10-25 mg/week); no other DMARDs were permitted. RESULTS: Significantly more patients who received 2 500-mg or 2 1,000-mg infusions of rituximab met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 24 (55% and 54%, respectively) compared with placebo (28%; P < 0.0001). ACR50 responses were achieved by 33%, 34%, and 13% of patients, respectively (P < 0.001), and ACR70 responses were achieved by 13%, 20%, and 5% of patients (P < 0.05). Changes in the Disease Activity Score in 28 joints (-1.79, -2.05, -0.67; P < 0.0001) and moderate to good responses on the European League Against Rheumatism criteria (P < 0.0001) reflected the ACR criteria responses. Glucocorticoids did not contribute significantly to the primary efficacy end point, ACR20 response at 24 weeks. Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion-associated events; oral glucocorticoids conferred no additional safety benefit. Rituximab was well tolerated; the type and severity of infections was similar to those for placebo. CONCLUSION: Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA. The primary end point (ACR20 response) was independent of glucocorticoids, although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion.
16859835 Methtrexate-associated lymphoproliferative disorders. A clinicopathological study of 13 Ja 2006 We conducted clinicopathological and immunohistochemical analyses to investigate the prevalence of Epstein-Barr virus (EBV) among 13 cases with methotrexate (MTX)-associated lymphoproliferative disorder (LPD). The subjects of this study were four men and nine women ranging in age from 53 to 78 years (mean: 63 years). All 13 patients had received low dose MTX therapy for 1-13 years before the onset of LPD (mean: 5.8 years). LPDs were found at extranodal sites in six cases, and the disease stage was advanced in seven cases. The present study confirmed certain aspects of a previous observation made in the USA, including the following findings (i) the cases commonly showed diffuse large B-cell lymphomas (n=4) and Hodgkin lymphomas (HL) (n=3), (ii) EBV-encoded small RNA (EBER) + cells were identified in seven cases (60%), which is a much higher percentage than would be expected in lymphomas occurring in a general population, and (iii) three cases of polymorphous small lymphocytic or lymphoplasmacytic infiltrate achieved spontaneous remission of LPDs after MTX withdrawal. Of seven cases of EBER + in our series, three cases were PSLLPI, and two were HL. EBER + tumor cells were detected in only two (30%) of the seven cases with non-Hodgkin lymphomas. The present study suggests that EBV- associated non-Hodgkin lymphomas comprise only a portion of all non-Hodgkin lymphomas among MTX-associated LPDs.
18975322 Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, 2008 Nov OBJECTIVE: Spleen tyrosine kinase (Syk) has been identified as an important modulator of immune signaling in B cells and cells bearing Fcgamma-activating receptors. R788, a prodrug of active metabolite R406, has been shown to be an inhibitor of Syk kinase, active in a variety of in vitro and in vivo models, suggesting potential activity in the treatment of rheumatoid arthritis (RA). METHODS: We enrolled 189 patients with active RA despite methotrexate therapy in a 3-month, multicenter, ascending-dose, double-blind, placebo-controlled trial. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. RESULTS: Twice-daily oral doses of 100 mg and 150 mg of R788 were significantly superior to placebo or twice-daily oral doses of 50 mg at week 12 (ACR20 achieved in 65% and 72% versus 38% and 32% of patients, respectively [P < 0.01]). ACR50 (achieved in 49% and 57% versus 19% and 17% of patients, respectively) and ACR70 (achieved in 33% and 40% versus 4% and 2% of patients, respectively) scores showed a similar pattern. Clinical effect was noted as early as 1 week after initiation of therapy. Reductions in serum interleukin-6 and matrix metalloproteinase 3 levels also occurred as early as week 1 in the groups receiving 100 mg and 150 mg R788. The major adverse effects were gastrointestinal side effects (predominantly diarrhea) and neutropenia (<1,500/mm3), both of which were dose related. CONCLUSION: These results indicate that an inhibitor of Syk kinase produces significant clinical benefits at 12 weeks in a population of patients with active RA receiving methotrexate therapy. Syk kinase may be an important new therapeutic target in RA and related autoimmune conditions.
17611980 The effect of low-dose aspirin on the decreased risk of development of dyspepsia and gastr 2007 Aug OBJECTIVE: To evaluate the risk of gastrointestinal (GI) symptoms and ulcers associated to the use of low-dose aspirin (ASA) among patients with rheumatoid arthritis (RA) and osteoarthritis (OA) treated with cyclooxygenase-2 (COX-2) drugs, to clarify the controversy in the literature. METHODS: Using a longitudinal databank, a prospective study using Cox proportional hazards models was performed in patients receiving COX-2 therapy for RA or OA to examine the effect of ASA on GI events. In 4 separate analyses patients reported dyspeptic symptoms and GI ulcers at semiannual intervals for up to 3 years. Ulcers were validated by review of medical records. RESULTS: Among 4240 patients taking COX-2-specific inhibitors, with no ulcer at study start, the age- and sex-adjusted hazard ratios for the effect of ASA on the development of epigastric pain, heartburn, nausea, and ulcers, without these previous events, were 1.11 (95% CI 0.97-1.29), 1.00 (95% CI 0.88-1.15), 1.32 (95% CI 1.13-1.54), and 1.27 (95% CI 0.78-2.05). The use of a propensity score to account for the risk of ASA prescription showed an even lower effect of ASA among all GI variables. This risk occurs within the setting of no prior GI symptoms or GI events, and independently of the use of proton pump inhibitors, other GI drugs, other nonsteroidal antiinflammatory drugs, prednisone, or methotrexate. CONCLUSION: In actual practice, the use of low-dose ASA has a small effect on the risk of developing dyspeptic symptoms in a group of patients with rheumatic disease.
17635334 Methods to enhance the safety of methotrexate prescribing. 2007 Aug The treatment of chronic inflammatory conditions often involves a difficult balance between the benefits of disease modification and the risks attendant with the use of disease-modifying agents. Methotrexate is a useful and commonly used disease-modifying agent but has a particularly notable reputation for causing morbidity and mortality. We explore ways in which the safety of methotrexate prescribing may be improved. There has been considerable debate as to the whether some of the side-effects can be mitigated by co-prescription of folate with methotrexate. Whereas no definitive conclusion can yet be reached, evidence suggests that the improvement in side-effect profile is limited to fewer elevations of liver enzymes, but that this may be at the expense of decreased methotrexate efficacy. The question remains as to whether the improved tolerability more than compensates for the decreased efficacy or whether folic acid should be used in a more circumspect way. However, a very specific danger arises from the fact that methotrexate is prescribed once weekly for inflammatory conditions, leading to errors at both the prescription and patient level. We highlight simple ways of improving safety to decrease such errors.
16766364 Interleukin-1beta influences the effect of infliximab on temporomandibular joint pain in r 2006 May OBJECTIVES: The aim of this study was to investigate the influence of plasma and synovial fluid tumour necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), IL-6, soluble TNF receptor II (TNF-sRII), IL-1 receptor antagonist (IL-1ra), soluble IL-1 receptor II (IL-1sRII) and IL-10 on the effect of the TNFalpha antibody infliximab on temporomandibular joint (TMJ) pain in patients with active rheumatoid arthritis (RA). METHODS: Fifteen patients with TMJ pain taking methotrexate were included in the study. The effect of intravenous infusions of infliximab was assessed after 14 or 22 weeks. TMJ resting and movement pain was assessed by a visual analogue scale (VAS) (0-100 mm) and samples of venous blood and TMJ synovial fluid were collected before and after treatment. RESULTS: The effect of infliximab on TMJ pain was influenced by pretreatment plasma levels of IL-1beta, IL-1ra, and IL-10 as well as pretreatment levels of TMJ synovial fluid IL-1sRII. High pretreatment levels of these cytokines and receptors as well as the presence of rheumatoid factor (RF) were associated with no or minor reduction in TMJ pain after treatment. CONCLUSIONS: Systemic treatment of RA with a combination of infliximab and methotrexate seems to be insufficient to alleviate TMJ pain in patients with RF or high pretreatment plasma levels of IL-1beta.
18625622 IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rhe 2008 Nov OBJECTIVES: The phase III RADIATE study examined the efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis (RA) refractory to tumour necrosis factor (TNF) antagonist therapy. METHODS: 499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. ACR20 responses, secondary efficacy and safety endpoints were assessed. RESULTS: ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p<0.001 both tocilizumab groups versus control). At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 <2.6) rates at week 24 were clearly dose related, being achieved by 30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Most adverse events were mild or moderate with overall incidences of 84.0%, 87.1% and 80.6%, respectively. The most common adverse events with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache. The incidence of serious adverse events was higher in controls (11.3%) than in the 8 mg/kg (6.3%) and 4 mg/kg (7.4%) groups. CONCLUSION: Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile. TRIAL REGISTRATION NUMBER: NCT00106522.
19108784 Infliximab and methotrexate in the treatment of rheumatoid arthritis: a systematic review 2008 Nov BACKGROUND: Because of its long-term effectiveness in clinical practice, methotrexate (MTX) is currently the preferred disease-modifying antirheumatic drug (DMARD) for patients with active rheumatoid arthritis (RRA). However, many patients do not experience remission and continue to have signs and symptoms of active disease while receiving a maximally tolerated dose. OBJECTIVES: The aims of this meta-analysis were to estimate the efficacy and tolerability of the various dosage schemes of infliximab versus MTX for the treatment of active RA, to eliminate size-related uncertainty of effects, and to identify subgroups of patients who benefit most from infliximab + MTX therapy. METHODS: Using the MEDLINE online database (inception through November 2006) and the Cochrane Database of Systematic Reviews (Issue 4, 2006), we identified English-language articles on randomized controlled clinical trials. Studies investigating infliximab + MTX regimens versus a control group receiving MTX alone to assess efficacy in active RA, using the American College of Rheumatology (ACR) criteria for 20% improvement (ACR20), 50% improvement (ACR50), and 70% improvement (ACR70), were considered eligible for the meta-analysis. Pooled odds ratios (ORs) and 95% CIs were calculated to compare the relative risks and benefits of adding infliximab to MTX. RESULTS: From a total of 78 initially identified studies, 42 were considered potentially eligible for this review and 12 were considered eligible for the meta-analysis. Overall, 4899 patients were randomized to either infliximab + MTX (3919 patients) or MTX alone (980 patients). Mean patient age ranged from 44.6 to 56 years in the MTX-only arms and from 45.8 to 56 years in the infliximab + MTX arms. The proportion of female patients ranged from 66.6% to 100% in the MTX arms and from 68% to 100% in the infliximab arms. Infliximab 3 mg/kkg + MTX was more effective than MTX alone (OR = 3.52 [2.14-5.79] for reaching ACR20; 2.87 [2.228-3.61] for ACR50; and 2.42 [1.87-3.13] for ACR70). Infliximab 10 mg/kkg + MTX was also more effective than MTX alone (OR = 5.06 [3.88-6.59] for reaching ACR20; 5.72 [4.05-8.08] for ACR50; and 7.32 [2.28-23.50] for ACR70). Infliximab 10-mm/kg regimens appeared to be more effective than infliximab 3-mg/kg regimens (P = NS, P = 0.001, and P = NS for reaching ACR20, ACR50, and ACR70, respectively), without being associated with an increased risk for adverse events. Infliximab 10 mg/kg appeared to be more effective in trials of longer duration (> or = 54 weeks) compared with those of shorter duration (P = 0.03, P = 0.02, and P = 0.01 for reaching ACR20, ACR50, and ACR70, respectively) and in those that enrolled patients with severe disease activity (P = 0.05, P = 0.05, and P = NS for reaching ACR20, ACR50, and ACR70, respectively). Steroid coadministration (P < 0.001, P < 0.001, and P = NS for reaching ACR20, ACR50, and ACR70, respectively), previous DMARD exposure (P < 0.001, P < 0.001, and P = 0.04 for reaching ACR20, ACR50, and ACR70, respectively), and MTX naivete (P = NS, P < 0.001, and P =0.013 for reaching ACR20, ACR50, and ACR70, respectively) correlated with higher infliximab efficacy. CONCLUSIONS: Based on this meta-analysis, higher dose infliximab (10 mg/kg) in combination with MTX appeared to be more effective than the standard 3 mg/kg dose, particularly for patients with severe disease activity.The benefits of high-dose treatment appeared to accrue over time, and patients who received higher doses of infliximab did not experience a higher incidence of severe adverse events. The addition of oral low-dose steroids significantly enhanced infliximab efficacy.
18316338 Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients 2008 Apr OBJECTIVE: To identify factors predicting response to first TNF blocking treatment course in patients with established RA with a special focus on gender differences. METHODS: Patients with active RA initiating their first treatment course of TNF-blocking therapy were enrolled. The study period was March 1999 through September 2006. The prospective protocol included information on demographics, clinical characteristics of patients and response measures. Fulfilment of ACR 50-70% improvement and European League Against Rheumatism (EULAR) good response or remission [28-joint disease activity score (DAS28) <2.6] at 3 months were chosen as primary outcome measures. Potential predictors of responses were identified using multivariate binary logistic regression models. RESULTS: In total, 1565 patients were included in the study. Gender did not influence treatment response. Consistently, concomitant methotrexate (MTX) was significantly associated with EULAR remission, EULAR good response, ACR50 response and ACR70 response with odds ratios (ORs) 1.97, 2.13, 2.10 and 1.75, respectively. Concurrent treatment with other DMARDs was also significantly associated with EULAR remission, EULAR good response and ACR50 response (OR: 1.96, 2.24 and 1.94, respectively). Likewise, low HAQ at baseline consistently predicted good clinical outcome. Disease activity at baseline was directly associated with favourable response when measured by ACR50 and ACR70 (OR: 1.59 and 1.60, respectively), whereas DAS28 score at baseline was inversely associated with EULAR remission (OR: 0.78). CONCLUSIONS: In this observational study of patients with established RA, gender did not predict response to anti-TNF therapy, whereas treatment with concomitant DMARDs, especially MTX and low disability were associated with good response. Choice of outcome measures may influence the predictive value of baseline features.
17241583 Urticaria as a cutaneous sign of adult-onset Still's disease. 2006 Mar BACKGROUND: The cardinal signs and symptoms of adult-onset Still's disease (AOSD) include periodic fever, arthralgia and arthritis, lymphadenopathy, hepatosplenomegaly, an evanescent rash accompanied by neutrophilic granulocytosis, and a negative rheumatoid factor and antinuclear antibody test. OBJECTIVE: To alert clinicians and dermatologists to internal diseases such as AOSD when assisting patients with urticarial eruptions and systemic symptoms. METHODS: A case report of a 52-year-old white woman who received conventional therapy for urticaria for 3 years, with no improvement. Following this period, a diagnosis of AOSD was performed based on the presence of systemic symptoms. RESULTS: The inflammatory activity markers decreased by the second month of methotrexate therapy; however, the cutaneous lesions failed to disappear. Thalidomide was initiated, and total improvement of the cutaneous lesions was observed after 2 weeks. CONCLUSION: Urticarial rash is an uncommon presentation of AOSD, and clinicians must be alert to the possibility of a misdiagnosis in these cases.
17646975 New antirheumatic drugs: any real added value? A critical overview of regulatory criteria 2007 Sep OBJECTIVE: Rheumatoid arthritis (RA) is a systemic autoimmune disorder causing chronic polyarticular synovial inflammation and progressive joint damage. New anti-rheumatic drugs, such as leflunomide, infliximab, etanercept, adalimumab and anakinra, have recently become available. The aim of this paper is to summarize and critically evaluate the type of studies and clinical endpoints accepted by the European Medicines Agency (EMEA) to approve these new drugs. MATERIALS AND METHODS: Information regarding the approval of antirheumatic drugs was obtained from European Public Assessment Reports (EPARs) and published pivotal studies. RESULTS: Leflunomide is the only non-biological disease-modifying anti-rheumatic drug (DMARD) to receive recent approval for RA treatment, but strong evidence of its superiority over conventional therapies is lacking. Anakinra in combination with methotrexate received approval as a DMARD for RA on the basis of two pivotal trials in which American College of Rheumatology response criteria (ACR 20 response) were used as the sole primary endpoint. For easier demonstration of efficacy, studies leading to first approval of etanercept, infliximab and adalimumab were carried out on non-responders to DMARDs. Once on the market, these drugs gained an extension of the indication to methotrexate-naïve patients. Studies that provided the basis for approval were not adequately designed, given the lack of an active control and the choice of ACR response as the only clinical endpoint. Consequently, only a weak proof of efficacy emerged for the treatment of signs and symptoms of RA, and these drugs failed to show real benefit in slowing radiographic progression. Serious infections, changes in blood cell counts, severe skin and hepatic infections were the main adverse events that emerged from the clinical studies. Therefore, the unconvincing benefit of the new antirheumatic drugs can scarcely outweigh the risk associated with their use. Moreover, the monthly costs in Italy of the new biological preparations are several fold higher than those of the reference drugs. CONCLUSIONS: Recently approved anti-RA products should be a therapeutic option only for patients refractory to conventional drugs.
18564666 Adult onset Still's disease as a cause of acute liver failure. 2008 Jan A 29-year old lady presented to the hospital with high-grade intermittent fever, arthritis and macular skin rash. Investigations revealed anaemia, polymorphonuclear leucocytosis and raised erythrocyte sedimentation rate. Other tests including those for antinuclear antibody and rheumatoid factor were normal. The serum ferritin level however was raised. On the basis of these parameters a diagnosis of Still's disease was made. Treatment comprising oral steroids and anti-inflammatory agents was instituted. The patient recovered and was discharged only to present ten days later following 3 episodes of generalised tonic clonic seizures. Investigations revealed a persistently high serum ferritin with abnormal liver function test results. Jaundice developed and the patient went into grade IV hepatic encephalopathy following which she died. Still's disease is an idiopathic disease, diagnosed purely on the basis of the typical clinical features of the illness which include persistent arthritis, high fever, anaemia and an erythematous rash. Treatment for Still's disease mainly includes steroids and non-steroidal anti-inflammatory agents. Second-line treatment includes that used for controlling the arthritis and comprises gold, hydroxychloroquine, penicillamine, azathioprine, methotrexate, and cyclophosphamide.
17227824 Parapharyngeal abscess in a patient receiving etanercept. 2007 Feb OBJECTIVE: To report a case of parapharyngeal abscess associated with Streptococcus viridans in a patient with rheumatoid arthritis receiving treatment with etanercept. CASE SUMMARY: A 40-year-old man diagnosed with rheumatoid arthritis had received treatment with nonsteroidal antiinflammatory drugs, methotrexate, and deflazacort. Six months prior to admission, the patient had a Disease Activity Score of 3.4; clinicians decided to start treatment with etanercept. Chest X-rays were normal and the tuberculin skin test was negative. Treatment with etanercept plus methotrexate was started. Three months later, methotrexate was discontinued. Six months after etanercept therapy was started, the patient presented to our emergency department with a swelling of his neck, odynophagia, otalgia, and trismus. The clinical course was consistent with parapharyngeal abscess. Etanercept treatment was suspended. The parapharyngeal abscess was drained and intravenous methylprednisolone, amoxicillin/clavulanic acid, and clindamycin were administered. The parapharyngeal abscess secretion culture was positive for S. viridans and Bacteroides spp. The patient's condition improved with antibiotic therapy; he was discharged 5 days after admission. DISCUSSION: Tumor necrosis factor-alpha plays an essential role in the immune-mediated response to infection. In our patient, the most possible cause of parapharyngeal abscess was considered to be etanercept because of the temporal relationship between exposure to the drug and onset of symptoms. Etanercept was the only drug administered before the abscess developed. Based on the Naranjo probability scale, an association between etanercept and the adverse reaction could be considered possible. CONCLUSIONS: Patients initiated on etanercept therapy should be closely monitored for the development of tuberculosis and other infections. During treatment, all febrile or novel illnesses should be evaluated promptly. If clinical evaluation leads to the suspicion of tuberculosis and other infections associated with etanercept, it should be discontinued immediately.
17510560 Chronic anemia and thrombocytosis as the initial presentation of Still's disease in an eld 2007 Still's disease is very rare in elderly patients. We report a case of Still's disease in an elderly patient that had an atypical initial presentation. A 76-year-old woman developed unexplained chronic anemia and thrombocytosis. Three years later she had acute onset of high fever, arthritis, maculopapular rash, pleuritic chest pain, abdominal pain, lymphadenopathy and elevated erythrocyte sedimentation rate. Rheumatoid factor and antinuclear antibodies were negative. She responded favorably to prednisone and methotrexate treatment. Anemia and thrombocytosis as well as Still's disease manifestations resolved.
18257609 Adult-onset Still's disease: pathogenesis, clinical manifestations and therapeutic advance 2008 Adult-onset Still's disease (AOSD) is a rare, systemic inflammatory disease of unknown aetiology, characterized by daily high spiking fevers, evanescent rash and arthritis. Our objective was to review the most recent medical literature regarding advances in the understanding of disease pathogenesis, diagnosis and treatment. There is no single diagnostic test for AOSD, and diagnosis is based on clinical criteria and usually necessitates the exclusion of infectious, neoplastic and autoimmune diseases. Laboratory tests are nonspecific and reflect heightened immunological activity with leukocytosis, elevated acute phase reactants and, in particular, extremely elevated serum ferritin levels. Abnormal serum liver function tests are common, while rheumatoid factor and antinuclear antibodies are usually absent. Recent studies of the pathogenesis of the disease have suggested an important role for cytokines. Interleukin (IL)-1, IL-6 and IL-18, macrophage colony-stimulating factor, interferon-gamma and tumour necrosis factor (TNF)-alpha are all elevated in patients with AOSD. Prognosis depends on the course of the disease and tends to be more favourable when systemic symptoms predominate. Treatment includes the use of corticosteroids, often in combination with immunosuppressants (e.g. methotrexate, gold, azathioprine, leflunomide, tacrolimus, ciclosporin and cyclophosphamide) and intravenous immunoglobulin. Biological agents (e.g. anti-TNFalpha, anti-IL-1 and anti-IL-6) have been successfully used in refractory cases. Further progress has been hampered by the rarity and heterogeneity of the disease, which has not permitted the execution of randomized controlled studies.
17355553 Disseminated necrotizing leukoencephalopathy following low-dose oral methotrexate. 2007 Mar Leukoencephalopathy is a recognized complication with intrathecal or intravenous methotrexate (MTX). We report a 59-year-old lady who developed MTX leukoencephalopathy with long-term low-dose oral MTX. She developed posterior leukoencephalopathy (PLE) that initially was reversible on discontinuation of oral MTX. Four months later, she developed disseminated necrotizing leukoencephalopathy (DNL), and was left with devastating neurological deficits. The sequential conventional magnetic resonance imaging (MRI), diffusion weighted imaging (DWI), MR perfusion (MRP) and MR spectroscopic (MRS) changes are highlighted in this report. MRP and MRS showed more wide spread abnormalities than DWI. Stereotactic biopsy from the lesion revealed demyelination with macrophagic infiltration, pericapillary lymphomononuclear aggregation, fibrinoid changes in the capillaries and neovascularization. Of the two cases of PLE with oral MTX reported in literature, one reversed clinically and radiologically with the discontinuation of MTX. To the best of our knowledge, this is the first reported case of DNL following oral MTX in the world literature.
17013436 [Are there any positive effects of TNF-alpha blockers on bone metabolism?]. 2006 Jul Secondary osteoporosis (OP) is a well-recognized complication of rheumatoid arthritis (RA). Treatment with TNF-alpha blockers, might influence bone metabolism and prevent structural bone damage in RA, in particular at the periarticular regions. OBJECTIVE: To assess the influence of anti-TNF-alpha therapy, on bone metabolism in RA patients. 36 RA patients were treated with stable therapy of prednisone (7.5 mg/day) and methotrexate (MTX=10 mg/week). Nine of these RA patients further received etanercept (25 mg, twice/weekly) and eleven infliximab (3mg/kg on 0, 2, 6, and every 8 weeks thereafter). A control group included 16 RA patients only with stable therapy (some dosage of prednisone and MTX). Quantitative Ultrasound (QUS) bone densitometry was obtained at the metaphyses of the proximal phalanges of both hands with a DBM Sonic 1200 QUS device (IGEA, Carpi, Italy). Bone mineral density (BMD) of the hip and lumbar spine were performed with a densitometer ( Lunar Prodigy, GE, USA) at baseline and after 12 months. Soluble bone turnover markers [osteocalcin (OC), bone alkaline phospatase (ALP) deoxypyridinoline/creatinine ratio (Dpd/Cr) and cross-linked N-telopeptide of type I collagen / creatinine ratio (NTx/Cr)] were measured using ELISA tests. RESULTS: AD-SoS values were found increased by +4.55% after 12 months of treatment in the RA patients treated with anti-TNF-alpha therapy. On the contrary, the Ad-SoS levels decreased by -4.48% during the same period in the control RA group. BMD increased by +3.64% at lumbar spine and +2.90% at the hip (both p<0.001) in TNF-alpha blockers-treated patients and decreased by -2.89% and -3.10% (both p<0.001, respectively at lumbar spine and at the hip) in RA patients without anti-TNF-alpha therapy. In RA patients treated with TNF-alpha blockers, OC and bone ALP levels were found significantly increased (p<0.01) and Dpd/Cr or NTx/Cr levels were found significantly decreased (p<0.01) at 12 months when compared to baseline values. CONCLUSION: During 12 months of treatment of RA patients with TNF-alpha blockers, bone formation seems increased while bone resorption seems decreased. The reduced rate of OP seems supported by the same mechanisms involved in the decreased bone joint resorption during anti-TNF-alpha therapy (i.e. increase of osteoblastic activity and decrease osteoclastic activity).
19707351 Update on the use of etanercept across a spectrum of rheumatoid disorders. 2008 Jun Etanercept is a soluble TNF receptor p75 fusion protein which is approved for subcutaneous use (50 mg weekly) in the treatment of patients with active rheumatoid arthritis (RA), juvenile RA, ankylosing spondylitis, and psoriatic arthritis. Etanercept binds to both TNFalpha and lymphotoxin and has quite a short mean half-life (70 hours). Numerous randomized clinical trials have demonstrated its efficacy to improve signs and symptoms in early and established RA and other inflammatory arthritis. Furthermore, etanercept has shown its ability to prevent radiographic progression and to improve health-related quality of life in patients with RA and psoriatic arthritis. A combination of etanercept plus methotrexate was more efficacious than etanercept monotherapy in RA patients but there is currently no evidence that such rheumatic combination is better than monotherapy in other disorders. Etanercept was generally well tolerated both in controlled trials with withdrawal rates being similar to the comparator groups and in large observational studies. Infections and injection-site reactions were the most frequently reported events. Serious infections were slightly increased but the occurrence of tuberculosis seemed less frequent than with anti-TNF monoclonal antibodies (infliximab and adalimumab). The benefit-risk ratio of etanercept appeared to be very positive, and this drug has now emerged as a major therapy in patients with active inflammatory arthritis. Furthermore, it is more frequently considered as an emerging and valuable option in patients with early disease.
19105841 Limited Wegener's granulomatosis presenting as lung nodules in a patient with rheumatoid a 2008 Dec 23 BACKGROUND: Rheumatoid arthritis has varied pleuroparenchymal manifestations. Wegener's granulomatosis can develop in an established case of rheumatoid arthritis and this association although previously reported is very rare. CASE PRESENTATION: A 60-year-old lady had been diagnosed with rheumatoid arthritis on the basis of her clinical symptoms and serological tests which were positive RA factor and anti-CCP antibodies. Her rheumatoid arthritis activity had been mild and well controlled with hydroxychloroquine and low dose prednisone. She presented with a productive cough and right-sided pleuritic chest pain. CT scan of the chest showed three lung nodules with increased uptake on PET CT scan, raising concerns for an inflammatory or malignant process. The differential diagnosis included rheumatoid nodules, infections or malignancy. A CT-guided needle biopsy of the largest nodule was undertaken which showed vasculitis typical of Wegener's granulomatosis. Stains and cultures of the biopsy specimen were negative for bacteria, fungi and acid fast bacilli. A panel of serological tests for vasculitis were checked and showed elevated titers of cANCA and anti-proteinase 3 antibodies. Urine analysis and CT scan of paranasal sinuses was normal. Since the upper respiratory tract and the kidneys were spared a diagnosis of limited Wegener's granulomatosis affecting only the lungs was made. Due to the toxicity of cyclophosphamide, her relatively mild disease sparing the kidneys and the underlying rheumatoid arthritis, weekly methotrexate was started and low dose prednisone was continued. She had marked symptomatic improvement and complete resolution of the nodules was documented on subsequent imaging. CONCLUSION: Wegener's granulomatosis developing in a patient with rheumatoid arthritis is very rare but should be considered as it warrants a different and possibly more aggressive treatment approach.
23105613 Positive influence of Methotrexate-Hydroxychloroquine combination on the expression of GM- 2006 Sep Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) has been inducted as a mediator of inflammation in rheumatoid arthritis. Methotrexate combination therapy forms an important component of the treatment regimen in rheumatoid arthritis. The present study was undertaken to evaluate the influence of Methotrexate-Hydroxychloroquine (MTX-HCQ) combination and Sulfsalazine- Hydroxychloroquine (SSZ-HCQ) combination on the expression GM-CSFR in neutrophils isolated from synovial fluids. 15 cases of confirmed rheumatoid arthritis patients who presented at the hospital for surgical correction of joint deformities were selected for the study. Neutrophils isolated from the synovial fluids were used as the source of the receptor for quantitation on an enzyme immunoassay (EIA). The EIA was developed and standardized in our laboratory for quantification of the GM-CSF R. The findings are suggestive of the fact that the administration of MTX-HCQ combination has positive influence on the expression of the GM-CSF R on neutrophils as against SSZ-HCQ combination. The physiological basis of this increase needs further investigation.