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ID PMID Title PublicationDate abstract
19174154 Metabolism-blocked antifolates as potential anti-rheumatoid arthritis agents: 4-amino-4-de 2009 Apr 1 4-Amino-4-deoxy-5,8,10-trideazapteroyl-d,l-4'-methyleneglutamic acid (CH-1504) is the prototype of a potentially therapeutically more selective class of antifolates for rheumatoid arthritis treatment. This class is characterized by retention of dihydrofolate reductase (DHFR; EC 1.5.1.3) as their locus of action and transport by the reduced folate carrier (RFC; SLC19A1), but their lack of metabolism by known pathways of antifolate (e.g., methotrexate (MTX)) metabolism. Five new CH-1504 analogs (CHL-001-CHL-005) were synthesized and diastereomers of CH-1504 itself were obtained by preparative chiral HPLC; all were characterized biochemically. The analogs are not metabolized by aldehyde oxidase (EC 1.2.3.1), carboxypeptidase G2 (EC 3.4.17.11), or (excepting CHL-003) folylpolyglutamate synthetase (EC 6.3.2.17) and thus, unlike MTX, are "metabolism-blocked". All analogs are potent DHFR inhibitors; several are nearly as potent as MTX or CH-1504. Each analog uses the RFC for transport, although with varying apparent affinities. In contrast, each weakly inhibits other enzymes of folate metabolism relevant to rheumatoid arthritis therapy (thymidylate synthase (EC 2.1.1.45), two formyltransferases of purine biosynthesis (EC 2.1.2.2 and EC 2.1.2.3), and 5,10-methylenetetrahydrofolate reductase (EC 1.5.1.20)). Biochemical characterization showed one 4'-diastereomer of racemic CH-1504 was significantly more active than the other. Based on literature data concerning the effect of d- and l-glutamic acid substitution on antifolate activity, it is likely that the diastereomer containing l-4'-methylene-glutamic acid is the more active. Because of concern about potential pharmacokinetic and biochemical effects of d-4'-methylene-glutamic acid-containing species, these data suggest that future analogs should contain only l-4'-methylene-glutamic acid. Overall, these data provide several interesting new leads for preclinical development.
20200692 Golimumab: A novel anti-TNF-alpha human monoclonal antibody for rheumatoid arthritis, psor 2010 Jan Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, has been implicated in the pathology of a variety of chronic autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. The introduction of TNF-alpha inhibitors represented a significant advance in the management of these diseases but the responses of individual patients to TNF-alpha inhibitors are not homogeneous and more therapeutic tools are needed. Golimumab (CNTO-148) is a novel anti-TNF-alpha human monoclonal antibody that blocks both soluble and transmembrane TNF-alpha. It is indicated in the treatment of adults with moderately to severely active rheumatoid arthritis in combination with methotrexate, in adults with active and progressive psoriatic arthritis either alone or in combination with methotrexate, and in adult patients with active ankylosing spondylitis who have had an inadequate response to conventional therapies. Golimumab has generally been well tolerated in clinical trials with a safety profile comparable to other currently available TNF-alpha inhibitors. Its advantages are that it can be administered s.c. once monthly, it is labeled for patient self-administration and is suitable for both s.c. and i.v. administration. Golimumab is currently being investigated in other chronic inflammatory diseases.
19517156 Does TNF-alpha blockade play any role in cardiovascular risk among rheumatoid arthritis (R 2009 Oct The aims of this study were to determine the association and potential mechanisms between TNF-antagonists and increased cardiovascular risk in rheumatoid arthritis (RA) patients. Three groups of RA patients were studied; ten treated with TNF-antagonists, 13 with methotrexate, and 14 were naïve to treatment. Mean age: 47.2 (SD 11.3), 52.3 (SD 16.6), and 51.2 (SD 13.3) years; mean disease duration 102 (SD 90.4), 72.9 (SD 67.3), and 71.3 (SD 87.1) months, and treatment duration 24.2 (SD 18.5), 34.7 (SD 32.2), and 0 months for each group. CLINICAL DATA: systolic and diastolic blood pressure and body mass index were assessed. Disease activity was determined by DAS-28 index. An ELISA assay for IL-6, sIL-6 R, IFN-gamma, TNF-alpha, sTNFRI, sTNFRII, IGF I, and adiponectin were performed. Fasting glucose, insulin, lipid profile, CRP, and ESR were also done. HOMA-IR and QUICKI indexes were calculated. Statistically significant differences observed between the TNF group and the other two groups were: TNF-alpha levels (p, 0.0014), soluble TNF RII (p, 0.0432), IFN-gamma (p, 0.008), and DAS-28 <2.6 (p, 0.033). Finding of elevated levels of sTNFRII and IFN-gamma in patients with RA on anti-TNF suggests that this therapy does not completely suppress the inflammatory process and may promote atherogenesis.
20098085 Composite cutaneous lymphoma in a patient with rheumatoid arthritis treated with methotrex 2010 Feb Patients with rheumatoid arthritis, whether treated or not with immunosuppressive agents including methotrexate, have an increased risk of lymphoproliferative disorders. Termed "iatrogenic immunodeficiency-associated lymphoproliferative disorders" in the 2008 World Health Organization classification of lymphoid neoplasms, they include Hodgkin and non-Hodgkin lymphomas. Composite lymphomas are rare, particularly in skin, with none reported in immunodeficiency states. We report the case of a 67 year-old woman with a long history of rheumatoid arthritis, on methotrexate treatment, who developed multiple skin lesions exhibiting a malignant infiltrate displaying both B- and T-cell phenotypes and dual clonal gene rearrangement by polymerase chain reaction, consistent with a cutaneous composite lymphoma. The patient received chemotherapy including rituximab with partial response, but the T-cell component recurred. To the best of our knowledge, this is the first case report of a cutaneous composite lymphoma in a patient with an iatrogenic immunodeficiency representing a dual challenge, diagnostic for the pathologist and therapeutic for the hematologist.
21275167 [Effect of Bizhongxiao decoction on proteomics of peripheral blood mononuclear cells in pa 2010 Nov OBJECTIVE: To probe in the possible acting mechanism of Bizhongxiao Decoction (BZXD) for treatment of early active rheumatoid arthritis (RA) by way of observing the two-dimensional gel electrophoresis map of proteins in peripheral blood mononuclear cells (PBMCs) of healthy persons and RA patients (intervened or un-intervened with BZXD), analyzing the differential proteins and seeking out the RA associated proteins. METHODS: Eighteen patients with early active RA were randomized into the BZXD group and the methotrexate (MTX) group, nine in each group, they were treated with BZXD (contained 15 Chinese herbs, as Herba Hedyotis diffusae, Herba Sarcandrae glabrae, Radix Salviae miltiorrhizae, Caulis Trachelosperi, Rhizoma Drynariae, Semen Coicis, etc.) and MTX combined with nimesulide Tablets respectively, three months as a treatment course, and their blood samples were collected for observation. Besides, blood samples from 9 healthy persons were taken as normal controls. PBMCs were isolated from blood using lymphozytes separation medium, and total protein in the cells was extracted through immobilized pH gradient two-dimensional gel electrophoresis. After Coomassie brilliant blue G250 staining, gel-image analysis was performed using PDQuest software. The differentially expressed proteins were identified by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF-MS). Then partial proteins were validated by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The 2-DE protein profile of PBMCs from healthy persons and RA patients before and 3 months after treatment were obtained, and 23 differential protein spots were found, 14 from 18 differential protein spots were successfully identified, of which 8 proteins were up-regulated and 6 proteins were down-regulated in RA patients as compared with control. After 3-month treatment, 5 differentially expressed proteins showed more obvious in the BZXD group than in the MTX group. RT-PCR verified that the expression of ApoA-I in all the three groups was consistent with the outcomes of 2-DE. CONCLUSIONS: Some differentially expressed proteins exist in the PBMCs of RA patients, which may play a potential role in the pathogenesis of RA; BZXD may treat RA by way of regulating the expression of some differential proteins in patients.
20979549 Tocilizumab for the treatment of rheumatoid arthritis. 2010 Nov Tocilizumab is a humanized anti-IL-6 receptor monoclonal antibody, which binds to circulating soluble IL-6 receptor and membrane-expressed IL-6 receptor, inhibiting IL-6 binding to both forms of IL-6 receptor. Several Phase III clinical trials demonstrate the clinical efficacy of tocilizumab as monotherapy or with disease-modifying anti-rheumatic drugs for adult patients with moderately to severely active rheumatoid arthritis. Tocilizumab in combination with methotrexate after 24 weeks of treatment could induce disease remission in 30% of patients with rheumatoid arthritis refractory to anti-TNF antagonist therapy. The most common adverse reactions reported in clinical studies are upper respiratory tract infection, nasopharyngitis, headache, hypertension and mild, reversible increases in alanine aminotransferase enzymes. Serious adverse reactions include infections, gastrointestinal perforations and hypersensitivity reactions, including anaphylaxis. The clinical efficacy and safety of tocilizumab has led to the approval of this innovative drug for the treatment of rheumatoid arthritis in more than 70 countries worldwide.
20444751 Radiographic progression and remission rates in early rheumatoid arthritis - MRI bone oede 2010 Oct OBJECTIVE: At 5 years' follow-up of early (<6 months) rheumatoid arthritis patients to (1) investigate whether initial combination therapy with methotrexate (MTX) and ciclosporin (CSA) (n=80) is superior to initial monotherapy with MTX (n=80) with respect to prevention of radiographic progression, (2) investigate whether the favourable clinical and radiographic response reported at 2 years in the CIMESTRA trial can be maintained and (3) identify predictors of radiographic outcome. METHODS: 139 patients completed 5 years' follow-up with maintained double-blinding and a strict synovitis suppressive treatment strategy with intra-articular betamethasone injections (intra-articular glucocorticosteroid (GC)) and escalation of disease-modifying anti-rheumatic drug treatment. Disease activity, total Sharp-van der Heijde Score (TSS) of hands, wrists and forefeet were assessed at baseline and after 3, 4 and 5 years. MRI of the wrist and anti-cyclic citrullinated peptide (anti-CCP) were assessed at baseline. RESULTS: At 5 years, TSS progression rate was <1 unit/year and 47% had not progressed radiographically since baseline. 78% were in Disease Activity Score remission, 56% in American College of Rheumatology remission and 17% withdrawn from treatment due to remission. There were no differences between initial treatment groups. MRI-bone marrow oedema, TSS and anti-CCP predicted radiographic progression at 5 years. CONCLUSION: Early and strict synovitis suppressive treatment with MTX and intra-articular GC lead to high remission rates and halting of erosive progression at 5 years. No additional effect of initial combination therapy with CSA was found. The results parallel those reported for tumour necrosis factor α antagonists. Baseline MRI-bone oedema, TSS and anti-CCP predicted radiographic progression.
20953815 Efficacy and tolerability of tocilizumab in rheumatoid arthritis patients seen in daily cl 2011 Apr Tocilizumab, a humanized monoclonal antibody to the interleukin 6 (IL-6) receptor, was approved for use as rheumatoid arthritis (RA) therapy in Japan in 2008, but its efficacy and tolerability in daily practice has not yet been reported. We report the results of a multicenter retrospective study on the efficacy and safety of tocilizumab involving all patients (n = 229) who were started on tocilizumab therapy at three rheumatology institutes in Japan from April 2008 through to March 2009. Tocilizumab was infused every 4 weeks at a dose of 8 mg/kg according to the drug labeling. Among the 229 patients, 55% concomitantly received methotrexate (MTX) and 63% had previously received anti-tumor necrosis factor (TNF) therapy. Average disease activity score (DAS) 28 of all 229 patients significantly decreased from 5.70 to 3.25 after 24 weeks of therapy. A European League Against Rheumatism (EULAR) good response and DAS28 remission was achieved in 57.4 and 40.7% of the patients, respectively, at 24 weeks. White blood cell counts significantly decreased and liver enzymes and total cholesterol slightly but significantly increased; however, liver enzyme levels did not increase in patients without MTX. Tocilizumab was discontinued in 47 cases (20.5%) due to lack of efficacy (5.2%), adverse events (11.4%), and other reasons (3.9%). The overall retention rate at 24 weeks was 79.5%. Based on these results, we conclude that tocilizumab therapy in daily rheumatology practice appears to be highly efficacious and well tolerated among active RA patients, including the anti-TNF therapy-refractory population. Tocilizumab infusion is therefore applicable not only as an alternative approach for anti-TNF therapy-resistant patients, but also as primary biologic therapy for active RA patients.
19255827 Pharmacokinetic study and Fcgamma receptor gene analysis in two patients with rheumatoid a 2009 The main aim of this study is to investigate the pharmacokinetics of infliximab and Fcgamma receptor (FcgammaR) polymorphism in two patients with rheumatoid arthritis (RA) who were well controlled by low-dose infliximab. A 57-year-old woman (Patient 1) and a 67-year-old woman (Patient 2) had active RA despite methotrexate and prednisolone treatments. They improved after the addition of infliximab (3 mg/kg), but developed pneumonia and sepsis, respectively. Although the infliximab doses were reduced to 1.5 mg/kg and 1 mg/kg, respectively, clinical improvements were maintained. Blood samples were obtained at 1 h after infliximab administration and at eight weeks (just before the next dose). The elimination half-life was determined by the serum concentration of infliximab. We also analyzed the polymorphisms of FcgammaRIIA, FcgammaRIIIA, and FcgammaRIIIB for the genomic DNA samples from the two patients and three controls. Amplification of the FcgammaR-genomic regions in allotype-specific polymerase chain reactions was used to distinguish the genotypes. Decresed clearance of infliximab was proven by a pharmacokinetic study of these patients under low-dose infliximab therapy. 131H/H (FcgammaRIIA) and 176F/F (FcgammaRIIIA) were detected in both patients. NA1/NA2 and NA2/NA2 (FcgammaRIIIB) were detected in Patients 1 and 2, respectively. These patients were well controlled over the long term by low-dose infliximab. The mechanism of the reduced clearance of infliximab might possibly be explained in part by the FcgammaR polymorphisms.
21078715 Factors associated with radiographic progression in patients with rheumatoid arthritis who 2011 Feb OBJECTIVE: To identify factors associated with radiographic progression at 52 weeks in patients with rheumatoid arthritis (RA) after 12 weeks of methotrexate (MTX) therapy. METHODS: The study population consisted of patients from the MTX arm of the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO). Logistic regression analysis was used to identify clinical and laboratory assessments performed at Week 12 of MTX therapy that might be associated with Week 52 radiographic outcome (modified total Sharp score). Classification and regression tree (CART) modeling of the Week 12 assessments was used to determine the subgroups of patients with the best and worst radiographic outcomes. RESULTS: A total of 169 patients were analyzed: 116 patients in the best radiographic outcome group and 53 patients in the worst radiographic outcome group. Logistic regression analysis showed that Week 12 C-reactive protein (CRP) level, erythrocyte sedimentation rate, tender joint count, swollen joint count (SJC), and Health Assessment Questionnaire scores were significantly associated with radiographic progression at Week 52 (p < 0.05 for each assessment). CART modeling showed that patients with Week 12 CRP > 0.67 mg/dl and SJC > 1 and patients with Week 12 CRP ≤ 0.67 mg/dl and SJC > 10 were likely to show the worst radiographic progression at Week 52. The CART model had a sensitivity of 85%, specificity of 60%, and overall classification accuracy of 68%. CONCLUSION: In patients with RA, measures of CRP and SJC after 12 weeks of MTX therapy emerged as the factors most associated with radiographic progression at Week 52.
19368420 Tocilizumab: a review of its use in the management of rheumatoid arthritis. 2009 Tocilizumab (RoActemra or Actemra) is a recombinant humanized monoclonal antibody that acts as an interleukin (IL)-6 receptor antagonist. Intravenous tocilizumab 8 mg/kg (and no less than 4.8 mg), in combination with methotrexate, is approved in the EU for the treatment of moderate to severe active rheumatoid arthritis in adult patients with inadequate response to, or who are intolerant of, prior disease-modifying anti-rheumatic drug (DMARD) or tumour necrosis factor (TNF) antagonist therapy. It may also be administered as monotherapy in patients intolerant of methotrexate or in whom methotrexate therapy is inappropriate. Tocilizumab is also approved in Japan for the treatment of polyarticular-course juvenile idiopathic arthritis, systemic-onset juvenile idiopathic arthritis and Castleman's disease. Intravenous tocilizumab was effective and generally well tolerated when administered either as monotherapy or in combination with conventional DMARDs in several well designed clinical studies in adult patients with moderate to severe rheumatoid arthritis. Tocilizumab-based therapy was consistently more effective than placebo, methotrexate or other DMARDs in reducing disease activity, and some trials also showed significant benefits with tocilizumab in terms of reducing structural joint damage and improving health-related quality of life (HR-QOL). Notably, tocilizumab-based therapy was effective in patients with long-standing disease in whom anti-TNF therapy had previously failed. More data are required to determine the comparative efficacy and safety of tocilizumab versus other biological agents and to establish their relative cost effectiveness. However, the present data suggest that tocilizumab is an important emerging treatment option in adult patients with moderate to severe rheumatoid arthritis.
19116913 Folate receptor beta as a potential delivery route for novel folate antagonists to macroph 2009 Jan OBJECTIVE: To determine the expression of folate receptor beta (FRbeta) in synovial biopsy tissues and peripheral blood lymphocytes from rheumatoid arthritis (RA) patients and to identify novel folate antagonists that are more selective in the targeting and internalization of FRbeta than methotrexate (MTX). METHODS: Immunohistochemistry and computer-assisted digital imaging analyses were used for the detection of FRbeta protein expression on immunocompetent cells in synovial biopsy samples from RA patients with active disease and in noninflammatory control synovial tissues. FRbeta messenger RNA (mRNA) levels were determined by reverse transcription-polymerase chain reaction analysis. Binding affinities of FRbeta for folate antagonists were assessed by competition experiments for 3H-folic acid binding on FRbeta-transfected cells. Efficacy of FRbeta-mediated internalization of folate antagonists was evaluated by assessment of antiproliferative effects against FRbeta-transfected cells. RESULTS: Immunohistochemical staining of RA synovial tissue showed high expression of FRbeta on macrophages in the intimal lining layer and synovial sublining, whereas no staining was observed in T cell areas or in control synovial tissue. Consistently, FRbeta mRNA levels were highest in synovial tissue extracts and RA monocyte-derived macrophages, but low in peripheral blood T cells and monocytes. Screening of 10 new-generation folate antagonists revealed 4 compounds for which FRbeta had a high binding affinity (20-77-fold higher than for MTX). One of these, the thymidylate synthase inhibitor BCG 945, displayed selective targeting against FRbeta-transfected cells. CONCLUSION: Abundant FRbeta expression on activated macrophages in synovial tissue from RA patients deserves further exploration for selective therapeutic interventions with high-affinity-binding folate antagonists, of which BCG 945 may be a prototypical representative.
19122432 [Targeting therapy for inflammatory diseases by anti-TNFalpha biologics]. 2009 Jan TNFalpha (tumor necrosis factor-alpha) plays a critical role in the pathogenesis of inflammatory diseases including rheumatoid arthritis and Crohn's disease. Infliximab is a monoclonal antibody that recognizes human TNFalpha. Clinical trials have been persuasive that infliximab is effective and far superior to the conventional drug therapy in various inflammatory diseases. Combination of infliximab plus methotrexate is effective in patients with active rheumatoid arthritis who have not responded adequately to traditional disease-modifying anti-rheumatic drugs, and has produced significant improvement in clinical, radiographic, and functional outcomes. Infliximab is also an important treatment option in patients with active Crohn's disease who have not responded to conventional therapy and in those with this disease who have fistulae. Moreover, infliximab treatment has resulted in effective suppression of ankylosing spondylitis, psoriasis and ocular inflammation in patients with refractory uveoretinitis due to Behçet's disease. Thus, biologics targeting TNFalpha have revolutionized the therapy of inflammatory diseases. Here, the current status of clinical application of anti-TNFalpha biologics is reviewed by describing the clinical outcome of infliximab and future prospects of biologics are discussed.
19950299 MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmac 2009 Dec OBJECTIVE: To assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of the CC chemokine receptor CCR1 antagonist MLN3897 in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX). METHODS: In this phase IIa, proof-of-concept study, patients meeting the American College of Rheumatology (ACR) criteria for RA who had been taking MTX for >or=6 months with evidence of active disease were randomly assigned to receive either 10 mg oral MLN3897 or matching placebo once daily for 12 weeks (days 1-83) while continuing to receive MTX once a week. Clinical assessments, safety monitoring, and sampling for pharmacokinetic and pharmacodynamic analyses were performed throughout the study. The primary efficacy end point was the difference in the percentage of patients meeting the ACR 20% improvement criteria (achieving an ACR20 response) on day 84 in the MLN3897-treated group compared with that in the placebo-treated group. RESULTS: MLN3897 was well tolerated, with no evidence of systemic immunosuppression. In the intent-to-treat population, there was no significant difference in day 84 ACR20 response rates between MLN3897-treated patients and placebo-treated patients (35% versus 33%, respectively; P=0.72). Results were similar for the per-protocol population. Pharmacokinetic analyses demonstrated no interactions between MLN3897 and MTX. MLN3897 was associated with a high degree of CCR1 occupancy (>or=90% on days 28, 56, and 84 in 82% of patients, by macrophage inflammatory protein 1alpha internalization assay). CONCLUSION: MLN3897 at a concentration of 10 mg once daily had no discernible activity in patients with RA who were also receiving MTX. The results suggest that CCR1 antagonism is unlikely to be a viable strategy for the treatment of RA when used in isolation at the receptor occupancy levels reached in this study.
20445285 [Secondary osteoporosis UPDATE. Rheumatoid arthritis and bone damage: trends in treatment] 2010 May Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis and bone damage. The bone manifestation in RA consists of joint destruction and systemic osteoporosis, which are brought about by different mechanisms. During the pathological processes, inflammatory cytokines such as TNF are largely produced from inflamed synovium and cause activation of osteoclasts deviated from bone remodelling cycle, resulting in joint destruction. But by the combinational use of methotrexate and TNF-inhibitors, clinical remission, structural remission and functional remission have become possible for the treatment of RA. Especially TNF-inhibitors remarkably suppress the progression of joint destruction in the vast majority of the patients. On the other side, systemic osteoporosis, mainly caused by menopause and glucocorticoid (GC), is often complicated in RA. However, bisphosphonate is well known to be effective for not only treatment but also prevention of GC-induced osteoporosis. Furthermore, anti-RANKL antibody denosumab possesses a potential to inhibit joint destruction as well as systemic and GC-mediated osteoporosis.
19812228 Response of elderly patients with rheumatoid arthritis to methotrexate or TNF inhibitors c 2009 Dec OBJECTIVE: To compare the efficacy of MTX and MTX+TNF inhibitors (TNFis) in elderly patients with RA with that in patients of younger age. METHODS: Data from two large, randomized, controlled, double-blind trials in patients with early RA using adalimumab or infliximab+MTX or MTX alone were obtained and pooled. Composite disease activity indices were calculated at baseline and 1 year of treatment, and compared in groups of patients classified by quartiles of age with the highest age group comprising 61-82 years using analysis of variance or Kruskal-Wallis test. RESULTS: Across all age quartiles, improvement on MTX was similar with respect to changes of composite disease activity indices, assessment of physical function and X-ray progression. Likewise, TNFi+MTX had similar effects across all age groups, but the effects of the combination were more profound than those of MTX monotherapy. Also in 10% of the patients with the highest age, primarily septuagenarians, improvement was seen to a similar degree as in the younger ones. CONCLUSIONS: Responsiveness of elderly patients with RA to MTX or TNFi+MTX is similar to that observed in patients of younger age.
20810498 Pharmacologic immunomodulation and cutaneous malignancy in rheumatoid arthritis, psoriasis 2010 Nov OBJECTIVE: It is unclear if skin cancer risk is affected by the use of immunomodulatory medications in rheumatoid arthritis (RA), psoriasis, and psoriatic arthritis (PsA). The purpose of this study is to evaluate and summarize the available data pertinent to this question. METHODS: The English language literature on PubMed was searched with a combination of phrases, including "malignancy," "skin cancer," "squamous cell carcinoma," "basal cell carcinoma," "melanoma," "psoriasis," "psoriatic arthritis," and "rheumatoid arthritis" in addition to the generic names of a variety of common immunomodulatory drugs. Relevant articles were identified and data were extracted. RESULTS: In total, 2218 potentially relevant articles were identified through the search process. After further screening, 20 articles relevant to RA were included. An additional 19 articles relevant to either psoriasis or PsA were included as well. RA may be a risk factor for the development of cutaneous malignancy. Treatment with tumor necrosis factor inhibitors increases the rates of non-melanoma skin cancer (NMSC) in RA and psoriasis. This risk doubles when combination methotrexate therapy is used in RA. Methotrexate may increase the risk of malignant melanoma in patients with RA and the risk of NMSC in psoriasis. Cyclosporine and prior phototherapy significantly increase the risk of NMSC. CONCLUSION: RA may potentiate the risk of cutaneous malignancy and therefore dermatologic screening in this population should be considered. The use of immunomodulatory therapy in RA, psoriasis, and PsA may further increase the risk of cutaneous malignancy and therefore dermatologic screening examinations are warranted in these groups. More careful recording of skin cancer development during clinical trials and cohort studies is necessary to further delineate the risks of immunomodulatory therapy.
20722036 A case of progressive multifocal leukoencephalopathy in a patient treated with infliximab. 2010 Nov We describe a 72-year-old white man with erosive rheumatoid arthritis in whom subacute neurologic and psychiatric symptoms developed after 3 years of treatment with infliximab, prednisone, and methotrexate. White matter demyelination was seen on magnetic resonance imaging of the brain, and progressive multifocal leukoencephalopathy (PML) was ultimately confirmed by brain biopsy. The patient was treated with supportive therapy and discontinuation of disease-modifying antirheumatic drugs, resulting in stabilization of the disease process. The patient survived, but neurologic and cognitive deficits persisted. The distribution and pathology of this patient's disease are unique from almost all reported incidents of oral methotrexate-associated leukoencephalopathy. The pathogenesis of disease may be linked to a T cell-mediated process that is potentially impacted by infliximab. This case provides the first reported evidence that PML can be seen in association with infliximab therapy.
19916871 Unexplained amenorrhea in a patient taking methotrexate for the treatment of rheumatoid ar 2010 Mar BACKGROUND: The cause of secondary amenorrhea in the following case cannot be explained by traditional etiologies. We therefore questioned whether long-term methotrexate treatment played a role as an endometrial inhibitor. CASE: A 44-year-old G4P2, with a 5-year history of rheumatoid arthritis, presented with a 2-year history of secondary amenorrhea. The patient took methotrexate since diagnosis. Her FSH, estrogen, prolactin, TSH and T4 levels were normal, her B-HCG was negative, her BMI was 22 and she had no history of Asherman's syndrome. CONCLUSION: There is no information, based on our search, on whether long-term methotrexate treatment has an effect on the menstrual cycle. This case highlights the need for the elucidation of the effects of long-term methotrexate treatment on the menstrual cycle in patients with rheumatoid arthritis.
19877104 Effect of certolizumab pegol with methotrexate on home and work place productivity and soc 2009 Nov 15 OBJECTIVE: To assess the impact of certolizumab pegol (CZP), a novel PEGylated anti-tumor necrosis factor, in combination with methotrexate (MTX) on productivity outside and within the home, and on participation in family, social, and leisure activities in adult patients with rheumatoid arthritis (RA). METHODS: The efficacy and safety of CZP (200 mg and 400 mg) plus MTX were assessed in 2 phase III, multicenter, double-blind, placebo-controlled trials (Rheumatoid Arthritis Prevention of Structural Damage [RAPID] 1 and RAPID 2). The novel, validated, RA-specific Work Productivity Survey (WPS-RA) was used to assess work place and home productivity. WPS-RA responses were collected at baseline and every 4 weeks until withdrawal/study completion. RESULTS: At baseline, 41.6% and 39.8% of subjects were employed outside the home in RAPID 1 and RAPID 2, respectively. Compared with placebo plus MTX, CZP plus MTX significantly reduced work absenteeism and presenteeism among patients working outside the home. Significant reductions in number of household days lost, household days with productivity reduced by >/=50%, and days lost due to RA for participation in family, social, and leisure activities were reported by patients in active treatment relative to placebo plus MTX. Improvements in all measures were observed with CZP plus MTX as early as week 4, and maintained until the study end (12 months in RAPID 1, 6 months in RAPID 2). Findings were consistent with clinical improvements with CZP plus MTX in both trials. CONCLUSION: CZP plus MTX improved productivity outside and within the home and resulted in more participation in social activities compared with placebo plus MTX. These observations suggest that considerable indirect cost gains might be achieved with this therapeutic agent in RA.