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ID PMID Title PublicationDate abstract
27904705 Paclitaxel suppresses collagen-induced arthritis: a reevaluation. 2016 OBJECTIVE: To reevaluate the suppressive effect of paclitaxel (PTX) liposome on collagen-induced arthritis (CIA) in rats and explore its mechanisms. METHODS: Female Lewis rats were immunized with bovine type II collagen (CII) to induce arthritis. The rats with CIA were randomly divided into three groups: 5% GS control group, 2.5 mg/kg PTX treatment group and 1 mg/kg methotrexate (MTX) positive control group. The drugs were administered by intraperitoneal injection on the second day after arthritis onset. The body weights, arthritis scores and paw volumes were observed consecutively. The ankle joints of rats were collected for X-ray examination and histological evaluation. Serum samples were collected to test the levels of anti-CII antibodies and cytokines. RESULTS: Body weights were not significantly affected after PTX or MTX treatments (p>0.05). Compared with 5% GS control or MTX treatment groups, PTX group showed significant decrease of arthritis scores and paw volumes (p<0.05). Radiographic and histologic evaluation provided evidence that rats with PTX treatment had less synovial proliferation and bone erosion. In addition, the levels of anti-CII antibodies as well as serum tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) levels were remarkably lower in PTX group than those in 5% GS controls (p<0.05). CONCLUSIONS: PTX inhibits the progression of CIA in rats and prevents the destruction of joints. The mechanism might be related to its inhibition on the levels of serum anti-CII antibodies, TNF-α and VEGF.
26970681 Response rate of initial conventional treatments, disease course, and related factors of p 2016 May BACKGROUND: Adult-onset Still's disease (AOSD) is a rare condition, and treatment choices are frequently dependent on expert opinions. The objectives of the present study were to assess treatment modalities, disease course, and the factors influencing the outcome of patients with AOSD. METHODS: A multicenter study was used to reach sufficient patient numbers. The diagnosis of AOSD was based on the Yamaguchi criteria. The data collected included patient age, gender, age at the time of diagnosis, delay time for the diagnosis, typical AOSD rash, arthralgia, arthritis, myalgia, sore throat, lymphadenopathy, hepatomegaly, splenomegaly, pleuritis, pericarditis, and other rare findings. The laboratory findings of the patients were also recorded. The drugs initiated after the establishment of a diagnosis and the induction of remission with the first treatment was recorded. Disease patterns and related factors were also investigated. A multivariate analysis was performed to assess the factors related to remission. RESULTS: The initial data of 356 patients (210 females; 59%) from 19 centers were evaluated. The median age at onset was 32 (16-88) years, and the median follow-up time was 22 months (0-180). Fever (95.8%), arthralgia (94.9%), typical AOSD rash (66.9%), arthritis (64.6%), sore throat (63.5%), and myalgia (52.8%) were the most frequent clinical features. It was found that 254 of the 306 patients (83.0%) displayed remission with the initial treatment, including corticosteroids plus methotrexate with or without other disease-modifying antirheumatic drugs. The multivariate analysis revealed that the male sex, delayed diagnosis of more than 6 months, failure to achieve remission with initial treatment, and arthritis involving wrist/elbow joints were related to the chronic disease course. CONCLUSION: Induction of remission with initial treatment was achieved in the majority of AOSD patients. Failure to achieve remission with initial treatment as well as a delayed diagnosis implicated a chronic disease course in AOSD.
27478959 Effective transdermal delivery of methotrexate through nanostructured lipid carriers in an 2016 Nov 1 Rheumatoid arthritis (RA), an autoimmune and inflammatory pathology, is resulted due to the disruption of immune-homeostasis and failure of host immune-surveillance mechanism leading to cartilage degradation and bone erosion. Orally and parenterally administered methotrexate (MTX) have had adverse systemic complications in RA therapeutics. Therefore, transdermal application of MTX is recommended for the treatment of RA [1]. Present study is designed to develop MTX loaded nanostructured lipid carriers and chemical enhancer co-incorporated hydrogel (gel-(MTX-NLCs+CE)) for an efficient transdermal delivery of MTX in a Freund's adjuvants induced experimental animal model of RA. A gel-(MTX-NLCs+CE) was formulated and evaluated for its biocompatibility in hyper keratinocytes (HaCaT) and human monocytic cells (U937). Further, systemic and local inflammation was assessed by the estimation of pro-inflammatory cytokines & joint-destructive enzymes (TNF-α, IL-6, MMP-1 & IL-1β,; iNOS & COX-2) in the serum and synovial fluid, respectively in an experimentally induced RA animal model. Prepared formulations were also evaluated with respect to arthritis index, arthritis score and histopathology of paw and ankle bones. The biocompatibility study of formulation on U937 and HaCaT is suggestive of safe and greater therapeutic efficacy of the developed formulations. Our results show that transcutaneous ability of MTX loaded nanostructured lipid carries (NLCs) and chemical enhancer (CE) co-incorporated hydrogel significantly (p<0.001) decreases the inflammation in RA animal model. In conclusion, developed NLCs-based gel formulation loaded with MTX opens new avenues for developing novel therapeutic modality for RA patients with the acceptably minimum adverse effects.
25586964 Anti-inflammatory activity of sappanchalcone isolated from Caesalpinia sappan L. in a coll 2015 Jun Sappanchalcone, a bioactive flavonoid isolated from the heartwood of Caesalpinia sappan L. possesses anti-inflammatory effects. We studied the efficacy of sappanchalcone in attenuating collagen-induced arthritis (CIA) in a mouse model of rheumatoid arthritis. Sappanchalcone was purified to homogeneity from the chloroform fraction of the methanolic extract of C. sappan, and identified using mass spectrometry and (1)H-nuclear magnetic resonance spectroscopy. CIA-induced male DBA/1J mice were divided into control, sappanchalcone-treated, and methotrexate-treated groups (n = 10 per group). Paw swelling, arthritis severity, radiographic and histomorphometric changes were assessed to measure the protective role of sappanchalcone against chronic disease progression. Sappanchalcone administration significantly reduced clinical arthritis and inflammatory edema in paws. Bone mineral density and trabecular structure were maintained in CIA mice administered sappanchalcone. The levels of pro-inflammatory cytokines (TNF-α, IL-6, and 1L-1β) were significantly lower in the serum of sappanchalcone-treated mice as compared with the control group. Our results suggest that sappanchalcone could be used as an anti-inflammatory and bone-protective agent during the treatment of rheumatoid arthritis.
28878854 Composite Cutaneous Lymphoma (Iatrogenic Immunodeficiency-Associated Lymphoproliferative D 2017 Sep A 67 year old woman with a 10 year history of rheumatoid arthritis (RA) treated with methotrexate and prednisone, presented with a 2 year history of worsening multiple cutaneous plaques of variable appearance. Two distinct skin lesions were biopsied to reveal a composite cutaneous lymphoma, possibly caused by long term methotrexate therapy. An [18F] fluoro-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) was performed to stage the malignancy, and was later repeated to evaluate response to chemotherapy, which guided subsequent management. We present the PET/CT imaging findings of this very rare iatrogenic (methotrexate induced) immunodeficiency-associated lymphoproliferative disorder.
26925251 Predictive factors of radiological progression after 2 years of remission-steered treatm 2016 OBJECTIVES: To identify predictive factors of radiological progression in early arthritis patients treated by remission-steered treatment. METHODS: In the IMPROVED study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and a tapered high dose of prednisone. Patients in early remission (disease activity score (DAS) <1.6 after 4 months) tapered prednisone to zero. Patients not in early remission were randomised to arm 1: MTX plus hydroxychloroquine, sulfasalazine and prednisone, or to arm 2: MTX plus adalimumab. Predictors of radiological progression (≥0.5 Sharp/van der Heijde score; SHS) after 2 years were assessed using logistic regression analysis. RESULTS: Median (IQR) SHS progression in 488 patients was 0 (0-0) point, without differences between RA or UA patients or between treatment arms. In only 50/488 patients, the SHS progression was ≥0.5: 33 (66%) were in the early DAS remission group, 9 (18%) in arm 1, 5 (10%) in arm 2, 3 (6%) in the outside of protocol group. Age (OR (95% CI): 1.03 (1.00 to 1.06)) and the combined presence of anticarbamylated protein antibodies (anti-CarP) and anticitrullinated protein antibodies (ACPA) (2.54 (1.16 to 5.58)) were independent predictors for SHS progression. Symptom duration <12 weeks showed a trend. CONCLUSIONS: After 2 years of remission steered treatment in early arthritis patients, there was limited SHS progression in only a small group of patients. Numerically, patients who had achieved early DAS remission had more SHS progression than other patients. Positivity for both anti-CarP and ACPA and age were independently associated with SHS progression. TRIAL REGISTRATION NUMBERS: ISRCTN Register number 11916566 and EudraCT number 2006 06186-16.
25977895 Predictors of European League Against Rheumatism (EULAR) good response, DAS-28 remission a 2015 The aim of this study was to survey factors related to EULAR good response, the DAS-28 definition of remission, ACR 50 response, sustained response to tumor necrosis factor inhibitors (TNF-I) therapy in biologic naïve patients with refractory rheumatoid arthritis. This was a single center observational clinical prospective 2 years' study, EULAR response criteria, DAS 28, HAQ and radiographic changes were recorded. Eighty patients included (64 females and 16 males, mean age was 48.4 + -17.9 years, mean disease duration 7.3 + -5.9 years). At 6 months 70% achieved EULAR good response, 51.8% achieved DAS-28 remission. Good response/sustained responses inversely correlated with baseline DAS-28 and radiographic erosions P <0.05. EULAR good response/remission by 6 months, sustained response at 2 years positively correlated with the decline in RF titers (r = 0.33, P < 0.05 & r = 0.30, P < 0.03 respectively), negatively correlated with the baseline HAQ. Regression analysis identified higher serum hemoglobin concentration, lower baseline HAQ scores, and the absence of radiographic erosions as significant predictors of good as well as sustained responses after adjustment for potential covariates. Methotrexate was associated with favorable responses and remission at 6 months (ORs = 1.13, 1.30 respectively). The study concluded that a lower baseline DAS-28 and HAQ scores, the lack of radiographic erosions favored EULAR good response and were significant predictors of sustained response to TNF-I.
26884826 Changes in focal adhesion kinase expression in rats with collagen-induced arthritis and ef 2015 Focal adhesion kinase (FAK) is known to promote the proliferation, migration and survival of synovial cells and plays an important role in the occurrence, development and pathological process of rheumatoid arthritis (RA). The aim of the present study was to observe FAK changes in synovial cells of rats with collagen-induced arthritis (CIA) and after intervention with disease modifying anti-rheumatic drugs (DMARDs) alone or in combination in a CIA female SD rat model induced by collagen type II. The rats were randomized to 8 groups: normal control group, CIA model control group, methotrexate (MTX, 0.9 mg/kg/w) group, cyclophosphamide (CTX, 24 mg/kg/3 w) group, leflunomide (LEF, 1.2 mg/kg/d) group, MTX + CTX group, LEF + CTX group, and MTX + LEF group. They were intervened with DMARDs alone or in combination for six weeks. The experiment lasted a total of 9 weeks in vivo. Articular inflammation was measured during the process of drug intervention in terms of the degree of swelling degree in the right hind foot using a venire caliper. All animals were sacrificed by breaking the neck after 9 weeks. Then, the ankle was fixed, decalcified, embedded, and HE stained, and prepared into slices to observe pathological changes in the synovial tissue. FAK expression in synovial cells was assayed by immunohistochemistry and the mean optical density (OD) value was measured using the HPIAS-2000 image analysis system. It was found that FAK expression was negative in normal control group, positive in CIA model control group, and decreased in the three DMARD combination treatment groups significantly as compared with that in the three single-drug groups (P < 0.05). FAK expression in LEF + CTX group or MTX + CTX group decreased more significantly than that in MTX + LEF group (P < 0.05), and there was no statistically significant difference between LEF + CTX and MTX + CTX groups. The arthritis index and pathological change in the synovial tissue in LEF + CTX group or MTX + CTX group were improved more significantly than those in MTX + LEF group or single-drug groups. Our results showed that FAK expression was positive in CIA rats, indicating that it played an important role in the pathogenesis of RA, and that intervention with DMARDs could reduce the FAK expression in synovial cells of CIA rats. We hope these findings would contribute to the treatment of RA and other rheumatic diseases by reducing adhesion, proliferation and migration of synovial cells and inhibiting the over-expression of FAK.
28040332 Rheumatoid arthritis seems to have DMARD treatment decision influenced by fibromyalgia. 2016 Dec 18 OBJECTIVE: To compare DMARD use in patients with and without FM over time, including overtreatment and undertreatment rates in both groups. METHODS: A prospective cohort study with patients attending an RA outpatient clinic was conducted. Participants were consecutively recruited between March 2006 and June 2007 and were followed through December 2013. Data on DMARD use (prevalences, doses and escalation rates), DAS28, HAQ and radiographic progression were compared among RA patients with FM and without FM. Mistreatment clinical scenarios were allegedly identified and compared between groups. RESULTS: 256 RA patients (32 with FM) were followed for 6.2±2.0 (mean±SD) years comprising 2,986 visits. At baseline, RA duration was 11.1±7.4 years. DAS28 and HAQ were greater in RA with FM group, and were closer to RA without FM group towards the end. RA patients with FM used higher doses of tricyclic antidepressants, leflunomide and prednisone, and lower doses of methotrexate. When compared to RA patients without FM, participants with RA and FM used more often tricyclic antidepressants, leflunomide, prednisone, continuous analgesics and less often methotrexate. Groups presented similar 7-year biologic-free survival, and radiographic progression-free survival in Cox regression. RA patients with FM had greater proportions of visits in mistreatment scenarios when compared to RA patients without FM (28.4 vs. 19.8%, p<0.001). CONCLUSIONS: RA patients with FM used more leflunomide and prednisone, and RA mistreatment was more frequent in FM patients. Certainly, RA patients with FM will benefit from a personalized T2T strategy, including ultrasound (when suitable) and proper FM treatment.
27175294 When rheumatologists report that they agree with a guideline, does this mean that they pra 2016 INTRODUCTION: The European League Against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) and the treat-to-target (T2T) principles have been developed in order to improve the treatment outcome of patients with RA, and have received broad attention. It is not clear, though, whether these recommendations are indeed followed up in clinical practice. OBJECTIVE: To investigate if rheumatologists that report to agree with existing guidelines indeed follow them up in clinical practice. METHODS: The International Recommendation Implementation Study (IRIS) included 132 participating rheumatologists from 14 countries. Participating rheumatologists received a questionnaire measuring their awareness/commitment with the EULAR/T2T recommendations and followed a dedicated educational programme. Subsequently, they were asked to enrol 5-10 patients with new-onset RA in the online IRIS database and monitor disease activity and treatment for a period of 1-2 years. Four recommendations (3 from the EULAR recommendations and one from the T2T recommendations) were selected on the basis of testability, and analysed with regard to compliance by participating rheumatologists. RESULTS: In total, 72 of the 132 participating rheumatologists contributed 378 patients to the database. Of these participants, 70 (98%) agreed upfront with the recommendation that disease-modifying antirheumatic drug (DMARD) therapy should be started as soon as possible after diagnosis in every patient; 69 (96%) of the rheumatologists agreed with the recommendation that methotrexate (MTX) should be part of the first treatment strategy. When measuring the actual performance, it was found that the recommendation on early DMARD start was met in 253 (67%) of the recorded patients, and the recommendation on MTX in 225 (60%) of the recorded patients. Of the participants, 60 (83%) agreed that composite measures should be recorded regularly, but only in 134(54%) of the patients were composite scores actually recorded in ≥50% of patient visits. CONCLUSION: Reporting to be compliant with EULAR recommendations and T2T principles, even after dedicated education does not mean they actually comply with it in clinical practice.
25789049 Primary central nervous system lymphoma mimicking recurrent depressive disorder: A case re 2015 Apr Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal non-Hodgkin lymphoma, which is limited to the central nervous system. Few studies are available reporting psychiatric symptoms as the initial and dominant presentation of PCNSL. The current study reports the case of a PCNSL patient with a history of major depressive disorder and coexisting rheumatoid arthritis (treated with methotrexate), who initially presented with recurrent depressive disorder that showed no response to antidepressant drug therapy. Magnetic resonance imaging revealed multiple mass lesions in the brain, and pathological examination of the biopsy confirmed the diagnosis of diffuse large B cell lymphoma of the central nervous system. The present case demonstrated that PCNSL may affect mood in the early stages of the disease and thus, clinicians must be aware of this manifestation in patients with depressive disorder co-existing with immunosuppressive conditions, as early detection and appropriate treatment are important prognostic factors for PCNSL.
27175297 Exploring a new ultrasound score as a clinical predictive tool in patients with rheumatoid 2016 OBJECTIVES: To explore whether changes in a composite (power Doppler/greyscale ultrasound (PDUS)) synovitis score, developed by the OMERACT-EULAR-Ultrasound Task Force, predict disease activity outcomes in rheumatoid arthritis (RA). METHODS: Patients with RA who were methotrexate inadequate responders starting abatacept were evaluated. Individual joint PDUS scores were combined in the Global OMERACT-EULAR Synovitis Score (GLOESS) for metacarpophalangeal joints (MCPs) 2-5, all joints (22 paired) and a reduced (9 paired) joint set. The predictive value of changes in GLOESS at week 1-16 evaluations for clinical status and response (Disease Activity Score (DAS)28 (C reactive protein, CRP) <2.6; DAS28(CRP) ≤3.2; DAS28(CRP) ≥1.2 improvement) up to week 24, and correlations between DAS28 and GLOESS were assessed. RESULTS: Eighty-nine patients completed the 24-week treatment period. Changes in GLOESS (MCPs 2-5) from weeks 1 to 16 were unable to predict DAS28 outcomes up to week 24. However, significant improvements in GLOESS (MCPs 2-5) were observed at week 12 in patients with DAS28 ≥1.2 improvement at week 24 versus those who did not achieve that clinical response. In patients achieving DAS28 ≥1.2 improvement or DAS28 ≤3.2 at week 24, changes in GLOESS (22 and 9 paired joint sets) were greater in patients who already achieved DAS28 ≥1.2 at week 12 than in those who did not. No significant correlations were found between changes in DAS28 and GLOESS definitions at any time point. CONCLUSIONS: PDUS was not correlated with clinical status or response as measured by DAS28-derived criteria, and PDUS changes were not predictive of clinical outcome. The discrepancies require further exploration. TRIAL REGISTRATION NUMBER: NCT00767325; Results.
27559311 Disentangling Rheumatoid Arthritis Patients' Implicit and Explicit Attitudes toward Methot 2016 Medication non-adherence is a major public health problem that has been termed an 'invisible epidemic.' Non-adherence is not only associated with negative clinical consequences but can also result in substantial healthcare costs. Up to now, effective adherence interventions are scarce and a more comprehensive model of adherence determinants is required to target the determinants for not taking the medication as prescribed. Current approaches only included explicit attitudes such as self-reported evaluations of medication as determinants, neglecting the role of associative processes that shape implicit attitudes. Implicit processes can predict daily behavior more accurately than explicit attitudes. Our aim is to assess explicit and implicit attitudes toward medication and explore the relation with beliefs, adherence and clinical (laboratory) outcomes in chronically ill patients. Fifty two Rheumatic Arthritis (RA) patients' attitudes toward Methotrexate (MTX) were explicitly (self-reported) and implicitly (Single-Category Implicit Association Test) assessed and related to the Beliefs about Medicine Questionnaire, the Compliance Questionnaire on Rheumatology and laboratory parameters [Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP)]. Results show that explicit attitudes were positive and health-related. Implicit attitudes were, however, negative and sickness-related. Half of the patients displayed explicitly positive but implicitly negative attitudes. Explicit attitudes were positively related to ESR. A positive relationship between implicit attitudes and disease duration was observed. In this study, we have obtained evidence suggesting that the measurement of implicit attitudes and associations provides different information than explicit, self-reported attitudes toward medication. Since patients' implicit attitudes deviated from explicit attitudes, we can conclude that the relationship between implicit attitudes and medication adherence is worthwhile to be further explored. With this information we can improve our understanding of the subconscious, automatic processes underlying adherence and we can develop interventions that target these implicit attitudes.
27747494 Characteristics Associated with Biologic Monotherapy Use in Biologic-Naive Patients with R 2015 Jun INTRODUCTION: The aim of this study was to describe factors associated with initiating a biologic as monotherapy vs in combination with a conventional disease-modifying antirheumatic drug (DMARD) in biologic-naive patients with rheumatoid arthritis (RA) enrolled in the Corrona registry. METHODS: First biologic initiations were classified as monotherapy (Bio MT) or combination therapy (Bio CMB). Baseline demographic and clinical characteristics were evaluated. Odds ratios (OR) based on mixed effects regression models estimated the association of covariates and use of monotherapy. Median odds ratios (MOR) based on estimated physician random effects quantified variation in individual physician use of monotherapy. RESULTS: Between October 2001 and April 2012, 3,923 previously biologic-naive patients initiated biologic therapy, of which 19.1 % initiated as monotherapy. Baseline characteristics of patients initiating Bio MT and Bio CMB were similar for age, sex, duration of RA, and clinical disease activity index. Significantly higher proportions of Bio CMB initiators had prior conventional DMARD (97.23 vs 85.60 %; P < 0.01) and methotrexate (MTX) use (91.68 vs 71.87 %; P < 0.01) compared with Bio MT initiators. Variation in individual physician use of monotherapy [MOR 1.89; 95 % confidence interval (CI), 1.66-2.23] and use of biologics approved by the United States Food and Drug Administration for monotherapy (OR 1.47; 95 % CI, 1.20-1.81) significantly influenced the odds of initiating Bio MT. Patient history of hepatic disease, neutropenia, and malignancy were associated with increased odds of being prescribed Bio MT. CONCLUSION: In addition to regulatory approval for monotherapy and specific pre-existing comorbidities, significant variation in physician use of monotherapy was associated with increased likelihood of initiating Bio MT, independent of patient factors.
27752357 Tofacitinib versus methotrexate in rheumatoid arthritis: patient-reported outcomes from th 2016 OBJECTIVES: To compare patient-reported outcomes (PROs) in methotrexate (MTX)-naive patients (defined as no prior treatment or ≤3 doses) receiving tofacitinib versus MTX. METHODS: In the 24-month, phase III, randomised, controlled, ORAL Start trial (NCT01039688), patients were randomised 2:2:1 to receive tofacitinib 5 mg two times per day (n=373), tofacitinib 10 mg two times per day (n=397) or MTX (n=186). PROs assessed included Patient Global Assessment of disease (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and health-related quality of life (Short Form-36 [SF-36]). RESULTS: PROs improved following tofacitinib and MTX treatment: benefits were sustained over 24 months. Patients receiving tofacitinib reported earlier responses which were significantly different between each tofacitinib dose and MTX at month 3 through month 24. At month 6 (primary end point), significant improvements versus MTX were observed in PtGA, pain, HAQ-DI, SF-36 Physical Component Summary (PCS), 5/8 domain scores and FACIT-F with tofacitinib 5 mg two times per day; all PROs, except SF-36 Mental Component Summary Score and Medical Outcomes Survey-Sleep, with tofacitinib 10 mg two times per day. At month 6, the proportion of patients reporting improvements ≥minimum clinically important difference were significant versus MTX with tofacitinib 5 mg two times per day in PtGA and 3/8 SF-36 domains; and with tofacitinib 10 mg two times per day in PtGA, pain, HAQ-DI, SF-36 PCS, 4/8 domains and FACIT-F. CONCLUSIONS: Patients with rheumatoid arthritis receiving tofacitinib 5 and 10 mg two times per day monotherapy versus MTX reported statistically significant and clinically meaningful improvements in multiple PROs over 24 months; onset of benefit with tofacitinib treatment occurred earlier. TRIAL REGISTRATION NUMBER: NCT01039688.
27747511 Effect of Methotrexate Plus Adalimumab on the Achievement of Rheumatoid Arthritis Therapeu 2016 Jun INTRODUCTION: There is insufficient evidence regarding the appropriate dose of methotrexate (MTX) required to achieve specific treatment goals in patients with rheumatoid arthritis (RA) receiving biologic drugs in Japan. The present study aimed to assess the dose-response effect of MTX in combination with adalimumab (ADA) to achieve low disease activity (LDA) and/or remission at 24 weeks in RA patients. METHODS: This analysis used data of the ADA all-case survey in Japan (n = 7740), and 5494 patients who received ADA and MTX were classified into five groups by weighted average MTX dose (>0-<4, 4-<6, 6-<8, 8-< 10, and ≥10 mg/week). Of the 5494 patients, 3097 with baseline 28-joint disease activity score based on erythrocyte sedimentation rate >3.2 were analyzed for effectiveness by MTX dose. RESULTS: In biologic-naïve patients (n = 1996/3097), LDA/remission rates increased with MTX up to 6-<8 mg/week and then plateaued at higher doses (LDA, p = 0.0440; remission, p = 0.0422). In biologic-exposed patients (n = 1101/3097), LDA/remission rates increased with MTX dose (LDA, p = 0.0009; remission p = 0.0143). The incidences of serious adverse drug reactions (ADRs) and serious infections did not differ by MTX dose, but total ADRs and infections were significantly higher (p < 0.05) with increased MTX doses. CONCLUSION: The appropriate MTX doses in combination with ADA to achieve LDA and/or remission at week 24 were different between biologic-naïve and biologic-exposed patients with RA, suggesting that 8 mg/week of MTX would be enough for biologic-naïve patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01076959. FUNDING: AbbVie and Eisai Co., Ltd.
27703452 Anti-rheumatoid Activity of Secondary Metabolites Produced by Endophytic Chaetomium globos 2016 The aim of the present study was to investigate the anti-rheumatoid activity of secondary metabolites produced by endophytic mycobiota in Egypt. A total of 27 endophytic fungi were isolated from 10 dominant medicinal plant host species in Wadi Tala, Saint Katherine Protectorate, arid Sinai, Egypt. Of those taxa, seven isolates of Chaetomium globosum (CG1-CG7), being the most frequent taxon, were recovered from seven different host plants and screened for production of active anti-inflammatory metabolites. Isolates were cultivated on half - strength potato dextrose broth for 21 days at 28°C on a rotatory shaker at 180 rpm, and extracted in ethyl acetate and methanol, respectively. The probable inhibitory effects of both extracts against an adjuvant induced arthritis (AIA) rat model were examined and compared with the effects of methotrexate (MTX) as a standard disease-modifying anti-rheumatoid drug. Disease activity and mobility scoring of AIA, histopathology and transmission electron microscopy (TEM) were used to evaluate probable inhibitory roles. A significant reduction (P < 0.05) in the severity of arthritis was observed in both the methanolic extract of CG6 (MCG6) and MTX treatment groups 6 days after treatment commenced. The average arthritis score of the MCG6 treatment group was (10.7 ± 0.82) compared to (13.8 ± 0.98) in the positive control group. The mobility score of the MCG6 treatment group (1.50 ± 0.55) was significantly lower than that of the positive control group (3.33 ± 0.82). In contrast, the ethyl acetate extract of CG6 (EACG6) treatment group showed no improvements in arthritis and mobility scores in AIA model rats. Histopathology and TEM findings confirmed the observation. Isolate CG6 was subjected to sequencing for confirmation of phenotypic identification. The internal transcribed spacer (ITS) 1-5.8 s - ITS2 rDNA sequences obtained were compared with those deposited in the GenBank Database and registered with accession number KC811080 in the NCBI Database. The present study revealed that the methanol extract of endophytic fungus C. globosum (KC811080) recovered from maidenhair fern has an inhibitory effect on inflammation, histopathology and morphological features of rheumatoid arthritis in an AIA rat model.
27350791 Squamous cell carcinoma of the rectum: a consequence of immunosuppression resulting from i 2016 Treatment with tumour necrosis factor (TNF) antagonists may lead to enhanced susceptibility to certain malignancies. In particular, an association is seen emerging between TNF antagonists and development of squamous cell carcinomas (SCCs) of the skin (in association with psoriasis), the oral cavity, and in the anogenital areas (possibly related to prior human papilloma virus infection). We present here a case of a 53-year old woman with a history of severe rheumatoid arthritis (RA), most recently treated with the TNF antagonist etanercept plus methotrexate, presented to our service after several months of increasing left pelvis and buttock pain. Evaluation with a computerised tomography (CT)-directed biopsy of a pelvic side wall mass revealed a metastatic SCC. On a fluorodeoxyglucose (FDG) positron-emission tomography (PET) an additional area of uptake was identified in the left posterior rectum corresponding to a 1 cm nodule palpable on digital exam. Colonoscopic biopsy revealed a basaloid SCC of the rectum as the likely primary site. Immunosuppression following TNF antagonist therapy may have given arise to this unrestrained neoplastic growth. It thereby underscores the need for an initial baseline study of risk factors and identification of patients who are at higher risk for development of a malignancy, in order to achieve a diagnosis at an early stage.
25707965 Clinical impact of concomitant immunomodulators on biologic therapy: Pharmacokinetics, imm 2015 Mar Immune-mediated inflammatory diseases encompass a variety of different clinical syndromes, manifesting as either common diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis, or rare diseases such as cryopyrin-associated periodic syndromes. The therapy for these diseases often involves the use of a wide range of drugs including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, immunomodulators, and biologic therapies. Due to the abundance of relevant clinical data, this article provides a general overview on the clinical impact of the concomitant use of immunomodulators and biologic therapies, with a focus on anti-tumor necrosis factor-α agents (anti-TNFα), for the treatment of RA and Crohn's disease (CD). Compared to biologic monotherapy, concomitant use of immunomodulators (methotrexate, azathioprine, and 6-mercaptopurine) often increases the systemic exposure of the anti-TNFα agent and decreases the formation of antibodies to the anti-TNFα agent, consequently enhancing clinical efficacy. Nevertheless, long-term combination therapy with immunomodulators and anti-TNFα agents may be associated with increased risks of serious infections and malignancies. Therefore, the determination whether combination therapy is suitable for a patient should always be based on an individualized benefit-risk evaluation. More research should be undertaken to identify and validate prognostic markers for predicting patients who would benefit the most and those who are at greater risk from combination therapy with immunomodulators and anti-TNFα agents.
26508914 Atypical Presentation of Disseminated Zoster in a Patient with Rheumatoid Arthritis. 2015 Patients with rheumatoid arthritis (RA) have 2-fold increased risk of herpes zoster. In literature, limited information exists about disseminated cutaneous zoster in RA patients. An 83-year-old African-American female with RA presented with generalized and widespread vesicular rash covering her entire body. Comorbidities include hypertension, type II diabetes, and dyslipidemia. Patient was on methotrexate 12.5 mg and was not receiving any corticosteroids, anti-TNF therapy, or other biological agents. The patient was afebrile (98 F) with no SIRS criteria. Multiple vesicular lesions were present covering patient's entire body including face. Lesions were in different stages, some umbilicated with diameter of 2-7 cm. Many lesions have a rim of erythema with no discharge. On admission, patient was also pancytopenic with leukocyte count of 1.70 k/mm(3). Biopsies of lesions were performed, which were positive for Varicella antigen. Subsequently, patient was started on Acyclovir. The patient's clinical status improved and rash resolved. Our patient presented with "atypical" clinical picture of disseminated cutaneous zoster with no obvious dermatome involvement. Disseminated zoster is a potentially serious infection that can have an atypical presentation in patients with immunocompromised status. High index of suspicion is needed to make the diagnosis promptly and to initiate therapy to decrease mortality and morbidity.