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ID PMID Title PublicationDate abstract
25557658 The effect of tocilizumab on bone mineral density, serum levels of Dickkopf-1 and bone rem 2015 Mar Previous studies showed that the control of inflammation by biological therapies has a positive effect on bone in inflammatory diseases. The objective of this study was to assess the effects on bone mineral density (BMD) and bone remodeling of an anti-IL-6 monoclonal antibody (tocilizumab (TCZ)) in patients with rheumatoid arthritis (RA). METHODS: One hundred and three patients (75% women, 52±12years) with active RA were treated with TCZ 8mg/kg + methotrexate (MTX) every 4 weeks during 48 weeks. Hip and lumbar spine BMDs were measured at baseline and after 48 weeks by dual energy X-ray absorptiometry (DXA). Pro-collagen serum type I N-terminal propeptide (PINP), serum C-terminal cross-linked telopeptide of type I collagen (CTX-I), and serum levels of total Dickkopf-1 (Dkk-1) and sclerostin were assessed at baseline, 12 and 48 weeks. RESULTS: BMD was available for 76 patients at baseline and at the end of the study. There was no change in lumbar spine and hip BMD over 48 weeks. Serum PINP increased from baseline by 22% (P≤0.001) and 19% (P≤0.001) at week 12 and week 48, whereas serum CTX-I remained stable. Serum DKK-1 significantly decreased from baseline by -31% (P≤0.001) and -25% (P=0.025) at week 12 and 48. Similar results were observed in the patients receiving low doses of oral corticosteroids. CONCLUSION: In this 1-year prospective open study, patients with active RA receiving TCZ and MTX had no change in BMD, a decrease in serum DKK-1 and an increase in bone formation marker.
24320747 A comparison of incidence and risk factors for serious adverse events in rheumatoid arthri 2014 Jul OBJECTIVE: To compare the incidence and risk factors of serious adverse events (SAEs) in rheumatoid arthritis (RA) patients treated with etanercept (ETN) or adalimumab (ADA) between Korean and Japanese registries. METHODS: We recruited 416 RA patients [505.2 patient-years (PYs)] who started ETN or ADA from Korean registry and 537 RA patients (762.0 PY) from Japanese registry. The patient background, incidence rate (IR) of SAE in 2 years, and risk factors for SAEs were compared. RESULTS: Korean patients were younger and used more nonbiologic DMARDs, higher doses of methotrexate, and lower doses of prednisolone (PSL). The IR of SAEs (/100 PY) was higher in the Japanese registry compared to the Korean [13.65 vs. 6.73]. In both registries, infection was the most frequently reported SAE. The only significant risk factor for SAEs in Korean registry was age by decade [1.45]. In Japanese registry, age by decade [1.54], previous use of nonbiologic DMARDs ≥ 4 [1.93], and concomitant use of oral PSL ≥ 5 mg/day [2.20] were identified as risk factors for SAEs. CONCLUSIONS: The IR of SAE in Japan, especially infection, was higher than that of Korea, which was attributed to the difference of demographic and clinical characteristics of RA patients and treatment profiles.
23666316 Induction of response with etanercept-methotrexate therapy in patients with moderately act 2013 Sep Biologics have mainly been assessed in patients with severe rheumatoid arthritis (RA) globally. Less attention has been paid to moderately active disease, especially in Central and Eastern Europe (CEE). Access to biologics and the disease features of RA patients may differ in CEE, relative to other regions. We assessed the clinical and patient-reported outcomes (PROs) of treatment from CEE patients in the multinational PRESERVE study ( NCT00565409 ). Patients with moderate RA 28-joint disease activity score ((DAS28) erythrocyte sedimentation rate (ESR) >3.2 and ≤5.1) despite methotrexate (MTX) treatment received open-label etanercept (ETN) 50 mg QW + MTX for 36 weeks. Low disease activity (DAS28 low disease activity (LDA) ≤3.2) and remission (DAS28 ESR <2.6) were assessed. PROs included Health Assessment Questionnaire Disability Index (HAQ-DI), patient global assessment (PGA), EuroQol-5 Dimension (EQ-5D), pain visual analogue scale (VAS), Medical Outcomes Study sleep questionnaire (MOS Sleep), Functional Assessment of Chronic Illness Therapy (FACIT), and Work Productivity and Activity Impairment for RA (WPAI-RA). Descriptive summary statistics were employed. Of the 834 enrolled patients, 302 were from CEE. At baseline, CEE patients had similar disease states versus the overall population. By week 36, LDA was achieved by 87 %, remission by 67 %, and normal HAQ-DI (≤0.5) by 53 % of patients. Mean scores (SDs) for PROs significantly improved by week 36 as follows: HAQ-DI total by -0.6 (0.5); PGA by -2.4 (2.1); EQ-5D total index by 0.2 (0.2). Pain VAS, MOS Sleep, FACIT, and WPAI-RA also showed significant improvements. In conclusion, induction therapy with ETN + MTX led to DAS28 LDA, remission, and improvements in PROs in most CEE patients with moderately active RA despite treatment with MTX. These results are similar to the overall study population in the PRESERVE trial.
24811204 Methotrexate-associated lymphoproliferative disorder arising in the retromolar triangle an 2014 Oct We report an extremely rare case of massive methotrexate-associated lymphoproliferative disorder (MTX-LPD) arising in the retromolar triangle and lung of a patient with rheumatoid arthritis. The patient was a 75-year-old woman who was referred to our department because of severe pain associated with a unilateral ulcer on the left retromolar triangle. The tumor had an extranodal location in the retromolar triangle and in the right lung. A clinicopathologic examination found a lymphocytic infiltrate with increasingly atypical histopathologic features. Atypical large cells were strongly positive in Epstein-Barr virus-encoded small RNA in situ hybridization and in staining with CD20 antibodies. MTX-LPD was diagnosed based on the medical history and histopathologic results. The lesion responded well to withdrawal of MTX followed by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. There have been no signs of recurrence for 4 years since withdrawal of MTX.
24362788 The concomitant use of meloxicam and methotrexate does not clearly increase the risk of si 2014 Jun We investigated whether the concomitant use of meloxicam and methotrexate might induce kidney and liver damages in patients with rheumatoid arthritis (RA). We enrolled 101 RA patients with normal kidney and liver functions taking meloxicam and methotrexate concomitantly for more than 6 months. Blood and urine tests were performed. Estimated glomerular filtration rate (eGFR) and liver stiffness measurement (LSM) were used for evaluating silent kidney and liver damages. Ultrasonography was also performed to exclude structural abnormalities. We adopted 90 mL/min/1.73 mm(2) and 5.3 kPa as the cutoff for an abnormal eGFR and LSM. The mean age (85 women) was 51.9 years. The mean eGFR was 97.0 mL/min/1.73 m(2) and the mean LSM was 4.7 kPa. The mean weekly dose of methotrexate was 13.4 mg. The mean weekly dose of methotrexate did not correlate with eGFR or LSM. Neither the cumulative dose of meloxicam or methotrexate nor the mean weekly dose of methotrexate showed the significant odds ratio or relative risk for abnormal eGFR and LSM values. The use of higher-dose MTX, above 15 mg per week, with meloxicam did not significantly increase the risk for abnormal LSM and eGFR (RR = 2.042, p = 0.185; RR = 0.473, p = 0.218). The concomitant use of meloxicam and MTX did not clearly increase the risk of silent kidney or liver damage in RA patients with normal laboratory results taking MTX and meloxicam concurrently for over 6 months.
23877486 The effectiveness of tofacitinib, a novel Janus kinase inhibitor, in the treatment of rheu 2013 Oct The aim of the present study was to conduct a meta-analysis of the effectiveness of tofacitinib, a novel oral Janus kinase inhibitor, recently approved for the treatment of active rheumatoid arthritis in patients who have failed previous treatment with methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs). A systematic literature search was conducted in PubMed, EMBASE, Cochrane Library, and other databases till 3 May 2013. All included studies were analyzed with the use of the Review Manager 5.1.0. software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol. Nine randomized controlled trials (RCTs) comparing tofacitinib with placebo were identified. Two of them additionally provided the comparison with adalimumab. However, only eight RCTs met the inclusion criteria for the meta-analysis. The overall results of the meta-analysis showed that tofacitinib provided a statistically significant improvement according to the response criteria (ACR20/50/70) after 12 weeks of treatment when compared to placebo (p < 0.00001). Moreover, it was demonstrated that tofacitinib was significantly superior to adalimumab in achieving the ACR50 response criteria at week 12 (p = 0.003). For the safety analysis, there were no statistically significant differences between tofacitinib-, adalimumab-, and placebo-treated patients in respect to the risk of serious adverse events or treatment discontinuation due to adverse reactions (p > 0.05). The findings of this systematic review with meta-analysis indicate that tofacitinib monotherapy or with background methotrexate provides early statistically significant and clinically important improvement in rheumatoid arthritis symptoms and has an acceptable safety profile comparable to that of placebo. The results of the present meta-analysis show that the frequency of serious adverse events was not increased after tofacitinib treatment. In addition, tofacitinib might provide an effective treatment option compared to intravenous or subcutaneous biological DMARDs, as suggested by the result of the comparison made regarding tofacitinib vs. adalimumab ACR50 response rate.
24723273 Biological agents in monotherapy for the treatment of rheumatoid arthritis. 2014 Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease, which results in joint destruction and permanent disability. The advent of disease-modifying antirheumatic drugs (DMARDs) has made a profound impact on the outcome and prognosis of RA. Methotrexate (MTX) is a central agent in RA therapy, and is used either alone or in combination with biological DMARDs. However, a large proportion of RA patients (20%-40%) either do not respond to or are unable to tolerate MTX or the alternative agents used in place of MTX (including leflunomide, sulfasalazine, azathioprine, hydroxycholoquine and combination DMARDs). For these patients, monotherapy with biological DMARDs is a key treatment option that balances tolerability with improved clinical outcomes. This article reviews the data for four biological agents approved for use as monotherapy in Switzerland (adalimumab, certolizumab pegol, etanercept and tocilizumab) in order to formulate a consensus statement on their roles in biologic monotherapy of RA.
23955089 Methotrexate enhances 3T3-L1 adipocytes hypertrophy. 2013 Aug Methotrexate (MTX) is broadly used in the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA). The prevalence of metabolic syndrome (MeS) in patients with this condition is relatively high. Given the importance of adipose tissue in the development of obesity metabolic complications, this study aimed to investigate the effect of methotrexate on preadipocyte proliferation, adipogenesis, and glucose uptake by adipocytes. 3T3-L1 preadipocytes proliferation was evaluated by sulforhodamine B staining and (3)H-thymidine incorporation, after 24 or 48 h of treatment with MTX (0.1 and 10 μM). Preadipocytes were induced to differentiate with an appropriate adipogenic cocktail in the presence or absence of MTX. Adipogenesis was determined by measuring lipid accumulation after staining with oil red O. (3)H-Deoxyglucose ((3)H-DG) uptake was determined by liquid scintillation counting. MTX treatment reduced culture protein content in a concentration-dependent manner and (3)H-thymidine incorporation (P < 0.05). MTX (0.1 μM) treatment increased lipid accumulation and basal (3)H-DG uptake by adipocytes (P < 0.05). In 0.1 μM MTX-treated adipocytes, insulin stimulation did not result in an increase of (3)H-DG uptake, contrarily to what was observed in control cells. These results demonstrate that methotrexate interferes with adipocyte proliferation and promotes the hypertrophic growth of adipocytes. These molecular effects may have implications on metabolic profile of RA patients treated with MTX.
24252050 Safety and efficacy of combination therapy of iguratimod with methotrexate for patients wi 2014 May OBJECTIVE: To obtain safety and efficacy data on combination treatment with iguratimod and methotrexate (MTX) in an open-label extension study in patients with active rheumatoid arthritis (RA). METHODS: Following a 28-week, randomized, double-blind trial of adding iguratimod or placebo to stable MTX therapy, patients entered a 24-week extension. Patients randomized to the iguratimod + MTX group continued treatment. Patients treated with placebo + MTX switched to iguratimod + MTX [the (placebo/iguratimod) + MTX group]. RESULTS: In the iguratimod + MTX group, the rate of 20% improvement in American College of Rheumatology criteria (ACR20) at week 52 (71.3%) was similar to that at week 24 (69.5%). ACR50, ACR70 and Health Assessment Questionnaire Disability Index at week 52 significantly improved compared with the values at week 24. In the (placebo/iguratimod + MTX) group, the switch to iguratimod treatment significantly improved ACR20 from 30.7% at week 24 to 72.1% at week 52. Frequent adverse events for 52 weeks in the iguratimod + MTX group were nasopharyngitis, upper respiratory tract inflammation, stomatitis, lymphocyte decrease, AST increase, ALT increase and blood iron decrease. These adverse events were predominantly mild or moderate in severity. No deaths occurred. CONCLUSION: Efficacy and tolerance of iguratimod + MTX therapy was maintained to 52 weeks in patients with active RA with inadequate response to MTX.
24108504 Methotrexate-induced nausea and vomiting in adolescent and young adult patients. 2014 Mar This study aims to determine the prevalence of methotrexate-induced nausea and vomiting in both adolescent and adult patients with inflammatory arthritis. A survey of methotrexate side effects was conducted on patients with inflammatory arthritis. We provided a brief questionnaire to unselected patients with inflammatory arthritis being treated with methotrexate attending adolescent and adult rheumatology clinics. The questions related to the presence, absence, and severity of nausea and vomiting, the temporal relationship with methotrexate and whether anti-emetics had been prescribed. A total of 106 patients from the age of 13 years and above--57 adults (over 20 years) and 49 adolescents (13-19 years) were included in this study. The median age for those experiencing nausea was 19 years (interquartile range (IQR) 7) and for those with no nausea 55 years (IQR 46) (p < 0.001). Thirty-six out of 49 adolescent patients reported nausea (73%) compared to only 20/57 adults (35%) (p < 0.001). Multiple logistic regression analysis showed that the nausea group had a significantly higher proportion of adolescents (p = 0.0002), patients taking subcutaneous (SC) methotrexate MTX (p = 0.002), and patients with duration of MTX of more than 1 year (p = 0.049). Adolescents were estimated to have over 6 times higher odds of nausea compared to adults (OR 6.31, 95% CI 2.38 to 16.75, p = 0.0002) after adjusting for SC MTX and duration of MTX. Only 22% of adolescents and 10% of adults were prescribed anti-emetics. There is a higher prevalence of MTX-induced nausea and vomiting in adolescents and younger adult patients with inflammatory arthritis compared to older adults. The role of anti-emetics in the treatment of these symptoms is unclear.
25223724 Effects of fostamatinib, an oral spleen tyrosine kinase inhibitor, in rheumatoid arthritis 2014 Dec OBJECTIVE: This phase III, 52-week study compared fostamatinib with placebo (for 24 weeks) in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) therapy. METHODS: Patients taking MTX were randomized (1:1:1) to receive fostamatinib 100 mg twice daily for 52 weeks (group A), fostamatinib 100 mg twice daily for 4 weeks and then 150 mg once daily (group B), or placebo for 24 weeks and then fostamatinib 100 mg twice daily (group C). At week 24, the co-primary end points were change from baseline in the American College of Rheumatology 20% (ACR20) improvement response rates and change in the modified total Sharp/van der Heijde score of radiographic damage (SHS). RESULTS: In this study, 918 patients were randomized and received ≥1 dose of study drug (fostamatinib or placebo); the demographic and baseline clinical characteristics were well balanced. Following treatment with both fostamatinib regimens, a statistically significant difference in the ACR20 improvement response was achieved at week 24 as compared with that in patients receiving placebo (49.0% [group A] and 44.4%, [group B] versus 34.2%; P < 0.001 and P = 0.006, respectively), but there was no statistically significant difference in the SHS between either fostamatinib group and placebo (P = 0.25 and P = 0.17, respectively). The most common adverse events in patients in groups A, B, and C were hypertension (15.8%, 15.1%, and 3.9%, respectively) and diarrhea (13.9%, 15.1%, and 3.9%, respectively). Elevated blood pressure (≥140/90 mm Hg) occurred at ≥1 visit in 44.2%, 41.6%, and 19.3% of patients in each respective group. CONCLUSION: With the use of either fostamatinib regimen in patients with RA, statistically significant, but not clinically significant, improvements in the ACR20 improvement response over placebo were achieved at 24 weeks, whereas a significant difference in the SHS was not seen. The overall level of response to treatment with fostamatinib was lower than had been observed in the phase II program, but similar adverse events were reported.
23378467 Effects of fostamatinib (R788), an oral spleen tyrosine kinase inhibitor, on health-relate 2013 Apr OBJECTIVE: To assess the influence of fostamatinib on patient-reported outcomes (PRO) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX). METHODS: Patients taking background MTX (N = 457) were enrolled in a phase II clinical trial (NCT00665925) and randomized equally to placebo, fostamatinib 100 mg twice daily (bid), or fostamatinib 150 mg once daily (qd) for 24 weeks. Self-administered PRO measures included pain, patient's global assessment (PtGA) of disease activity, physical function, health-related quality of life (HRQOL), and fatigue. Mean change from baseline and a responder analysis of the proportion of patients achieving a minimal clinically important difference were determined. RESULTS: At Week 24, there were statistically significant improvements in pain, PtGA, physical function, fatigue, and the physical component summary of the Medical Outcomes Study Short Form-36 (SF-36) for fostamatinib 100 mg bid compared with placebo. Mean (standard error) changes from baseline in the fostamatinib 100 mg bid group versus the placebo group were -31.3 (2.45) versus -17.8 (2.45), p < 0.001 for pain; -29.1 (2.26) versus -16.7 (2.42), p < 0.001 for PtGA; -0.647 (0.064) versus -0.343 (0.062), p < 0.001 for physical function; 7.40 (1.00) versus 4.50 (0.94), p < 0.05 for fatigue; 8.52 (0.77) versus 4.90 (0.78), p < 0.01 for SF-36 physical component score; and 3.99 (0.93) versus 3.71 (0.99), p = 0.83 for SF-36 mental component score. Patients receiving fostamatinib 150 mg qd showed improvements in some PRO, including physical function. CONCLUSION: Patients treated with fostamatinib 100 mg bid showed significant improvements in HRQOL outcomes.
23402255 [Wrong administration of methotrexate can lead to fatal haematological complications in el 2013 Feb 11 We present four cases of life-threatening methotrexate intoxications of patients with rheumatological disease. In two of the cases, the direct cause of intoxication was accidentally daily administration of the drug instead of weekly. The patients presented with uncharacteristic symptoms, including nausea, mucositis and fever. All of them had pancytopenia, and despite therapy with broad spectrum antibiotics three patients died in a state of septic shock. These cases demonstrate the importance of adequate communication between health-care professionals, who are involved in the administration of methotrexate and in particular it emphazises that methotrexate should be administrated as weekly doses.
23729801 Subcutaneously administered ofatumumab in rheumatoid arthritis: a phase I/II study of safe 2013 Jul OBJECTIVE: To investigate the safety and tolerability of a single subcutaneous (SC) dose of ofatumumab, a fully human anti-CD20 monoclonal antibody, in patients with rheumatoid arthritis (RA) taking background methotrexate (MTX). Secondary objectives included characterizing pharmacokinetics and pharmacodynamics. METHODS: In this single-blind, phase I/II study, 35 patients with RA were randomized in 5 cohorts to receive a single subcutaneous (SC) ofatumumab dose ranging from 0.3 to 100 mg, or placebo, following premedication with oral acetaminophen and antihistamine. Patients were followed for 24 weeks with extended followup to monitor B cell and immunoglobulin recovery for up to 2 years if required. RESULTS: Thirty-five patients received the following treatment: 0.3 mg, n = 4; 3 mg, n = 6; 30 mg, n = 8; 60 mg, n = 6; 100 mg, n = 3; placebo, n = 8. The most common adverse events in the combined ofatumumab groups were headache, nausea, and upper respiratory tract infection. Because of tolerability concerns, only 3 patients were given 100 mg. For the 30-100 mg doses, median maximum plasma concentration values ranged from 4.02 to 4.49 days. Mean elimination half-life values ranged from 5.20 to 6.83 days. Increasing peripheral median B cell depletion was observed from 0.3 mg up to 30 mg, and full target B cell depletion was achieved with 30 mg, 60 mg, and 100 mg. CONCLUSION: Treatment of RA patients with SC ofatumumab doses of 30 mg or higher resulted in profound and prolonged B cell depletion in blood. Single doses up to 60 mg were tolerated without glucocorticoid premedication. (ClinicalTrials.gov identifier NCT00686868).
25372086 Sustained remission with etanercept tapering in early rheumatoid arthritis. 2014 Nov 6 BACKGROUND: We assessed the effects of reduction and withdrawal of treatment in patients with rheumatoid arthritis who had a remission while receiving etanercept-plus-methotrexate therapy. METHODS: Patients with early active disease who had not previously received methotrexate or biologic therapy received 50 mg of etanercept plus methotrexate weekly for 52 weeks (open-label phase). We then randomly assigned patients who had qualifying responses at weeks 39 and 52 to receive 25 mg of etanercept plus methotrexate (combination-therapy group), methotrexate alone, or placebo for 39 weeks (double-blind phase). Patients who had qualifying responses at week 39 of the double-blind phase had all treatment withdrawn at that time and were followed to week 65 (treatment-withdrawal phase). The primary end point was the proportion of patients with sustained remission in the double-blind phase. RESULTS: Of 306 patients enrolled, 193 underwent randomization in the double-blind phase; 131 qualified for the treatment-withdrawal phase. More patients in the combination-therapy group than in the methotrexate-alone group or the placebo group met the criterion for the primary end point (40 of 63 [63%] vs. 26 of 65 [40%] and 15 of 65 [23%], respectively; P=0.009 for combination therapy vs. methotrexate alone; P<0.001 for combination therapy vs. placebo). At 65 weeks, 28 patients (44%) who had received combination therapy, 19 (29%) who had received methotrexate alone, and 15 (23%) who had received placebo were in remission (P=0.10 for combination therapy vs. methotrexate alone; P=0.02 for combination therapy vs. placebo; P=0.55 for methotrexate alone vs. placebo). No significant between-group differences were observed in radiographic progression of disease. Serious adverse events were reported in 3 patients (5%) in the combination-therapy group, 2 (3%) in the methotrexate-alone group, and 2 (3%) in the placebo group. CONCLUSIONS: In patients with early rheumatoid arthritis who had a remission while receiving full-dose etanercept-plus-methotrexate therapy, continuing combination therapy at a reduced dose resulted in better disease control than switching to methotrexate alone or placebo, but no significant difference was observed in radiographic progression. (Funded by Pfizer; ClinicalTrials.gov number, NCT00913458.).
24012040 Comparative effectiveness and survival of infliximab, adalimumab, and etanercept for rheum 2014 Feb OBJECTIVE: To compare effectiveness, drug survival, and safety between infliximab, adalimumab, and etanercept, in a nationwide cohort of rheumatoid arthritis (RA) patients. METHODS: This study is a prospective cohort study of 1208 active RA patients. Effectiveness, drug survival, and serious adverse events during entire follow-up (median 2.9 years) were monitored. RESULTS: EULAR and CDAI responses were comparable between the three agents (EULAR good/moderate responses at 12 months ranged 76-79%). At 12 months, 15-23% achieved remission. For adalimumab and etanercept, adjusted hazard rate (HR) for EULAR/ACR remission (reference: infliximab) was 2.7 and 2.1 (95% confidence interval was 1.7-4.1 and 1.3-3.4, respectively); males (HR 1.6; 1.1-2.4), use of glucocorticoids (HR 2.0; 1.3-3.0), and swollen joint count >7 (HR 0.36; 0.24-0.55) were independent predictors. Five-year drug survival was 31%, 43%, and 49% for infliximab, adalimumab, and etanercept, respectively (p = 0.010). Infliximab was associated with significantly more withdrawals due to adverse events. Disease activity, CRP, and use of glucocorticoids predicted efficacy-related drug survival; age, use of methotrexate, and prior DMARDs failures predicted safety-related survival. Risk for serious infections was lower with adalimumab (odds ratio [OR] 0.62; 0.38-1.00) or etanercept (OR 0.39; 0.21-0.72) than infliximab, independent of the effects of age (OR 1.65; 1.37-2.00 per 10 years), tender joint count >10 (OR 1.86; 1.21-2.86), and glucocorticoids >35mg/week (OR 1.83; 1.12-2.99). CONCLUSIONS: Response rates were comparable among anti-TNF agents. Overall, 5-year drug survival was below 50%, with infliximab demonstrating increased safety-related discontinuations. Remission rates are low in clinical practice. Strategies to increase effectiveness and long-term survival of anti-TNF agents in RA are needed.
23601229 Oral mucositis in patients receiving low-dose methotrexate therapy for rheumatoid arthriti 2013 May BACKGROUND: The differential diagnosis of ulcerative oral lesions is diverse. This report discusses the rare causes of oral mucosal ulceration and suggests approaches for diagnosis and treatment. METHODS: Two cases of methotrexate-induced stomatitis in patients receiving low dose methotrexate for rheumatoid arthritis are presented with a review of the current literature. In case 1, mucositis was caused by an unintended methotrexate overdose. In case 2, oral lesions were the result of chronic methotrexate toxicity. The treatment for methotrexate-induced mucositis required hospitalization in case 1, methotrexate discontinuation in both cases and oral folic acid supplementation in case 2. RESULTS: In both cases, the mucositis healed and no relapse was observed. CONCLUSION: Mucositis may be an early sign of systemic conditions, and dental providers are often the first doctors involved in the assessment of oral mucosal diseases. Meticulous questioning of the patient's history and the physical examination is important for elucidating the underlying cause.
24737913 Folic acid and folinic acid for reducing side effects in patients receiving methotrexate f 2014 Jun OBJECTIVE: To perform a systematic review of the benefits and harms of folic acid and folinic acid in reducing the mucosal, gastrointestinal, hepatic, and hematologic side effects of methotrexate (MTX); and to assess whether folic or folinic acid supplementation has any effect on MTX benefit. METHODS: We searched the Cochrane Library, MEDLINE, EMBASE, and US National Institutes of Health clinical trials registry from inception to March 2012. We selected all double-blind, randomized, placebo-controlled clinical trials in which adult patients with rheumatoid arthritis (RA) were treated with MTX (dose ≤ 25 mg/week) concurrently with folate supplementation. We included only trials using low-dose folic or folinic acid (a starting dose of ≤ 7 mg weekly) because the high dose is no longer recommended or used. Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria. RESULTS: Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as "moderate" for each outcome as assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group, with the exception of hematologic side effects, which were rated as "low." There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled. For patients supplemented with any form of exogenous folate (either folic or folinic acid) while receiving MTX therapy for RA, a 26% relative (9% absolute) risk reduction was seen for the incidence of gastrointestinal side effects such as nausea, vomiting, or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; p = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; p < 0.00001), as well as reducing patient withdrawal from MTX for any reason [60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; p < 0.00001]. CONCLUSION: The results support a protective effect of supplementation with either folic or folinic acid for patients with RA during treatment with MTX. There was a clinically important significant reduction shown in the incidence of GI side effects and hepatic dysfunction (as measured by elevated serum transaminase levels), as well as a clinically important significant reduction in discontinuation of MTX treatment for any reason.
24498318 Safety with ocrelizumab in rheumatoid arthritis: results from the ocrelizumab phase III pr 2014 OBJECTIVE: The objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA). METHODS: This was an analysis of the double-blind, placebo-controlled periods and long-term follow-up of 4 OCR phase III trials in RA (SCRIPT, STAGE, FILM and FEATURE). Safety data per study and the results of a meta-analysis of serious infectious events (SIEs) are presented. RESULTS: Overall, 868 patients received placebo, 1064 patients OCR 200 mg×2 (or 400 mg×1) (OCR200), and 827 patients OCR 500 mg×2 (OCR500) plus background methotrexate (MTX) at baseline and 24 weeks. During the double-blind, placebo-controlled periods, the incidence of adverse events and serious adverse events was comparable between the OCR+MTX and placebo +MTX groups. Infusion-related reactions were more common with OCR+MTX and decreased in frequency with subsequent infusions. Serious infusion-related reactions were rare (0.1%). Serious infections occurred more frequently with OCR500+MTX. In the meta-analysis, a statistically significant difference from placebo +MTX in incidence of SIEs per 100 patient-years of 2.4 (95% CI, 0.3-4.5) was observed with OCR500+MTX, but not with OCR200+MTX (0.6; 95% CI, -1.3 to 2.4). Patients recruited in Asia exhibited a higher risk of serious infections (hazard ratio, 1.78; 95% CI, 1.03-3.06). The incidence of human anti-human antibodies was <5%. Long-term follow-up indicated no differences in malignancy rates between the treatment groups. There was no apparent difference in time to B-cell repletion between the OCR dose groups. CONCLUSIONS: In placebo-controlled clinical trials of RA, OCR500+MTX was associated with a higher risk of serious infections compared with placebo +MTX. The safety profile of OCR 200+MTX was comparable with placebo+MTX. TRIAL REGISTRATION: STAGE ClinicalTrials.gov NCT00406419 SCRIPT ClinicalTrials.gov NCT00476996 FILM ClinicalTrials.gov NCT00485589 FEATURE ClinicalTrials.gov NCT00673920.
25548435 Elevated serum IgG4 defines specific clinical phenotype of rheumatoid arthritis. 2014 OBJECTIVES: To explore the correlation of serum IgG4 (sIgG4) with clinical manifestations or therapeutic response in rheumatoid arthritis (RA). METHODS: Consecutive 136 RA patients were recruited and followed up at regular interval. SIgG4 was detected by immunonephelometry. Serial synovial tissue sections from 46 RA patients were stained immunohistochemically for IgG4. RESULTS: Forty-six percent of 136 RA patients had elevated sIgG4. Patients with elevated sIgG4 had higher sIgG4/sIgG ratio, C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and anticyclic citrullinated peptide antibodies than those with normal sIgG4 (all P < 0.05). Among 45 patients who received methotrexate and leflunomide therapy, 50% (9/18) of patients with elevated sIgG4 and 85% (23/27) of patients with normal sIgG4 reached therapeutic target (disease activity score of 28 joints < 3.2) at 6-month visit (χ(2) = 6.508, P = 0.011). IgG4-positive plasma cell count correlated positively with sIgG4, total synovitis score, and CD3-, CD20-, and CD38-positive cell counts (all P < 0.05). CONCLUSIONS: Our results showed that elevated sIgG4 in RA is common and disproportional to total IgG and RA with elevated sIgG4 may be a specific clinical phenotype with higher disease activity, higher level of autoantibodies, and poor response to methotrexate and leflunomide therapy.