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ID PMID Title PublicationDate abstract
24773727 Dose reduction of tocilizumab in rheumatoid arthritis patients with low disease activity. 2014 May OBJECTIVES: Tocilizumab is effective in the treatment of rheumatoid arthritis (RA). A proportion of patients achieve low disease activity using a lower than registered starting dose. We investigated the feasibility of dose reduction to 4 mg/kg in patients who reached low disease activity at the registered dose of 8 mg/kg. METHODS: In this retrospective study, data were collected of 22 patients successfully treated with tocilizumab 8 mg/kg for about 6 months and tapered to 4 mg/kg because of low disease activity. In case of loss of disease control, the dose could be increased again to 8 mg/kg. The percentage of patients with successful dose reduction and difference in DAS28 was described. RESULTS: Mean DAS28 at time of dose reduction was 2.3 (SD 0.9). After 3 and 6 months follow-up, 77% (95% CI 54-91) and 55% (95% CI 32-76) of patients had successfully reduced the dose without losing disease control, respectively. DAS28 at 3 and 6 months was somewhat higher than baseline, 2.7 (SD 1.2) and 2.5 (SD 1.0) respectively. All patients who experienced worsening of disease activity after dose reduction regained low disease activity after dose escalation. CONCLUSIONS: Dose reduction of tocilizumab seems feasible in a substantial proportion of patients. Dose escalation after flare was effective in all patients.
24261753 Post-marketing surveillance of the safety and effectiveness of tacrolimus in 3,267 Japanes 2014 Jan OBJECTIVES: A post-marketing surveillance (PMS) program was implemented to assess the safety and effectiveness of tacrolimus (TAC) in Japanese rheumatoid arthritis (RA) patients and to identify risk factors related to adverse drug reactions (ADRs). METHODS: Patients were registered centrally and monitored for all adverse events (AEs) for 24 weeks. Effectiveness was evaluated using the Disease Activity Score 28-CRP (DAS28-CRP). RESULTS: Data from 3,172 patients (mean age 62.2 years) were evaluated in the safety analysis. Of the safety population, 78.5 %were female and 25.9 % were in Steinbrocker's functional class 3 or 4. TAC was prescribed as monotherapy in 52.5 % and the most common concomitant disease modifying antirheumatic drug (DMARD) was methotrexate, used in 28.9 % of the patients. The incidence of AEs, serious AEs (SAEs), ADRs and serious ADRs were 41.2, 6.4, 36.0, and 4.9 %, respectively. The most frequent serious ADR category was infections and infestations. Age ≥ 65 years, concurrent renal dysfunction, and concurrent diabetes mellitus were identified as significant risk factors for ADR. Based on EULAR response criteria, 65.4 % of the patients showed moderate or good response. CONCLUSIONS: The results demonstrate that TAC is well tolerated by Japanese patients with active RA, including those receiving concomitant methotrexate, in the real world.
24252035 Addition of another disease-modifying anti-rheumatic drug to methotrexate reduces the flar 2014 Jul OBJECTIVES: We examined whether the addition of another conventional disease-modifying anti-rheumatic drugs (DMARDs) to methotrexate (MTX) upon infliximab (IFX) discontinuation in well-controlled rheumatoid arthritis (RA) patients could suppress subsequent disease flare. METHODS: RA patients maintaining DAS28-CRP (Disease Activity Score of 28 joints with C-reactive protein) scores < 2.6 for ≥ 6 months with IFX were randomized either to receive addition of bucillamine (BUC) to MTX (BUC + MTX group; n = 24) or not (MTX group; n = 31) upon discontinuing IFX. The primary endpoint was the flare rate within 2 years of IFX discontinuation. RESULTS: Six patients discontinuing MTX during the study were excluded from analyses. Seventeen patients (63.0%) experienced flares in the MTX group, which was significantly reduced in the BUC + MTX group (31.8%; p = 0.045). Further, the flare rates differed significantly between remission and non-remission by a Boolean definition upon IFX discontinuation in the MTX group (40.0% vs. 91.7%, respectively; p = 0.014), but they were comparable in the BUC + MTX group. BUC treatment was interrupted in seven patients due to rash, proteinuria and incompliance. CONCLUSIONS: DMARDs combination therapy may be a better treatment strategy than MTX monotherapy for maintaining RA control after successful discontinuation of biological agents.
23329349 The relationship between depressive symptoms, illness perceptions and quality of life in a 2013 May Anxiety and depressive symptoms as well as cognitive variables are important in determining outcome in rheumatic diseases. We aimed to compare psychological distress symptoms and illness perceptions in ankylosing spondylitis (AS) and rheumatoid arthritis (RA) and to test whether their associations with health-related quality of life (HRQoL) were similar in these rheumatologic disorders. In 55 AS and 199 RA patients, we administered the Patient Health Questionnaire (PHQ-9), the Symptom Check-List and the Brief-Illness Perception Questionnaire to assess psychological variables and the World Health Organization Quality of Life Instrument, Short Form to assess HRQoL. We used hierarchical regression analyses to determine the associations between psychological variables and HRQoL after adjusting for demographic variables and disease parameters. The prevalence of clinically significant depressive symptoms (PHQ-9 ≥ 10) was 14.8 % in AS and 25.1 % in RA patients, but adjustment for demographics rendered these differences in depressive symptoms' severity non-significant. Psychological distress levels and HRQoL were similar in both disorders. Illness concern (b = -0.37) was the only significant independent correlate of physical HRQoL in AS. In RA, depression (b = -0.25), illness concern (b = -0.14) and worries about the consequences of the disease (b = -0.31) were the independent correlates of physical HRQoL. These findings suggest that cognitive variables are important correlates of HRQoL in AS, whereas in RA depressive symptoms and illness perceptions equally contribute to HRQoL. Our data encourage the design of psychotherapeutic trials targeting disease-related cognitions in AS in an attempt to improve patient's physical HRQoL.
25283268 Clinical endpoint sensitivity in rheumatoid arthritis: modeling and simulation. 2014 Oct The commonly used efficacy endpoints in Rheumatoid Arthritis (RA) clinical trials are American College of Rheumatology 20 % improvement criteria (ACR20), ACR50, and ACR70 response rates, and the 28-joint disease activity score (DAS28). Longitudinal models to quantitate the exposure-response relationships for ACRs and DAS28 score were developed for four biologics used for the management of RA. The models were then used to simulate the clinical outcome at various time points following different treatment regimens. Discriminative sensitivity of these endpoints was assessed using a power analysis. The trial simulation and subsequent power analysis showed that both ACR20 and DAS28 exhibit much lower power in distinguishing between two doses investigated compared with distinguishing treatment effect over placebo/Methotrexate (MTX) control. ACR20 response rate is generally more powerful in detecting treatment effect over placebo/MTX control as compared to DAS28. The findings of current study provide useful information which will help future clinical trial design for the treatment of patients with RA.
24561407 Treating rheumatoid arthritis to target: a Canadian patient survey. 2014 Mar BACKGROUND: Recently, many countries, including Canada, evaluated rheumatologists' acceptance and agreement with a set of 10 Treat to Target (T2T) recommendations for rheumatoid arthritis (RA), developed by an international task force. In this study, the Canadian T2T steering committee evaluated how Canadian patients with RA perceive these recommendations. OBJECTIVES: The objectives of this study were to assess the current state of RA management in Canada from a patient perspective and to assess whether and to what extent Canadians with RA agree with each of the 10 T2T recommendations and to compare the results with a previous survey completed by physicians. METHODS: Participating rheumatologists were asked to invite consecutive RA patients to complete a 20-question survey. The survey was designed to assess relevant sociodemographic variables, the current treatment, and the approach to RA management as seen from the patient's perspective, as well as their agreement with the T2T recommendations. RESULTS: A total of 959 patients (77% were female) were recruited by 22 participating rheumatologists from 6 Canadian provinces. Patients had a mean age of 59.1 years and mean disease duration of 12.9 years. Approximately 72% of patients were on methotrexate (76.1% combination therapy), and 36.7% were treated with biologics (6.4% monotherapy, 30.3% combination therapy). The agreement with T2T recommendations ranged from 8.6 for recommendation 4 (frequency of adjustment of drug therapy) to 9.5 for recommendation 8 (maintenance of treatment targets). These results are comparable to a previous physicians' survey except that there was more acceptance on the part of patients for more frequent visits (recommendation 5; patient agreement score was 9.06 vs physician agreement score of 6.92) and evaluations for adjustments of therapy (recommendation 6 patient agreement score was 9.39 vs physician agreement score of 7.49) to achieve the stated goal. CONCLUSIONS: The results of this survey showed that Canadian patients are being treated for their RA according to the published treatment recommendations with combination disease-modifying antirheumatic drugs and biologics and a small percentage with oral corticosteroids. The majority of patients seems to be satisfied with their management and is in agreement with the T2T recommendations, although they tended to place greater emphasis than did physicians on flexibility of visit frequency and detailed assessments.
24297378 The comparative effectiveness of abatacept versus anti-tumour necrosis factor switching fo 2015 Feb OBJECTIVE: We compared the effectiveness of abatacept (ABA) versus a subsequent anti-tumour necrosis factor inhibitor (anti-TNF) in rheumatoid arthritis (RA) patients with prior anti-TNF use. METHODS: We identified RA patients from a large observational US cohort (2/1/2000-8/7/2011) who had discontinued at least one anti-TNF and initiated either ABA or a subsequent anti-TNF. Using propensity score (PS) matching (n:1 match), effectiveness was measured at 6 and 12 months after initiation based on mean change in Clinical Disease Activity Index (CDAI), modified American College of Rheumatology (mACR) 20, 50 and 70 responses, modified Health Assessment Questionnaire (mHAQ) and CDAI remission in adjusted regression models. RESULTS: The PS-matched groups included 431 ABA and 746 anti-TNF users at 6 months and 311 ABA and 493 anti-TNF users at 12 months. In adjusted analyses comparing response following treatment with ABA and anti-TNF, the difference in weighted mean change in CDAI (range 6-8) at 6 months (0.46, 95% CI -0.82 to 1.73) and 12 months was similar (-1.64, 95% CI -3.47 to 0.19). The mACR20 responses were similar at 6 (28-32%, p=0.73) and 12 months (35-37%, p=0.48) as were the mACR50 and mACR70 (12 months: 20-22%, p=0.25 and 10-12%, p=0.49, respectively). Meaningful change in mHAQ was similar at 6 and 12 months (30-33%, p=0.41 and 29-30%, p=0.39, respectively) as was CDAI remission rates (9-10%, p=0.42 and 12-13%, p=0.91, respectively). CONCLUSIONS: RA patients with prior anti-TNF exposures had similar outcomes if they switched to a new anti-TNF as compared with initiation of ABA.
23073787 Associations between interferon regulatory factor 5 polymorphisms and rheumatoid arthritis 2013 Feb The aim of this study was to determine whether interferon regulatory factor 5 (IRF5) polymorphisms confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. We searched the literature using the Pubmed and Embase databases and conducted meta-analyses on associations between the four IRF5 polymorphisms (rs2004640, rs729302, rs752637, and rs2280714) and RA susceptibility, using fixed and random effects models. A total of 12 comparison studies were considered in this meta-analysis, which in total involved 7,916 RA patients and 6,452 controls, and eight European, three Asian, and one Argentinean population. Meta-analysis showed an association between the minor allele of rs2004640 and RA in all subjects (odds ratio [OR] = 0.928, 95 % confidence interval [CI] = 0.865-0.996, P = 0.037). After stratification by ethnicity, analysis indicated that the minor allele was significantly associated with RA in Europeans (OR = 0.889, 95 % CI = 0.839-0.941, P = 5.03 × 10(-6)), but not in Asians (OR = 1.057, 95 % CI = 0.978-1.144, P = 0.164). A direct comparison between anti-citrullinated peptide antibody-positive and -negative patients revealed no difference of the frequency of the rs2004640 minor allele (OR = 1.047, 95 % CI = 0.813-1.348, P = 0.724). Meta-analysis identified a significant association between RA and the minor allele of the rs729302 polymorphism in the overall population (OR = 0.896, 95 % CI = 0.826-0.972, P = 0.009) and in Asians (OR = 0.862, 95 % CI = 0.795-0.935, P = 3.50 × 10(-5)), but not in Europeans (OR = 0.951, 95 % CI = 0.877-1.031, P = 0.225). Meta-analysis showed an association between the minor allele of rs752637 and RA in Europeans (OR = 0.858, 95 % CI = 0.789-0.932, P = 3.03 × 10(-5)), but not in Asians (OR = 1.035, 95 % CI = 0.918-1.168, P = 0.572). No association was found between the rs2280714 polymorphism and RA susceptibility. This meta-analysis confirms that the IRF5 rs2004640, rs729302 and rs752637 polymorphisms are associated with RA susceptibility in different ethnic groups, especially in Europeans and Asians, but further study of this association is required in other ethnic groups.
25560583 Myelosuppressive and hepatotoxic potential of leflunomide and methotrexate combination in 2015 Feb BACKGROUND: Safety of the combination of leflunomide and methotrexate was examined in several studies with inconclusive results. The present study was designed to compare the efficacy and safety of the combination of leflunomide and methotrexate in adjuvant-induced arthritis (AIA) in rats focusing on immunosuppressive and hepatotoxic effects. METHODS: Eighty four rats were divided into seven groups. Group 1: Sham control, group 2: the vehicle control, group 3: methotrexate group, group 4-5: leflunomide (5 and 10mg/kg/day) groups, group 6-7: combination 1 and 2 [methotrexate+leflunomide (5 and 10mg/kg/day)] groups, respectively. RESULTS: The current results indicated that combination therapies improved the ankle circumference and clinical scores compared to monotherapies; histopathological examination confirmed these findings. The myelosuppressive effect of leflunomide (10mg/kg/day) was comparable to that produced by methotrexate as indicated by the complete blood count and bone marrow cellularity; however their combination resulted in greater toxicity. Furthermore, methotrexate greatly affected the splenic histopathology compared to leflunomide and the combination therapy produced a greater effect compared to leflunomide not methotrexate. Differently, assessment of the hepatotoxic potential of the two drugs highlighted that leflunomide induced a dose-dependent increase in the fibrosis score which was higher in their magnitude than that induced by methotrexate. Leflunomide (10mg/kg/day) and combination 2 groups showed the greatest degree of liver fibrosis. CONCLUSIONS: In rats with AIA, current drug combinations provided higher therapeutic benefit compared to monotherapies, however, greater toxicities were observed. Therefore, continuous monitoring of hematologic parameters and liver function will be recommended in clinical settings.
24387801 TLR dependent XBP-1 activation induces an autocrine loop in rheumatoid arthritis synoviocy 2014 May X-box binding protein 1 (XBP1) is a central regulator of the endoplasmic reticulum (ER) stress response. It is induced via activation of the IRE1 stress sensor as part of the unfolded protein response (UPR) and has been implicated in several diseases processes. XBP1 can also be activated in direct response to Toll-like receptor (TLR) ligation independently of the UPR but the pathogenic significance of this mode of XBP1 activation is not well understood. Here we show that TLR-dependent XBP1 activation is operative in the synovial fibroblasts (SF) of patients with active rheumatoid arthritis (RA). We investigated the expression of ER stress response genes in patients with active RA and also in patients in remission. The active (spliced) form of (s)XBP1 was significantly overexpressed in the active RA group compared to healthy controls and patients in remission. Paradoxically, expression of nine other ER stress response genes was reduced in active RA compared to patients in remission, suggestive of a UPR-independent process. However, sXBP1 was induced in SF by TLR4 and TLR2 stimulation, resulting in sXBP1-dependent interleukin-6 and tumour necrosis factor (TNF) production. We also show that TNF itself induces sXBP1 in SF, thus generating a potential feedback loop for sustained SF activation. These data confirm the first link between TLR-dependent XBP1 activation and human inflammatory disease. sXBP1 appears to play a central role in this process by providing a convergence point for two different stimuli to maintain activation of SF.
24724574 Assessing the citrullinome in rheumatoid arthritis synovial fluid with and without enrichm 2014 Jun 6 Protein citrullination is a posttranslational modification that has attracted increased attention, especially for its involvement in rheumatoid arthritis (RA). Here, we assess the citrullinome in RA synovial fluid by direct LC-MS/MS analysis and by the use of an enrichment strategy based on citrulline specific biotinylation. RA synovial fluid was depleted for abundant proteins, and total and depleted fractions were analyzed. Frequency of citrullinated peptides and their degree of citrullination could be determined for four known RA autoantigens, as well as a novel in vivo autocitrullination site of peptidylarginine deiminase 4. From the analysis of total and depleted synovial fluid after enrichment we could estimate the numbers of citrullinated peptides to be approximately 3600 and 2100, respectively. However, identification of these biotinylated peptides by MS/MS turned out to be very difficult due to fragmentation of the biotin moiety. By direct MS analysis of the total and depleted synovial fluid without enrichment, 119 and 157 citrullinated peptides were identified, respectively. This indicates that direct analysis allows identification of only a fraction of the citrullinated proteins present in synovial fluid and that specific enrichment is still needed for a comprehensive in-depth elucidation of the citrullinome.
22791271 Risk factors of severe infections in patients with rheumatoid arthritis treated with leflu 2013 Jul OBJECTIVES: To determine the risk of severe infection requiring or complicating hospitalization associated with leflunomide therapy in patients with rheumatoid arthritis (RA). METHODS: We performed a retrospective study of RA patients who were prescribed leflunomide between 2004 and 2011. Background clinical and laboratory features were compared between patients who suffered severe leflunomide-associated infections and those who did not. RESULTS: Since January 2005, 401 RA patients have started on leflunomide. Among those, 33 (8.2%) developed severe infections: pneumonia, oral candidiasis, pyelonephritis, pulmonary tuberculosis, cellulitis, disseminated herpes zoster, tonsillitis, and pulmonary cryptococcosis. Logistic regression showed that age at entry, the presence of DM, and daily dosage of corticosteroid were associated with development of severe infections. CONCLUSIONS: These results showed that some patients with RA who were taking leflunomide developed severe infections requiring hospitalization, and that older age, DM, and a higher daily dosage of corticosteroid were risk factors associated with leflunomide-associated severe infections.
23194301 Targeted chemo-photothermal treatments of rheumatoid arthritis using gold half-shell multi 2013 Jan 22 We have developed RGD-attached gold (Au) half-shell nanoparticles containing methotrexate (MTX) for the treatment of rheumatoid arthritis (RA), where MTX is the most widely used disease-modifying anti-rheumatic drug (DMARD) for the treatment of RA, and RGD peptide is a targeting moiety for inflammation. Upon near-infrared (NIR) irradiation, heat is locally generated due to Au half-shells, and the drug release rate is enhanced, delivering heat and drug to the inflamed joints simultaneously. RA is a chronic inflammatory disease characterized by synovial inflammation in multiple joints within the penetration depth of NIR light. When combined with NIR irradiation, these nanoparticles containing a much smaller dosage of MTX (1/930 of MTX solution) showed greater therapeutic effects than that of a conventional treatment with MTX solution in collagen-induced arthritic mice. This novel drug delivery system is a good way to maximize therapeutic efficacy and minimize dosage-related MTX side effects in the treatment of RA. Furthermore, these multifunctional nanoparticles could be applied to other DMARDs for RA or other inflammatory diseases.
25526976 Spanish Rheumatology Society and Hospital Pharmacy Society Consensus on recommendations fo 2015 Jul OBJECTIVE: The aim of this study was to establish guidelines for the optimization of biologic therapies for health professionals involved in the management of patients with RA, AS and PsA. METHODS: Recommendations were established via consensus by a panel of experts in rheumatology and hospital pharmacy, based on analysis of available scientific evidence obtained from four systematic reviews and on the clinical experience of panellists. The Delphi method was used to evaluate these recommendations, both between panellists and among a wider group of rheumatologists. RESULTS: Previous concepts concerning better management of RA, AS and PsA were reviewed and, more specifically, guidelines for the optimization of biologic therapies used to treat these diseases were formulated. Recommendations were made with the aim of establishing a plan for when and how to taper biologic treatment in patients with these diseases. CONCLUSION: The recommendations established herein aim not only to provide advice on how to improve the risk:benefit ratio and efficiency of such treatments, but also to reduce variability in daily clinical practice in the use of biologic therapies for rheumatic diseases.
24355236 Latent virus reactivation risk and biological drugs: chronic inflammatory and immune-media 2013 Oct Psoriasis vulgaris, psoriatic arthritis and rheumatoid arthritis are chronic inflammatory and immune-mediated disorders, widely distributed in the population and induced by several environmental factors in genetically predisposed individuals. Different therapies are currently used to treat these diseases. Since these pathologies are characterized by an altered production of proinflammatory cytokines and chemokines, and biological therapy is based on the development of monoclonal antibodies or recombinant proteins against these molecules, this therapy represents an important option. Nevertheless, it was recently reported that biological agents have been associated with serious life-threatening infections. This article aims to summarize literature data on viral reactivation risk that clinicians need to take into account when selecting the most appropriate biological therapy for such patients.
24664818 Sustainability of rituximab therapy in different treatment strategies: results of a 3-year 2014 Nov OBJECTIVE: To compare the approved treatment of rheumatoid arthritis using rituximab + methotrexate (RTX + MTX) versus the off-label treatment variants of RTX in monotherapy or RTX in combination with leflunomide (RTX + LEF). METHODS: We included RTX-naive patients enrolled in the German biologics register RABBIT (Rheumatoid Arthritis: Observation of Biologic Therapy) between 2007 and 2012 (n = 907) who started treatment with RTX. Three treatment regimens (RTX + MTX, RTX + LEF, and RTX monotherapy) were analyzed regarding therapy discontinuation, dropout, RTX retreatment, and concomitant glucocorticoid therapy. Effectiveness was evaluated with linear mixed models. RESULTS: Baseline patient characteristics were similar across treatment regimens, except for poorer functional status and more comorbidities in RTX monotherapy. Average doses of glucocorticoids were lower in RTX + LEF compared to the 2 other groups. The frequency and timing of RTX retreatment (P > 0.62) as well as improvement in the Disease Activity Score in 28 joints (DAS28) over time (P > 0.15) were similar in all treatment regimens. Within the first 12 months of treatment, the DAS28 decreased by 1.5 units, and between months 12 and 36, by a further 0.4 unit equally in all groups. Nevertheless, therapy discontinuation and dropout were significantly increased on RTX monotherapy (hazard ratio [HR] 1.7 [95% confidence interval (95% CI) 1.2-2.3]), and additionally when patients were rheumatoid factor negative (HR 1.5 [95% CI 1.0-2.1]). CONCLUSION: In patients who continue therapy, RTX + LEF, RTX monotherapy, and RTX + MTX seem to be equally effective. However, given the lower adherence rates on monotherapy, this treatment option is not sufficient for all patients. Since many patients are intolerant to MTX, more licensed RTX treatment options are needed.
24108586 Systemic rheumatoid vasculitis in the era of modern immunosuppressive therapy. 2014 Jan OBJECTIVES: Systemic rheumatoid vasculitis (SRV) is a rare but potentially serious systemic disease manifestation of rheumatoid arthritis (RA) characterized by the development of necrotizing vasculitis. The incidence of SRV appears to be decreasing possibly reflecting progress in RA treatment. The aims of this study were to review the clinical manifestations of SRV in a stable well-defined population during 2001-10 and to compare with our previous cohort (1988-2000) and also a cohort from 1975 to 1981. METHODS: Using Norfolk Vasculitis Register, a prospective register of patients with systemic vasculitis since 1988, all patients with a diagnosis of SRV from 1 January 2001 until 31 December 2010 were identified. SRV was defined according to the Scott and Bacon criteria (1984). Clinical features were obtained by retrospective case note review. RESULTS: Eighteen patients with SRV were identified (10 male), median age at diagnosis was 72 years and average disease duration 15.6 years. The average annual incidence for 2001-10 was 3.9 per million. One-year mortality was 12% and 5-year mortality 60%. The clinical manifestations were similar apart from systemic and cutaneous features which were more common in the earlier cohorts. CONCLUSION: The incidence of SRV has declined significantly in the last 40 years; but the clinical manifestations remain similar. Systemic symptoms, and cutaneous manifestations such as infarcts and nodules, are slightly less common in the recent cohort. Despite modern immunosuppressive therapy the prognosis remains poor.
24699939 Sirukumab, a human anti-interleukin-6 monoclonal antibody: a randomised, 2-part (proof-of- 2014 Sep OBJECTIVES: The safety and efficacy of sirukumab, an anti-interleukin-6 (IL-6) monoclonal antibody, were evaluated in a 2-part, placebo-controlled phase II study of patients with active rheumatoid arthritis (RA) despite methotrexate therapy. METHODS: In Part A (proof-of-concept), 36 patients were randomised to placebo or sirukumab 100 mg every 2 weeks (q2w) through week 10, with crossover treatment during weeks 12-22. In Part B (dose finding), 151 patients were randomised to sirukumab (100 mg q2w, 100 mg q4w, 50 mg q4w, or 25 mg q4w) through week 24, or placebo through week 10 with crossover to sirukumab 100 mg q2w (weeks 12-24). The proportion of patients with an American College of Rheumatology 50 (ACR50) response and the change from baseline in the 28-joint count disease activity score using C-reactive protein (DAS28-CRP) were determined. Safety was evaluated through week 38 in both parts. RESULTS: The primary endpoint (ACR50 at week 12 in Part B) was achieved only with sirukumab 100 mg q2w versus placebo (26.7% vs 3.3%; p=0.026). Greater improvements in mean DAS28-CRP at week 12 were observed with sirukumab 100 mg q2w versus placebo in Parts A (2.1 vs 0.6, p<0.001) and B (2.2 vs 1.1; p<0.001). The incidence of adverse events (AEs) was similar for sirukumab-treated and placebo-treated patients through week 12 in Part A (70.6% and 63.2%, respectively) and B (67.8% and 66.7%, respectively). Infections were the most common type of AE; one death occurred (Part B, sirukumab 100 mg q2w, brain aneurysm). CONCLUSIONS: Sirukumab-treated patients experienced improvements in the signs/symptoms of RA. Safety results through 38 weeks were consistent with other IL-6 inhibitors. TRIAL REGISTRATION NUMBER: NCT00718718.
24663107 Rheumatoid arthritis and pregnancy: impediments to optimal management of both biologic use 2014 May PURPOSE OF REVIEW: Tumour necrosis factor inhibitors (TNFi) and other biologic response modifiers are being increasingly used for the treatment of rheumatoid arthritis (RA) among women of childbearing age, raising concerns regarding the potential safety of inadvertent or intentional exposure of these agents to the developing fetus. RECENT FINDINGS: TNFi and other biologics whose constructs contain a functional IgGFc piece are actively transported across the placenta during the second and third trimesters of pregnancy. Very little drug passively diffuses to the fetal circulation during the first trimester, when organogenesis occurs. Cumulative data from both the rheumatology and gastroenterology literature suggest that the rate of birth defects following antenatal TNFi exposure does not appear to be higher than that seen in the general population. There are very little data available on pregnancy outcomes following antenatal exposure to other biologic medications for RA. SUMMARY: Cumulative evidence suggests that TNFi use during pregnancy carries low risk for teratogenicity. A single case of fatal BCG infection in an exposed neonate following live virus vaccination highlights the potential need to defer live virus vaccines for at least 6 months in exposed neonates until more data of risk factors for infection susceptibility are available.
23247552 Debridement of painful forefoot plantar callosities in rheumatoid arthritis: the CARROT ra 2013 May The objective of this study was to evaluate the long-term benefits of sharp scalpel debridement of painful forefoot plantar callosities in rheumatoid arthritis (RA). The null hypothesis: sharp scalpel debridement would offer no additional long-term advantage in terms of pain and function. Sixty-five people with RA were randomised to receive regular sharp scalpel debridement of painful forefoot plantar callosities in conjunction with a combined therapeutic approach or a combined therapeutic approach alone. The primary outcome measure was change at 18 months in participant-reported forefoot plantar pain measured by a 100-mm visual analogue scale (VAS). Secondary outcome measures were recorded at baseline and study exit and included revised Foot Function Index, Health Assessment Questionnaire, Foot Impact Scale and gait parameters. At 18 months, there were no differences between groups for the primary outcome VAS-measured forefoot plantar pain (left foot (F = 0.23, p = 0.635), right foot (F = 2.14, p = 0.148)). Within-group changes were highly significant (treatment arm, difference = 16.9 (95 % confidence interval (CI) 9.4, 24.4), t = 4.6, p < 0.0001; control arm, difference = 17.5 (95 % CI 9.4, 25.5), t = 4.4, p < 0.0001). There was little change in scores of overall function and foot impact in either group and there were no significant changes in gait parameters noted. The long-term effects of sharp scalpel debridement of painful forefoot plantar callosities in people with RA, when used in conjunction with a combined therapeutic approach, produced no additional benefit over the combined therapeutic approach alone. Trial registration http://www.controlled-trials.com/ISRCTN05190231.