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ID PMID Title PublicationDate abstract
21496415 Efficacy and safety of leflunomide or methotrexate plus subcutaneous tumour necrosis facto 2011 Jan Several smaller retrospective case series have concluded that leflunomide (LEF) in combination with anti-TNF-alpha blocking agents appears to be effective and safe. Prospective case series and cohort studies have generally confirmed the efficacy of this combination. Overall, there is currently no evidence from controlled trials that an anti-TNF-alpha combination with LEF is as effective as an anti-TNF-alpha combination with methotrexate (MTX). We compared the effectiveness and safety of a therapeutic regimen associating subcutaneous anti-TNF-alpha agents, etanercept (ETN) and adalimumab (ADA), with leflunomide (LEF) or methotrexate (MTX), in a two year open-label study performed in clinical practice. We evaluated 96 patients with active rheumatoid arthritis undergoing therapy with ADA at the dose of 40 mg every other week, or with ETN at the dose of 50 mg/week for two years added to prednisolone (PDN) at the mean dose of 5.2±2.6 mg/day. Fifty-four of these patients were also undergoing therapy with MTX at the mean dose of 11.7±2.6 mg/week, while 42 patients were undergoing therapy with LEF at the daily dose of 20 mg. At 12 months, the analysis of variance showed an improvement of DAS28 in both groups (p<0.001), with a reduction in 33.3% of the patients in treatment with LEF and in 51.8% of the patients in treatment with MTX (p = 0.20). At 18 months, improvement was present in 33.3% of the patients in the LEF group and in 81.5% of the patients in the MTX group (p=0.001). This improvement seems to be independent of the anti-TNF-alpha agent, even if MTX produces the highest DAS28 reduction when used in association with ETN (p<0.078). We found no difference in drug discontinuation rates or in effectiveness measures between anti-TNFalpha+MTX and anti-TNFalpha+LEF. Our data showed a greater reduction of DAS28 in the MTX group and, in combination with ETN, better results after two years of therapy.
21636020 Universal total wrist arthroplasty: midterm follow-up study. 2011 Jun PURPOSE: We reviewed 21 consecutive patients who underwent a total wrist arthroplasty as a primary procedure between October 2001 and February 2007. The purposes of the present study were to communicate our midterm results and to compare them with previously published series. METHODS: We evaluated all patients clinically and radiologically. We used the Patient-Related Wrist Evaluation a primary outcome measure. The mean follow-up was 5.5 years (range, 3-8 years). A total of 14 patients had rheumatoid arthritis, including 1 with juvenile arthritis, and 1 each had psoriatic arthritis, systemic lupus erythematosus, and undifferentiated spondyloarthropathy. Of the remaining 4 patients, 2 had grade IV Kienböck disease, 1 had degenerative arthrosis, and 1 had chondrocalcinosis. RESULTS: Postoperative Patient-Related Wrist Evaluation scores averaged 24 points (SD, 21 pints) out of 100 (worst score). When the patients were specifically asked about pain and function of the arthroplasty, 20 claimed to be satisfied or very satisfied with the procedure. Two early and 3 late complications occurred. One patient had a wound hematoma and another had a superficial wound infection, both of which resolved with no further complications during the immediate postoperative period. In 2 patients, there was some osteolysis around the screw inserted into the medullary canal of the index metacarpal, but not in the trapezoid bone. One patient had a slight loosening of the distal component with subsidence on the ulnar side of the carpus. There have been no dislocations or surgical revisions of the components. CONCLUSIONS: Based on our study, a total wrist arthroplasty should be considered as a good alternative to arthrodesis for patients who wish to preserve some degree of mobility of the wrist. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.
22170479 Brief report: a phase IIa, randomized, double-blind, placebo-controlled trial of apilimod 2012 Jun OBJECTIVE: To investigate the safety, tolerability, pharmacokinetics, and efficacy of apilimod mesylate, an oral interleukin-12 (IL-12)/IL-23 inhibitor, in patients with rheumatoid arthritis (RA). METHODS: We performed a phase IIa, randomized, double-blind, placebo-controlled proof-of-concept study of apilimod, in combination with methotrexate, in 29 patients with active RA (3:1 ratio of apilimod-treated to placebo-treated patients) in 3 stages. Patients received apilimod 100 mg/day or placebo for 4 weeks (stage 1) or 8 weeks (stage 2). In stage 3, patients received apilimod 100 mg twice a day or placebo for 8 weeks, with an optional extension of 4 weeks. Clinical response (Disease Activity Score in 28 joints [DAS28] and American College of Rheumatology [ACR] criteria) was assessed throughout; synovial tissue samples collected at baseline and on day 29 (stages 1 and 2) or day 57 (stage 3) were stained for cellular markers and cytokines for immunohistochemistry analysis. RESULTS: While only mild adverse events were observed in stages 1 and 2, in stage 3, all patients experienced headache and/or nausea. Among apilimod-treated patients (100 mg/day), there was a small, but significant, reduction in the DAS28 on day 29 and day 57 compared with baseline. ACR20 response was reached in only 6% of patients on day 29 and 25% of patients on day 57, similar to the percentage of responders in the placebo group. Increasing the dosage (100 mg twice a day) did not improve clinical efficacy. Consistent with clinical results, apilimod did not have an effect on expression of synovial biomarkers. Of importance, we also did not observe an effect of apilimod on synovial IL-12 and IL-23 expression. CONCLUSION: Our results do not support the notion that IL-12/IL-23 inhibition by apilimod is able to induce robust clinical improvement in RA.
20736390 Anti-cyclic citrullinated peptide antibodies are a collection of anti-citrullinated protei 2011 Jan OBJECTIVE: Anti-citrullinated protein antibodies (ACPA) and anti-cyclic citrullinated peptide (anti-CCP) antibodies are a hallmark of rheumatoid arthritis and are believed to play a role in disease pathogenesis. These antibodies are typically detected in ELISA with citrullinated peptides (eg, CCP2) or proteins as antigens. The absolute concentration of anti-CCP antibodies in serum is unknown. Although antibodies to several citrullinated proteins can mainly be detected within anti-CCP-positive sera, it is currently unknown whether anti-CCP antibodies are in fact ACPA. Likewise, it is unknown to what extent antibody responses to different citrullinated antigens are crossreactive. METHODS: An affinity purification method was established in which citrullinated antigen-specific antibodies were eluted from ELISA plates and then used for detection of other citrullinated antigens in ELISA or western blot. For additional crossreactivity studies, ELISA-based inhibition assays were performed with citrullinated or control peptides as inhibitors. RESULTS: The concentration of anti-CCP IgG antibodies was estimated to be at least 30 μg/ml in patients with high anti-CCP levels (>1600 μg/ml). Affinity-purified anti-CCP antibodies were able to recognise citrullinated fibrinogen (cit-fib) and citrullinated myelin basic protein (cit-MBP) on western blot. Furthermore, antibodies specific for cit-fib and cit-MBP were crossreactive. However, additional crossreactivity studies indicated that non-overlapping antibody responses to citrullinated peptides can also exist in patients. CONCLUSIONS: This report shows for the first time that anti-CCP antibodies recognise multiple citrullinated proteins and are thus a collection of ACPA. More importantly, the data indicate that different ACPA responses are crossreactive, but that crossreactivity is not complete, as distinct non-crossreactive responses can also be detected in patients with RA.
21498482 Incidence and risk factors for serious infection in patients with rheumatoid arthritis tre 2011 Jul OBJECTIVE: To compare tumor necrosis factor-α (TNF-α) inhibitors to nonbiological disease-modifying antirheumatic drugs (DMARD) for the risk of serious infection in Japanese patients with rheumatoid arthritis (RA). METHODS: Serious infections occurring within the first year of the observation period were examined using the records for patients recruited to the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety (REAL), a hospital-based prospective cohort of patients with RA. The analysis included 1144 patients, 646 of whom were treated with either infliximab or etanercept [exposed group: 592.4 patient-years (PY)]. The remaining 498 patients received nonbiological DMARD with no biologics (unexposed group: 454.7 PY). RESULTS: In the unexposed group, the incidence rate for all serious adverse events (SAE) was 9.02/100 PY and for serious infections, 2.64/100 PY. In the exposed group, SAE occurred in 16.04/100 PY and serious infections in 6.42/100 PY. The crude incidence rate ratio comparing serious infections in the exposed group with the unexposed group was 2.43 (95% CI 1.27-4.65), a significant increase. A multivariate analysis revealed that the use of TNF inhibitors is a significant independent risk factor for serious infection (relative risk 2.37, 95% CI 1.11-5.05, p = 0.026). CONCLUSION: Our study has provided the first epidemiological data on Japanese patients with RA for the safety of TNF inhibitors compared to nonbiological DMARD for up to 1 year of treatment. Anti-TNF therapy was associated with a significantly increased risk for serious infections, compared to treatment with nonbiological DMARD.
21397455 Radiographic analysis of a hand-held surgical navigation system for tibial resection in to 2011 Dec Tibial intramedullary or extramedullary alignment guides have not been shown to be highly accurate in performing the tibial resection in total knee arthroplasty (TKA). Since May 2010, a total of 42 knees underwent a TKA using a hand-held, accelerometer-based surgical navigation system for performing the tibial resection (KneeAlign; OrthAlign Inc, Aliso Viejo, Calif). Postoperative standing anteroposterior hip-to-ankle and lateral knee-to-ankle radiographs demonstrated that 97.6% of the tibial components were placed within 90° ± 2° to the mechanical axis in the coronal plane, and 96.2% of the components were placed within 3° ± 2° to the mechanical axis in the sagittal plane. The KneeAlign greatly improves the accuracy of tibial component alignment in TKA.
21330347 Exocytosis of azurophil and arginase 1-containing granules by activated polymorphonuclear 2011 May ARG1, expressed by human PMNs, inhibits T cell proliferation by depleting extracellular L-arginine. Here, we report that ARG1, released from gelatinase granules by PMNs, is inactive at physiological pH unless activated by factor(s) stored in azurophil granules. Whereas ARG1 exocytosis was induced by TNF-α or ionomycin, only the latter mediated the release of both granules, resulting in extracellular ARG enzyme activity at physiological pH. Furthermore, after fractionation of the different classes of granules, only the mixture of gelatinase and azurophil granules resulted in ARG1 activity at physiological pH. The use of protease inhibitors indicated the involvement of a PMSF- and leupeptin-susceptible serine protease in ARG1 processing and activation. Finally, the supernatant of viable PMNs undergoing frustrated phagocytosis, which mediates gelatinase and azurophil granule release, inhibited T cell proliferation through ARG-dependent mechanisms. In vivo, high ARG1 concentrations and increased ARG enzyme activity, sufficient to inhibit T cell proliferation, were observed in synovial fluids from RA. These findings suggest that PMNs, recruited at sites of immune complex deposition, induce ARG1-dependent immune suppression through concomitant exocytosis of gelatinase and azurophil granules.
22879465 Effectiveness of etanercept vs cyclophosphamide as treatment for patients with amyloid A a 2012 Nov OBJECTIVES: To compare the effectiveness of an alkylating agent with that of a biologic agent in the treatment of patients with amyloid A (AA) amyloidosis secondary to RA and to assess the association of the serum AA (SAA) 1.3 allele with treatment. METHODS: CYC and etanercept (ETN) were administered to 62 and 24 RA patients, respectively, who were confirmed with biopsy as having AA amyloidosis. We evaluated whether the SAA1.3 allele, a factor indicating genetic risk and poor prognosis of Japanese RA patients with AA amyloidosis, influenced treatments and retrospectively analysed the effectiveness of both agents via statistical methods. RESULTS: Two treatment groups were similar, except for the SAA1.3 genotype (P = 0.015) and duration of AA amyloidosis since diagnosis (P < 0.001). Also, patients given ETN had somewhat worse renal function, i.e. 24-h proteinuria (P = 0.02), at the initiation of treatment. ETN demonstrated greater effectiveness than CYC, as shown by significantly improved levels of serum CRP and serum albumin (both P < 0.01) and estimated glomerular filtration rate (eGFR; P = 0.032). ETN improved survival (P = 0.025), and the hazard ratios for the risk of death endpoint with eGFR and 24-h proteinuria were significant by P = 0.024 and P = 0.025, respectively. The SAA1.3 allele did not affect the response to medications in AA amyloidosis secondary to RA. CONCLUSION: ETN treatment was more effective than CYC treatment, and CRP, albumin and eGFR may be valuable biomarkers for analysis. The SAA1.3 allele was not a factor affecting treatment in Japanese patients with AA amyloidosis secondary to RA.
21952978 Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimu 2012 Mar OBJECTIVE: To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs. METHODS: In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12. RESULTS: Treatment with tofacitinib at a dose of ≥3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P ≤ 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%). CONCLUSION: Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.
22179737 Epidemiology of eight common rheumatic diseases in China: a large-scale cross-sectional su 2012 Apr OBJECTIVE: To investigate the prevalence of eight common rheumatic diseases in a large Chinese population. METHODS: A population-based epidemiological investigation of the prevalence of eight common rheumatic diseases in a suburb of Beijing was conducted in 14 642 individuals. A community-based survey was carried out using a screening questionnaire. Positive responders were included in a clinical and laboratory examination. Diagnosis was based on the criteria of ACR or those used widely in literature. RESULTS: A total of 10 556 inhabitants were interviewed. Forty-three cases of RA were identified with an age-adjusted prevalence of 0.28% (95% CI 0.19%, 0.41%). Gout was diagnosed with a crude prevalence of 0.09% (95% CI 0.05%, 0.17%). Psoriasis was reported in 28 individuals with a prevalence of 0.27% (95% CI 0.18%, 0.38%). This included two cases diagnosed with PsA, resulting in a prevalence of 7.14% (95% CI 0.88%, 23.5%) in psoriasis patients and 0.02% (95% CI 0%, 0.07%) in the general population. Three individuals were identified with SLE, with a prevalence of 0.03% (95% CI 0%, 0.06%). One individual was identified with SSc and the calculated prevalence was 0.01% (95% CI 0%, 0.05%). One case of Behçet's disease was identified, giving a prevalence of 0.01% (95% CI 0%, 0.05%). CONCLUSION: This large-scale epidemiological survey provides an estimate of the burden of rheumatic diseases in China.
22679301 Induction therapy with a combination of DMARDs is better than methotrexate monotherapy: fi 2013 Jan OBJECTIVE: To determine the most effective induction disease-modifying antirheumatic drug (DMARD) strategy in early rheumatoid arthritis (RA), second to compare one single dose of intramuscular glucocorticoids (GCs) with daily oral GCs during the induction phase. METHODS: The 3-month data of a single-blinded clinical trial in patients with recent-onset arthritis (tREACH) were used. Patients were included who had a high probability (>70%) of progressing to persistent arthritis, based on the prediction model of Visser. Patients were randomised into three induction therapy strategies: (A) combination therapy (methotrexate (MTX) + sulfasalazine + hydroxychloroquine) with GCs intramuscularly; (B) combination therapy with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. A total of 281 patients were randomly assigned to strategy (A) (n=91), (B) (n=93) or (C) (n=97). RESULTS: The Disease Activity Score (DAS) after 3 months was lower in patients receiving initial combination therapy than in those receiving MTX monotherapy (0.39 (0.67 to 0.11, 95% CI)). DAS did not differ between the different GC bridging treatments. After 3 months 50% fewer biological agents were prescribed in the combination therapy groups. Although the proportion of patients with medication adjustments differed significantly between the treatment arms, no differences were seen in these adjustments due to adverse events after stratification for drug. CONCLUSION: Triple DMARD induction therapy is better than MTX monotherapy in early RA. Furthermore, no differences were seen in medication adjustments due to adverse events after stratification for drug. Intramuscular and oral GCs are equally effective as bridging treatments and both can be used.
21287227 Adalimumab (Humira™): a promising monoclonal anti-tumor necrosis factor alpha in ophthal 2011 Apr Tumor necrosis factor alpha (TNF-α) is a key soluble mediator involved in the inflammatory cascade of many disorders including uveitis. Among the anti-TNF-α agents, one of the most used in immune-mediated diseases, such as inflammatory arthropathies, is adalimumab (Humira™, Abbott Pharmaceutical Inc.), a fully humanized antibody. The purpose of this review is to analyze the main pharmacological and clinical aspects of adalimumab and its efficacy both in systemic and ocular inflammatory disorders. Adalimumab was effective in treating several autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. In recent years, adalimumab has been used successfully in refractory cases of intraocular inflammation. Moreover, this biological agent showed good safety and efficacy profiles in ocular use including childhood uveitis. Switching from other anti-TNF-α agents to adalimumab may offer several advantages, such as easier administration, better patient compliance, and lower rate of adverse events. Adalimumab is a promising drug for the therapy of uveitis, although further studies are needed on its application in uveitis.
23031374 Cutaneous leishmaniasis with histopathologic pattern of non-necrotizing granulomatous derm 2012 Sep 15 Human leishmaniasis produced by Leishmania infantum is endemic in Mediterranean countries. In the context of a leishmaniasis outbreak in the town of Fuenlabrada, Madrid, Spain, we had two patients with cutaneous leishmaniasis that developed non-necrotizing cutaneous granulomas. They had both been receiving anti-TNF treatment with adalimumab for rheumatic diseases. Neither of them developed visceral disease and did not require anti-TNF treatment withdrawal to control the cutaneous disease. It is well known that anti-TNF therapy is associated with opportunistic diseases, especially with those in which granuloma formation is an important part of the host defence, as in tuberculosis. We think that granuloma formation through activation of Toll-like receptor-9 and via induction of a Th17 response may be precipitated by the parasites in the dermis.
22153557 Survival of TNF-alpha antagonists in rheumatoid arthritis: a long-term study. 2012 Jan OBJECTIVES: To investigate the efficacy, safety and survival of tumour necrosis factor (TNF) α antagonists in patients with rheumatoid arthritis (RA). METHODS: One hundred and fifty-one RA patients treated with TNF-α inhibitors during the time period 2000 to 2009 were studied. Kaplan-Meier statistic analysis was applied, in which discontinuation from anti-TNF-α therapy was used as the terminal event. RESULTS: Eighty-two patients received infliximab, 49 adalimumab and 20 etanercept: they were followed up over 7, 5 and 4 years, respectively. Anti-TNF-α therapy resulted in a rapid clinical improvement associated with a reduction in inflammatory markers in the first year of the treatment, which was sustained throughout the following years. Ninety (59.6%) patients were withdrawn during the observational period overall. The patients who discontinued infliximab, adalimumab and etanercept therapy were 55/82 (67.1%), 27/49 (55.1%) and 8/20 (40%) respectively. The main reasons for discontinuation were drug adverse events and inefficacy. According to Kaplan-Meier methods, the 'survival rate' of infliximab after the first year of treatment reached 82.9%, while after 7 years the proportion was 32.9%. With regard to adalimumab, after the first year of treatment its 'survival rate' was 83.7% and after 5 years it reached 44.9%. As far as etanercept is concerned, after the first year of treatment, the 'survival rate' reached 70% and after 4 years it remained 60%. CONCLUSIONS: TNF-α antagonists constitute an effective therapeutic option for patients with RA refractory to disease-modifying anti-rheumatic drugs. They demonstrate an acceptable safety profile. Their survival rate is high in the first years of treatment, while after the fifth year it decreases considerably.
22527338 Factors associated with prolonged length of stay following a total knee replacement in pat 2012 Aug PURPOSE: The aim of this study was to examine factors associated with a prolonged length of stay (LOS) in patients over 75 undergoing a total knee replacement (TKR). METHODS: Patients over 75 undergoing a TKR at our institution from January 2008 to February 2009 were identified (n = 112). Patient and operative factors previously shown to affect length of stay were identified. Patient notes were reviewed for details on each of these and data analysed for their effect on length of stay. Discrete data were analysed for their effect on post-operative length of stay using either the Mann-Whitney U test or the Kruskall-Wallis test and continuous data analysed with the Spearman's rank correlation coefficient. RESULTS: The following factors were associated with length of stay at the 95 % confidence level: patient age, pre-operative mobility and the use of walking aids, BMI, whether the patient was able to mobilise within 24 or 48 hours of the surgery, the day on which the patient first walked ten metres and achieved 90° active knee flexion, pre and post-operative haemoglobin and the need for a blood transfusion. CONCLUSIONS: Pre-operative use of walking aids, peri-operative haemoglobin concentration, failure to mobilise early following the operation and post-operative complications (including the need for a blood transfusion) seem to be the significant factors associated with a prolonged stay in hospital in the over 75 year olds.
22367266 Characterization of effector memory CD8+ T cells in the synovial fluid of rheumatoid arthr 2012 Aug Little is known about the cellular characteristics of CD8(+) T cells in rheumatoid arthritis (RA). We addressed this by investigating whether the frequency of the CD8(+) T cell subsets and their phenotypic characteristics are altered in the peripheral blood and synovial fluid (SF) from patients with RA. In this study, CD8(+) T cells, mainly CD45RA(-) effector memory (EM) CD8(+) T cells, were increased significantly in the SF, but not in the peripheral blood from RA patients, compared with healthy controls. The synovial EM CD8(+) T cells were activated phenotypes with high levels of CD80, CD86, and PD-1, and had a proliferating signature in vivo upon Ki-67 staining, whereas the Fas-positive cells were prone to apoptosis. In addition, EM CD8(+) T cells in the SF were less cytotoxic, as they expressed less perforin and granzyme B. In particular, the proportions of synovial fluid mononuclear cells that were CCR4(+)CD8(+) T cells and IL-4-producing CD8(+) T cells (i.e., Tc2 cells) were significantly higher than those in peripheral blood mononuclear cells of patients with RA and healthy controls. In addition, the number of IL-10-producing CD8(+) suppressor T (Ts) cells increased significantly in the SF of RA patients. Especially, CD8(+) T cells were inversely correlated with disease activity. These findings strongly suggest that EM CD8(+) T cells in the SF are increased, likely because of inflammation, and they may be involved in modulating inflammation, thereby affecting the development and progression of RA.
21590794 Bayesian procedures for phase I/II clinical trials investigating the safety and efficacy o 2011 Jul 20 Many formal statistical procedures for phase I dose-finding studies have been proposed. Most concern a single novel agent available at a number of doses and administered to subjects participating in a single treatment period and returning a single binary indicator of toxicity. Such a structure is common when evaluating cytotoxic drugs for cancer. This paper concerns studies of combinations of two agents, both available at several doses. Subjects participate in one treatment period and provide two binary responses: one an indicator of benefit and the other of harm. The word 'benefit' is used loosely here: the response might be an early indicator of physiological change which, if induced in patients, is of potential therapeutic value. The context need not be oncology, but might be any study intended to meet both the phase I aim of establishing which doses are safe and the phase II goal of exploring potential therapeutic activity. A Bayesian approach is used based on an assumption of monotonicity in the relationship between the strength of the dose-combination and the distribution of the bivariate outcome. Special cases are described, and the procedure is evaluated using simulation. The parameters that define the model have immediate and simple interpretation. Graphical representations of the posterior opinions about model parameters are shown, and these can be used to inform the discussions of the trial safety committee.
23221326 Changes in bone mineral density during long-term treatment with adalimumab in patients wit 2013 Mar OBJECTIVE: To investigate the effect of long-term adalimumab treatment on BMD of the lumbar spine, total hip and hands in patients with RA. METHODS: In 184 established RA patients treated with adalimumab for at least 1 year, BMD measurements of the total hip and lumbar spine were performed using dual-energy X-ray absorptiometry. Metacarpal cortex BMD was measured using digital X-ray radiogrammetry. RESULTS: After 1 year of treatment, BMD of the hip and lumbar spine remained stable, while BMD of the hands decreased significantly by -1.41% (P < 0.0001). After a mean follow-up of 4.0 (s.d. 1.0) years, mean BMD change per year was -0.58% and 0.07% for the hip and lumbar spine, respectively (overall P-value of hip was <0.0001 and spine was 0.67). Predictors for BMD loss of the hip were anti-CCP positivity, non-use of bisphosphonates at baseline and BMI. In European League Against Rheumatism (EULAR) non-responders at 52 weeks, BMD change of the hip and spine was -1.25% and 1.08%, respectively, for moderate responders -0.61% and -1.87%, respectively, and in EULAR good responders, BMD remained stable: -0.02% and 0.06%, respectively. BMD of the hands decreased in non-, moderate and good responders (-2.85%, -1.47% and -1.26%, respectively). CONCLUSION: In patients with severe, established RA, loss of BMD in the spine was arrested over 4 years of adalimumab treatment, whereas BMD of the hands and hip continued to decrease after 1 and 4 years, respectively. The changes in BMD are related to disease activity, underlining the importance of monitoring disease activity.
22147207 Risk of lymphoma in patients receiving antitumor necrosis factor therapy: a meta-analysis 2012 Apr The 2008 edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid tissues recognizes a new diagnostic entity termed "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" highlighting lymphomas arising in patients treated with immunosuppressive agents for autoimmune disorders. The role of antitumor necrosis factor alpha therapy (anti-TNFα) and lymphoma risk in rheumatoid arthritis (RA) patients remains unclear; therefore, the goal of our study was to determine whether anti-TNFα therapy is associated with iatrogenic lymphomas. A meta-analysis of all randomized controlled clinical trials published (2000-2009) in RA patients receiving anti-TNFα therapy was performed. Fourteen studies fulfilled all search criteria and included 2,306 control patients and 5,179 patients treated with anti-TNFα therapy, namely etanercept, adalumimab, and infliximab. Clinical information including the number of patients, age, gender, lymphoma rates, and follow-up time was recorded. The overall rate and rate differences were analyzed using the DerSimonian and Laird method. Of the control group, four (4/2,306, 0.17%) patients developed hematolymphoid neoplasms. Eleven (11/5,179, 0.21%) patients receiving anti-TNFα therapy developed lymphomas. The adjusted overall rates are 0.36 lymphomas per 1,000 person-years in patients who did not receive anti-TNFα therapy versus 1.65 lymphomas per 1,000 person-years in patients who received anti-TNFα therapy. The corresponding 95% confidence interval for this rate difference is (-0.214, 2.79). The adjusted rate difference is 1.29 lymphomas per 1,000 person-years (95% CI, -0.21, 2.8; p value = 0.093). The corresponding p value is p = 0.0928. There is a suggestion of increased lymphomas in the treated group, with the predominant subset being B-cell lymphomas. Since the outcome of lymphoma is rare, it does not reach statistical significance of p < 0.05.
21234632 Sonographically guided hydrodissection and corticosteroid injection for scleroderma hand. 2011 Jun Scleroderma is associated with intractable hand pain from vasospasm, digital ischemia, tenosynovitis, and nerve entrapment. This study investigated the effect of hydrodissection of the carpal tunnel followed by corticosteroid injection for the painful scleroderma hand. Twenty-six consecutive subjects [12 with painful scleroderma hand and 14 with rheumatoid arthritis and carpal tunnel syndrome (RA/CTS)] underwent sonographically observed carpal tunnel hydrodissection with 3 ml of 1% lidocaine administered with a 25-gauge 1-in. needle on a 3-ml RPD mechanical syringe (reciprocating procedure device). After hydrodissection, a syringe exchange was performed, and 80 mg of triamcinolone acetonide was injected. Baseline pain, procedural pain, pain at outcome, responders, therapeutic duration, and reinjection interval were determined. Hydrodissection and injection with corticosteroid significantly reduced pain scores by 67% in scleroderma (p < 0.001) and by 47% in RA/CT (p < 0.001). Scleroderma and RA/CTS were similar in outcome measures: injection pain (p = 0.47), pain scores at outcome (p = 0.13), responders (scleroderma, 83.3%; RA/CTS, 57.1%, p = 0.15), pain at 6 months (p = 0.15), and therapeutic duration (p = 0.07). Scleroderma patients responded better in time to next injection (scleroderma, 8.5 ± 3.0 months; RA/CTS, 5.2 ± 3.1 months, p = 0.03). Reduced Raynaud's attacks and healing of digital ulcers occurred in 83% of subjects. There were no complications. Hydrodissection with lidocaine followed by injection of triamcinolone reduces pain and vasomotor changes in the scleroderma hand. The mechanism may be a combination of hydrodissection-mediated mechanical freeing of entrapped arteries, nerves, and tendinous structures and corticosteroid-induced reduction of inflammatory vasospasm.