Tofacitinib in Patients With Psoriatic Arthritis and Metabolic Syndrome: A Post hoc Analysis of Phase 3 Studies

Objective: Metabolic syndrome (MetS) is a cluster of concurrent risk factors for cardiovascular disease and type 2 diabetes. This post hoc analysis explored key efficacy and safety endpoints in patients with psoriatic arthritis (PsA) and MetS treated with tofacitinib. Methods: Tofacitinib 5 and 10 mg twice daily and placebo data were pooled from two Phase 3 studies (OPAL Broaden [12 months; ClinicalTrials.gov identifier NCT01877668]; OPAL Beyond [6 months; ClinicalTrials.gov identifier NCT01882439]); patients received one background conventional synthetic disease‐modifying antirheumatic drug. Patients were stratified by baseline presence/absence of MetS. Efficacy and safety were reported to month 3 (tofacitinib and placebo) and 6 (tofacitinib only). Efficacy outcomes included: American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire‐Disability Index (HAQ‐DI) response, Psoriasis Area Severity Index (PASI)75 response, and enthesitis/dactylitis resolution rates; and changes from baseline (Δ) in C‐reactive protein, HAQ‐DI, Patient’s/Physician’s Global Assessment of Arthritis, and patient‐reported outcomes. Safety outcomes included treatment‐emergent all‐causality adverse events (AEs), Δ in lipid/hepatic values, and liver parameter increases. Results: Of 710 patients, 41.4% (n = 294) had baseline MetS. All efficacy outcomes improved with both tofacitinib doses versus placebo, to month 3; tofacitinib efficacy was consistent to month 6, regardless of MetS status. MetS did not appear to affect the incidence of AEs or Δ in lipid/hepatic values with tofacitinib up to month 3 or 6. Arterial thromboembolism and myocardial infarction (adjudicated major adverse cardiovascular events) were each reported once in tofacitinib‐treated patients with MetS. Conclusion: Regardless of baseline MetS status, tofacitinib showed greater efficacy versus placebo in patients with active PsA. The tofacitinib safety profile appeared similar in patients with versus without MetS

Bilateral dilation of the urinary tract due to iliopsoas pyomyositis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pyomyositis is an acute bacterial infection of the skeletal muscles that arises from hematogenous spread and is caused predominantly by Gram-positive cocci.</p> <p>Case presentation</p> <p>We report a case of iliopsoas pyomyositis in a 25-year-old Greek Caucasian woman with a history of intravenous drug use. Her condition was complicated by bilateral dilation of the ureters and renal calyces as a result of mechanical pressure from inflammation and edema of the involved muscle. The patient did not present aggravation of renal function and was treated successfully solely with intravenous antibiotics, without surgical intervention. This is the first case report describing iliopsoas pyomyositis with reversible bilateral dilation of the urinary tract that was treated successfully with intravenous antibiotics, without surgical intervention.</p> <p>Conclusion</p> <p>We present the first described case of iliopsoas pyomyositis with reversible bilateral hydroureteronephrosis that was treated successfully with intravenous antibiotics, without the necessity of surgical intervention. To our knowledge, this is the first report of its kind in the literature regarding an unexpected event in the course of treating a patient with iliopsoas pyomyositis, and it should be of particular interest to different clinical medical specialties such as internal medicine, infectious disease and urology.</p

Kahler Moduli Inflation Revisited

We perform a detailed numerical analysis of inflationary solutions in Kahler moduli of type IIB flux compactifications. We show that there are inflationary solutions even when all the fields play an important role in the overall shape of the scalar potential. Moreover, there exists a direction of attraction for the inflationary trajectories that correspond to the constant volume direction. This basin of attraction enables the system to have an island of stability in the set of initial conditions. We provide explicit examples of these trajectories, compute the corresponding tilt of the density perturbations power spectrum and show that they provide a robust prediction of n_s approximately 0.96 for 60 e-folds of inflation.Comment: 27 pages, 9 figure

Clinical presentation, demographics and outcome of Tuberculosis (TB) in a low incidence area: a 4-year study in Geneva, Switzerland

<p>Abstract</p> <p>Background</p> <p>The incidence of tuberculosis (TB) in developed countries has decreased since the 1990s, reflecting worldwide efforts to identify and treat TB according to WHO recommendations. However TB remains an important public health problem in industrialized countries with a high proportion of cases occurring among subjects originating from high prevalence countries. The aim of this study was to describe clinical and social characteristics of patients with TB and their outcome in a low incidence area with a high immigration rate.</p> <p>Methods</p> <p>Four-year retrospective study based on a computerized database and subsequent review of medical records of all patients with TB followed at the outpatient section of the Division of Pulmonary Diseases, Geneva University Hospital, Switzerland.</p> <p>Results</p> <p>252 patients (84% foreigners, 25% asylum seekers) aged 38 ± 19 yrs were studied (11% co-infected with HIV). TB was intrapulmonary (TBP) in 158 cases (63%), extrapulmonary (TBE) in 137 (54%), and both in 43 cases (17%). TBP was smear (S)+/culture (C)+ in 59%, S-/C+ in 37%, S-/C- in 4%. Smoking was significantly associated with cavitary disease.</p> <p>Time from onset of symptoms to diagnosis was 2.1 ± 3.1 months. Initially, 10% were asymptomatic; 35% had no general symptoms. Despite systematic sputum analysis (induced or spontaneous), TBP was confirmed only by bronchoscopy in 38 subjects (24% of TBP). Side effects requiring changes in treatment occurred in 38 cases (11%).</p> <p>Treatment was completed in 210 (83%) patients. In 42 cases, follow up was unsuccessful; causes were: failure (n = 2; 0.8%), defaulters (n = 8; 3%), transfer out (n = 28; 11%) and death (n = 4; 1.6%). Relapse rate was 0.24 per 100 patient-years. Considering S+ TBP only, success rate was 87%.</p> <p>Conclusion</p> <p>TB in our area is predominantly a disease of young foreign-born subjects. Smoking appears as a possible risk factor for cavitary TBP. Time to diagnosis remains long. Compliance to treatment is satisfactory. Success rate for S+ TBP is within WHO objectives.</p

An open-label pilot study of the effectiveness of adalimumab in patients with rheumatoid arthritis and previous infliximab treatment: relationship to reasons for failure and anti-infliximab antibody status

This prospective open-label pilot study evaluated the effectiveness and safety of adalimumab and the relationship to antibodies against infliximab (IFX) in adult patients with active rheumatoid arthritis (RA) who had been treated previously with IFX and experienced treatment failure owing to lack or loss of response or intolerance. Patients self-administered adalimumab 40 mg subcutaneously every other week for 16 weeks, followed by maintenance therapy for up to Week 56. Measures of effectiveness included American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria, 28-joint Disease Activity Score, and the Health Assessment Questionnaire Disability Index. Serum IFX concentrations, human antichimeric antibody against IFX (HACA), adalimumab serum concentrations, antiadalimumab antibody, and safety also were assessed. Of the 41 enrolled patients, 37 completed 16 weeks and 30 completed 56 weeks of treatment. Patients experienced clinically meaningful improvements in all measures of RA activity, with greater response rates observed for patients who had experienced loss of initial response to or intolerance of IFX. At Week 16, 46% of patients achieved an ACR20 and 28% achieved an ACR50; 61% achieved an at least moderate and 17% achieved a good EULAR response. Clinical benefit was maintained through Week 56 in all effectiveness parameters. Baseline HACA status did not significantly impact effectiveness. No new safety signals were observed; neither former IFX intolerance status nor baseline HACA status had a clinically relevant impact on adverse event frequency or severity. Adalimumab was effective and well-tolerated in patients with RA who previously failed IFX therapy, irrespective of reason for discontinuation and of HACA status

Lack of association between the chemokine receptor 5 polymorphism CCR5delta32 in rheumatoid arthritis and juvenile idiopathic arthritis

<p>Abstract</p> <p>Background</p> <p>The chemokine receptor CCR5 has been detected at elevated levels on synovial T cells, and a 32 bp deletion in the <it>CCR5 </it>gene leads to a non-functional receptor. A negative association between the <it>CCR5Δ32 </it>and rheumatoid arthritis (RA) has been reported, although with conflicting results. In juvenile idiopathic arthritis (JIA), an association with CCR5 was recently reported. The purpose of this study was to investigate if the <it>CCR5Δ32 </it>polymorphism is associated with RA or JIA in Norwegian cohorts.</p> <p>Methods</p> <p>853 RA patients, 524 JIA patients and 658 controls were genotyped for the <it>CCR5Δ32 </it>polymorphism.</p> <p>Results</p> <p>The <it>CCR5Δ32 </it>allele frequency was 11.5% in the controls vs. 10.4% in RA patients (OR = 0.90; <it>P </it>= 0.36) and 9.7% in JIA patients (OR = 0.85; <it>P </it>= 0.20). No decreased homozygosity was observed for <it>CCR5Δ32</it>, as previously suggested.</p> <p>Conclusion</p> <p>Our data do not support an association between the <it>CCR5Δ32 </it>allele and Norwegian RA or JIA patients. Combining our results with those from a recently published meta-analysis still provide evidence for a role for <it>CCR5Δ32 </it>in RA, albeit substantially weaker than the effect first reported.</p

DAS-28-based EULAR response and HAQ improvement in rheumatoid arthritis patients switching between TNF antagonists

<p>Abstract</p> <p>Introduction</p> <p>No definitive data are available regarding the value of switching to an alternative TNF antagonist in rheumatoid arthritis patients who fail to respond to the first one. The aim of this study was to evaluate treatment response in a clinical setting based on HAQ improvement and EULAR response criteria in RA patients who were switched to a second or a third TNF antagonist due to failure with the first one.</p> <p>Methods</p> <p>This was an observational, prospective study of a cohort of 417 RA patients treated with TNF antagonists in three university hospitals in Spain between January 1999 and December 2005. A database was created at the participating centres, with well-defined operational instructions. The main outcome variables were analyzed using parametric or non-parametric tests depending on the level of measurement and distribution of each variable.</p> <p>Results</p> <p>Mean (± SD) DAS-28 on starting the first, second and third TNF antagonist was 5.9 (± 2.0), 5.1 (± 1.5) and 6.1 (± 1.1). At the end of follow-up, it decreased to 3.3 (± 1.6; Δ = -2.6; p > 0.0001), 4.2 (± 1.5; Δ = -1.1; p = 0.0001) and 5.4 (± 1.7; Δ = -0.7; p = 0.06). For the first TNF antagonist, DAS-28-based EULAR response level was good in 42% and moderate in 33% of patients. The second TNF antagonist yielded a good response in 20% and no response in 53% of patients, while the third one yielded a good response in 28% and no response in 72%. Mean baseline HAQ on starting the first, second and third TNF antagonist was 1.61, 1.52 and 1.87, respectively. At the end of follow-up, it decreased to 1.12 (Δ = -0.49; p < 0.0001), 1.31 (Δ = -0.21, p = 0.004) and 1.75 (Δ = -0.12; p = 0.1), respectively. Sixty four percent of patients had a clinically important improvement in HAQ (defined as ≥ -0.22) with the first TNF antagonist and 46% with the second.</p> <p>Conclusion</p> <p>A clinically significant effect size was seen in less than half of RA patients cycling to a second TNF antagonist.</p

Genetic polymorphisms in TNF genes and tuberculosis in North Indians

<p>Abstract</p> <p>Background</p> <p>Pulmonary tuberculosis, the most common clinical form of mycobacterial diseases, is a granulomatous disease of the lungs caused by <it>Mycobaterium tuberculosis</it>. A number of genes have been identified in studies of diverse origins to be important in tuberculosis. Of these, both tumor necrosis factor α (TNF-α) and lymphotoxin α (LT-α) play important immunoregulatory roles.</p> <p>Methods</p> <p>To investigate the association of <it>TNF </it>polymorphisms with tuberculosis in the Asian Indians, we genotyped five potentially functional promoter polymorphisms in the <it>TNFA </it>gene and a <it>LTA_NcoI </it>polymorphism (+252 position) of the <it>LTA </it>gene in a clinically well-defined cohort of North-Indian patients with tuberculosis (N = 185) and their regional controls (N = 155). Serum TNF-α (sTNF-α) levels were measured and correlated with genotypes and haplotypes.</p> <p>Results</p> <p>The comparison of the allele frequencies for the various loci investigated revealed no significant differences between the tuberculosis patients and controls. Also, when the patients were sub-grouped into minimal, moderately advanced and far advanced disease on the basis of chest radiographs, TST and the presence/absence of cavitary lesions, none of the polymorphisms showed a significant association with any of the patient sub-groups. Although a significant difference was observed in the serum TNF-α levels in the patients and the controls, none of the investigated polymorphisms were found to affect the sTNF-α levels. Interestingly, it was observed that patients with minimal severity were associated with lower log sTNF-α levels when compared to the patients with moderately advanced and far advanced severity. However, none of these differences were found to be statistically significant. Furthermore, when haplotypes were analyzed, no significant difference was observed.</p> <p>Conclusions</p> <p>Thus, our findings exclude the <it>TNF </it>genes as major risk factor for tuberculosis in the North Indians.</p

A comparison of an interferon-gamma release assay and tuberculin skin test in refractory inflammatory disease patients screened for latent tuberculosis prior to the initiation of a first tumor necrosis factor α inhibitor

Treatment with TNFα inhibitors increases risk of reactivating a latent tuberculosis\infection (LTBI). Therefore screening, prior to therapy with TNFα inhibitors, has been recommended, even in low-endemic areas such as well-developed Western Europe countries. We evaluated interferon-gamma release assay (IGRA), as opposed to tuberculin skin test (TST), for detection of LTBI in refractory inflammatory disease patients prior to the initiation of a first TNFα inhibitor. In addition, we evaluated the impact of impaired cellular immunity on IGRA. Patients starting on TNFα inhibition were screened for LTBI by TST and IGRA (Quantiferon-TB Gold). Data on tuberculosis exposure and Bacillus Calmette–Guérin (BCG) vaccination were obtained. Cellular immunity was assessed by CD4+ T lymphocyte cell count. Nine out of 56 patients (16.1%) tested positive for LTBI. A concordant positive result was present in three patients with a medical history of tuberculosis exposure. Six patients with discordant test results had either: (1) a negative TST and positive IGRA in combination with a medical history of tuberculosis exposure (n = 1) or (2) a positive TST and negative IGRA in combination with BCG vaccination (n = 3) or a medical history of tuberculosis exposure (n = 2). CD4+ T lymphocyte cell counts were within normal limits, and no indeterminate results of IGRA were present. IGRA appears reliable for confirming TST and excluding a false positive TST (due to prior BCG vaccination) in this Dutch serie of patients. In addition, IGRA may detect one additional case of LTBI out of 56 patients that would otherwise be missed using solely TST. Immune suppression appears not to result significantly in lower CD4+ T lymphocyte cell counts and indeterminate results of IGRA, despite systemic corticosteroid treatment in half of the patients. Confirmation in larger studies, including assessment of cost-effectiveness, is required