Comparison of ASAS improvement criteria for ankylosing spondylitis with clinically relevant improvement according to an expert panel

Objective: To investigate whether the recently developed (statistically derived) "ASsessment in Ankylosing Spondylitis Working Group" improvement criteria (ASAS-IC) for ankylosing spondylitis (AS) reflect clinically relevant improvement according to the opinion of an expert panel. Methods: The ASAS-IC consist of four domains: physical function, spinal pain, patient global assessment, and inflammation. Scores on these four domains of 55 patients with AS, who had participated in a non-steroidal anti-inflammatory drug efficacy trial, were presented to an international expert panel (consisting of patients with AS and members of the ASAS Working Group) in a three round Delphi exercise. The number of (non-) responders according to the ASAS-IC was compared with the final-consensus of the experts. The most important domains in the opinion of the experts were identified, and also selected with discriminant analysis. A number of provisional criteria sets that best represented the consensus of the experts were defined. Using other datasets, these clinically derived criteria sets as well as the statistically derived ASAS-IC were then tested for discriminative properties and for agreement with the end of trial efficacy by patient and doctor. Results: Forty experts completed the three Delphi rounds. The experts considered twice as many patients to be responders than the ASAS-IC (42 v 21). Overall agreement between experts and ASAS-IC was 62%. Spinal pain was considered the most important domain by most experts and was also selected as such by discriminant analysis. Provisional criteria sets with an agreement of greater than or equal to 80% compared with the consensus of the experts showed high placebo response rates (27-42%), in contrast with the ASAS-IC with a predefined placebo response rate of 25%. All criteria sets and the ASAS-IC discriminated well between active and placebo treatment (chi(2) = 36-45; p < 0.001). Compared with the end of trial efficacy assessment, the provisional criteria sets showed an agreement of 71-82%, sensitivity of 67-83%, and specificity of 81-88%. The ASAS-IC showed an agreement of 70%, sensitivity of 62%, and specificity of 89%. Conclusion: The ASAS-IC are strict in defining response, are highly specific, and consequently show lower sensitivity than the clinically derived criteria sets. However, those patients who are considered as responders by applying the ASAS-IC are acknowledged as such by the expert panel as well as by. patients' and doctors' judgments, and are therefore likely to be true responders.

Systematic review and analysis of evidences on clinical efficacy and cost-effectiveness of biological drugs for the treatment of Ankylosing Spondylitis

Technology: Infliximab and comparator biological such as adalimumab, etanercept, golimumab. Conditions: Ankylosing spondylitis (AS) Issue: Infliximab is registered to be used in patients with AS. The aim of the Report is to evaluate the clinical efficacy and safety of infliximab and comparator biologicals for the treatment of adult AS. Methods: Systematic literature review and analysis as well as meta-analysis (direct and indirect comparison) of published randomised controlled clinical trials (RCT) were performed, all relevant health economics literature were identified ad analysed. Results: Clinical efficacy of biological therapies is based on good clinical evidences regarding to all clinical efficacy endpoints (ASAS20, ASAS40, ASAS 5/6, and BASDAI 50% response). Altogether, 22 trials are included in our meta-analysis, 12 infliximab, 3 adalimumab studies, 6 etanercept and 1 golimumab. Efficacy of biological treatments for the treatment of AS has been established by clinical scientific evidences, significant improvement at all outcomes considered was confirmed. According to the results of indirect comparison, there were no significant difference between biological treatments and placebo in terms of safety and tolerability endpoints. We found no significant difference between the clinical efficacy and safety of infliximab, adalimumab, etanercept and golimumab therapies. Cost-utility analysis of adalimumab and/or infliximab, etanercept and golimumab treatment for AS were performed in the UK, Canada, The Netherlands, Germany, Spain and France. There are no cost-utility studies from Eastern Central Europe. Implications for decision making: Efficacy of infliximab and comparator biologicals for the treatment of Ankylosing Spondylitis (AS) was proved by clinical evidence, significant improvement at all outcomes considered was confirmed. We found no significant differences in efficacy and safety of different biological treatments. Health economics results suggest that biological therapies are cost-effective alternatives for the treatment of AS in group of developed high income countries. There is a lack of health economics results in Central-Eastern European countries however these data are more and more required by governments and funders as part of the company economic dossiers.

Comparative efficacy and safety of biosimilar infliximab and other biological treatments in ankylosing spondylitis: systematic literature review and meta-analysis.

OBJECTIVES: To compare the efficacy and safety of infliximab-biosimilar with other biological drugs for the treatment of active ankylosing spondylitis (AS). METHODS: Systematic literature review for randomized controlled trials (RCTs) with adalimumab, etanercept, golimumab, infliximab and infliximab-biosimilar in AS was performed and indirect meta-analysis (Bayesian mixed treatment comparison) was carried out. The proportion of patients reaching 20 % improvement by the assessment of Spondyloarthritis International Society response criteria (ASAS20) at weeks 12 and 24 was used as efficacy endpoints, and the occurrence of serious adverse events at week 24 was applied to compare the safety of the biologicals. RESULTS: Altogether, 13 RCTs, identified by the systematic literature search, were included in the analysis. Results on the ASAS20 efficacy endpoint were reported for week 12 in 12 RCTs involving 2,395 patients, and for week 24 in 5 RCTs comprising 1,337 patients. All the five biological agents proved to be significantly superior to placebo. Infliximab showed the highest odds ratio (OR) of 7.2 (95 % CI 3.68-13.19) compared to placebo, followed by infliximab-biosimilar with OR 6.25 (95 % CI 2.55-13.14), both assessed at week 24. No significant difference was found between infliximab-biosimilar and other biological treatments regarding their efficacy and safety. CONCLUSIONS: This is the first study which includes a biosimilar drug in the meta-analysis of biological treatments in AS. The results have proven the similar efficacy and safety profile of infliximab-biosimilar treatment compared to other biologicals.

Differences in the prevalence of ankylosing spondylitis in primary and secondary care : only one-third of patients are managed in rheumatology

Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: G.T.J. and G.J.M. have received research funding from Pfizer and AbbVie. L.E.D. conducted the analysis while funded by an Medical Research Council PhD studentship

Spanish Rheumatology Society and Hospital Pharmacy Society Consensus on recommendations for biologics optimization in patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis

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. 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. 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. 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

Inhibitors of TACE and Caspase-1 as anti-inflammatory drugs

TNF-alpha neutralising agents such as Infliximab (Remicade(R)), Etanercept (Enbrel(R)) and the IL-1 receptor antagonist Anakinra (Kineret(R)), are currently used clinically for the treatment of many inflammatory diseases such as Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis and psoriasis. These protein preparations are expensive to manufacture and administer, need to be injected and can cause allergic reactions. An alternative approach to lowering the levels of TNF-alpha and IL-1 beta in inflammatory disease, is to inhibit the enzymes that generate these cytokines using cheaper small molecules. This paper is a broad overview of the progress that has been achieved so far, with respect to small molecule inhibitor design and pharmacological studies (in animals and humans), for the metalloprotease Tumour Necrosis Factor-alpha Converting Enzyme (TACE) and the cysteine protease Caspase-1 (Interieukin-1 beta Converting Enzyme, ICE). Inhibitors of these two enzymes are currently considered to be good therapeutic targets that have the potential to provide relatively inexpensive and orally bioavailable anti-inflammatory agents in the future.

Bacterial triggers and autoimmune rheumatic diseases

Autoimmune rheumatic diseases are generally considered as a multifactorial aetiology, mainly genetic susceptibility combined with environmental triggers of which bacteria are considered one of the most prominent. Among the rheumatic diseases where bacterial agents are more clearly involved as triggers are: reactive arthritis (ReA), rheumatic fever (RF) and Lyme disease. The role of bacterial infections in inducing other seronegative spondyloarthritis and antiphospholipid antibody syndrome has been hypothesized but is still not proven. The classic form of ReA is associated with the presence of HLA-B27 and is triggered by the urethritis or enteritis causing pathogens Chlamydia trachomatis and the enterobacteria Salmonella, Shigella, and Yersinia, respectively. But several other pathogens such as Brucella, Leptospira, Mycobacteria, Neisseria, Staphylococcus and Streptococcus have also been reported to cause ReA. RF is due to an autoimmune reaction triggered by an untreated throat infection by Streptococcus pyogenes in susceptible individuals. Carditis is the most serious manifestation of RF and HLA-DR7 is predominantly observed in the development of valvular lesions. Lyme disease is a tick-transmitted disease caused by the spirochete Borrelia burgdorferi. Knowledge is limited about how this spirochete interacts with human tissues and cells. Some data report that Borrelia burgdorferi can manipulate resident cells towards a pro- but also anti-inflammatory reaction and persist over a long period of time inside the human body or even inside human cells.

Metabolic syndrome in rheumatological diseases

Metabolic syndrome is characterized by a combination of various cardiovascular risk factors (age, gender, smoking, hypertension and dyslipidemia) that imply additional cardiovascular morbidity that is greater than the sum of the risks associated with each individual component. Herein, the authors review the rheumatological diseases in which metabolic syndrome has been studied: gout, osteoarthritis, systemic lupus erythematosus, rheumatoid arthritis, Sjogren`s syndrome and ankylosing spondylitis. The prevalence of metabolic syndrome in these disorders varies from 14% to 62.8%. The great majority of these studies demonstrated that this frequency was higher in rheumatological diseases than in the control populations, suggesting that either the presence or the treatment of those diseases seems to influence the risk of developing metabolic syndrome. (C) 2009 Elsevier B.V. All rights reserved.

Immunogenicity and safety of the 2009 non-adjuvanted influenza A/H1N1 vaccine in a large cohort of autoimmune rheumatic diseases

Background Despite the WHO recommendation that the 2010-2011 trivalent seasonal flu vaccine must contain A/California/7/2009/H1N1-like virus there is no consistent data regarding its immunogenicity and safety in a large autoimmune rheumatic disease (ARD) population. Methods 1668 ARD patients (systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic sclerosis, psoriatic arthritis (PsA), Behcet`s disease (BD), mixed connective tissue disease, primary antiphospholipid syndrome (PAPS), dermatomyositis (DM), primary Sjogren`s syndrome, Takayasu`s arteritis, polymyositis and Granulomatosis with polyangiitis (Wegener`s) (GPA)) and 234 healthy controls were vaccinated with a non-adjuvanted influenza A/California/7/2009(H1N1) virus-like strain flu. Subjects were evaluated before vaccination and 21 days post-vaccination. The percentage of seroprotection, seroconversion and the factor increase in geometric mean titre (GMT) were calculated. Results After immunisation, seroprotection rates (68.5% vs 82.9% p < 0.0001), seroconversion rates (63.4% vs 76.9%, p < 0.001) and the factor increase in GMT (8.9 vs 13.2 p < 0.0001) were significantly lower in ARD than controls. Analysis of specific diseases revealed that seroprotection significantly reduced in SLE (p < 0.0001), RA (p < 0.0001), PsA (p=0.0006), AS (p=0.04), BD (p=0.04) and DM (p=0.04) patients than controls. The seroconversion rates in SLE (p < 0.0001), RA (p < 0.0001) and PsA (p=0.0006) patients and the increase in GMTs in SLE (p < 0.0001), RA (p < 0.0001) and PsA (p < 0.0001) patients were also reduced compared with controls. Moderate and severe side effects were not reported. Conclusions The novel recognition of a diverse vaccine immunogenicity profile in distinct ARDs supports the notion that a booster dose may be recommended for diseases with suboptimal immune responses. This large study also settles the issue of vaccine safety. (ClinicalTrials.gov #NCT01151644)

Undifferentiated Spondyloarthritis: A Longterm Followup

Objective. To analyze the longterm followup of a series of Brazilian patients with undifferentiated spondyloarthritis (uSpA). Methods. Prospective study analyzing a group of 111 patients with the diagnosis of uSpA, fulfilling the European Spondylarthropathy Study Group and the Amor criteria, who were followed for 5 to 10 years in a single university referral center. Patients had their outcome analyzed at 5, 7, and 10 years. Results. There was a predominance of men (81.1%), white ethnicity (78.4%), and positive HLA-B27 (61.3%), with a mean age at onset of 27.2 years. Twenty-seven patients presented development to ankylosing spondylitis (AS; 24.3%) and 3 to psoriatic arthritis (PsA; 2.7%), while 25 patients (22.5%) went into remission during the followup. Univariate logistic regression analysis revealed that ethnicity, HLA-B27, buttock pain, inflammatory low back pain, ankle involvement, grade I sacroiliitis at the beginning of the study, and the use of sulfasalazine were statistically associated with progression to AS. Multivariate logistic regression analysis revealed that HLA-B27 (p = 0.035, OR 6.720.95% CI 11.45-39.43) and buttock pain (p = 0.009, OR 6.211, 95% CI 1.591-24.25) were statistically associated with progression to AS. Conclusion. In a longterm followup of 111 Brazilian patients with uSpA, HLA-B27 and buttock pain were significant predictors of progression to a definite disease. (First Release May 1 2010; J Rheumatol 2010;37:1195-9; doi:10.3899/jrheum.090625)

Frequency of HLA-B27 alleles in Brazilian patients with psoriatic arthritis

This prospective study analyzed the frequency of HLA-B27 and its alleles in 102 Brazilian patients with psoriatic arthritis (PsA). The association of the HLA-B27 alleles with these variants was compared to a control healthy HLA-B27 positive group of 111 individuals. There was a predominance of male gender (59.8%), Caucasian race (89.2%), and negative HLA-B27 (79.4%) patients. Asymmetric oligoarthritis (62.7%) was the most frequently observed clinical PsA subgroup, followed by spondylitis (16.7%), and polyarthritis (15.7%). Male gender and the spondylitis subgroup were statistically associated to the positive HLA-B27, and the oligoarthritis subgroup was associated to the negative HLA-B27. Among the 21 HLA-B27-positive PsA patients, there was a significant prevalence of the HLA-B*2705 allele (90.5%), similar to that observed in the control group (80.2%); HLA-B*2703 and HLA-B*2707 were statistically associated to the control group.

Frequency of HLA-B27 and its alleles in patients with Reiter syndrome: comparison with the frequency in other spondyloarthropathies and a healthy control population

This retrospective study analyzed the HLA-B*27 alleles in a group of 20 consecutive patients with the diagnosis of Reiter syndrome (RS) followed in a tertiary referral university hospital in Brazil, during the period 1990-2006, and compared the data with that observed in other patients with spondyloarthropathies followed at the same institution. Eight cases were associated to gastrointestinal infection, eight cases to previous urethritis, and four cases presented no established preceding infection. HLA-B*27 alleles were typed by polymerase chain reaction-amplified DNA hybridized with sequence-specific oligonucleotide probes (HLA-B*2701 to HLA-B*2721). They were compared to a group of 108 patients with ankylosing spondylitis (AS), 40 with undifferentiated spondyloarthropathy (uSpA) and 111 healthy controls. Among the 20 patients, 17 were HLA-B*27 positive (85%). Two HLA-B*27 alleles were observed: HLA-B*2705 (65%) and HLA-B*2702 (35%). In the other spondyloarthropathies, the observed alleles were HLA-B*2705 (90% in AS and 92.5% in uSpA), HLA-B*2702 (8% in AS and 5% in uSpA), HLA-B*2704 (1% in AS and 2.5% in uSpA) and HLA-B*2713 (1% in AS). Among the 111 healthy controls, 80% presented HLA-B*2705, followed by HLA-B*2702 in 10%, HLA-B*2703 in 6%, HLA-B*2707 in 3% and HLA-B*2713 in 1%. Concluding, in the HLA-B*27 positive patients with RS in this study there was predominance of HLA-B*2705 allele, in a lower frequency than that observed in patients with other spondyloarthropathies and healthy controls.

Epidemiology of Spondyloarthritis in Brazil

During the period of 2006 to 2007, 28 university centers in Brazil used a standardized protocol of investigation to study the epidemiological, clinical and radiological variables of 1036 consecutive patients with the diagnosis of spondyloarthritis (SpA). Validated translated (Portuguese) versions of the Bath Ankylosing Spondylitis (AS) Disease Activity Index and the Bath AS Functional Index were applied. Patient diagnoses were predominantly AS (72.3%), followed by psoriatic arthritis (13.7%), undifferentiated SpA (6.3%), reactive arthritis (3.6%), juvenile SpA (3.1%) and arthritis related to inflammatory bowel disease (1.0%). There was a predominance of male (73.6%) and white (59.5%) patients. Pure axial disease was observed in 36.7% of the patients, whereas the mixed pattern (axial, peripheral and entheseal) was observed in 47.9%. The most common extra-articular involvement was anterior uveitis (20.2%). HLA-B27 was positive in 69.5% of the tested patients.

GLOBAL POSTURAL REEDUCATION AND STATIC STRETCHING EXERCISES IN THE TREATMENT OF MYOGENIC TEMPOROMANDIBULAR DISORDERS: A RANDOMIZED STUDY

Objective: The purpose of this study was to compare 2 different interventions, global postural reeducation (GPR) and static stretching exercises (SS), in the treatment of women with temporomandibular disorders (TMDs). Methods: A total of 28 subjects with TMDs were randomized into 2 treatment groups: GPR, where therapy involved muscle global chain stretching, or SS, with conventional static stretching; but only 24 completed the study. Eight treatment sessions lasting 40 minutes each (weekly) were performed. Assessments were conducted at baseline, immediately after treatment end, and 2 months later. Measurements included pain intensity at the temporomandibular joint, headache, cervicalgia, teeth clenching, ear symptoms, restricted sleep, and difficulties for mastication, using a visual analogue scale. In addition, electromyographic activity and pain thresholds were measured at the masseter, anterior temporalis, stemocleidomastoid, and upper trapezius muscles. Two-way analysis of variance with Tukey post hoc test was used for between-group comparisons. Significance level was .05. Results: Comparing the pain assessments using the visual analogue scale, no significant differences were seen with the exception of severity of headaches at treatment end (GPR, 3.92 +/- 2.98 cm; SS, 1.64 +/- 1.66 cm; P < .024). In addition, no significant differences were seen for pain thresholds and for electromyographic activity (P > .05). Conclusions: For the subjects in this study, both GPR and SS were similarly effective for the treatment of TMDs with muscular component. They equally reduced pain intensity, increased pain thresholds, and decreased electromyographic activity. (J Manipulative Physiol Ther 2010;33:500-507)