Summary The term axial spondyloarthritis covers both patients with non-radiographic and radiographic axial spondyloarthritis, which is also termed ankylosing spondylitis. The disease usually starts ...in the third decade of life with a male to female ratio of two to one for radiographic axial spondyloarthritis and of one to one for non-radiographic axial spondyloarthritis. More than 90% heritabilty has been estimated, the highest genetic association being with HLA-B27. The pathogenic role of HLA-B27 is still not clear although various hypotheses are available. On the basis of evidence from trials the cytokines tumour necrosis factor (TNF)-α and interleukin-17 appear to have a relevant role in pathogenesis. The mechanisms of interaction between inflammation and new bone formation is still not completely understood but clarification will be important for the prevention of long-term structural damage of the bone. The development of new criteria for classification and for screening of patients with axial spondyloarthritis have been crucial for the early indentification and treatment of such patients, with MRI being the most important existing imaging method. Non-steroidal anti-inflammatory drugs and TNF blockers are effective therapies. Blockade of interleukin-17 is a new and relevant treatment option.
Summary Ankylosing spondylitis is a common inflammatory rheumatic disease that affects the axial skeleton, causing characteristic inflammatory back pain, which can lead to structural and functional ...impairments and a decrease in quality of life. New imaging techniques and therapies have substantially changed the management of this disease in the past decade. Whether inhibition of radiographic progression and structural damage can be reached with available drugs is as yet unclear. Furthermore, treatment with non-steroidal anti-inflammatory agents and physiotherapy remains an important approach to long-term management of patients with ankylosing spondylitis. The new treatment options with tumour necrosis factor blockers seems a breakthrough for patients refractory to conventional treatment.
The cytokines IL-23 and IL-17 have an important role in the pathogenesis of, and as a therapeutic target in, both animal models of chronic inflammation and some human chronic inflammatory diseases. ...The traditional view is that a main source of IL-17 is T cells and that IL-17 production is under the control of IL-23. IL-17 inhibition has shown good efficacy in clinical trials for ankylosing spondylitis (AS), a subtype of axial spondyloarthritis (axSpA) characterized by radiographic evidence of sacroiliitis. On the basis of data from animal models, genetic studies and the investigation of tissue and blood samples from patients with AS, IL-23 had also been predicted to be important in the pathogenesis of this disease and was therefore considered a potential therapeutic target for axSpA. However, two placebo-controlled, double-blind clinical trials in axSpA of monoclonal antibodies directed against either the p40 protein or the p19 protein of the IL-23 molecule had clear negative results. These findings indicate that IL-23 and IL-17 are at least partly uncoupled in axSpA. Reasons as to why, when and how such an uncoupling might occur are discussed in this Review, with special reference to the unique microenvironment of the subchondral bone marrow in axSpA.
Secukinumab is an anti-interleukin-17A monoclonal antibody that has been shown to control the symptoms of ankylosing spondylitis in a phase 2 trial. We conducted two phase 3 trials of secukinumab in ...patients with active ankylosing spondylitis.
In two double-blind trials, we randomly assigned patients to receive secukinumab or placebo. In MEASURE 1, a total of 371 patients received intravenous secukinumab (10 mg per kilogram of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8. In MEASURE 2, a total of 219 patients received subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline; at weeks 1, 2, and 3; and every 4 weeks starting at week 4. At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg. The primary end point was the proportion of patients with at least 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16.
In MEASURE 1, the ASAS20 response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for both comparisons with placebo); in MEASURE 2, the rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for the 150-mg dose and P=0.10 for the 75-mg dose). The significant improvements were sustained through 52 weeks. Infections, including candidiasis, were more common with secukinumab than with placebo during the placebo-controlled period of MEASURE 1. During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn's disease were 0.7, 0.9, and 0.7 cases per 100 patient-years, respectively, in secukinumab-treated patients.
Secukinumab at a subcutaneous dose of 150 mg, with either subcutaneous or intravenous loading, provided significant reductions in the signs and symptoms of ankylosing spondylitis at week 16. Secukinumab at a subcutaneous dose of 75 mg resulted in significant improvement only with a higher intravenous loading dose. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT01358175 and NCT01649375.).
The human lymphocyte antigen B27 (HLA B27) is a member of the HLA class I family of genes in the major histocompatibility complex whose name goes back to its discovery in studies of transplanted ...tissue compatibility. Its prevalence in the mid-European population is about 8%. The association of HLA B27 alleles with ankylosing spondylitis (AS), a highly heritable disease, which is part of the spectrum of axial spondyloarthritis (axSpA), was discovered 50 years ago. HLA B27 explains less than 30% of the total genetic load. About 60%–90% of axSpA patients worldwide carry HLA B27. The prevalence of the disease is linked to the frequency of HLA B27 in the population which implies that there are relevant differences. Among the roughly 200 subtypes known there are two which are not disease associated. The function of HLA class I molecules is to present peptides to the immune system to defend the organism against microbes targeted by CD8+T cells. This is much supported by the role of the endoplasmic reticulum aminopeptidase 1 (ERAP 1) in AS, an enzyme that is responsible for the intracellular trimming of peptides, since polymorphisms of this gene are only associated with HLA-B27+ disease. The arthritogenic peptide hypothesis trying to explain the pathogenesis of AS is based on that very immune function assuming that also self peptides can be presented. HLA-B27 also plays an important role in classification, diagnosis and severitiy of axSpA.
Functional status and spinal mobility in patients with axial spondyloarthritis (axSpA) are known to be determined both by disease activity and by structural damage in the spine. The impact of ...structural damage in the sacroiliac joints (SIJ) on physical function and spinal mobility in axSpA has not been studied so far. The objective of the study was to analyze the impact of radiographic sacroiliitis on functional status and spinal mobility in patients with axSpA.
In total, 210 patients with axSpA were included in the analysis. Radiographs of SIJ obtained at baseline and after 2 years of follow up were scored by two trained readers according to the modified New York criteria grading system (grade 0-4). The mean of two readers' scores for each joint and a sum score for both SIJ were calculated for each patient giving a sacroiliitis sum score between 0 and 8. The Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI) at baseline and after 2 years were used as outcome measures.
Longitudinal mixed model analysis adjusted for structural damage in the spine (modified Stoke Ankylosing Spondylitis Spine Score - mSASSS), disease activity (Bath Ankylosing Spondylitis Disease Activity Index - BASDAI and C-reactive protein level) and gender, revealed an independent association of the sacroiliitis sum score with the BASFI: b = 0.10 (95% CI 0.01-0.19) and the BASMI: b = 0.12 (95% CI 0.03-0.21), respectively, indicating that change by one radiographic sacroiliitis grade in one joint is associated with BASFI/BASMI worsening by 0.10/0.12 points, respectively, independently of disease activity and structural damage in the spine.
Structural damage in the SIJ might have an impact on functional status and spinal mobility in axSpA independently of spinal structural damage and disease activity.
ClinicalTrials.gov, NCT01277419 . Registered on 14 January 2011.
The burden of non-radiographic axial spondyloarthritis Boonen, Annelies, MD, PhD; Sieper, Joachim, MD, PhD; van der Heijde, Désirée, MD, PhD ...
Seminars in arthritis and rheumatism,
04/2015, Volume:
44, Issue:
5
Journal Article
Peer reviewed
Abstract Objectives To identify patients earlier, new classification criteria have been introduced for axial spondyloarthritis (axSpA). Patients who satisfy the clinical or imaging criteria for axSpA ...in the absence of definite sacroiliac joint changes on pelvic x-rays are classified as having non-radiographic axSpA. Although the burden associated with radiographic axSpA (i.e., ankylosing spondylitis) has been extensively studied, the impact of non-radiographic disease is not well understood. The purpose of this review is to provide an overview of the burden of illness in non-radiographic axSpA, including epidemiology and effects on patients׳ functioning and health-related quality of life (HR-QoL). Methods A PubMed search was performed using relevant key words (e.g., “spondyloarthritis,” “ankylosing spondylitis,” “epidemiology,” and “quality of life”) to examine literature published from 2003 to 2013. Results Studies conducted to date suggest that radiographic progression is detected in approximately 10% of patients with non-radiographic axSpA over 2 years. Differences between patients with non-radiographic and radiographic axSpA were found in age, symptom duration, and gender distribution. Although less inflammation (i.e., lower C-reactive protein levels and less spinal inflammation on MRI) and less impairment in spinal mobility are observed in non-radiographic than in radiographic axSpA, the 2 conditions pose a similar burden in terms of disease activity, physical function, HR-QoL impairment. Conclusions Patients with non-radiographic axSpA are more frequently female. Although patients with non-radiographic axSpA have shorter disease duration and lack radiological changes, they demonstrate a substantial burden of illness, with self-reported disease activity and functional impairments comparable to those found in patients with radiographic disease.
To detail the greatest areas of unmet scientific and clinical needs in rheumatology.
The 21st annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic ...scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. During the meeting, breakout sessions were convened, consisting of 5 disease-specific groups with 20-30 experts assigned to each group based on expertise. Specific groups included: rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and other systemic autoimmune rheumatic diseases. In each group, experts were asked to identify unmet clinical and translational research needs in general and then to prioritise and detail the most important specific needs within each disease area.
Overarching themes across all disease states included the need to innovate clinical trial design with emphasis on studying patients with refractory disease, the development of trials that take into account disease endotypes and patients with overlapping inflammatory diseases, the need to better understand the prevalence and incidence of inflammatory diseases in developing regions of the world and ultimately to develop therapies that can cure inflammatory autoimmune diseases.
Unmet needs for new therapies and trial designs, particularly for those with treatment refractory disease, remain a top priority in rheumatology.
Objective
To assess the efficacy of etanercept in the treatment of early active nonsteroidal antiinflammatory drug (NSAID)–refractory nonradiographic axial spondyloarthritis (SpA).
Methods
The study ...population consisted of patients who met the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA but not the modified New York radiographic criteria for ankylosing spondylitis (as assessed by a radiologist at the central trial site), had a symptom duration of >3 months but <5 years, had a score of ≥4 on the Bath Ankylosing Spondylitis Disease Activity Index, and had been treated unsuccessfully with ≥2 NSAIDs. Patients were randomized to receive etanercept 50 mg/week or placebo and continued background NSAID treatment for 12 weeks (double‐blind study); during the subsequent open‐label period, all patients received etanercept 50 mg/week. The primary study end point was meeting the ASAS criteria for 40% improvement (ASAS40) at week 12. Magnetic resonance imaging (MRI) of the sacroiliac joints and spine was performed at baseline and week 12.
Results
One hundred six patients were randomized to the etanercept group and 109 to the placebo group. Of the 215 patients, the mean ± SD age at baseline was 32.0 ± 7.8 years, 154 (72%) were HLA–B27 positive, and 174 (81%) had MRI‐confirmed sacroiliitis. At 12 weeks, the proportion of patients with improvement according to the ASAS40 was significantly higher in the etanercept group than in the placebo group (34 of 105 32% versus 17 of 108 16%; P = 0.006). Patients who received etanercept exhibited a greater reduction in MRI‐based scores for sacroiliac joint inflammation (−46.9% versus −10.9%; P < 0.001) and spinal inflammation (−45.4% versus −33.4%; P = 0.04) compared with placebo‐treated patients at week 12. Post hoc analyses suggested a possible association between higher baseline C‐reactive protein levels or MRI sacroiliac joint inflammation scores and higher rates of ASAS40 response to etanercept. At week 24, patients in the placebo group who had switched to etanercept at 12 weeks exhibited improvement similar to that observed in patients who had received etanercept for 24 weeks.
Conclusion
In patients with nonradiographic axial SpA, etanercept treatment was associated with rapid, significant improvement in symptomatic disease activity, function, and systemic and skeletal inflammation over 12 weeks; clinical/functional improvement was sustained over 24 weeks.
Previous research indicates a role of adipokines in inflammation and osteogenesis. Hence adipokines might also have a pathophysiological role in inflammation and new bone formation in patients with ...ankylosing spondylitis (AS). The aim of this study was to investigate the role of adipokine serum levels as predictors of radiographic spinal progression in patients with AS.
A total of 120 patients with definite AS who completed a 2-year follow up in the ENRADAS trial were included in the current study. Radiographic spinal progression was defined as: (1) worsening of the modified Stoke Ankylosing Spondylitis spine (mSASSS) score by ≥2 points and/or (2) new syndesmophyte formation or progression of existing syndesmophytes after 2 years. Serum levels of adipokines (adiponectin (APN) and its high molecular weight form (HMW-APN), chemerin, leptin, lipocalin-2, omentin, resistin, visfatin) were measured using enzyme-linked immunosorbent assays.
There was a significant association between radiographic spinal progression and both leptin and HMW-APN. Baseline serum levels of both adipokines were lower in patients who showed radiographic spinal progression after 2 years. This association was especially evident in men; they had generally lower leptin and HMW-APN serum levels as compared to women. The inverse association between adipokines and radiographic spinal progression was confirmed in the logistic regression analysis: the odds ratios (OR) for the outcome "no mSASSS progression ≥2 points" were 1.16 (95% CI 1.03 to 1.29) and 1.17 (95% CI 0.99 to 1.38), for leptin and HMW-APN, respectively; for "no syndesmophyte formation/progression" the respective OR were 1.29 (95% CI 1.11 to 1.50) and 1.18 (95% CI 0.98 to 1.42), adjusted for the presence of syndesmophytes at baseline, C-reactive protein at baseline, sex, body mass index (BMI), non-steroidal anti-inflammatory drugs intake score over 2 years, and smoking status at baseline.
Serum leptin and HMW-APN predict protection from spinal radiographic progression in patients with AS. Women generally have higher leptin and HMW-APN serum levels that might explain why they have less structural damage in the spine as compared to male patients with AS.
EudraCT: 2007-007637-39. ClinicalTrials.gov, NCT00715091 . Registered on 14 July 2008.
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