M. Rudwaleit

Ankylosing spondylitis: an overview

Ankylosing spondylitis (AS) is a complex, potentially debilitating disease that is insidious in onset, progressing to radiological sacroiliitis over several years. Patients with symptomatic AS lose productivity owing to work disability and unemployment, have a substantial use of healthcare resources, and reduced quality of life. The pathogenesis of AS is poorly understood. However, immune mediated mechanisms involving human leucocyte antigen (HLA)-B27, inflammatory cellular infiltrates, cytokines (for example, tumour necrosis factor α and interleukin 10), and genetic and environmental factors are thought to have key roles. The detection of sacroiliitis by radiography, magnetic resonance imaging, or computed tomography in the presence of clinical manifestations is diagnostic for AS, although the presence of inflammatory back pain plus at least two other typical features of spondyloarthropathy (for example, enthesitis and uveitis) is highly predictive of early AS. Non-steroidal anti-inflammatory drugs (NSAIDs) effectively relieve inflammatory symptoms and are presently first line drug treatment. However, NSAID treatment has only a symptomatic effect and probably does not alter the disease course. For symptoms refractory to NSAIDs, second line treatments, including corticosteroids and various disease modifying antirheumatic drugs, are employed but are of limited benefit. Emerging biological therapies target the inflammatory processes underlying AS, and thus, may favourably alter the disease process, in addition to providing symptom relief.

Baseline radiographic damage, elevated acute-phase reactant levels, and cigarette smoking status predict spinal radiographic progression in early axial spondylarthritis

OBJECTIVE To assess prospectively the rates and to explore predictors of spinal radiographic progression over 2 years in a cohort of patients with early axial spondylarthritis (SpA). METHODS Two hundred ten patients with axial SpA from the German Spondyloarthritis Inception Cohort were selected for this analysis based on the availability of radiographs at baseline and after 2 years of followup. Spinal radiographs were scored by 2 trained readers in a blinded, randomly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Spinal radiographic progression was defined as worsening of the mean mSASSS by ≥2 units over 2 years. RESULTS Among the patients with axial SpA, 14.3% showed spinal radiographic progression after 2 years (20% of those with AS and 7.4% of those with nonradiographic axial SpA). The following parameters were independently associated with spinal radiographic progression: presence of syndesmophytes at baseline (odds ratio [OR] 6.29, P < 0.001), elevated levels of markers of systemic inflammation (for the erythrocyte sedimentation rate, OR 4.04, P = 0.001; for C-reactive protein level time-averaged over 2 years, OR 3.81, P = 0.001), and cigarette smoking (OR 2.75, P = 0.012). These associations were confirmed by multivariate logistic regression analysis. No clear association with spinal radiographic progression was observed for HLA-B27 status, sex, age, disease duration, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, presence of peripheral arthritis, enthesitis, psoriasis, treatment with nonsteroidal antiinflammatory drugs, or treatment with disease-modifying antirheumatic drugs at baseline. CONCLUSION The presence of radiographic damage at baseline (syndesmophytes), elevated levels of acute-phase reactants, and cigarette smoking were all independently associated with spinal radiographic progression in patients with early axial SpA.

Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48-week randomised controlled trial

Purpose To evaluate the potential of etanercept versus sulfasalazine to reduce active inflammatory lesions on whole-body MRI in active axial spondyloarthritis with a symptom duration of less than 5 years. Methods Patients were randomly assigned to etanercept (n=40) or sulfasalazine (n=36) treatment over 48 weeks. All patients showed active inflammatory lesions (bone marrow oedema) on MRI in either the sacroiliac joints or the spine. MRI was performed at weeks 0, 24 and 48 and was scored for active inflammatory lesions in sacroiliac joints and the spine including posterior segments and peripheral enthesitis by two radiologists, blinded for treatment arm and MRI time point. Results In the etanercept group, the reduction of the sacroiliac joint score from 7.7 at baseline to 2.0 at week 48 was significantly (p=0.02) larger compared with the sulfasalazine group from 5.4 at baseline to 3.5 at week 48. A similar difference in the reduction of inflammation was found in the spine from 2.2 to 1.0 in the etanercept group versus from 1.4 to 1.3 in the sulfasalazine group between baseline and week 48, respectively (p=0.01). The number of enthesitic sites also improved significantly from 26 to 11 in the etanercept group versus 24 to 26 in the sulfasalazine group (p=0.04 for difference). 50% of patients reached clinical remission in the etanercept group versus 19% in the sulfasalazine group at week 48. Conclusion In patients with early axial spondyloarthritis active inflammatory lesions detected by whole-body MRI improved significantly more in etanercept versus sulfasalazine-treated patients. This effect correlated with a good clinical response in the etanercept group.

Progression of radiographic damage in patients with ankylosing spondylitis - Defining the central role of syndesmophytes

Background: Structural changes such as erosions, syndesmophytes and ankylosis are characteristic of ankylosing spondylitis (AS). These can be quantified by the modified Stokes Anklylosing Spondylitis Spinal Score (mSASSS). It is unknown which radiographic feature is most relevant for the assessment of change and the prediction of future damage in AS. Objectives: To analyse radiographic progression in AS by using different assessments to define the most important changes. Methods: Spinal radiographs of 116 patients with AS were scored by the mSASSS at baseline (BL) and after 2 years. Radiographic progression was assessed by differentiating (1) any change; (2) progression to syndesmophytes/ankylosis (definite change); and (3) changes exceeding the smallest detectable change (SDC) as predefined. A growth angle of 45° was used to differentiate syndesmophytes from spondylophytes. Results: Some radiographic progression after 2 years was detected in 42% of patients, novel syndesmophytes in 31% of patients, and, using the SDC (calculated at 2 mSASSS units) as cut-off, progression was seen in 28% of patients. Thus, in 74% of the patients changes were because of syndesmophytes and/or ankylosis. Using the predefined cut-off, only 12% of all syndesmophytes were spondylophytes. Patients with such changes were of older age. Definite radiographic progression was found in 44% of the patients with syndesmophytes/ankylosis at BL (n = 57) versus 19% (p = 0.03) of the patients without such changes (n = 59). Conclusions: Syndesmophytes and ankylosis are the most relevant structural changes in AS, and also in the mSASSS. Development of just one syndesmophyte within 2 years indicates progression of structural changes in AS; this is relevant for clinical practice. Syndesmophytes are the best predictors of radiographic progression.

Rates and predictors of radiographic sacroiliitis progression over 2 years in patients with axial spondyloarthritis

Objective To assess the progression of radiographic sacroiliitis in a cohort of patients with early axial spondyloarthritis over a period of 2 years and to explore predictors of progression. Methods 210 patients with axial spondyloarthritis from the German Spondyloarthritis Inception Cohort have been selected for this analysis based on availability of radiographs at baseline and after 2 years of follow-up. Radiographs were centrally digitised and the sacroiliac joints were scored independently according to the grading system of the modified New York criteria for ankylosing spondylitis (AS) by two trained readers. The readers scored both time points simultaneously but were blinded for the time point and for all clinical data. Results 115 patients (54.8%) fulfilled the modified New York criteria for AS in their radiographic part in the opinion of both readers at baseline, while 95 patients (45.2%) were classified as non-radiographic axial spondyloarthritis. More patients with non-radiographic spondyloarthritis (10.5%) compared with AS (4.4%) showed an estimated ‘true’ progression by at least one grade according to both readers, although the difference between the two groups was statistically non-significant. The rate of progression from non-radiographic axial spondyloarthritis to AS was 11.6% over 2 years. An elevated level of C-reactive protein (CRP) at baseline was a strong positive predictor of radiographic sacroiliitis progression in non-radiographic axial spondyloarthritis and AS (OR 3.65 and 5.08, respectively, p<0.05). Conclusion Progression of radiographic sacroiliitis by at least one grade after 2 years occurs only in a small percentage of patients with early axial spondyloarthritis. An elevated level of CRP was found to be a strong positive predictor of sacroiliitis progression.

Inflammation in ankylosing spondylitis: a systematic description of the extent and frequency of acute spinal changes using magnetic resonance imaging

Background: Magnetic resonance imaging (MRI) is increasingly used to detect inflammation in the spine of patients with ankylosing spondylitis (AS). Objectives: To detect differentially the presence and extent of inflammation in the three spinal segments of patients with AS by MRI. Methods: In 38 patients with active AS, acute spinal lesions were assessed by T1 weighted, gadolinium enhanced, spin echo MRI (T1/Gd-DTPA) and short τ inversion recovery (STIR) sequences. MRI was quantified by the validated scoring system ASspiMRI-a. Acute spinal lesions were detected in the whole spine and in each spinal segment. One vertebral unit (VU) was defined as the region between two virtual lines drawn through the middle of each vertebral body. Results: A greater number of inflammatory spinal lesions were found by the STIR sequence than by Gd-DTPA: inflammation was present in 30.6% of the VUs as assessed by STIR, compared with 26.8% of the same VUs assessed by T1/Gd-DTPA. Inflammation was found more commonly in the thoracic spine (TS) than in the cervical (CS) or the lumbar spine (LS) with both techniques. When STIR was used, spinal inflammation in the CS, the TS, and LS was detected in 10/38 (26%), 28/38 (74%), and 9/38 (24%) patients, respectively. The VU T7/8 was found to be the VU most often affected by both techniques (27.8% by T1/Gd-DTPA and 34.5% by STIR). Conclusions: Spinal inflammation is a common manifestation in patients with AS, and appears more frequently in the TS. The scoring system ASspiMRI-a can be used for evaluation of acute spinal changes in AS.

No efficacy of subcutaneous methotrexate in active ankylosing spondylitis: a 16-week open-label trial

Objective: To examine the potential therapeutic effect of methotrexate 20 mg given weekly as subcutaneous injections to 20 patients with ankylosing spondylitis refractory to non-steriodal antirheumatic drugs. Patients and methods: 20 patients with ankylosing spondylitis, a mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 5.6 (range 4–9.3) and predominantly axial manifestations were treated with weekly 15 mg methotrexate subcutaneously for 4 weeks, which was then increased to 20 mg subcutaneously for the next 12 weeks. Clinical outcome assessments included, among others, BASDAI score physical function, spinal mobility, patients’ and physicians’ global assessment (visual analogue scale), peripheral joint assessment, quality of life (Short Form 36) and C reactive protein. The primary end point of the study was a 20% improvement on the ASsessments in Ankylosing Spondylitis (ASAS 20) scale. Results: Using an intention-to-treat analysis, ASAS 20 was achieved in only 25% of patients. An ASAS 40 response was achieved in 10% of patients, and no patient reached an ASAS 70 response or the ASAS criteria for partial remission. For the mean BASDAI score, no change was observed between baseline and week 16 (baseline 5.6 v week 16, 5.6). No improvement was observed in any of the clinical parameters or C reactive protein, except a small but non-significant decrease in the number of swollen joints. Conclusions: In this open study, methotrexate did not show any benefit for axial manifestations in patients with active ankylosing spondylitis beyond the expected placebo response.

Up regulation of the production of tumour necrosis factor α and interferon γ by T cells in ankylosing spondylitis during treatment with etanercept

Background: Treatment of active ankylosing spondylitis (AS) with the recombinant, soluble tumour necrosis factor α (TNFα) receptor molecule etanercept has been shown to be clinically highly effective. The precise mechanism of action, however, is not known. Objective: To assess the change in the cytokine secreting ability of CD4+ and CD8+ T cells and macrophages during etanercept treatment. Patients and methods: Peripheral blood mononuclear cells from 10 patients with AS treated with 25 mg etanercept and 10 patients with AS treated with placebo were investigated during treatment given twice weekly subcutaneously. Production of cytokines by T cells was investigated after in vitro stimulation by flow cytometry. Results: Twelve weeks of etanercept treatment induced a significant increase in the number of interferon γ (IFNγ) positive (14.2% (9.6–19.5%) before v 24.4% (13.4–36.4%) after) and TNFα positive CD4+ T cells (p=0.008 for both cytokines) and IFNγ positive (37.5% (19.0–45.4%) before v 52.9% (33.2–60.0%) after) and TNFα positive CD8+ T cells (p=0.008 for both cytokines) upon phorbol myristate acetate/ionomycin stimulation, but not in the placebo group. Furthermore, etanercept treatment induced a significant increase in the number of IFNγ positive CD8+ T cells (p=0.024 at 12 weeks) and a non-significant increase of TNFα positive CD8+ T cells after in vitro stimulation with the aggrecan derived peptides. Conclusions: Neutralisation of peripheral TNFα does not induce a down regulation of the ability of T cells to produce TNFα but rather an up regulation, possibly due to a counterregulatory mechanism.

Atopic disorders in ankylosing spondylitis and rheumatoid arthritis

Background: The prevalence of atopic disorders in ankylosing spondylitis (AS) is unknown. AS and rheumatoid arthritis (RA) exhibit divergent T helper (Th) cell cytokine patterns. Objective: To test the hypothesis that Th2 polarised atopic disorders may be decreased in Th1 polarised RA but increased in AS, which is characterised by an impaired Th1 cytokine pattern, by assessing the prevalence of atopic disorders in AS and RA. Methods: 2008 subjects (380 patients with AS, 728 patients with RA, 900 controls) from Berlin, Germany, were considered in this cross sectional study. A questionnaire incorporating questions from the European Community Respiratory Health Service (ECRHS) and the International Study of Asthma and Allergies in Childhood (ISAAC) protocol was mailed to all subjects. Disease severity was assessed by the modified Health Assessment Questionnaire (mHAQ). Results: 1271 (63.3%) people responded to the questionnaire. The prevalence of any atopic disorder was 24.6% (61/248) in patients with AS, 20.7% (111/536) in controls, and 13.1% (64/487) in patients with RA (p=0.0009 for AS v RA; p=0.001 for controls v RA). Hay fever was reported by 40/248 (16.1%) patients with AS, 82/536 (15.3%) controls, and 42/487 (8.6%) patients with RA (p=0.002 for AS v RA; p=0.001 for controls v RA). Atopic dermatitis was reported by 19/248 (7.7%) patients with AS, 26/536 (4.9%) controls, and 14/487 (2.9%) patients with RA (p=0.003 for AS v RA), and asthma by 18/248 (7.3%) patients with AS, 35/536 (6.5%) controls, and 21/487 (4.3%) patients with RA. The differences were related neither to age nor to drugs. Disease severity was less in atopic patients with RA who had the atopic disorder before the onset of RA (median mHAQ 0.75) than in patients in whom RA preceded the atopic disorder (median mHAQ 1.75; p=0.027). Conclusions: Atopic disorders are decreased in RA but only slightly and non-significantly increased in AS. This may imply that atopy confers some protection from RA but only little if any susceptibility to AS. It may further indicate that the cytokine deviation towards an impaired Th1 pattern in AS is less strong than the cytokine deviation towards Th1 in RA, a finding which may affect future therapeutic approaches.

Development of a radiographic scoring tool for ankylosing spondylitis only based on bone formation: addition of the thoracic spine improves sensitivity to change.

OBJECTIVE The modified Stokes Ankylosing Spondylitis Spinal Score (mSASSS) quantifies radiographic changes in the cervical spine (C-spine) and the lumbar spine (L-spine), but not in the thoracic spine (T-spine). Our objective was to study the contribution of the lower part of the T-spine to structural damage in patients with ankylosing spondylitis (AS). METHODS Radiographs of 80 AS patients obtained at baseline and after 2 years were scored by 2 readers using the mSASSS. In addition, changes in the lower T-spine (T10-T12) were quantified. On this basis, a new scoring tool was developed: the Radiographic Ankylosing Spondylitis Spinal Score (RASSS). The RASSS includes 2 changes: no scoring of erosions in order to confine the scoring to new bone formation, and no scoring of squaring in the C-spine for anatomic and feasibility reasons. RESULTS The mean +/- SD change was 0.9 +/- 2.5 units using the mSASSS and 1.6 +/- 2.8 units using the RASSS (P < 0.001). Although the mSASSS identified new syndesmophytes in mean +/- SD 1.4 +/- 2.9 vertebral edges over 2 years, an additional 0.6 +/- 1.2 vertebral edges were seen in the lower T-spine. New syndesmophytes or ankylosis were found in 15 patients (21.4%; 95% confidence interval [95% CI] 13.1-32.4%) in the C-spine/L-spine and in 6 patients (8.6%; 95% CI 3.8-17.2%) in the T-spine alone. The reliability of the RASSS and the agreement between readers was excellent. CONCLUSION The lower T-spine improves the sensitivity to change of scoring radiographic progression in AS. The tool developed in this study, the RASSS, showed better face and content validity than the mSASSS and was proven to be superior in the quantification of new bone formation in AS.