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ObjectivesTo study the sequential relationship between MRI vertebral corner inflammation (VCI), vertebral corner fat deposition (VCFD) and the development/growth of radiographic syndesmophytes at the same vertebral corner (VC).MethodsBaseline, 24 and 102 weeks spinal MRIs were assessed for the presence/absence of VCI and VCFD. Anterior VCs of lateral radiographs of the cervical and lumbar spine (baseline and 102 weeks) were assessed for the development of new bone (syndesmophyte formation or syndesmophyte formation/growth combined). Data from 161 to 177 patients were analysed at the VC level using two-way and multilevel analyses adjusting for within-patient correlation and MRI reader (generalised estimating equations for binomial outcomes).ResultsThe presence of VCI (adjusted (adj) OR 1.75 to 1.98) as well as the presence of VCFD (adjOR 1.60 to 2.32) at any time point (TP) were significantly associated with the development of new bone. The combination of VCI and VCFD at the same VC increased the strength of the association, both for the sequential or simultaneous presence of VCI and VCFD across the three TPs (adjOR 2.12 to 2.73), as well as for the development of new VCFD preceded by VCI at a previous TP (adjOR 2.12 to 3.01). The complete absence of both VCI and VCFD across the three TPs ‘protected’ against new bone formation (adjOR 0.45 to 0.62). However, 40–66% of new bone still developed in VCs without MRI inflammation or fat degeneration at any of the three TPs.ConclusionsBoth VCI and VCFD contribute to new bone formation in ankylosing spondylitis (AS), especially if VCI precedes VCFD. However, VCI, VCFD and this particular sequence of events only partially explain the development of new bone in AS.

Ankylosing spondylitis is a chronic immune-mediated inflammatory disease characterised by spinal inflammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key inflammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. We assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis. We did a randomised double-blind proof-of-concept study at eight centres in Europe (four in Germany, two in the Netherlands, and two in the UK). Patients aged 18–65 years were randomly assigned (in a 4:1 ratio) to either intravenous secukinumab (2×10 mg/kg) or placebo, given 3 weeks apart. Randomisation was done with a computer-generated block randomisation list without a stratification process. The primary efficacy endpoint was the percentage of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. This study is registered with ClinicalTrials.gov, number NCT00809159. 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned to receive either intravenous secukinumab (n=24) or placebo (n=6). The final efficacy analysis included 23 patients receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99·8% probability that secukinumab is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in the secukinumab-treated group. Secukinumab rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well tolerated. It is the first targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to reach its primary endpoint in a phase 2 trial. Novartis.

Objectives:To evaluate various validity aspects of four disease activity scores (ASDAS) for ankylosing spondylitis (AS) in comparison with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), its individual components and physician and patient global assessment of disease activity.Methods:The analyses were performed in two cohorts of patients with AS: (1) the NOR-DMARD database which includes patients starting on a disease-modifying antirheumatic drug or tumour necrosis factor (TNF) blocker and (2) patients participating in double-blind placebo controlled randomised clinical trials with TNF blockers in four centres. Discrimination between patients with low versus high disease activity according to various definitions and between various levels of change were analysed as the standardised mean difference (difference in the group means divided by the pooled SD of the group means) and t score.Results:The four ASDAS versions were highly discriminatory in differentiating patients with different levels of disease activity and patients with different levels of change. The ASDAS scores outperformed the BASDAI and its single components in all settings: patient- or physician-based, reflecting status or change, with normal or raised C-reactive protein (CRP), in the presence or absence of peripheral arthritis. There were no major differences between the four ASDAS scores. Based on feasibility, the ASAS membership selected the ASDAS version which included back pain, duration of morning stiffness, patient global assessment, peripheral joint complaints and CRP as the preferred version.Conclusions:The ASDAS is a validated, highly discriminatory instrument for assessing disease activity in AS, including patient-reported outcomes and CRP levels.

Objectives Although MRI data supports a link between spinal inflammation and formation of new bone in ankylosing spondylitis, anti-tumour necrosis factor α therapies have not been shown to prevent new bone formation. The authors aimed to demonstrate that while acute lesions resolve completely, more advanced lesions, characterised by evidence of reparation, are associated with new bone formation. Methods MRI scans were performed at baseline, 12 and 52 weeks in 76 ankylosing spondylitis patients recruited to a placebo-controlled trial of adalimumab therapy. New syndesmophytes were assessed on lateral radiographs of the cervical and lumbar spine at baseline and 104 weeks. Anonymised MRI scans were read independently by two readers who recorded the presence/absence of acute (type A) and advanced (type B) vertebral corner inflammatory lesions (CIL) and fat lesions. The authors used generalised linear latent and mixed models analysis to adjust for the extent of syndesmophytes/ankylosis at baseline. Results New syndesmophytes developed significantly more frequently from type B CIL (16.7%) compared with type A CIL (2.9%) (p=0.002) or no CIL (2.5%) (p<0.0001). This was also observed for both baseline and new vertebral corner fat lesions evolving over 52 weeks (11.1% (p<0.001) and 6.8% (p=0.03), respectively). The association with type B CIL (OR (95% CI 3.88, 1.20 to –12.57) and fat (OR 95% CI 4.83, 2.38– to 9.80), p<0.0001) was significant after adjustment for the extent of syndesmophytes/ankylosis at baseline. Conclusions Our data supports the hypothesis that new bone formation is more likely in advanced inflammatory lesions and proceeds through a process of fat metaplasia, supporting a window of opportunity for disease modification.

BackgroundVenous thromboembolism (VTE), including pulmonary embolism (PE) and deep venous thrombosis (DVT), can be life threatening. An increased frequency of VTE has been found in inflammatory conditions. To date, evidence assessing whether this risk is also greater in patients with ankylosing spondylitis (AS) is scarce.MethodsUsing the provincial British Columbia, Canada healthcare database that encompasses all residents within the province, we conducted matched cohort analyses of incident PE, DVT and overall VTE among incident cases of AS and compared them with individuals randomly selected from the general population without AS. We calculated incidence rates (IRs) of VTE and multivariable analyses after adjusting for traditional risk factors using Cox models.ResultsAmong 7190 incident cases of AS, 35 developed PE and 47 developed DVT. IRs of PE, DVT and overall VTE per 1000 person-years for patients with AS were 0.79, 1.06, 1.56 compared with 0.40, 0.50, 0.77 in the control cohort. Corresponding fully adjusted HRs (95% CI) of PE, DVT and VTE were 1.36 (0.92 to 1.99), 1.62 (1.16 to 2.26) and 1.53 (1.16 to 2.01), respectively. The risks of PE, DVT and VTE were highest in the first year of diagnosis with HR (95% CI) of 2.88 (0.87 to 9.62), 2.20 (0.80 to 6.03) and 2.10 (0.88 to 4.99), respectively.ConclusionsThese findings demonstrate an increased risk of VTE in the general AS population. This risk appears the most prominent in the first year after diagnosis.

Background The value of clinical items defining inflammatory back pain to identify patients with axial spondyloarthritis (SpA) in primary care is unclear. Objective To identify predictive clinical parameters for a diagnosis of axial SpA in patients with chronic back pain presenting in primary care. Methods Consecutive patients aged <45 years (n=950) with back pain for >2 months who presented to orthopaedic surgeons (n=143) were randomised based on four key questions for referral to rheumatologists (n=36) for diagnosis. Results The rheumatologists saw 322 representative patients (mean age 36 years, 50% female, median duration of back pain 30 months). 113 patients (35%) were diagnosed as axial SpA (62% HLA B27+), 47 (15%) as ankylosing spondylitis (AS) and 66 (21%) as axial non-radiographic SpA (nrSpA). Age at onset ≤35 years, improvement by exercise, improvement with non-steroidal anti-inflammatory drugs, waking up in the second half of the night and alternating buttock pain were identified as most relevant for diagnosing axial SpA by multiple regression analysis. Differences between AS and nrSpA were detected. No single item was predictive, but ≥3 items proved useful for good sensitivity and specificity by receiver operating characteristic modelling. Conclusion This study shows that a preselection in primary care of patients with back pain based on a combination of clinical items is useful to facilitate the diagnosis of axial SpA.

In this study, we aimed to examine the effect of vitamin D deficiency on all-cause mortality in ankylosing spondylitis (AS) patients and in the general population. This is a retrospective-cohort study based on the electronic database of the largest health-maintenance organization in Israel. AS patients who were first diagnosed between 2002–2007 were included. Controls were matched by age, gender and enrollment-time. Follow-up continued until death or end of study follow-up on 1 July 2019. Laboratory measures of serum 25-hydroxyvitamin-D levels during the entire follow-up period were obtained. A total of 919 AS patients and 4519 controls with a mean time of follow-up of 14.3 years were included. The mean age at the time of enrollment was 52 years, and 22% of them were females. AS was associated with a higher proportion of vitamin D deficiency (odds ratio 1.27 [95% confidence-interval (CI) 1.03–1.58]). In AS patients, insufficient levels of vitamin D (<30 ng/mL) were significantly associated with increased incidence of all-cause mortality (hazard ratio (HR) 1.59 [95% CI 1.02–2.50]). This association was more prominent with the decrease in vitamin D levels (< 20 ng/mL, HR 1.63 [95% CI 1.03–2.60]; <10 ng/mL, HR 1.79 [95% CI 1.01–3.20]) and among male patients (<30 ng/mL, HR 2.11 [95% CI 1.20–3.72]; <20 ng/mL, HR 2.12 [95% CI 1.19–3.80]; <10 ng/mL, HR 2.23 [95% CI 1.12–4.43]). However, inadequate levels of vitamin D among controls were not associated with an increased all-cause mortality. Our study has shown that vitamin D deficiency is more common in AS patients than controls and is linked to an increased risk for all-cause mortality. These results emphasize the need for randomized-controlled trials to evaluate the benefits of vitamin D supplementation as a secondary prevention of mortality in patients with chronic inflammatory rheumatic disease.

Background Ankylosing spondylitis (AS) is characterized by excessive production of inflammatory cytokines. Recent evidence suggests that inflammation underlies the neurodegenerative process of Parkinson’s disease (PD). Whether AS has an influence on the development of PD is unclear. We aimed to examine a relationship, if any exists between AS and PD. Methods A population-based matched cohort study was performed using data from the 2000–2010 Taiwan National Health Insurance database. 6440 patients with AS and 25,760 randomly selected, age- and sex-matched controls were included in this study. The risk of PD in the AS cohort was evaluated by using a Cox model. Results This study revealed a positive association between AS and the risk of PD regardless of sex and age (aHR 1.75, p  < .001). Particularly, AS cohort to non-AS cohort relative risk of PD significantly increased for the patients aged below 49 and above 65 years (aHR 4.70, p  < .001; aHR 1.69, p  < .001, respectively) and the patients with and without comorbidities (aHR 1.61, p  < .001; aHR 2.71, p  < .001, respectively). Furthermore, NSAID use was associated with lower risk of PD (aHR 0.69, p  < .05). However, the risk of PD was higher (aHR 2.40, p  < .01) in patients with AS receiving immunosuppressants than in those not receiving (aHR 1.70, p  < .001). Conclusions Patients with AS had an increased risk of PD which might be related to underlying chronic inflammation. Further research is required to elucidate the underlying mechanism.

BackgroundAnkylosing spondylitis (AS) impacts quality of life. We assessed patient-reported outcomes (PROs), pain, fatigue, health-related quality of life (HRQoL) and work productivity in a phase III trial of tofacitinib.MethodsAdults with AS and with inadequate response/intolerance to ≥2 non-steroidal anti-inflammatory drugs received tofacitinib 5 mg twice daily or placebo for 16 weeks. Afterwards, all received open-label tofacitinib until week 48. Change from baseline to week 48 was determined for PROs: total back pain; nocturnal spinal pain; Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) overall spinal pain (Q2); Functional Assessment of Chronic Illness Therapy-Fatigue; BASDAI fatigue (Q1); AS Quality of Life (ASQoL); Short Form-36 Health Survey Version 2 (SF-36v2); EuroQoL-Five Dimension-Three Level health profile and Visual Analogue Scale; and the Work Productivity and Activity Impairment (WPAI) questionnaire. Improvements from baseline ≥minimum clinically important difference, and scores ≥normative values at week 16 were evaluated.ResultsIn 269 randomised and treated patients, at week 16, there were greater least squares mean improvements from baseline with tofacitinib 5 mg twice daily versus placebo in BASDAI overall spinal pain (–2.85 vs –1.34), BASDAI fatigue (–2.36 vs –1.08), ASQoL (–4.03 vs –2.01) and WPAI overall work impairment (–21.49 vs –7.64) (all p<0.001); improvements continued/increased to week 48. Improved spinal pain with tofacitinib was seen by week 2. Patients receiving tofacitinib reported clinically meaningful PRO improvements at week 16. Percentages with PRO scores ≥normative values at week 16 were greater with tofacitinib in SF-36v2 Physical Component Summary, physical functioning and bodily pain domains (p≤0.05).ConclusionsIn patients with AS, treatment with tofacitinib 5 mg twice daily resulted in clinically meaningful improvements in pain, fatigue, HRQoL and work productivity versus placebo to week 16, which were sustained to week 48.Trial registration numberNCT03502616.

Objectives To describe the efficacy and safety through 5 years of adalimumab treatment in patients with ankylosing spondylitis (AS), and to identify predictors of remission. Methods Patients with active AS were followed up to 5 years during a 24-week randomised, controlled period, followed by an open-label extension. Disease activity and clinical improvement were evaluated by Assessment in Spondyloarthritis International Society (ASAS) responses, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS). Kaplan–Meier was used to identify patients with sustained ASAS partial remission (PR) or ASDAS inactive disease (ID) for three or more consecutive visits spanning ≥6 months. Logistic regression was used to identify factors associated with remission. Explanatory variables included baseline demographic and disease characteristics and week 12 responses. Results Of the 311 patients who received at least one dose of adalimumab, 202 (65%) completed the 5-year study. Among 125 patients who received 5 years of adalimumab, 70%, 77%, 51% and 61% achieved ASAS40, BASDAI 50, ASAS PR and ASDAS ID, respectively. Of 311 adalimumab-treated patients, 45% and 55% achieved sustained ASAS PR and ASDAS ID at any time during study participation. The strongest predictor of remission at years 1 and 5 and of sustained remission was achieving remission at 12 weeks of treatment; baseline characteristics showed weaker associations. Adverse events were comparable with previous reports on adalimumab safety. Conclusions In patients with active AS, the efficacy and safety of adalimumab were maintained through 5 years with about half of the patients experiencing sustained remission at any time during the study. Early achievement of remission was the best predictor of long-term and sustained remission.