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ObjectiveThe Assessment of Spondyloarthritis international Society Health Index (ASAS HI) measures global functioning and health in patients with axial spondyloarthritis (axSpA) covering domains of physical, emotional, and social functioning. The main aim of this study was to investigate the sensitivity to change of ASAS HI in comparison with established variables of disease activity, function, and mental health.MethodsPatients with axSpA from the disease register RABBIT-SpA with follow-up time of at least 12 months and available ASAS HI questionnaires were included. Patients received questionnaires addressing disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Ankylosing Spondylitis Disease Activity Score [ASDAS]), physical function (Bath Ankylosing Spondylitis Functional Index [BASFI]), mental health (5-item World Health Organization Well-Being Index [WHO-5]), and global functioning (ASAS HI). Standardized response means (SRMs) were calculated to compare the sensitivity to change of different variables.ResultsSix hundred and sixty-seven patients were included, 552 treated with biologic disease-modifying antirheumatic drugs (bDMARDs) and 115 with conventional synthetic DMARDs and/or nonsteroidal antiinflammatory drugs (control group). Between baseline and month 12, the mean ASAS HI declined from 6.9 to 5.1 in the bDMARD group and from 5.9 to 5.6 in the conventionally treated group. In the bDMARD group, the SRM of ASAS HI was 0.52, compared to 0.59 for BASFI, 0.65 for WHO-5, 0.73 for BASDAI, and 0.90 for ASDAS. The following ASAS HI domains were most frequently affected: pain (78% agreed), maintaining body position (75%), and energy/drive (73%). In the patients receiving bDMARDs, there was an improvement in all items. In the control group, the largest improvement was seen in pain.ConclusionAs expected, ASDAS and BASDAI as disease activity scores showed high sensitivity to change, whereas changes in physical function (BASFI), mental health (WHO-5), and the broader concept of functioning and health (ASAS HI) were moderate.

Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to evaluate the efficacy and safety of ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X.

The JAK pathway is a potential therapeutic target in ankylosing spondylitis. This study assessed the efficacy and safety of upadacitinib, a selective JAK1 inhibitor, in patients with ankylosing spondylitis.

To evaluate the performance of the extended modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) incorporating information from anteroposterior (AP) lumbar radiographs as compared to the conventional mSASSS in detection of radiographic spinal progression in patients with axial spondyloarthritis (axSpA) A total of 210 patients with axSpA, 115 with radiographic axSpA (r-axSpA), and 95 with non-radiographic axSpA (nr-axSpA), from the GErman SPondyloarthritis Inception Cohort (GESPIC), were included in the analysis based on the availability of spinal radiographs (cervical spine lateral, lumbar spine lateral, and AP views), at baseline and year 2. Two trained readers independently scored lateral cervical and lumbar spine images according to the mSASSS system (0–3 per vertebral corner, 0–72 in total). In addition, all vertebral corners of vertebral bodies visible on lumbar AP radiographs (lower T12 to upper S1) were assessed according to the same scoring system that resulted in a total range for the extended mSASSS from 0 to 144. Reliability and sensitivity to detect radiographic spinal progression of the extended mSASSS as compared to the conventional mSASSS were evaluated. The reliability of conventional and extended scores was excellent with intraclass correlation coefficients (ICCs) of 0.926 and 0.927 at baseline and 0.920 and 0.933 at year 2, respectively. The mean ± SD score for mSASSS and extended mSASSS at baseline were 4.25 ± 8.32 and 8.59 ± 17.96, respectively. The change score between baseline and year 2 was 0.73 ± 2.34 and 1.19 ± 3.73 for mSASSS and extended mSASSS, respectively. With the extended mSASSS, new syndesmophytes after 2 years were detected in 4 additional patients, new syndesmophytes or growth of existing syndesmophytes in 5 additional patients, and progression by ≥ 2 points in the total score in 14 additional patients meaning a 25%, 28%, and 46% increase in the proportion of patients with progression according to the respective definition as compared to the conventional score. Incorporation of lumbar AP radiographs in the assessment of structural damage in the spine resulted into detection of additional patients with radiographic spinal progression not captured by the conventional mSASSS score.

Low back pain is a very common symptom. It occurs in high-income, middle-income, and low-income countries and all age groups from children to the elderly population. Globally, years lived with disability caused by low back pain increased by 54% between 1990 and 2015, mainly because of population increase and ageing, with the biggest increase seen in low-income and middle-income countries. Low back pain is now the leading cause of disability worldwide. For nearly all people with low back pain, it is not possible to identify a specific nociceptive cause. Only a small proportion of people have a well understood pathological cause—eg, a vertebral fracture, malignancy, or infection. People with physically demanding jobs, physical and mental comorbidities, smokers, and obese individuals are at greatest risk of reporting low back pain. Disabling low back pain is over-represented among people with low socioeconomic status. Most people with new episodes of low back pain recover quickly; however, recurrence is common and in a small proportion of people, low back pain becomes persistent and disabling. Initial high pain intensity, psychological distress, and accompanying pain at multiple body sites increases the risk of persistent disabling low back pain. Increasing evidence shows that central pain-modulating mechanisms and pain cognitions have important roles in the development of persistent disabling low back pain. Cost, health-care use, and disability from low back pain vary substantially between countries and are influenced by local culture and social systems, as well as by beliefs about cause and effect. Disability and costs attributed to low back pain are projected to increase in coming decades, in particular in low-income and middle-income countries, where health and other systems are often fragile and not equipped to cope with this growing burden. Intensified research efforts and global initiatives are clearly needed to address the burden of low back pain as a public health problem.

Background: Upadacitinib, a Janus kinase inhibitor, has demonstrated efficacy and an acceptable safety profile in patients with ankylosing spondylitis (AS) in the phase III SELECT-AXIS programs. We report the 1-year efficacy and safety in patients with AS and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) from the SELECT-AXIS 2 study. Methods: Patients ≥ 18 years with active AS who met the modified New York criteria for AS and were bDMARD-IR received double-blind upadacitinib 15 mg once daily (QD) or placebo for 14 weeks. Patients who completed 14 weeks could enter an open-label extension and receive upadacitinib 15 mg QD for up to 2 years. Efficacy endpoints included the percentage of patients achieving ≥ 40% improvement in Assessment of SpondyloArthritis international Society response (ASAS40), Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA), and ASDAS inactive disease (ID); and change from baseline in total and nocturnal back pain, and Bath Ankylosing Spondylitis Functional Index (BASFI). Subgroup analyses (bDMARD lack of efficacy versus intolerance, and prior tumor necrosis factor inhibitor [TNFi] versus interleukin-17 inhibitor [IL-17i] exposure) were conducted. Binary and continuous efficacy endpoints were assessed using non-responder imputation with multiple imputation (NRI-MI) and as observed (AO) analyses; and mixed-effects model repeated measures (MMRM) and AO, respectively. Safety was assessed based on adverse events. Data through week 52 are reported. Results: Of 420 randomized patients, 366 (continuous upadacitinib: n= 181; placebo to upadacitinib: n= 185) completed 52 weeks of treatment. At week 52, in the continuous upadacitinib and placebo to upadacitinib groups, ASAS40, ASDAS LDA, and ASDAS ID were achieved by 66% and 65%, 57% and 55%, and 26% and 25% (all NRI-MI); and change from baseline in total back pain, nocturnal back pain, and BASFI was -4.5 and -4.3, -4.6 and -4.4, and -3.6 and -3.5 (all MMRM), respectively. No new safety risks were identified. Subgroup analyses were consistent with the overall study population. Conclusions: Upadacitinib 15 mg QD demonstrated sustained improvement up to 52 weeks in bDMARD-IR patients with AS. Efficacy was generally similar in patients with lack of efficacy versus intolerance to bDMARDs and prior TNFi versus IL-17i exposure. Trial registration: NCT02049138.

Objective.To compare proton density–weighted short-tau inversion recovery (PD-STIR) and T2-weighted fat-suppressed turbo spin echo (T2-FS) sequences for detecting osteitis lesions of the sacroiliac joints (SIJ) in patients with chronic low back pain (CLBP).Methods.This prospective study included 110 patients with CLBP and suspected spondyloarthritis and 18 healthy controls. All 128 participants (age range: 19–57 yrs) underwent 3.0 Tesla magnetic resonance imaging (MRI) of the SIJ including PD-STIR and T2-FS. Two readers independently scored PD-STIR and T2-FS images for osteitis in separate sessions. Sum scores and signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated. Images were further analyzed as to whether they fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criterion of a positive MRI (MRI+). Interreader agreement was calculated using intraclass correlation coefficients.Results.Average osteitis sum scores were higher for T2-FS images (mean sum score of 4.10 in T2-FS vs 2.55 in PD-STIR, p = 0.017). Mean SNR was 16.54 for PD-STIR and 37.30 for T2-FS (p = 0.0289). Mean CNR was 4.14 for PD-STIR and 20.20 for T2-FS (p = 0.0212). For both readers, the ASAS MRI+ definition was more often fulfilled by T2-FS than by PD-STIR images, resulting in more patients being classified as having axial spondyloarthritis (axSpA): 68 patients using T2-FS versus 58 patients using PD-STIR. Interreader intraclass correlation coefficients were very good for both PD-STIR (0.91) and T2-FS (0.86).Conclusion.T2-FS sequences improve image quality and hence the detection of osteitis compared to the PD-STIR sequence. More patients were classified as axSpA based on a positive MRI by T2-FS.

Biological disease-modifying anti-rheumatic drugs (bDMARDs) are recommended for radiographic axial spondyloarthritis, otherwise known as ankylosing spondylitis, when conventional therapies are not effective. We report efficacy and safety data on ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A (IL-17A), in patients with radiographic axial spondyloarthritis who have not previously been treated with bDMARDs.

The Assessment of SpondyloArthritis international Society (ASAS) defines a positive family history (PFH) of spondyloarthritis (SpA) as the presence of ankylosing spondylitis (AS), acute anterior uveitis (AAU), reactive arthritis (ReA), inflammatory bowel disease (IBD), and/or psoriasis in first-degree relatives (FDR) or second-degree relatives (SDR). In two European cohorts, a PFH of AS and AAU, but not other subtypes, was associated with human leukocyte antigen B27 (HLA-B27) carriership in patients suspected of axial SpA (axSpA). Because the importance of ethnicity or degree of family relationship is unknown, we investigated the influence of ethnicity, FDR, or SDR on the association between a PFH and HLA-B27 carriership in patients suspected of axSpA. Baseline data from the ASAS cohort of patients suspected of axSpA were analyzed. Univariable analyses were performed. Each disease (AS, AAU, psoriasis, IBD, ReA) in a PFH according to the ASAS definition was a determinant in separate models with HLA-B27 carriership as outcome. Analyses were stratified for self-reported ethnicity, FDR, and SDR. Analyses were repeated in multivariable models to investigate independent associations. A total of 594 patients were analyzed (mean [SD] age 33.7 [11.7] years; 46% male; 52% HLA-B27+; 59% white, 36% Asian, 5% other). A PFH was associated with HLA-B27 carriership in patients with a white (OR, 2.3, 95% CI, 1.4–3.9) or Asian ethnicity (OR, 3.1, 95% CI, 1.6–5.8) and with a PFH in FDR (OR, 2.9, 95% CI, 1.8–4.5), but not with a PFH in SDR (OR, 1.7, 95% CI, 0.7–3.8) or in other ethnicities. A PFH of AS was positively associated with HLA-B27 carriership in all subgroups (white OR, 7.1; 95% CI, 2.9–17.1; Asian OR, 5.7; 95% CI, 2.5–13.2; FDR OR, 7.8; 95% CI, 3.8–16.0; SDR OR, 3.7; 95% CI, 1.2–11.6). A PFH of AAU, ReA, IBD, or psoriasis was never positively associated with HLA-B27 carriership. In the multivariate analysis, similar results were found. In the ASAS cohort, a PFH of AS, but not of AAU, ReA, IBD, or psoriasis, was associated with HLA-B27 carriership regardless of white or Asian ethnicity or degree of family relationship. This cohort and two European cohorts show that a PFH of AS and possibly a PFH of AAU can be used to identify patients who are more likely to be HLA-B27-positive and therefore may have an increased risk of axSpA.

Therapeutic targeting of tumour necrosis factor (TNF)-α is highly effective in ankylosing spondylitis (AS) patients. However, since one-third of anti-TNF-treated AS patients do not show an adequate clinical response there is an urgent need for new biomarkers that would aid clinicians in their decision-making to select appropriate therapeutic options. Thus, the aim of this explorative study was to identify cell-based biomarkers in peripheral blood that could be used for a pre-treatment stratification of AS patients. A high-dimensional, multi-parametric flow cytometric approach was applied to identify baseline predictors in 31 AS patients before treatment with the TNF blockers adalimumab (TNF-neutralisation) and etanercept (soluble TNF receptor). As the major result, the frequencies of natural killer (NK) cells, and in particular CD8-positive (CD8+) NK cell subsets, were most predictive for therapeutic outcome in AS patients. While an inverse correlation between classical CD56+/CD16+NK cells and reduction of disease activity was observed, the CD8+NK cell subset behaved in the opposite direction. At baseline, responders showed significantly increased frequencies of CD8+NK cells compared with non-responders. This is the first study demonstrating that the composition of the NK cell compartment has predictive power for prediction of therapeutic outcome for anti-TNF-α blockers, and we identified CD8+NK cells as a potential new player in the TNF-α-driven chronic inflammatory immune response of AS.

Adalimumab was effective in treating patients with nonradiographic axial spondyloarthritis (nr-axSpA) in the 12-week ABILITY-1 trial. We present long-term efficacy and safety results of adalimumab from the open-label ABILITY-1 extension, including the relationship between clinical and magnetic resonance imaging (MRI) remission and impact of sustained clinical remission on physical function. Patients received adalimumab 40 mg every other week or placebo for 12 weeks, then open-label adalimumab for up to 144 weeks. Clinical and safety data were collected through 3 years, and MRI data were collected until 2 years. Analyses were performed in the total population and subpopulation with positive MRI and/or elevated C-reactive protein (MRI/CRP-positive) at baseline. Clinical and MRI remission definitions included Ankylosing Spondylitis Disease Activity Score inactive disease (ASDAS ID; score < 1.3) and Spondyloarthritis Research Consortium of Canada (SPARCC) MRI score < 2 for sacroiliac joints (SIJs), spine, or both. Physical function was assessed using the Bath Ankylosing Spondylitis Functional Index. Overall, 185 patients were included in the total population and 142 in the MRI/CRP-positive subpopulation; 65% and 68%, respectively, completed 3 years. Clinical, functional, and MRI improvements were similar and equally sustainable in both populations. At year 3, the percentages of patients in ASDAS ID in the MRI/CRP-positive subpopulation were 30%/33% (nonresponder imputation) and 46%/49% (observed) for those initially receiving adalimumab/placebo. At years 1 and 2, patients in ASDAS ID vs not had significantly greater improvements in SPARCC SIJ scores from baseline (P< 0.001). Among patients with baseline MRI scores ≥ 2 who achieved ASDAS ID at year 2, 44–68% also had MRI remission. Significantly more patients with sustained ASDAS ID through year 2 or 3 vs without achieved normal physical function (100% vs 48%; 100% vs 44%; both P< 0.001). No new safety concerns were observed. In the ABILITY-1 study of nr-axSpA, adalimumab therapy provided sustained clinical and functional improvements through 3 years, as well as suppression of MRI axial inflammation, which was greater in patients who achieved clinical remission. Sustained clinical remission was associated with increased attainment of normal physical function. The safety profile of adalimumab was consistent with prior studies. ClinicalTrials.gov, NCT00939003; registered on July 10, 2009.

Success of treatment withdrawal in patients with non-radiographic axial spondyloarthritis who are in remission remains unknown. The ABILITY-3 study explored the ability to withdraw adalimumab treatment in patients with non-radiographic axial spondyloarthritis who achieved sustained clinical remission after open-label treatment with adalimumab.

Many clinical practice guidelines recommend similar approaches for the assessment and management of low back pain. Recommendations include use of a biopsychosocial framework to guide management with initial non-pharmacological treatment, including education that supports self-management and resumption of normal activities and exercise, and psychological programmes for those with persistent symptoms. Guidelines recommend prudent use of medication, imaging, and surgery. The recommendations are based on trials almost exclusively from high-income countries, focused mainly on treatments rather than on prevention, with limited data for cost-effectiveness. However, globally, gaps between evidence and practice exist, with limited use of recommended first-line treatments and inappropriately high use of imaging, rest, opioids, spinal injections, and surgery. Doing more of the same will not reduce back-related disability or its long-term consequences. The advances with the greatest potential are arguably those that align practice with the evidence, reduce the focus on spinal abnormalities, and ensure promotion of activity and function, including work participation. We have identified effective, promising, or emerging solutions that could offer new directions, but that need greater attention and further research to determine if they are appropriate for large-scale implementation. These potential solutions include focused strategies to implement best practice, the redesign of clinical pathways, integrated health and occupational interventions to reduce work disability, changes in compensation and disability claims policies, and public health and prevention strategies.

Low back pain is the leading worldwide cause of years lost to disability and its burden is growing alongside the increasing and ageing population.1Because these population shifts are more rapid in low-income and middle-income countries, where adequate resources to address the problem might not exist, the effects will probably be more extreme in these regions. Most low back pain is unrelated to specific identifiable spinal abnormalities, and our Viewpoint, the third paper in this LancetSeries,2,3is a call for action on this global problem of low back pain.

Peripheral spondyloarthritis refers to spondyloarthritis with predominant peripheral (arthritis, enthesitis or dactylitis) involvement. Diagnosis can be challenging, particularly in the absence of SpA extra-articular manifestations such as uveitis, psoriasis or inflammatory bowel disease. Evaluation of disease activity should always include assessment of objective signs of inflammation, particularly in the presence of enthesitis as the sole peripheral manifestation, mainly due to the potential misdiagnosis with fibromyalgia tender points. Several recommendations for management/treatment of psoriatic arthritis have been published by EULAR and GRAPPA but none for peripheral SpA in general. NSAIDs and glucocorticoids are recommended as the first step of treatment in all peripheral manifestations, while conventional synthetic (cs) DMARDs seem only efficacious in arthritis. Several biologics and targeted synthetic (ts) DMARDs (TNFi, anti-IL17 and JAK-inhibitors) have been proven to be efficacious in peripheral involvement in PsA (arthritis and enthesitis), but studies on peripheral SpA are lacking.

Objective.To investigate sex differences in connection with the effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with ankylosing spondylitis (AS).Methods.A total of 440 patients with AS (294 men; 146 women) initiating a first TNFi in the prospective Swiss Clinical Quality Management Cohort were included. We evaluated the proportion of patients achieving the 20% and 40% improvement in the Assessment of Spondyloarthritis international Society criteria (ASAS20 and ASAS40) as well as Ankylosing Spondylitis Disease Activity Score (ASDAS) improvement and status scores at 1 year. Patients having discontinued TNFi were considered nonresponders. Logistic regression analyses were performed to adjust for important predictors of response.Results.Compared to men, female patients had lower mean C-reactive protein levels, better spinal mobility, and more peripheral disease at the start. There was no sex disparity with regard to the ASDAS, the Bath Ankylosing Spondylitis Disease Activity and Functional indices, and the quality of life. At 1 year, 52% of women and 63% of men achieved an ASAS20 response (OR 0.63, 95% CI 0.37–1.07, p = 0.09). An inactive disease status (ASDAS < 1.3) was reached by 18% of women and 26% of men (OR 0.65, 95% CI 0.32–1.27, p = 0.22). These sex differences in response to TNFi were more pronounced in adjusted analyses (OR 0.34, 95% CI 0.16–0.71, p = 0.005 for ASAS20 and OR 0.10, 95% CI 0.03–0.31, p < 0.001 for ASDAS < 1.3) and confirmed for all the other outcomes assessed.Conclusion.In AS, fewer women respond to TNFi and women show a reduced response in comparison to men.

Objective.To determine the prevalence of fat metaplasia and other structural lesions of the sacroiliac joints associated with axial spondyloarthritis in a nonrheumatological patient population.Methods.Magnetic resonance imaging examinations that included the pelvis and were performed in patients without known rheumatological disease were used for this retrospective cross-sectional study. These images were evaluated for sacroiliac fat metaplasia, sclerosis, osteophytes, and joint space alterations such as erosions or ankylosis. Patients were divided into 7 age groups (15–24 to ≥ 75 yrs). Prevalence of lesions across age groups was calculated. Possible clinical confounders (e.g., status post radiation, suspected inflammatory bowel disease) were investigated regarding their effect on lesion prevalence and extent, to exclude bias.Results.A total of 485 patients were enrolled. Fat metaplasia was very common and increased with age, from a prevalence of 50.6% in the age groups < 45, to 94.4% in patients ≥ 75 years. Erosions were uncommon: 0.6% of patients < 45, and 2.6% of the entire study population exhibited this feature, with no detectable age-dependent increase. Sclerosis and osteophytes were detected in 13.7% and 37.0% of patients, respectively. None of the investigated clinical confounders had a significant effect on lesion prevalence.Conclusion.Our study shows a very high prevalence of fat metaplasia adjacent to the sacroiliac joint in asymptomatic patients, while erosions are extremely uncommon.

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.

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.

To evaluate the long‐term clinical and imaging efficacy of etanercept in patients with early, active nonradiographic axial spondyloarthritis (SpA). Adult patients who satisfied the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA (but not the modified New York radiographic criteria), with symptom duration >3 months to <5 years, and who were unresponsive to ≥2 nonsteroidal antirheumatic drugs (NSAIDs) received double‐blind etanercept 50 mg/week or placebo for 12 weeks, followed by open‐label etanercept 50 mg/week to week 104. Clinical, magnetic resonance imaging (MRI; Spondyloarthritis Research Consortium of Canada [SPARCC] scores), and safety outcomes at 104 weeks were analyzed. Of 215 randomized patients (etanercept: n = 106; placebo: n = 109), 205 entered the study (etanercept/etanercept: n = 100; placebo/etanercept: n = 105) and 169 completed the open‐label period (etanercept/etanercept: n = 83; placebo/etanercept: n = 86). At week 104, 61 of 81 (75%), 49 of 81 (61%), 48 of 80 (60%), and 57 of 81 (70%) patients who received etanercept throughout the trial achieved ASAS20, ASAS40, Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease, and Bath Ankylosing Spondylitis Disease Activity Index criteria for 50% improvement (BASDAI 50) scores, respectively (observed). From baseline to week 104, continued improvements in clinical outcomes (ASDAS–C‐reactive protein: −1.5 and −1.7; BASDAI: −3.3 and −3.8 [last observation carried forward]), and SPARCC MRI scores (sacroiliac joint: −6.0 and −3.4; spinal: −2.1 and −0.8 [observed]) were seen in patients receiving etanercept/etanercept and placebo/etanercept. During the study, 8% in the etanercept/etanercept group and 7% in the placebo/etanercept group had serious adverse events; no new safety signals were seen. Patients with early, active nonradiographic axial SpA and an inadequate response to at least 2 NSAIDs demonstrated improvement in clinical and imaging outcomes that were sustained through 104 weeks of etanercept treatment.

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.

Objective.To evaluate the validity of enthesitis indices in patients with peripheral spondyloarthritis (pSpA).Methods.The ABILITY-2 study evaluated the efficacy of adalimumab (ADA) versus placebo (PBO) in patients with active pSpA over 12 weeks. Patients received open-label ADA for an additional 144 weeks. Twenty-nine enthesitis sites used in 3 enthesitis scoring systems [Leeds Enthesitis Index (LEI), Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index, Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)] were assessed; discriminatory capacity and treatment response at Week 12 were calculated by standardized mean difference (SMD) and Guyatt’s effect size (ES). Sites showing resolution or new-onset enthesitis from baseline to Week 12 were analyzed.Results.Overall, 165 patients (ADA, n = 84; PBO, n = 81) were randomized; 143 had ≥ 1 enthesitis site at baseline. The LEI (SMD −0.73, ES −1.07) and SPARCC (SMD −0.56, ES −0.99) enthesitis indices showed higher discriminatory ability and treatment response than MASES (SMD −0.32, ES −0.81). At Week 12, among sites that were positive at baseline, significantly more (p < 0.05) showed resolution among patients treated with ADA versus PBO in the Achilles tendon (60.4% and 36.5%, respectively), medial epicondyle (73.2%, 48.7%), lateral epicondyle (80.6%, 52.8%), and iliac crest (73.5%, 47.2%). Among negative sites at baseline, significantly less (p < 0.05) new-onset enthesitis was observed with ADA versus PBO for Achilles tendon (3.6% and 10.9%, respectively), greater trochanter (3.4%, 14.4%), lateral epicondyle humerus (4.7%, 15.1%), medial femoral condyle (1.6%, 9.2%), and quadriceps insertion superior patella (1.5%, 7.0%).Conclusion.The LEI and SPARCC enthesitis indices showed better discriminatory capacity and treatment response in patients with pSpA versus MASES, likely because these indices contain more peripheral sites. Trial registration number: ClinicalTrials.govNCT01064856.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment for patients with symptomatic axial spondyloarthritis (SpA), who seem to respond best if treated early in the course of disease. The effect of NSAIDs on radiographic disease progression is less clear. Conventional disease-modifying antirheumatic drugs (DMARDs) are not recommended in the treatment of axial SpA, either alone or in combination with TNF blockers. Patients with nonradiographic axial SpA (nr-axSpA) seem to respond as well to TNF blockers as do patients with radiographic axial SpA (ankylosing spondylitis (AS)). However, patients with nr-axSpA should, in addition to a high severity of symptoms, also have objective signs of inflammation, detectable by MRI or by C-reactive protein testing, to be treated with TNF blockers. Whether early TNF-blocker treatment can retard new bone formation needs clarification. In clinical trials, anti-IL-17 agents and TNF blockers showed similar efficacy in patients with AS. The potential of IL-23 blockade for treatment of axial SpA needs to be further investigated. Treatment options for peripheral SpA have been much less thoroughly investigated than those for axial SpA. However, some data indicate that TNF blockers are effective for treating peripheral arthritis, enthesitis and dactylitis, the typical manifestations of peripheral SpA.

Axial spondyloarthritis (SpA) is a spectrum of inflammatory disease with stages characterized by both nonradiographic and radiographic sacroiliitis. Nonradiographic axial SpA is associated with health-related quality-of-life impairment and may progress to ankylosing spondylitis. Axial SpA has a low prevalence in some countries in North Africa and the Middle East, and pooling of data and resources is needed to increase understanding of the regional picture. Early diagnosis and effective treatment are required to reduce disease burden and prevent progression. Anti-TNF therapy is recommended for patients with persistently high disease activity despite conventional treatment, and has been shown to be effective in patients without radiographic damage. Diagnostic delays can be an obstacle to early treatment and appropriate referral strategies are needed. In some countries, restricted access to magnetic resonance imaging and anti-TNF agents presents a challenge. In this article, a group of experts from North Africa and the Middle East evaluated the diagnosis and management of axial SpA with particular reference to this region.

Objective.The aim of the study was to investigate the effect of radiographic spinal progression and disease activity on function and spinal mobility in patients with ankylosing spondylitis (AS) treated with tumor necrosis factor-α (TNF-α) inhibitors for up to 10 years.Methods.Patients with AS who participated in 2 longterm open-label extensions of clinical trials with TNF-α inhibitors (43 receiving infliximab and 17 receiving etanercept) were included in this analysis based on the availability of spinal radiographs performed at baseline and at a later timepoint (yr 2, 4, 6, 8, and 10) during followup. Spinal radiographs were scored according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Function was assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI), spinal mobility by the Bath Ankylosing Spondylitis Metrology Index (BASMI), and disease activity by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).Results.After the initial improvement, BASFI and BASMI remained remarkably stable at low levels over up to 10 years despite radiographic spinal progression. In the generalized mixed effects model analysis, no association between the mSASSS and the BASFI change (β = 0.0, 95% CI −0.03 to 0.03) was found, while there was some effect of mSASSS changes on BASMI changes over time (β = 0.05, 95% CI 0.01–0.09). BASDAI showed a strong association with function (β = 0.64, 95% CI 0.54–0.73) and to a lesser extent, with spinal mobility (β = 0.14, 95% CI 0.01–0.26).Conclusion.Functional status and spinal mobility of patients with established AS remained stable during longterm anti-TNF-α therapy despite radiographic progression. This indicates that reduction and continuous control of inflammation might be able to outweigh the functional effect of structural damage progression in AS.

Objective.To compare clinical examination versus whole-body magnetic resonance imaging (WB-MRI) of enthesitis in patients with early axial spondyloarthritis during 3 years of continuous etanercept (ETN) treatment.Methods.Forty-one patients underwent clinical and WB-MRI examinations for enthesitis at baseline and after 2 and 3 years of treatment. Twenty-one sites were assessed in 4 anatomic regions — anterior chest wall, pelvis, knee, and foot.Results.Clinical examination at baseline detected enthesitis in 57% of the patients (85 lesions, mean 2.1 lesions, SD 2.9), most of them in the pelvis (42 lesions in 17 patients) and anterior chest wall (19 lesions in 10 patients). The proportion of patients with clinically detected enthesitis decreased to 19% at Year 2 (mean 0.5, SD 1.5) and 14% at Year 3 (mean 0.7, SD 1.8). WB-MRI detected enthesitis at baseline in 21% of patients (22 lesions, mean 0.5 lesions, SD 1.1), also most frequently in the pelvis (12 lesions) and anterior chest wall (7 lesions). MRI-positive enthesitis decreased to 13% at Year 2 (mean 0.2 lesions, SD 0.5) and 14% at Year 3 (mean 0.2 lesions, SD 0.5). There was positive correlation of clinical and MRI findings at baseline at the anterior chest wall (p = 0.001) and the pelvis (p = 0.0001). No correlation was found at the knee and foot at baseline and for all regions at followup.Conclusion.Both clinical examination and WB-MRI show a decrease in enthesitis after 2 and 3 years of ETN treatment, but correlation was limited to the pelvis and anterior chest wall at baseline.

Innate immune responses, including monocyte functions, seem to play an important role in the pathogenesis of axial spondyloarthritis (axSpA). Therefore, we characterized the phenotype and functional state of monocytes of patients with axSpA. Fifty-seven patients with axSpA, 11 patients with rheumatoid arthritis (RA), and 29 healthy controls were included in the study. We determined the percentage of classic, intermediate, and non-classic monocytes according to CD14 and CD16 expression and the expression of Toll-like receptor (TLR) 1, 2, and 4 in whole blood by flow cytometry. The percentage of monocytes producing interleukin (IL)-1beta, IL-6, tumor necrosis factor alpha (TNFα), IL-12/23p40, and IL-1 receptor antagonist (IL-1ra) was detected by flow cytometry after stimulation of whole blood without and with different TLR and nucleotide-binding oligomerization domain ligands—i.e., lipopolysaccharide (LPS), fibroblast-stimulating lipopeptid-1, PAM3CSK4, and muramyl dipeptide (MDP)—for 5 h. IL-10 production was measured after 18 h of stimulation in supernatants by enzyme-linked immunosorbent assay. In patients with axSpA but not patients with RA, we found higher frequencies of classic monocytes than in controls (median of 90.4 % versus 80.4 %, P< 0.05), higher frequencies of monocytes spontaneously producing IL-1beta and IL-1ra (P< 0.05), and a higher percentage of monocytes producing IL-1beta after MDP stimulation (P< 0.05). Elevated cytokine production was confined to axSpA patients under conventional therapy (non-steroidal anti-inflammatory drugs) and not found in patients under TNFα inhibitor treatment. The LPS-induced production of IL-6 and IL-10 was lower in axSpA patients compared with controls (P< 0.05). Monocytic TLR expression was unaffected in patients with axSpA. Enhanced spontaneous and MDP-induced cytokine secretion by monocytes suggests in vivopre-activation of monocytes in axSpA patients under conventional therapy which is reverted under TNF inhibitor treatment.

In ankylosing spondylitis (AS), joint remodeling leading to joint ankylosis involves cartilage fusion. Here, we analyzed whether chondrocyte hypertrophy is involved in cartilage fusion and subsequent joint remodeling in AS. We assessed the expression of chondrocyte hypertrophy markers runt-related transcription factor 2 (Runx2), type X collagen (COL10), matrix metalloproteinase 13 (MMP13), osteocalcin and beta-catenin and the expression of positive bone morphogenic proteins (BMPs) and negative regulators (dickkopf-1 (DKK-1)), sclerostin, (wingless inhibitory factor 1 (wif-1)) of chondrocyte hypertrophy in the cartilage of facet joints from patients with AS or osteoarthritis (OA) and from autopsy controls (CO) by immunohistochemistry. Sex determining region Y (SRY)-box 9 (Sox9) and type II collagen (COL2) expression was assessed as indicators of chondrocyte integrity and function. The percentage of hypertrophic chondrocytes expressing Runx2, COL10, MMP13, osteocalcin or beta-catenin was significantly increased in OA but not in AS joints compared to CO joints. Frequencies of sclerostin-positive and DKK-1-positive chondrocytes were similar in AS and CO. In contrast, wif-1- but also BMP-2- and BMP-7-expressing and Sox9-expressing chondrocytes were drastically reduced in AS joints compared to CO as well as OA joints whereas the percentage of COL2-expressing chondrocytes was significantly higher in AS joints compared to CO joints. We found no evidence for chondrocyte hypertrophy within hyaline cartilage of AS joints even in the presence of reduced expression of the wntinhibitor wif-1 suggesting that chondrocyte hypertrophy is not a predominant pathway involved in joint fusion and remodeling in AS. In contrast, the reduced expression of Sox9, BMP-2 and BMP-7 concomitantly with induced COL2 expression rather point to disturbed cartilage homeostasis promoting cartilage degeneration in AS.

Objective.The Assessment of Spondyloarthritis international Society (ASAS) classification criteria for axial spondyloarthritis (axSpA) have added nonradiographic axSpA (nr-axSpA) to the classic ankylosing spondylitis (AS) as defined by the modified New York criteria. However, some confusion remains about differences between classification and diagnosis of axSpA. Our objective was to analyze differences between classification and diagnostic criteria by discussing each feature of the classification criteria based on real cases.Methods.The clinical features of the ASAS classification criteria were evaluated in relation to their significance for an expert diagnosis of axSpA. Twenty cases referred to our tertiary center outpatient clinic were selected because of an incorrect diagnosis of axSpA: 10 cases in which axSpA had been excluded initially because the classification criteria were not fulfilled, and 10 patients who had been previously diagnosed with axSpA because the classification criteria were fulfilled. Upon reevaluation, the former were diagnosed with axSpA while the latter had other diseases.Results.All items that are part of the classification criteria show some variability related to their relevance for a diagnosis of axSpA. There are clinical features suggestive of axSpA that are not part of the classification criteria. Misinterpretation of imaging procedures contributed to false-positive results. Rarely, other diseases may mimic axSpA.Conclusion.Because the sensitivity and specificity of the axSpA classification criteria have been around 80% in clinical trials, some false-positive and false-negative cases were expected. It is hoped that their detailed description and discussion will help to increase the understanding of diagnosing axSpA in relation to the ASAS classification criteria.

Recognition, diagnosis, and management of axial spondyloarthritis (axial SpA) continue to advance.

The concept of axial spondyloarthritis with two forms or subtypes (nonradiographic and radiographic) has been established over the last few years. However, debates concerning especially the nonradiographic form of the disease are still ongoing. Here we summarise recent data on similarities and differences (and their possible explanations) between nonradiographic axial spondyloarthritis and radiographic axial spondyloarthritis (ankylosing spondylitis).