Alexandre Sepriano

2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis

To update and integrate the recommendations for ankylosing spondylitis and the recommendations for the use of tumour necrosis factor inhibitors (TNFi) in axial spondyloarthritis (axSpA) into one set applicable to the full spectrum of patients with axSpA. Following the latest version of the European League Against Rheumatism (EULAR) Standardised Operating Procedures, two systematic literature reviews first collected the evidence regarding all treatment options (pharmacological and non-pharmacological) that were published since 2009. After a discussion of the results in the steering group and presentation to the task force, overarching principles and recommendations were formulated, and consensus was obtained by informal voting. A total of 5 overarching principles and 13 recommendations were agreed on. The first three recommendations deal with personalised medicine including treatment target and monitoring. Recommendation 4 covers non-pharmacological management. Recommendation 5 describes the central role of non-steroidal anti-inflammatory drugs (NSAIDs) as first-choice drug treatment. Recommendations 6–8 define the rather modest role of analgesics, and disprove glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (DMARDs) for axSpA patents with predominant axial involvement. Recommendation 9 refers to biological DMARDs (bDMARDs) including TNFi and IL-17 inhibitors (IL-17i) for patients with high disease activity despite the use (or intolerance/contraindication) of at least two NSAIDs. In addition, they should either have an elevated C reactive protein and/or definite inflammation on MRI and/or radiographic evidence of sacroiliitis. Current practice is to start with a TNFi. Switching to another TNFi or an IL-17i is recommended in case TNFi fails (recommendation 10). Tapering, but not stopping a bDMARD, can be considered in patients in sustained remission (recommendation 11). The final two recommendations (12, 13) deal with surgery and spinal fractures. The 2016 Assessment of SpondyloArthritis international Society-EULAR recommendations provide up-to-date guidance on the management of patients with axSpA.

Prevalence of rheumatic and musculoskeletal diseases and their impact on health-related quality of life, physical function and mental health in Portugal: results from EpiReumaPt– a national health survey

Objectives To estimate the national prevalence of rheumatic and musculoskeletal diseases (RMDs) in the adult Portuguese population and to determine their impact on health-related quality of life (HRQoL), physical function, anxiety and depression. Methods EpiReumaPt is a national health survey with a three-stage approach. First, 10 661 adult participants were randomly selected. Trained interviewers undertook structured face-to-face questionnaires that included screening for RMDs and assessments of health-related quality of life, physical function, anxiety and depression. Second, positive screenings for ≥1 RMD plus 20% negative screenings were invited to be evaluated by a rheumatologist. Finally, three rheumatologists revised all the information and confirmed the diagnoses according to validated criteria. Estimates were computed as weighted proportions, taking the sampling design into account. Results The disease-specific prevalence rates (and 95% CIs) of RMDs in the adult Portuguese population were: low back pain, 26.4% (23.3% to 29.5%); periarticular disease, 15.8% (13.5% to 18.0%); knee osteoarthritis (OA), 12.4% (11.0% to 13.8%); osteoporosis, 10.2% (9.0% to 11.3%); hand OA, 8.7% (7.5% to 9.9%); hip OA, 2.9% (2.3% to 3.6%); fibromyalgia, 1.7% (1.1% to 2.1%); spondyloarthritis, 1.6% (1.2% to 2.1%); gout, 1.3% (1.0% to 1.6%); rheumatoid arthritis, 0.7% (0.5% to 0.9%); systemic lupus erythaematosus, 0.1% (0.1% to 0.2%) and polymyalgia rheumatica, 0.1% (0.0% to 0.2%). After multivariable adjustment, participants with RMDs had significantly lower EQ5D scores (β=−0.09; p<0.001) and higher HAQ scores (β=0.13; p<0.001) than participants without RMDs. RMDs were also significantly associated with the presence of anxiety symptoms (OR=3.5; p=0.006). Conclusions RMDs are highly prevalent in Portugal and are associated not only with significant physical function and mental health impairment but also with poor HRQoL, leading to more health resource consumption. The EpiReumaPt study emphasises the burden of RMDs in Portugal and the need to increase RMD awareness, being a strong argument to encourage policymakers to increase the amount of resources allocated to the treatment of rheumatic patients.

Predictive validity of the ASAS classification criteria for axial and peripheral spondyloarthritis after follow-up in the ASAS cohort: a final analysis

Objective To establish the predictive validity of the Assessment of SpondyloArthritis international Society (ASAS) spondyloarthritis (SpA) classification criteria. Methods 22 centres (N=909 patients) from the initial 29 ASAS centres (N=975) participated in the ASAS-cohort follow-up study. Patients had either chronic (>3 months) back pain of unknown origin and age of onset below 45 years (N=658) or peripheral arthritis and/or enthesitis and/or dactylitis (N=251). At follow-up, information was obtained at a clinic visit or by telephone. The positive predictive value (PPV) of the baseline classification by the ASAS criteria was calculated using rheumatologists diagnosis at follow-up as external standard. Results In total, 564 patients were assessed at follow-up (345 visits; 219 telephone) with a mean follow-up of 4.4 years (range: 1.9; 6.8) and 70.2% received a SpA diagnosis by the rheumatologist. 335 patients fulfilled the axial SpA (axSpA) or peripheral SpA (pSpA) criteria at baseline and of these, 309 were diagnosed SpA after follow-up (PPV SpA criteria: 92.2%). The PPV of the axSpA and pSpA criteria was 93.3% and 89.5%, respectively. The PPV for the ‘clinical arm only’ was 88.0% and for the ‘clinical arm’±‘imaging arm’ 96.0%, for the ‘imaging arm only’ 86.2% and for the ‘imaging arm’+/-‘clinical arm’ 94.7%. A series of sensitivity analyses yielded similar results (range: 85.1–98.2%). Conclusions The PPV of the axSpA and pSpA criteria to forecast an experts diagnosis of ‘SpA’ after more than 4 years is excellent. The ‘imaging arm’ and ‘clinical arm’ of the axSpA criteria have similar predictive validity and are truly complementary.

Efficacy and safety of biological and targeted-synthetic DMARDs: a systematic literature review informing the 2016 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis

Objectives To update the evidence for the efficacy and safety of (b)biological and (ts)targeted-synthetic disease-modifying anti-rheumatic drugs (DMARDs) in patients with axial spondyloarthritis (axSpA) to inform the 2016 update of the Assessment of SpondyloArthritis international Society/European League Against Rheumatism (ASAS/EULAR) recommendations for the management of axSpA. Methods Systematic literature review (2009–2016) for randomised controlled trials (RCT), including long-term extensions, strategy trials and observational studies (the latter was only for safety assessment and a comparator was required). Interventions were any bDMARD or tsDMARD. All relevant efficacy and safety outcomes were included. Results 76 papers and 24 abstracts fulfilled the inclusion criteria. Large treatment effects were found both in radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA) for all tumour necrosis factor inhibitors (TNFi) (NNT to achieve ASAS40 response ranged between 2.6–5.2 for r-axSpA and 2.3–5.4 for nr-axSpA). For nr-axSpA, efficacy was superior for those who had objective signs of inflammation (positive C reactive protein or inflammation on MRI-SI). Secukinumab 150 mg has shown efficacy in two phase 3 RCTs (NNT to achieve ASAS40 response: 3.4 and 4.0). Ustekinumab and tofacitinib have shown positive results in phase 2/proof-of-concept trials; trials with apremilast, rituximab, interleukin (IL)-6 antagonists and abatacept have failed their primary end points. New (unknown) safety signals were not found in the trials but long-term observational safety data for TNFi are still scarce. Conclusions New evidence supports the efficacy and safety of TNFi both in r-axSpA and nr-axSpA. Secukinumab is the first drug targeting the IL-17 pathway in r-axSpA that has shown efficacy.

Low osteocalcin/collagen type I bone gene expression ratio is associated with hip fragility fractures

INTRODUCTION Osteocalcin (OC) is the most abundant non-collagenous bone protein and is determinant for bone mineralization. We aimed to compare OC bone expression and serum factors related to its carboxylation in hip fragility fracture and osteoarthritis patients. We also aimed to identify which of these factors were associated with worse mechanical behavior and with the hip fracture event. METHODS In this case-control study, fragility fracture patients submitted to hip replacement surgery were evaluated and compared to a group of osteoarthritis patients submitted to the same procedure. Fasting blood samples were collected to assess apolipoproteinE (apoE) levels, total OC and undercarboxylated osteocalcin (ucOC), vitamin K, LDL cholesterol, triglycerides and bone turnover markers. The frequency of the apoε4 isoform was determined. Femoral epiphyses were collected and trabecular bone cylinders drilled in order to perform compression mechanical tests. Gene expression of bone matrix components was assessed by quantitative RT-PCR analysis. RESULTS 64 patients, 25 submitted to hip replacement surgery due to fragility fracture and 39 due to osteoarthritis, were evaluated. Bone OC/collagen expression (OC/COL1A1) ratio was significantly lower in hip fracture compared to osteoarthritis patients (p<0.017) adjusted for age, gender and body mass index. Moreover, OC/COL1A1 expression ratio was associated with the hip fracture event (OR ~0; p=0.003) independently of the group assigned, or the clinical characteristics. Apoε4 isoform was more frequent in the hip fracture group (p=0.029). ucOC levels were higher in the fracture group although not significantly (p=0.058). No differences were found regarding total OC (p=0.602), apoE (p=0.467) and Vitamin K (p=0.371). In hip fracture patients, multivariate analysis, adjusted for clinical characteristics, serum factors related to OC metabolism and gene expression of bone matrix proteins showed that low OC/COL1A1 expression ratio was significantly associated with worse trabecular strength (β=0.607; p=0.013) and stiffness (β=0.693; p=0.003). No association was found between ucOC and bone mechanics. Moreover, in osteoarthritis patients, the multivariate analysis revealed that serum total OC was negatively associated with strength (β=-0.411; p=0.030) and stiffness (β=-0.487; p=0.009). CONCLUSION We demonstrated that low bone OC/COL1A1 expression ratio was an independent predictor of worse trabecular mechanical behavior and of the hip fracture event. These findings suggest that in hip fracture patients the imbalance of bone OC/COL1A1 expression ratio reflects disturbances in osteoblast activity leading to bone fragility.

Sacroiliac radiographic progression in recent onset axial spondyloarthritis: the 5-year data of the DESIR cohort

Objective To estimate sacroiliac joint radiographic (X-SIJ) progression in patients with axial spondyloarthritis (axSpA) and to evaluate the effects of inflammation on MRI (MRI-SIJ) on X-SIJ progression. Methods X-SIJ and MRI-SIJ at baseline and after 2 and 5 years in patients with recent onset axSpA from the DESIR cohort were scored by three central readers. Progression was defined as (1) the shift from non-radiographic (nr) to radiographic (r) sacroiliitis (by modified New York (mNY) criteria) or alternative criteria, (2) a change of at least one grade or (3) a change of at least one grade but ignoring a change from grade 0 to 1. The effects of baseline inflammation on MRI-SIJ on 5-year X-SIJ damage (mNY) were tested by generalised estimating equations. Results In 416 patients with pairs of baseline and 5-year X-SIJ present, net progression occurred in 5.1% (1), 13.0% (2) and 10.3% (3) respectively, regarding a shift from nr-axSpA to r-axSpA (1), a change of at least one grade (2) or a change of at least one grade but ignoring a change from grade 0 to 1 (3). Baseline MRI-SIJ predicted structural damage after 5 years in human leukocyte antigen-B27 (HLA-B27) positive (OR 5.39 (95% CI 3.25 to 8.94)) and in HLA-B27 negative (OR 2.16 (95% CI 1.04 to 4.51)) patients. Conclusions Five-year progression of X-SIJ damage in patients with recent onset axSpA is limited but present beyond measurement error. Baseline MRI-SIJ inflammation drives 5-year radiographic changes.

Efficacy and safety of non-pharmacological and non-biological pharmacological treatment: a systematic literature review informing the 2016 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis

To assess the efficacy and safety of non-biological therapies in patients with axial spondyloarthritis (axSpA) to inform the update of the Assessment of SpondyloArthritis international Society (ASAS)/European League Against Rheumatism (EULAR) recommendations for the management of axSpA. A systematic literature review (2009–2016) of all non-pharmacological treatments, non-biological drugs (except targeted synthetic disease-modifying antirheumatic drugs (DMARDs)) and surgical therapies was performed. Randomised controlled trials (RCTs) and clinical controlled trials were assessed for efficacy and safety, while observational studies with a comparator were assessed for safety. All relevant efficacy and safety outcomes were included. Study heterogeneity precluded data pooling. If possible, Cohens effect size was calculated for non-pharmacological treatments. In total, 45 papers and 2 abstracts were included. Studies on non-pharmacological treatments were very heterogeneous but overall confirmed a benefit for regular exercises, with small improvements in disease activity, function and spinal mobility. New studies on non-steroidal anti-inflammatory drugs (NSAIDs) confirmed their efficacy and new safety signals were not found. NSAIDs used continuously compared with on-demand did not reduce the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) mean change over 2 years in patients with ankylosing spondylitis with normal C reactive protein (CRP; ≤5 mg/L) (1 ‘negative’ RCT (0.9 vs 0.8; p=0.62)), while for patients with high CRP, conflicting results were found (1 ‘positive’ RCT (0.2 vs 1.7; p=0.003), 1 ‘negative’ RCT (1.68 vs 0.96; p=0.28)). No new trials were found for conventional synthetic DMARDs (csDMARDs). Short-term high-dose systemic glucocorticoids showed limited efficacy. Regular exercises may improve several outcomes. Efficacy and safety of NSAIDs in axSpA are confirmed. Glucocorticoids are not proven to be effective in axSpA and new data on csDMARDs are lacking.

Effect of Comedication With Conventional Synthetic Disease-Modifying Antirheumatic Drugs on Retention of Tumor Necrosis Factor Inhibitors in Patients With Spondyloarthritis: A Prospective Cohort Study.

To evaluate whether use of comedication with conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs) influences the retention of tumor necrosis factor inhibitors (TNFi) in patients with spondyloarthritis (SpA).

Five-year follow-up of radiographic sacroiliitis: progression as well as improvement?

Determining the presence of radiographic sacroiliitis is a key feature in the diagnostic process of radiographic axial spondyloarthritis (r-axSpA), synonymous to ankylosing spondylitis according to the modified New York criteria (mNY).1 Its presence is considered prognostically relevant and paves the way for treatment with biological drugs.2 Multiread and multireader exercises have proven that radiographic sacroiliitis is an ambiguous finding, as reflected by large inter-reader and intrareader variability.3 ,4 Determining progression of radiographic sacroiliitis, which marks the arbitrary but irreversible change from non-radiographic axSpA (nr-axSpA) to r-axSpA, is even more ambiguous. The mNY lack sensitivity-to-change in this slowly progressing condition, and it is conceivable that regression of radiographic sacroiliitis is very rare if not impossible.5 Previous studies addressing progression from nr-axSpA to …

Imaging in diagnosis, outcome prediction and monitoring of large vessel vasculitis: a systematic literature review and meta-analysis informing the EULAR recommendations

Objectives To perform a systematic literature review on imaging techniques for diagnosis, outcome prediction and disease monitoring in large vessel vasculitis (LVV) informing the European League Against Rheumatism recommendations for imaging in LVV. Methods Systematic literature review (until 10 March 2017) of diagnostic and prognostic studies enrolling >20 patients and investigating ultrasound, MRI, CT or positron emission tomography (PET) in patients with suspected and/or established primary LVV. Meta-analyses were conducted, whenever possible, obtaining pooled estimates for sensitivity and specificity by fitting random effects models. Results Forty-three studies were included (39 on giant cell arteritis (GCA), 4 on Takayasu arteritis (TAK)). Ultrasound (‘halo’ sign) at temporal arteries (8 studies, 605 patients) and MRI of cranial arteries (6 studies, 509 patients) yielded pooled sensitivities of 77% (95% CI 62% to 87%) and 73% (95% CI 57% to 85%), respectively, compared with a clinical diagnosis of GCA. Corresponding specificities were 96% (95% CI 85% to 99%) and 88% (95% CI 81% to 92%). Two studies (93 patients) investigating PET for GCA diagnosis reported sensitivities of 67%–77% and specificities of 66%–100% as compared with clinical diagnosis or temporal artery biopsy. In TAK, one study each evaluated the role of magnetic resonance angiography and CT angiography for diagnostic purposes revealing both a sensitivity and specificity of 100%. Studies on outcome prediction and monitoring disease activity/damage were limited and mainly descriptive. Conclusions Ultrasound and MRI provide a high diagnostic value for cranial GCA. More data on the role of imaging for diagnosis of extracranial large vessel GCA and TAK, as well as for outcome prediction and monitoring in LVV are warranted.