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.

Upadacitinib in active ankylosing spondylitis: results of the 2-year, double-blind, placebo-controlled SELECT-AXIS 1 study and open-label extension.

INTRODUCTION: Long-term safety and efficacy of upadacitinib in patients with active ankylosing spondylitis (AS) has not been previously reported. METHODS: In SELECT-AXIS 1, patients receiving placebo were switched to upadacitinib 15 mg once daily at week 14 while patients initially randomised to upadacitinib continued their regimen through week 104. Efficacy was assessed using as-observed (AO) and non-responder imputation (NRI). RESULTS: Of 187 patients randomised, 144 patients (77%) completed week 104. Among patients receiving continuous upadacitinib, 85.9% (AO) and 65.6% (NRI) achieved Assessment of SpondyloArthritis international Society 40 response (ASAS40) at week 104. Similar magnitude of ASAS40 responses were observed among patients who switched from placebo to upadacitinib (88.7% and 63.8%, respectively). The mean change from baseline to week 104 in Spondyloarthritis Research Consortium of Canada MRI spine and sacroiliac joint inflammation scores were -7.3 and -5.3, respectively, in the continuous upadacitinib group and -7.9 and -4.9 in the placebo-to-upadacitinib switch group. The mean (95% CI) change from baseline to week 104 in the modified Stoke Ankylosing Spondylitis Spine Score was 0.7 (0.3, 1.1) in the total group. Adverse event rate was 242.7/100 patient-years. No serious infections, adjudicated major adverse cardiovascular events, lymphoma, non-melanoma skin cancer, or gastrointestinal perforations were observed. CONCLUSIONS: Upadacitinib 15 mg once daily showed sustained and consistent efficacy over 2 years for ASAS40 and other clinically relevant endpoints. A low rate of radiographic progression was observed and no new safety findings were observed.

Effect of tofacitinib on pain, fatigue, health-related quality of life and work productivity in patients with active ankylosing spondylitis: results from a phase III, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Ankylosing 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. METHODS: Adults 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. RESULTS: In 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). CONCLUSIONS: In 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 NUMBER: NCT03502616.

Secukinumab Efficacy on Enthesitis in Patients With Ankylosing Spondylitis: Pooled Analysis of Four Pivotal Phase III Studies.

OBJECTIVE: To assess the efficacy of secukinumab on axial and peripheral enthesitis in patients with ankylosing spondylitis (AS) using pooled data from randomized controlled phase III studies. METHODS: In this posthoc analysis, data were pooled from patients originally randomized to secukinumab 150 mg, 300 mg, or placebo (PBO) from phase III MEASURE 1-4 studies (ClinicalTrials.gov: NCT01358175, NCT01649375, NCT02008916, and NCT02159053). Maastricht AS Enthesitis Score (MASES) was used for assessments of enthesitis through Week 52. Efficacy outcomes were mean change in MASES score and complete resolution (MASES = 0) of enthesitis in patients with baseline MASES > 0. RESULTS: A total of 693 (71.5%) patients had enthesitis at baseline in secukinumab 300 mg, 150 mg, and PBO groups (58 [76.3%], 355 [70.4%], and 280 [72%], respectively) out of 969 patients pooled in this analysis. At Week 16, mean changes from baseline for overall MASES and enthesitis at axial MASES sites, respectively, were as follows: -2.9 (P < 0.01) and -2.9 (P < 0.01) for secukinumab 300 mg; -2.4 (P < 0.015) and -2.3 (P < 0.05) for secukinumab 150 mg; and -1.9 and -1.8 for PBO, with improvements seen through Week 52. More than one-third of secukinumab-treated patients (300 mg: 36.2%; 150 mg: 40.8%) achieved complete resolution of enthesitis at Week 16. CONCLUSION: Secukinumab improved enthesitis at overall MASES and axial sites in patients with AS.

Secukinumab in non-radiographic axial spondyloarthritis: subgroup analysis based on key baseline characteristics from a randomized phase III study, PREVENT.

BACKGROUND: To investigate the efficacy of secukinumab in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) grouped by disease activity as assessed by C-reactive protein (CRP) levels and/or magnetic resonance imaging (MRI) scores, human leukocyte antigen (HLA)-B27 status, and sex. METHODS: The phase III PREVENT study randomized (1:1:1) 555 patients to receive subcutaneous secukinumab 150 mg with (LD) or without (NL) loading dose or placebo weekly, followed by every 4 weeks starting at week 4. Here, we report the results of a post hoc analysis reporting the efficacy outcomes (pooled secukinumab) to 16 weeks by CRP, MRI, HLA-B27, and sex. RESULTS: Efficacy differences between the secukinumab and the placebo groups were highest in the CRP+, MRI+, HLA-B27+, and male subgroups, particularly for Ankylosing Spondylitis Disease Activity Score-CRP inactive disease and Assessment of SpondyloArthritis international Society (ASAS) partial remission outcomes. ASAS40 response rates in the CRP+/MRI+ subgroup was 52.3% (secukinumab) versus 21.8% (placebo; P < 0.0001) at week 16. ASAS40 response rates (secukinumab versus placebo) were 43.9% versus 32.6% in HLA-B27+, 32.7% versus 16.4% in HLA-B27- subgroups, 51.2% versus 30.8% in male, and 31.7% versus 25.3% in female patients, respectively. CONCLUSIONS: Secukinumab improved the signs and symptoms of nr-axSpA across patients grouped by CRP (+/-) and/or MRI (+/-) status, HLA-B27 (+/-) status, and sex. The highest treatment differences between secukinumab and placebo were observed in patients with both elevated CRP and evidence of sacroiliitis on MRI. Treatment difference was minimal between HLA-B27 (+) and (-) subgroups. Male patients had higher relative responses than female patients. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02696031 . Registered on 02 March 2016.

ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update

To update the Assessment of SpondyloArthritis international Society (ASAS)-EULAR recommendations for the management of axial spondyloarthritis (axSpA). Following the EULAR Standardised Operating Procedures, two systematic literature reviews were conducted on non-pharmacological and pharmacological treatment of axSpA. In a task force meeting, the evidence was presented, discussed, and overarching principles and recommendations were updated, followed by voting. Five overarching principles and 15 recommendations with a focus on personalised medicine were agreed: eight remained unchanged from the previous recommendations; three with minor edits on nomenclature; two with relevant updates (#9, 12); two newly formulated (#10, 11). The first five recommendations focus on treatment target and monitoring, non-pharmacological management and non-steroidal anti-inflammatory drugs (NSAIDs) as firstchoice pharmacological treatment. Recommendations 6­8 deal with analgesics and discourage long-term glucocorticoids and conventional synthetic diseasemodifying antirheumatic drugs (DMARDs) for pure axial involvement. Recommendation 9 describes the indication of biological DMARDs (bDMARDs, that is, tumour necrosis factor inhibitors (TNFi), interleukin-17 inhibitors (IL-17i)) and targeted synthetic DMARDs (tsDMARDs, ie, Janus kinase inhibitors) for patients who have Ankylosing Spondylitis Disease Activity Score ≥2.1 and failed ≥2 NSAIDs and also have either elevated C reactive protein, MRI inflammation of sacroiliac joints or radiographic sacroiliitis. Current practice is to start a TNFi or IL-17i. Recommendation 10 addresses extramusculoskeletal manifestations with TNF monoclonal antibodies preferred for recurrent uveitis or inflammatory bowel disease, and IL-17i for significant psoriasis. Treatment failure should prompt re-evaluation of the diagnosis and consideration of the presence of comorbidities (#11). If active axSpA is confirmed, switching to another b/ tsDMARD is recommended (#12). Tapering, rather than immediate discontinuation of a bDMARD, can be considered in patients in sustained remission (#13). The last recommendations (#14, 15) deal with surgery and spinal fractures. The 2022 ASAS-EULAR recommendations provide up-to-date guidance on the management of patients with axSpA.

Impact of Participation in the Adalimumab (Humira) Patient Support Program on Rheumatoid Arthritis Treatment Course: Results from the PASSION Study.

INTRODUCTION: Patients with rheumatoid arthritis (RA) who are treated with adalimumab (ADA) are offered a proprietary patient support program (PSP, AbbVie Care®). The main objective of this study was to examine the effectiveness of ADA on RA treatment course over time in the context of PSP utilization. METHODS: PASSION was a 78-week post-marketing observational study of RA patients with an insufficient response to ≥1 DMARD newly initiating ADA in routine clinical care that was conducted in Europe, Israel, Mexico, Puerto Rico, and Australia. One prior biologic DMARD was allowed. The primary endpoint was percentage of patients achieving the minimal clinically important difference (MCID; improvement of ≥0.22 compared to baseline) in Health Assessment Questionnaire (HAQ) Disability Index (HAQ-DI) at week 78. Additionally, multiple clinical and patient-reported outcomes (PROs) were evaluated over time. Patients were categorized based on their participation in the PSP: ever (PSP users) vs. never (PSP non-users). Safety events were monitored throughout the study. RESULTS: Overall, 42.8% of PSP users achieved the MCID in HAQ-DI at week 78 (improvement of at least 0.22 compared to baseline). From 1025 enrolled, 48.7% of patients were PSP users while treated with ADA. The percentage of patients achieving MCID in the HAQ-DI was higher in PSP users vs. PSP non-users (48.1 vs. 37.8%) at week 78 (p < 0.001, NRI). Most of the studied clinical outcomes and PROs showed significant improvements (p < 0.05) from baseline to week 78 favoring PSP users over PSP non-users. CONCLUSIONS: In patients with moderate-to-severe RA who initiated ADA, improvements in clinical, functional, and PROs were achieved in real-world settings with significantly greater improvements among PSP users in comparison with PSP non-users. FUNDING: AbbVie. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01383421.

American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.

American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.

Therapy for spondyloarthritis: the role of extra-articular manifestations (eye, skin).

Spondyloarthritis can be considered one of the prototypes (besides rheumatoid arthritis) of an inflammatory rheumatic disease. The locomotor system is prominently involved with arthritis, enthesitis, dactylitis, sacroiliitis, and/or axial disease; but besides the rheumatologic component, other body systems are frequently affected. Extra-articular manifestations are all the medical conditions and symptoms that are not directly related to the locomotor system. Besides inflammatory bowel diseases, the major concept-related extra-articular manifestations are located in the eye (acute anterior uveitis) and the skin (psoriasis). This review focuses on the possible implications of these nonrheumatologic manifestations regarding the treatment of spondyloarthritis.

Tumor necrosis factor-alpha blockade in ankylosing spondylitis: a potent but expensive anti-inflammatory treatment or true disease modification?

Blocking tumor necrosis factor-alpha either with monoclonal antibodies or with soluble receptor constructs has been proven to be effective with an acceptable safety profile in patients with rheumatoid arthritis, and more recently also in the diseases belonging to the spondyloarthropathy concept. Nevertheless multiple questions still remain unresolved especially concerning longer-term treatment. Data from a recent manuscript by Baraliakos and colleagues seem to indicate that at least for the vast majority of ankylosing spondylitis patients treatment with infliximab can not be withdrawn, if one wants to control disease activity in a continuous way. Although still unproven, this might be of crucial importance with regard to structure modification and prevention of ankylosis in this chronic inflammatory disorder.

Immunomodulatory effects of etanercept on peripheral joint synovitis in the spondylarthropathies.

OBJECTIVE: Because different tumor necrosis factor alpha (TNFalpha) blockers may have distinct immunomodulatory effects on specific disease manifestations, the present study was carried out to investigate the immunomodulating effects of etanercept on peripheral synovitis in the spondylarthropathies (SpA). METHODS: Peripheral joint disease was assessed clinically, histologically, and radiologically in a prospective 2-year study of 20 patients with SpA treated with etanercept. Synovial tissue biopsy samples obtained at weeks 0, 12, and 52 were analyzed by histology and immunohistochemistry for the extent of inflammation, changes to tissue architecture, and matrix degradation. Serum levels of myeloid-related protein 8 (MRP-8)/MRP-14, matrix metalloproteinase 3 (MMP-3), and cartilage oligomeric matrix protein (COMP) were determined by enzyme-linked immunosorbent assay. RESULTS: Etanercept induced a rapid and sustained clinical improvement of peripheral joint disease. Histologic synovitis was down-regulated, with a profound reduction in global cellular infiltration and T lymphocytes, but not B lymphocytes. The most prominent change in markers of inflammation was a reduction in the different macrophage subsets (CD68, CD163, MRP-8, and MRP-14), but this was not paralleled by a decrease in serum MRP-8/MRP-14. Structural changes included normalization of lining layer hyperplasia and a moderate reduction in vascularity. However, no effect on the microarchitecture of lymphoid aggregates was observed. In terms of an effect on matrix degradation, the synovial expression of MMP-3 and MMP-9 was down-modulated in correlation with a rapid and profound decrease in serum MMP-3. At week 52, serum COMP levels were also reduced. No significant radiologic disease progression was observed in these patients over a 2-year period. CONCLUSION: Use of etanercept effectively down-modulated the immunopathologic processes of SpA synovitis, both in the short term and in the long term.