Identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood-derived extracellular matrix biomarkers.

OBJECTIVE: To explore the potential of a panel of ECM remodelling markers as endotyping tools for axial spondyloarthritis (axSpA) by separating patients into subtypes and investigate how they differ among each other in disease activity scores and response to treatment with adalimumab. METHODS: In three axSpA studies, a panel of 14 blood-based ECM biomarkers related to formation of collagen (PRO-C2, PRO-C3, PRO-C6), degradation of collagen by metalloproteinases (C1M, C2M, T2CM, C3M, C4M, C6M, C10C), matrix metalloproteinase (MMP)-degraded prolargin (PROM), MMP-degraded and citrullinated vimentin (VICM), basement membrane turnover (PRO-C4) and neutrophil activity (CPa9-HNE) were assessed to enable patient clustering (endotyping). MASH (n=41) was a cross-sectional study, while Adalimumab in Axial Spondyloarthritis study (ASIM,n=45) and Danish Multicenter Study of Adalimumab in Spondyloarthritis (DANISH, n=49) were randomised, double-blind placebo-controlled trials of adalimumab versus placebo every other week for 6 or 12 weeks, respectively, followed by active treatment. Biomarker data were log-transformed, standardised by mean centering and scaled by the SD prior to principal component analysis and K-means clustering. RESULTS: Based on all three studies, we identified two orthogonal dimensions reflecting: (1) inflammation and neutrophil activity (driven by C1M and CPa9-HNE) and (2) collagen turnover (driven by PRO-C2). Three endotypes were identified: high inflammation endotype (Endotype1), low inflammation endotype (Endotype 2) and high collagen turnover endotype (Endotype3). Endotype1 showed higher disease activity (Ankylosing Spondylitis Disease Activity Score (ASDAS)) at baseline compared with Endotype2 and Endotype3 and higher percentage of patients responding to adalimumab based on ASDAS clinical improvement at week 24. Endotype3 showed higher percentage of patients with 50% improvement in Bath Ankylosing Spondylitis Disease Activity Index response at week 24 compared with Endotype2. CONCLUSION: These endotypes differ in their tissue remodelling profile and may in the future have utility for patient stratification and treatment tailoring.

Complement Proteins L-Ficolin and M-Ficolin Are Increased in Patients With Axial Spondyloarthritis and Decrease After Tumor Necrosis Factor Inhibitor Treatment.

OBJECTIVE: We have previously reported elevated levels of the complement lectin pathway proteins L-ficolin and H-ficolin in patients with axial spondyloarthritis (axSpA) compared with healthy controls. The aim of the present study was to investigate these biomarkers in a cross-sectional cohort of patients suffering from low back pain (LBP). Further, we aimed to investigate changes in lectin pathway protein levels after initiation of adalimumab (ADA; a tumor necrosis factor inhibitor) in a longitudinal cohort of patients with axSpA. METHODS: Lectin pathway protein levels (mannan-binding lectin [MBL], collectin liver 1, H-ficolin, L-ficolin, M-ficolin, MBL-associated serine protease [MASP]-1, MASP-2, MASP-3, MBL-associated protein 19 [MAp19], and MAp44) in EDTA plasma were determined in 2 well-characterized cohorts: (1) a clinical cross-sectional cohort of patients with LBP, including patients with axSpA (n = 23), patients with unspecific LBP (uLBP) with ≥ 1 SpA features (n = 55), and patients with uLBP without SpA features or magnetic resonance imaging findings suggestive of axSpA (n = 64); and (2) a randomized double-blinded, placebo-controlled trial cohort of patients with axSpA (n = 49) initiating ADA therapy. Lectin pathway protein levels were determined using immunoassays. RESULTS: Plasma levels of L-ficolin and M-ficolin were significantly increased in the cross-sectional cohort of newly diagnosed patients with axSpA compared with clinically relevant controls with uLBP (all P < 0.05). Both L-ficolin and M-ficolin decreased significantly after ADA therapy (P < 0.05). CONCLUSION: L-ficolin and M-ficolin levels are elevated in newly diagnosed patients with axSpA compared with clinically relevant controls. Both L-ficolin and M-ficolin levels decrease significantly after initiating ADA therapy. These findings provide new insights into the inflammatory processes in axSpA and support the involvement of complement in axSpA pathogenesis.

Extracellular matrix turnover biomarkers reflect pharmacodynamic effects and treatment response of adalimumab in patients with axial spondyloarthritis-results from two randomized controlled trials.

OBJECTIVE: To investigate if extracellular matrix (ECM) blood-based biomarkers reflect the pharmacodynamic effect and response to TNF-α inhibitor therapy (adalimumab, ADA), in patients with axial spondyloarthritis (axSpA). METHODS: We investigated ECM biomarkers in two randomized, double-blind, placebo-controlled trials of axSpA patients (DANISH and ASIM, n = 52 and n = 49, respectively) receiving ADA 40 mg or placebo every other week for 12 and 6 weeks, respectively, and thereafter ADA to week 48. Serum concentrations of degraded type I (C1M), II (C2M, T2CM), III (C3M), IV (C4M), VI (C6M), type X (C10C) collagen; metabolite of C-reactive protein (CRPM), prolargin (PROM), citrullinated vimentin (VICM), calprotectin (CPa9-HNE); and formation of type II (PRO­C2), III (PRO­C3), and VI (PRO­C6) turnover of type IV collagen (PRO-C4) were measured at baseline and weeks 6 or 12, 24, and 48. The pharmacodynamic effect and treatment response to ADA was evaluated by linear mixed models, and correlations between biomarkers and clinical scores were assessed by Spearman's correlation. RESULTS: C1M, C3M, C4M, C6M, CRP, PRO-C4, and CPa9-HNE levels declined after 6 or 12 weeks in patients receiving ADA compared to placebo (all p < 0.05). Patients with AS Disease Activity Score C-reactive protein (ASDAS CRP) major improvement and/or clinically important improvement had significantly higher C1M, C3M, C4M, C6M, and PRO-C4 levels than patients with no/low improvement at baseline (all p < 0.05). Baseline levels of biomarkers showed weak to moderate correlations with ASDAS and structural damage scores. CONCLUSION: ECM metabolites showed a pharmacodynamic effect and were associated with ASDAS response during TNF-α inhibitor treatment in patients with axSpA.

Levels of extracellular matrix metabolites are associated with changes in Ankylosing Spondylitis Disease Activity Score and MRI inflammation scores in patients with axial spondyloarthritis during TNF inhibitor therapy.

BACKGROUND/PURPOSE: In axial spondyloarthritis (axSpA) inflammation of the sacroiliac joints and spine is associated with local extracellular matrix (ECM) remodeling of affected tissues. We aimed to investigate the association of ECM metabolites with treatment response in axSpA patients treated with TNF-α inhibitory therapy for 46 weeks. METHODS: In a prospective clinical study of axSpA patients (n=55) initiating a TNF inhibitor (infliximab, etanercept, or adalimumab), serum concentrations of formation of type I (PRO-C1), type III (PRO-C3), and type VI (PRO-C6) collagen; turnover of type IV collagen (PRO-C4), and matrix-metalloproteinase (MMP)-degraded type III (C3M) collagen, MMP-degraded type IV (C4M), type VI (C6M), and type VII (C7M) collagen, and cathepsin-degraded type X collagen (C10C), MMP-mediated metabolite of C-reactive protein (CRPM), citrullinated vimentin (VICM), and neutrophil elastase-degraded elastin (EL-NE) were measured at baseline, week 2, week 22, and week 46. RESULTS: Patients were mostly males (82%), HLA-B27 positive (84%), with a median age of 40 years (IQR: 32-48), disease duration of 5.5 years (IQR: 2-10), and a baseline Ankylosing Spondylitis Disease Activity Score (ASDAS) of 3.9 (IQR: 3.0-4.5). Compared to baseline, PRO-C1 levels were significantly increased after two weeks of treatment, C6M levels were significantly decreased after two and 22 weeks (repeated measures ANOVA, p=0.0014 and p=0.0015, respectively), EL-NE levels were significantly decreased after 2 weeks (p=0.0008), VICM levels were significantly decreased after two and 22 weeks (p=0.0163 and p=0.0374, respectively), and CRP were significantly decreased after two and 22 weeks (both p=0.0001). Baseline levels of PRO-C1, PRO-C3, C6M, VICM, and CRP were all associated with ASDAS clinically important and major improvement after 22 weeks (ΔASDAS ≥1.1) (Mann-Whitney test, p=0.006, p=0.008, p<0.001, <0.001, <0.001, respectively), while C6M, VICM and CRP levels were associated with ASDAS clinically important and major improvement after 46 weeks (ΔASDAS ≥2.0) (p=0.002, p=0.044, and p<0.001, respectively). PRO-C1 and C6M levels were associated with a Bath AS Disease Activity Score (BASDAI) response to TNF-inhibitory therapy after 22 weeks (Mann-Whitney test, p=0.020 and p=0.049, respectively). Baseline levels of PRO-C4 and C6M were correlated with the total SPARCC MRI Spine and Sacroiliac Joint Inflammation score (Spearman's Rho ρ=0.279, p=0.043 and ρ=0.496, p=0.0002, respectively). CONCLUSIONS: Extracellular matrix metabolites were associated with ASDAS response, MRI inflammation, and clinical treatment response during TNF-inhibitory treatment in patients with axSpA.

Extracellular matrix protein turnover markers are associated with axial spondyloarthritis-a comparison with postpartum women and other non-axial spondyloarthritis controls with or without back pain.

BACKGROUND: Axial spondyloarthritis (axSpA) is a common chronic inflammatory disease, associated with extracellular matrix (ECM) remodeling of the cartilage, bone, and connective tissues. The primary symptom of axSpA is back pain, caused by inflammation. However, there is a medical need to truly identify patients with axSpA from other subjects with buttock or low back pain attributable to other reasons. We aimed to investigate circulating biomarkers of ECM/inflammation (MMP-degraded type I (C1M), II (C2M, T2CM), III (C3M), IV (C4M), VI (C6M), and X (C10C, COL10NC) collagens, CRPM, PROM and VICM) and ECM formation of type II (PRO-C2), III (PRO-C3), IV (PRO-C4), and VI (PRO-C6) collagens as potential biomarkers to identify patients with axSpA. METHODS: We measured biomarkers from a cross-sectional study with 204 participants by enzyme-linked immunosorbent assay (ELISA). The study included axSpA patients (N = 41), women with postpartum buttock/pelvic pain (N = 46), disc herniation (N = 25), and a group of healthy subjects (including women without postpartum pelvic pain (N = 14), subjects with various types of physical strain (cleaning staff (N = 26) long-distance runners (N = 23)), and healthy men (N = 29)). Differences between the groups were calculated by ANCOVA and AUC, while Spearman's correlations were performed with ECM biomarkers and clinical scores. RESULTS: Patients with axSpA expressed significantly higher levels of C1M, C4M, and VICM (p < 0.05-p < 0.0001) compared to all the non-axSpA control groups. Further, C6M and PRO-C4 were significantly higher in patients with axSpA (both p < 0.0001) compared to women with postpartum pelvic pain and healthy subjects, whereas PRO-C3 was significantly lower compared to healthy subjects (p = 0.01). The best ECM common biomarker to differentiate between axSpA and the non-axSpA control groups was PRO-C4 (AUC ≥ 0.75; specificity ≥ 0.79, sensitivity = 0.65). Mild correlations were observed between collagen turnover and inflammation biomarkers and CRP and MRI (ρ ≥ 0.3; p < 0.05-p < 0.001). CONCLUSIONS: Biomarkers of type I, IV, and VI collagen and biomarkers of inflammation showed an altered turnover in patients with axSpA compared with the non-axSpA control groups. Such biomarkers may be useful in combination with MRI or independently to separate patients with axSpA from other back pain conditions.

Ultrasound of the Heel Improves Diagnosis-Tender Entheses in the Heel Region Rarely Corresponds to Inflammatory Enthesitis in Patients with Peripheral Spondyloarthritis.

Enthesitis is a key pathology in spondyloarthritis (SpA), but diagnosis may be clinically challenging. The objective of this study was to investigate the prevalence of ultrasound enthesitis lesions in tender entheses in the heel region in patients with peripheral SpA. In 27 patients with tenderness upon palpation at the Achilles tendon or the plantar fascia insertion, ultrasound assessment of the affected enthesis was performed using greyscale and color Doppler mode. Images were evaluated using the Outcome Measures in Rheumatology (OMERACT) scoring system for enthesitis, scoring presence/absence of hypoechogenicity, thickening, calcifications/enthesophytes, and erosions, and color Doppler activity semi quantitatively from 0 to 3. A total enthesitis sum score was calculated. A second examiner scanned 10 patients for inter-reader reliability. Ultrasound signs of inflammatory enthesitis (thickening/hypoechogenicity and/or Doppler activity) were found in 48%, and 19% showed Doppler activity-all in the Achilles enthesis. Inflammatory pathologies other than enthesitis (e.g., tendinitis, arthritis, bursitis) were identified in 26% of tender heels. The ultrasound OMERACT scoring system for enthesitis lesions showed excellent intra- and inter-reader agreement in a clinical setting. In conclusion, less than 50% of clinically tender entheses are related to inflammatory enthesitis when assessed by ultrasound. Ultrasound is useful for diagnosing other pathologies that may explain tenderness in the area.

Tapering of TNF inhibitors in axial spondyloarthritis in routine care - 2-year clinical and MRI outcomes and predictors of successful tapering.

OBJECTIVES: In a 2-year follow-up study of patients with axial spondyloarthritis (axSpA) in clinical remission who tapered TNF inhibitor (TNFi) treatment according to a clinical guideline, we aimed to investigate the proportion who successfully tapered/discontinued therapy and baseline predictors thereof. The proportion regaining clinical remission after flare and the progression on MRI/radiography were also assessed. METHODS: One-hundred-and-nine patients (78 [72%]/31 [28%] receiving standard and reduced dose, respectively) in clinical remission (BASDAI < 40, physician global score < 40) and no signs of disease activity the previous year tapered TNFi as follows: to two-thirds of standard dose at baseline, half at week 16, one-third at week 32 and discontinuation at week 48. Patients experiencing clinical, BASDAI or MRI flare (predefined criteria) stopped tapering and escalated to previous dose. Prediction analyses were performed by multivariable regression. RESULTS: One hundred and six patients (97%) completed 2 years' follow-up; 55 patients (52%) had successfully tapered: 23 (22%) receiving two-thirds, 15 (14%) half, 16 (15%) one-third dose and 1 (1%) discontinued. In patients at standard dose at baseline (n = 78), lower physician global score was the only independent predictor of successful tapering (odds ratio [OR] = 0.79 [95% CI: 0.64, 0.93]; P = 0.003). In the entire patient group lower physician global score (OR = 0.86 [0.75, 0.98]; P = 0.017), lower Spondyloarthritis Research Consortium of Canada (SPARCC) Sacroiliac Joint Erosion score (OR = 0.78 [0.57, 0.98]; P = 0.029) and current smoker (OR = 3.28 [1.15, 10.57]; P = 0.026) were independent predictors of successful tapering. At 2 years, 97% of patients were in clinical remission. Minimal changes in imaging findings were observed. CONCLUSION: After 2 years following a clinical guideline, 52% of patients with axSpA in clinical remission had successfully tapered TNFi, only 1% discontinued. Baseline physician global score was an independent predictor of successful tapering.

Do tender joints in active psoriatic arthritis reflect inflammation assessed by ultrasound and magnetic resonance imaging?

OBJECTIVE: To investigate the association between clinical joint tenderness and intra- and periarticular inflammation as assessed by ultrasound and MRI in patients with active PsA and to explore if the associations differ according to patient-reported outcomes (PROs) and structural damage. METHODS: Forty-one patients with active PsA and hand involvement had 76/78 joints examined for swelling/tenderness and ultrasound and MRI of 24 and 12 finger joints, respectively. Synovitis, tenosynovitis, periarticular inflammation and erosions were assessed using OMERACT definitions and scoring systems. Correlation between imaging inflammation sum-scores (intra-and periarticular) and tender/swollen joint counts were calculated using Spearman's rho, agreement at joint level was examined using prevalence and bias adjusted kappa (PABAK). Subgroup analyses explored the influence of PROs and radiographic erosive disease on these associations. RESULTS: No significant correlations were found between tender or swollen joint counts and imaging inflammation sum-scores (rho = -0.31-0.38). In patients with higher level of overall pain, disability and lower self-reported mental health, a tendency towards negative correlations were found. At joint level, intra- and periarticular imaging inflammatory lesions had slight agreement with joint tenderness (PABAK = 0.02-0.19) and slight to moderate with swelling (PABAK = 0.16-0.54). For tender joints, agreement with imaging inflammation was even weaker in patients with either high overall pain scores, high disability scores, and/or non-erosive disease. CONCLUSION: Joint tenderness had low association with imaging signs of inflammation in PsA patients, particularly in patients with high self-reported pain, disability and low mental health, indicating that tenderness is influenced by other parameters than local inflammation.

Morphological characteristics of sacroiliac joint MRI lesions in axial spondyloarthritis and control subjects.

OBJECTIVES: To investigate SI joint MRI inflammation, structural and degenerative lesion characteristics in patients with axial spondyloarthritis (axSpA) and various control groups. METHODS: Patients with axSpA (n = 41) and lumbar disc herniation (n = 25), women with (n = 46) and without (n = 14) post-partum (childbirth within 4-16 months) buttock/pelvic pain, cleaning assistants (n = 26), long-distance runners (n = 23) and healthy men (n = 29) had MRI of the SI joints prospectively performed. MRI lesions were assessed on nine slices covering the cartilaginous compartment by two experienced readers according to the definitions of the Spondyloarthritis Research Consortium of Canada SI joint inflammation and structural scores, and were evaluated according to depth and extent. Other morphological characteristics were also analysed. RESULTS: Total depth scores for bone marrow oedema (BME) and fat lesion (FAT) and total extent score for erosion were statistically significantly highest in axSpA, while scores for sclerosis were numerically highest in women with post-partum pain. Maximum BME depth >10 mm was frequently and exclusively found in axSpA and post-partum women (39% vs 14-17%) while FAT depth >5 mm was predominantly found in axSpA (76% vs 0-10%). Erosions were primarily seen in axSpA, especially when extensive (≥4 or confluent; 17% vs 0%). Capsulitis was absent in non-axSpA groups. BME and FAT in the ligamentous compartment were primarily found in axSpA (17/22% vs 0/2% in non-axSpA groups). In non-axSpA, osteophytes (axSpA vs non-axSpA: 0% vs 3-17%) and vacuum phenomenon (7% vs 30-66%) were more frequent, and the joint space was wider [mean (s.d.) 1.5 (0.9) vs 2.2 (0.5) mm]. CONCLUSIONS: FAT depth >5 mm, but not BME depth >10 mm, could almost differentiate axSpA patients from all other groups. When excluding post-partum women, BME >5 mm and erosion were highly specific for axSpA.

Musculoskeletal Pain in Patients with Psoriasis and its Influence on Health-related Quality of Life: Results from a Danish Population-based Survey.

This study used a nationwide e-based survey of patients with psoriasis to assess the pattern of musculoskeletal pain and its influence on patient-reported outcomes, including health-related quality of life and disability. A total of 561 respondents (56% of the screened psoriasis patients) reported physician-diagnosed psoriasis and completed the questionnaire. Respondents were grouped based on the presence of musculoskeletal pain and/or diagnosed psoriatic arthritis: 81% had psoriasis without arthritis (29% pain now, 23% pain previously, 39% no pain ever), and 19% had psoriatic arthritis. Patients with psoriasis with pain now had poorer quality of life compared with patients without pain and, importantly, similar to that of patients with arthritis. Furthermore, patients with pain now/previously reported higher self-assessed severity of psoriasis and lower satisfaction with current treatment than patients without pain. Two-thirds of patients with psoriasis with pain now/previously and one-third of patients with arthritis had never been examined by a rheumatologist, demonstrating an unmet need for adequate evaluation of such patients. A nationwide e-based survey of patients with psoriasis was preformed to assess the pattern of musculoskeletal pain and its influence on patient-reported outcomes, including health-related quality of life and disability. A total of 561 respondents (56% of the screened psoriasis patients) reported physician- diagnosed psoriasis and completed the questionnaire. Respondents were grouped based on the presence of musculoskeletal pain and/or diagnosed psoriatic arthritis: 81% had psoriasis without arthritis (29% pain now, 23% pain previously, 39% no pain ever), and 19% had psoriatic arthritis. Patients with psoriasis with pain now had poorer quality of life compared with patients without pain and, importantly, similar to that of patients with arthritis. Furthermore, patients with pain now/previously reported higher self-assessed severity of psoriasis and lower satisfaction with current treatment than patients without pain. Two-thirds of patients with psoriasis with pain now/previously and one-third of patients with arthritis had never been examined by a rheumatologist, demonstrating an unmet need for adequate evaluation of such patients.

Peripheral Enthesitis Detected by Ultrasonography in Patients With Axial Spondyloarthritis-Anatomical Distribution, Morphology, and Response to Tumor Necrosis Factor-Inhibitor Therapy.

Objectives: To investigate the anatomical distribution, morphological abnormalities and response to adalimumab therapy of ultrasound(US)-detected peripheral enthesitis in patients with axial spondyloarthritis (SpA). Methods: In a randomized, placebo-controlled, double-blinded, investigator-initiated trial (NCT01029847), patients with axial SpA according to the Assessment of Spondyloarthritis International Society criteria were randomized to subcutaneous adalimumab 40 mg every other week or placebo from baseline to week 6. From week 6 to 24, all patients received adalimumab 40 mg every other week. Of 49 patients enrolled, 21 patients participated in our observational US sub-study. US assessment applying the OMERACT US definitions for enthesitis of 10 peripheral entheseal regions of the upper and lower extremities and clinical examination were performed at baseline, weeks 6 and 24. US was performed by one experienced investigator. Hypo-echogenicity, increased thickness and Doppler activity of the enthesis were considered signs of active inflammation, whereas insertional bone erosions, intratendinous calcifications, and enthesophytes were regarded as signs of structural lesions. Results: Enthesitis on US was mostly present in the lower limbs, especially in the Achilles tendon (81%), the quadriceps tendon (62%), and the greater femoral trochanter (52%). Structural lesions were predominant (38 vs. 12% of examined entheses with inflammatory changes), particularly in the entheses of the lower limbs, and exhibited no change during treatment. Conclusion: US-detected structural lesions were common while inflammatory lesions were relatively rare in patients initiating adalimumab due to axial SpA. Structural lesions did not appear to change during 24 weeks follow-up, suggesting that these lesions may not be helpful outcome measures in short-term clinical trials.

The utility of magnetic resonance imaging lesion combinations in the sacroiliac joints for diagnosing patients with axial spondyloarthritis. A prospective study of 204 participants including post-partum women, patients with disc herniation, cleaning staff, runners and healthy persons.

OBJECTIVES: To investigate the diagnostic utility of different combinations of SI joint MRI lesions for differentiating patients with axial SpA (axSpA) from other conditions with and without buttock/pelvic pain. METHODS: A prospective cross-sectional study included patients with axSpA (n = 41), patients with lumbar disc herniation (n = 25), women with (n = 46) and without (n = 14) post-partum (birth within 4-16 months) buttock/pelvic pain and cleaning assistants (n = 26), long-distance runners (n = 23) and healthy men (n = 29) without pain. Two independent readers assessed SI joint MRI lesions according to the Spondyloarthritis Research Consortium of Canada MRI definitions and pre-defined MRI lesion combinations with bone marrow oedema (BME) and fat lesions (FAT), respectively. Statistical analyses included the proportion of participants with scores above certain thresholds, sensitivity, specificity, positive and negative predictive values and likelihood ratios. RESULTS: BME adjacent to the joint space (BME@joint space) was most frequent in axSpA (63.4%), followed by women with post-partum pain (43.5%), but was present in nearly all groups. BME adjacent to fat lesions (BME@FAT) and BME adjacent to erosions (BME@erosion) were only present in axSpA patients and in women with post-partum pain, but scores ≥3 and ≥4, respectively, were only seen in axSpA patients. FAT@erosion was exclusively recorded in axSpA patients. FAT@joint space and FAT@sclerosis were present in most groups, but with higher scores in the axSpA group. CONCLUSION: BME@joint space and FAT@joint space were frequent in axSpA but also in other conditions, reducing the diagnostic utility. FAT@erosion, and BME@FAT, BME@erosion and FAT@sclerosis above certain thresholds, were exclusively seen in axSpA patients and may thus have diagnostic utility in the differentiation of axSpA from other conditions.

Whole-body Magnetic Resonance Imaging Inflammation in Peripheral Joints and Entheses in Axial Spondyloarthritis: Distribution and Changes during Adalimumab Treatment.

OBJECTIVE: To investigate the distribution of whole-body magnetic resonance imaging (WB-MRI) inflammatory lesions of peripheral joints and entheses, and their response to adalimumab (ADA) treatment and agreement with clinical measures of disease activity in patients with axial spondyloarthritis (axSpA). METHODS: Explorative analysis of an investigator-initiated randomized controlled trial of ADA. WB-MRI was performed at weeks 0, 6, 24, and 48. Detailed analyses of WB-MRI lesions in peripheral joints and entheses were performed, including agreement with clinical measures of disease activity. RESULTS: WB-MRI inflammatory lesions were most frequently observed in the acromioclavicular, metatarsophalangeal, and wrist joints (> 10% of joints), and at the greater trochanter, calcaneal insertion of the Achilles tendon, and ischial tuberosity (> 15% of entheses). Inflammation resolved in ≥ 2/3 of involved sternoclavicular, metacarpophalangeal, first carpometacarpal, hip, and tarsometatarsal joints, and pubic symphyses and medial femoral condyles. In contrast, inflammation resolved in ≤ 1/6 of involved acromioclavicular joints, knee joints, and supraspinatus tendon insertions at humerus. Tenderness of joints and entheses agreed poorly with WB-MRI inflammation (κ < 0.40). Joint tenderness resolved more frequently in MRI-positive than MRI-negative joints (8/13, 62% vs 9/34, 26%) after 6 weeks of active treatment. CONCLUSION: Inflammatory lesions of peripheral joints and entheses in patients with predominantly axSpA, and changes therein, can be mapped using WB-MRI, and it may contribute to differentiate between inflammatory and noninflammatory joint tenderness. (Trial registration: ClinicalTrials NCT01029847).

Magnetic Resonance Imaging of Lesions in the Sacroiliac Joints for Differentiation of Patients With Axial Spondyloarthritis From Control Subjects With or Without Pelvic or Buttock Pain: A Prospective, Cross-Sectional Study of 204 Participants.

OBJECTIVE: To evaluate whether different types of sacroiliac (SI) joint lesions identified by magnetic resonance imaging (MRI) could differentiate axial spondyloarthritis (SpA) from conditions with buttock or pelvic pain attributable to other reasons, including postpartum women and healthy subjects. METHODS: The study was designed as a prospective, cross-sectional study involving 204 participants, comprising patients with axial SpA (n = 41) and control groups of subjects with or without SI joint pain, including patients with lumbar disc herniation (n = 25), women with (n = 46) or without (n = 14) postpartum buttock/pelvic pain (having given birth within the preceding 4-16 months), hospital cleaning staff (n = 26), long-distance runners (n = 23), and healthy men (n = 29). Participants underwent clinical examination and MRI, and MRIs were evaluated in a blinded manner by 2 readers according to the Spondyloarthritis Research Consortium of Canada (SPARCC) SI joint inflammation and structural lesion scores. SPARCC score cutoff levels were defined as scores above a certain threshold. Primary analyses were based on reader agreement with regard to the presence of SI joint pathologic features on MRI ("concordant reads"). Sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: SI joint ankylosis and backfill were detected by MRI only in patients with axial SpA (32% and 37%, respectively), while bone marrow edema (BME) and fat lesions were seen in all non-axial SpA control groups (3-39% with BME and 4-14% with fat lesions). SI joint erosion was present only in patients with axial SpA and in women with postpartum buttock/pelvic pain (at erosion score cutoffs of >1 and >4, 61% and 34%, respectively, in patients with axial SpA, and 9% and 2%, respectively, in women with postpartum buttock/pelvic pain). A SPARCC BME score of ≥5 was present only in patients with axial SpA (56%) and in women with postpartum buttock/pelvic pain (24%), while fat lesions were present, albeit rarely, at high SPARCC cutoff scores in nearly all groups. Of the 38 women from the non-postpartum control groups who had given birth (mean time since birth 9.7 years), 2 (5%) had BME, whereas none had SI joint erosion or fat lesions, and none had a BME score of ≥4. CONCLUSION: BME and fat lesions were most pronounced in patients with axial SpA, but also occurred in other groups, particularly women with postpartum buttock/pelvic pain. Erosion above a certain SPARCC score threshold as well as backfill and ankylosis were highly specific for axial SpA.

To switch or not to switch: results of a nationwide guideline of mandatory switching from originator to biosimilar etanercept. One-year treatment outcomes in 2061 patients with inflammatory arthritis from the DANBIO registry.

OBJECTIVES: Real-world evidence on effectiveness of switching to biosimila r etanercept is scarce. In Denmark, a nationwide guideline of mandatory switch from 50 mg originator (ETA) to biosimilar (SB4) etanercept was issued for patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA) in 2016. Clinical characteristics and treatment outcomes were studied in ETA-treated patients, who switched to SB4 (switchers) or maintained ETA (non-switchers). Retention rates were compared with that of a historic cohort of ETA-treated patients. Switchers who resumed ETA treatment (back-switchers) were characterised. METHODS: Observational cohort study based on the DANBIO registry. Treatment retention was explored by Kaplan-Meier plots and Cox regression (crude, adjusted). RESULTS: 1621 (79%) of 2061 ETA-treated patients switched to SB4. Disease activity was unchanged 3 months' preswitch/postswitch. Non-switchers often received 25 mg ETA (ETA 25 mg pens/syringes and powder solution were still available). One-year adjusted retention rates were: non-switchers: 77% (95% CI: 72% to 82%)/switchers: 83% (79% to 87%)/historic cohort: 90% (88% to 92%). Patients not in remission had lower retention rates than patients in remission, both in switchers (crude HR 1.7 (1.3 to 2.2)) and non-switchers (2.4 (1.7 to 3.6)). During follow-up, 120 patients (7% of switchers) back-switched to ETA. Back-switchers' clinical characteristics were similar to switchers, and reasons for SB4 withdrawal were mainly subjective. CONCLUSION: Seventy-nine per cent of patients switched from ETA to SB4. After 1 year, adjusted treatment retention rates were lower in switchers versus the historic ETA cohort, but higher than in non-switchers. Withdrawal was more common in patients not in remission. The results suggest that switch outcomes in routine care are affected by patient-related factors and non-specific drug effects.

Development and Validation of MRI Sacroiliac Joint Scoring Methods for the Semiaxial Scan Plane Corresponding to the Berlin and SPARCC MRI Scoring Methods, and of a New Global MRI Sacroiliac Joint Method.

OBJECTIVE: To develop semiaxial magnetic resonance imaging (MRI) scoring methods for assessment of sacroiliac joint (SIJ) bone marrow edema (BME) in patients with axial spondyloarthritis, and to compare the reliability with equivalent semicoronal scoring methods. METHODS: Two semiaxial SIJ MRI scoring methods were developed based on the principles of the semicoronal Berlin and Spondyloarthritis Research Consortium of Canada (SPARCC) methods. A global quadrant-based method was also developed. Baseline and 12-week MRI of the SIJ from 51 patients participating in a randomized double-blind placebo-controlled trial of adalimumab 40 mg every other week versus placebo were scored by the semiaxial and the corresponding semicoronal methods. Results were compared by linear regression analysis. The reproducibility and sensitivity were evaluated by intraclass correlation coefficients (ICC) and smallest detectable change [SDC, absolute values and percentage of the highest observed score (SDC-HOS)]. RESULTS: Interreader and intrareader ICC were moderate to very high for semiaxial scoring methods (baseline 0.83-0.88 and 0.85-0.97; change 0.33-0.78), while high to very high for semicoronal scoring methods (baseline 0.90-0.92 and 0.93-0.97; change 0.77-0.89). Association between semiaxial and semicoronal scores were high for both the Berlin and SPARCC method (baseline: R2 = 0.93 and 0.88; change: R2 = 0.82 and 0.87, respectively), while lower for the global method (baseline: R2 = 0.79; change: R2 = 0.54). The SDC-HOS were 9.8-18.6% and 5.9-10.7% for the semiaxial and semicoronal methods, respectively. CONCLUSION: Detection of SIJ BME in the semiaxial scan plane is feasible and reproducible. However, a slightly lower reliability of all 3 semiaxial methods supports the general practice of using the coronal scan-plane in therapeutic studies.

A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry.

OBJECTIVES: According to guidelines, a nationwide non-medical switch from originator (INX, Remicade) to biosimilar infliximab (Remsima, CT-P13) was conducted in Danish patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA). We investigated disease activity before/after switching and retention rates in the DANBIO registry. METHODS: Disease activities 3 months before and after switch and changes over time were calculated. Flare was defined as change in 28 Joint Disease Activity Score (∆DAS28) ≥1.2 (RA/PsA) or Ankylosing Spondylitis Disease Activity Score (∆ASDAS) ≥1.3 (AxSpA). Crude and adjusted retention rates were compared with a historic cohort of INX-treated patients. RESULTS: Eight hundred and two patients switched (403 RA/120 PsA/279 AxSpA; 51% women, age (median (IQR): 55 (44-66)) years). Follow-up was 413 (339-442) days. Prior INX treatment duration was 6.8 (4.3-9.5) years. Disease activities were similar 3 months before/after switch. Crude 1-year CT-P13 retention rate (84.1 (95% CI 81.3 to 86.5)) was similar to the historic IFX cohort (86.2 (95% CI 84.0 to 88.0), p=0.22). The adjusted absolute retention rates were 83.4 (95% CI 80.8 to 86.2) and 86.8% (95% CI 84.8 to 88.8), respectively (p=0.03). In total 132 patients withdrew (lack of effect: 71/132=54%, adverse events: 37/132=28%). Patients with previous INX treatment duration >5 years had longer CT-P13 retention. CONCLUSION: In 802 arthritis patients treated with INX for median >6 years, a nationwide non-medical switch to CT-P13 had no negative impact on disease activity. Adjusted 1-year CT-P13 retention rate was slightly lower than for INX in a historic cohort.