MRI-based synthetic CT: a new method for structural damage assessment in the spine in patients with axial spondyloarthritis - a comparison with low-dose CT and radiography.

OBJECTIVE: To investigate the ability of MRI-based synthetic CT (sCT), low-dose CT (ldCT) and radiography to detect spinal new bone formation (NBF) in patients with axial spondyloarthritis (axSpA). METHODS: Radiography of lumbar and cervical spine, ldCT and sCT of the entire spine were performed in 17 patients with axSpA. sCT was reconstructed using the BoneMRI application (V.1.6, MRIGuidance BV, Utrecht, NL), a quantitative three-dimensional MRI-technique based on a dual-echo gradient sequence and a machine learning processing pipeline that can generate CT-like MR images. Images were anonymised and scored by four readers blinded to other imaging/clinical information, applying the Canada-Denmark NBF assessment system. RESULTS: Mean scores of NBF lesions for the four readers were 188/209/37 for ldCT/sCT/radiography. Most NBF findings were at anterior vertebral corners with means 163 on ldCT, 166 on sCT and 35 on radiography. With ldCT of the entire spine as reference standard, the sensitivity to detect NBF was 0.67/0.13 for sCT/radiography; both with specificities >0.95. For levels that were assessable on radiography (C2-T1 and T12-S1), the sensitivity was 0.61/0.48 for sCT/radiography, specificities >0.90. For facet joints, the sensitivity was 0.46/0.03 for sCT/radiography, specificities >0.94. The mean inter-reader agreements (kappa) for all locations were 0.68/0.58/0.56 for ldCT/sCT/radiography, best for anterior corners. CONCLUSION: With ldCT as reference standard, MRI-based sCT of the spine showed very high specificity and a sensitivity much higher than radiography, despite limited reader training. sCT could become highly valuable for detecting/monitoring structural spine damage in axSpA, not the least in clinical trials.

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.

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.

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.

Anatomic Distribution of Sacroiliac Joint Lesions on Magnetic Resonance Imaging in Patients With Axial Spondyloarthritis and Control Subjects: A Prospective Cross-Sectional Study, Including Postpartum Women, Patients With Disc Herniation, Cleaning Staff, Runners, and Healthy Individuals.

OBJECTIVE: To investigate the anatomic location and distribution of lesions on magnetic resonance imaging (MRI) in the sacroiliac (SI) joints in patients with axial spondyloarthritis (SpA), women with and without postpartum pain (childbirth within 4-16 months), patients with disc herniation, cleaning staff, runners, and healthy persons. METHODS: In a prospective cross-sectional study of 204 participants, MRI of the entire cartilaginous compartment of the SI joint was scored blindly by 2 independent, experienced readers, according to Spondyloarthritis Research Consortium of Canada definitions of SI joint inflammation and structural lesions in each SI joint quadrant or half and in each of 9 slices. The locations of the lesions (unilateral/bilateral, upper/lower, sacral/iliac, and anterior/central/posterior slices) were analyzed based on concordant reads. RESULTS: Bone marrow edema (BME) occurred in all quadrants in nearly all participant groups, but rarely bilaterally, except in patients with axial SpA and women with postpartum pain. Fat lesions were mainly found in axial SpA and occurred in all quadrants, but mostly bilaterally in sacral quadrants. Erosion was rare, except in axial SpA, where it was mainly iliac and often bilateral. Sclerosis was exclusively iliac and most frequent in women with postpartum pain. CONCLUSION: The location and distribution of common SI joint lesions in axial SpA and non-axial SpA were reported, and group-specific patterns were revealed. BME distributed bilaterally or unilaterally, both locally and more widespread in the SI joint, is common in both postpartum women with pain and axial SpA patients, which limits the use of BME to differentiate these groups. This study indicates that the presence of fat lesions, especially when widespread, and/or erosion, particularly when located centrally or posteriorly, are diagnostically important and should be investigated further.

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.

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.

[Stiff person syndrome is a rare autoimmune disorder]. / Stiff person-syndrom er en sjælden autoimmun sygdom

Atypical symptoms raise classical diagnostic dilemmas of somatic versus functional disease. The challenge is greater when the condition is less frequent. Illustrating this issue is a case of stiff person syndrome (SPS) where a 46-year-old man was admitted with lower back and hip pain and stiffness of the musculature of the lower extremities resulting in stooped gait. Stiffness was absent while sleeping. Thorough clinical examination and tests were unable to explain the symptomology until suspicion of SPS was raised, supported by high levels of glutamic acid decarboxylase antibodies.