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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., Competing Interests: Competing interests: MØ: research grants from AbbVie, BMS, Merck, Novartis and UCB, and speaker and/or consultancy fees from AbbVie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Galapagos, Gilead, Hospira, Janssen, MEDAC, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB. SJP: speaker’s bureau MSD, Pfizer, AbbVie, UCB, Novartis. Consulting fees and/or honoraria: AbbVie, UCB, Novartis. Grant/research support: AbbVie, MSD and Novartis. HP: none. Frederik Christiansen: Employed at Nordic Bioscience A/S. SHN: employed and shareholder of Nordic Bioscience A/S. PF: none. A-CB-J: employed and shareholder of Nordic Bioscience A/S. MK Shareholder of: employed and shareholder of Nordic Bioscience A/S. SS: None. IJS: none. AGL: speaking and/or consulting fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, and UCB. Research grant from Novartis. ORM: none., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 (PRO‑C2), III (PRO‑C3), and VI (PRO‑C6) 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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.

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., (© 2020, American College of Rheumatology.)

Objectives: The apparent diffusion coefficient (ADC) may be used as a biomarker for diagnosis and/or monitoring treatment response in patients with axial spondyloarthritis (axSpA), but this requires reliable ADC measurements. This study assessed test-retest repeatability and reproducibility of ADC measurements using four different region of interest (ROI) settings., Methods: In this prospective study, the sacroiliac joints (SIJs) of 25 patients with axSpA and 24 age- and sex-matched healthy volunteers were imaged twice at a mean interval of 6.8 days in a 1.5 T scanner using, multishot echoplanar diffusion-weighted sequences. ADCs at four ROI settings were assessed: 5 mm and 10 mm anatomic band-shaped, 15 mm linear, and 40 mm 2 circular., Results: Intraclass correlation coefficient (ICC) assessments showed that the interstudy repeatability was good for median ADC (ADC med ) and 95th-percentile ADC (ADC 95 ) measurements in patients with axSpA (0.77-0.83 and 0.75-0.83, respectively), but poor-to-moderate in healthy subjects (0.27-0.55 and 0.13-0.37, respectively). For all ROI settings, intrareader reproducibility was excellent for ADC med -measurements (ICC:0.85-0.99) and moderate-to-excellent for ADC 95 measurements (ICC:0.68-0.96). The 5 mm ROI had the least estimated bias and highest level of agreement on Bland-Altman plots. The interreader reproducibility was moderate (ICC:0.71). The 15 mm linear ROI produced significantly greater ADC med and ADC 95 measurements than all other ROI settings ( p < 0.01-0.02), except for the circular ROI ADC 95 measurements., Conclusion: ROI settings influence ADC measurements. Interstudy repeatability of SIJ ADC measurements is independent of ROI settings. However, the 5 mm ROI showed the least bias and random error and seems preferable., Advances in Knowledge: ADC measurements are affected by ROI settings, and this should be taken into account when assessing ADC maps., (© 2020 The Authors. Published by the British Institute of Radiology.)

Purpose: To compare three region-of-interest (ROI) settings in the assessment of ADC in a clinical trial, and to evaluate the effectiveness of ADC in assessing therapy-induced changes and predicting clinical outcomes., Methods: In a 52-week clinical trial involving patients with axial spondyloarthritis, mean sacroiliac joint (SIJ) ADC measurements using structured, lesion-based, and index-lesion ROI-settings were assessed at baseline and weeks 4, 16, and 52. Variation among the three ROI-settings, correlations with Spondyloarthritis Research Consortium of Canada (SPARCC)-bone marrow edema (BME) SIJ inflammation indices, standardized response means (SRMs), and effectiveness in predicting clinical outcomes were analyzed., Results: Forty of the 53 patients had at least one assessable SIJ lesion on ADC at baseline. The mean of the structured ROI ADC (ADC struc ) was 230 μmm 2 /s (standard deviation [SD] = 120). This was significantly lower ( p  < 0.01) than the means of the lesion-based ROI ADC (ADC lesion  = 420 μmm 2 /s, SD = 210) and index-lesion ROI ADC (ADC index  = 471 μmm 2 /s, SD = 278), which did not differ. ADC correlated with SPARCC-BME scores at baseline ( p  < 0.01) as did changes over time in ADC- and SPARCC-BME ( p <0.05). At all follow-up time points, responsiveness was high for ADC lesion (SRM > 0.92) and ADC index (SRM > 0.87) while moderate for ADC struc (SRM:0.54-0.67). Baseline ADC and changes in ADC did not predict clinical outcomes., Conclusions: Lesion-based and index-lesion ROI ADC could both be used to evaluate the effectiveness of tumor necrosis factor inhibitor therapy. None of the methods could predict clinical outcomes., (© 2020 The Author(s).)

Objectives: To investigate criteria for treatment response and remission in patients with axial SpA as assessed by whole-body magnetic resonance imaging (WB-MRI) of axial and peripheral joints and entheses during treatment with golimumab., Methods: We performed an investigator-initiated cohort study of 53 patients who underwent WB-MRI at weeks 0, 4, 16 and 52 after initiation of golimumab. Images were assessed according to the Spondyloarthritis Research Consortium of Canada MRI SI joint inflammation index, Canada-Denmark MRI spine inflammation score and the MRI peripheral joints and entheses inflammation index., Results: At weeks 4, 16 and 52, WB-MRI demonstrated an at least 50% reduction of MRI inflammation of the sacroiliac joints in 16, 29 and 32 (30%, 55% and 60%) patients, of the spine in 20, 30 and 31 (38%, 57% and 58%) patients and of peripheral joints and entheses in 8, 17 and 15 (15%, 32% and 28%) patients, respectively. The BASDAI50 response was achieved by 29, 31 and 31 (55%, 58% and 58%) patients, while ASDAS clinically important improvement (ASDAS-CII) was achieved by 37, 40 and 34 (70%, 75% and 64%) patients. WB-MRI remission criteria for spine, sacroiliac joints and peripheral joints and entheses were explored; total WB-MRI remission was attained by 2, 6 and 3 (4%, 11% and 6%) patients. At week 16, among 35 patients with an at least 50% reduction in the MRI Axial Inflammation Index (sacroiliac joint and spine inflammation), 29 (83%) achieved BASDAI50 and 35 (100%) achieved ASDAS-CII; among 16 patients with MRI axial inflammation non-response, 14 (88%) were BASDAI50 non-responders and 11 (69%) did not achieve ASDAS-CII., Conclusion: WB-MRI demonstrated a significant reduction of inflammation in both the spine, sacroiliac joints and peripheral joints and entheses during golimumab treatment. Few patients achieved total WB-MRI remission. Combining spinal and sacroiliac joint inflammation in an MRI Axial Inflammation Index increased the ability to capture response., Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02011386., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (Copyright © 2020 Seven, Pedersen, Østergaard, Felbo, Sørensen, Døhn and Terslev.)

Background: The apparent diffusion coefficient (ADC) may be used as a biomarker to diagnose axial spondyloarthritis (axSpA) and monitor therapeutic response., Purpose: To measure the repeatability of the ADC in healthy individuals and in patients with axSpA with and without active sacroiliitis in a test-retest set-up, and to correlate ADC to conventional magnetic resonance imaging (MRI) bone marrow edema (BME) scores and clinical findings., Material and Methods: A total of 25 patients with axSpA and 24 sex- and age-matched healthy individuals were prospectively examined with MRI twice within 10 days. Short tau inversion recovery (STIR), T1-weighted and diffusion-weighted imaging sequences were performed. Mono-exponential ADC maps were based on four b-values: 0; 50; 500; and 800. Inter-study repeatability and intra-reader reproducibility were investigated in subgroups, as were associations with conventional MRI and clinical findings., Results: The inter-study repeatability for the median ADC was moderate for all individuals (intraclass correlation coefficient [ICC] 0.66); it was good in patients with axSpA (ICC 0.79) and poor in healthy individuals (ICC 0.27). Significant differences in ADC were found between women and men ( P  = 0.03), and between patients with versus without BME on STIR ( P  = 0.01). ADC was associated with an MRI BME score and with age in women., Conclusion: ADC seems to be a repeatable parameter in patients with axSpA but not in healthy individuals. ADC is correlated with MRI sacroiliac joint BME score and with age in women., (© The Foundation Acta Radiologica 2020.)

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., (© 2019, American College of Rheumatology.)

Background: The Canada-Denmark (CANDEN) definitions of spinal MRI lesions allow a detailed anatomy-based evaluation of inflammatory and structural lesions in vertebral bodies and posterior elements of the spine in patients with axial spondyloarthritis (axSpA). The objective was to examine the reliability, responsiveness and discrimination of scores for spinal inflammation, fat, bone erosion and new bone formation based on the CANDEN system and to describe patterns of inflammatory and structural lesions and their temporal development., Methods: 49 patients with axSpA from an investigator-initiated, randomised, placebo-controlled trial of adalimumab underwent spinal MRI at weeks 0/6/24/48. MR images were scored according to the CANDEN system and the Spondyloarthritis Research Consortium of Canada (SPARCC) method. Total scores, and various subscores, were created by summing individual lesion scores., Results: The CANDEN spine inflammation score had high responsiveness, similar to the SPARCC MRI spine index (Guyatt's responsiveness index 1.88 and 1.67, respectively), and discriminated between adalimumab and placebo treatment already at 6 weeks' follow-up (P=0.03). Anterior/posterior corner inflammation subscores showed similar responsiveness. Inter-reader reliability for the CANDEN spine inflammation and fat scores was good to very good for status and change scores (intraclass correlation coefficient (ICC)=0.71-0.92). Reliability for CANDEN new bone formation and erosion scores was good to very good for status scores (ICC=0.61-0.75) but, due to minimal progression, poor for change scores (ICC≤0.40)., Conclusions: The CANDEN spine inflammation score showed good responsiveness, discrimination between active treatment and placebo and reliability. The CANDEN spine structural scores had good cross-sectional reliability, but longer studies are needed to investigate their sensitivity to change., Trial Registration Number: NCT01029847; Results., Competing Interests: Competing interests: None declared.

Objectives: Electronic platforms have been developed to help the clinician monitor disease activity in rheumatoid arthritis (RA) to support at treat-to-target strategy. We present an initiative to interactively improve disease control in patients with rheumatoid arthritis., Methods: In patients who presented with one or more swollen joints AND moderate/high disease activity (i.e. either CDAI≥10.1 and/or DAS-28CRP>3.2, which is automatically calculated in the DANBIO registry), a red alert was shown, which activated a pop-up: "This patient has at least one swollen joint AND either CDAI≥ 10.1 or DAS28CRP>3.2. Which action do you as a physician take today: □ Intensify treatment, □ Treatment intensification is not possible currently/awaiting results of additional investigations, □ No further treatment intensification is possible, □ The patient does not want to intensify treatment, □ Other decisions taken" RESULTS: Of 21,056 patients with RA, 40% fulfilled the criteria for getting the alert message. The pop-up was activated and completed by the physician in 65% of those (5,428 patients). Treatment was intensified in 67%. In 2% of patients, no additional treatment intensification was possible, and 8% of the patients objected to intensification., Conclusions: In >8,000 RA patients who presented with objective signs of active disease in routine care, an interactive feature of the DANBIO registry was introduced, which prompted the physician to take action and consider treatment intensification. In two-thirds of the cases, the treating physician reported that treatment was intensified.

Objective: To investigate changes in magnetic resonance imaging (MRI)-assessed inflammation and structural lesions in the sacroiliac (SI) joints during treatment with adalimumab versus placebo., Methods: In a 48-week double-blind, placebo-controlled trial, 52 patients with spondyloarthritis were randomized to receive subcutaneous injections of either adalimumab 40 mg (n = 25) or placebo (n = 27) every other week for 12 weeks. Patients in the adalimumab group continued to receive and patients in the placebo group were switched to adalimumab 40 mg every other week for an additional 12 weeks. MRI of the SI joints was performed at weeks 0, 12, 24, and 48, and the images were assessed independently in a blinded manner using the modified Berlin and the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores for inflammation and structural lesions of the SI joints., Results: At baseline, 56% of the adalimumab group and ∼72% of the placebo group had an MRI-assessed inflammation score of ≥1. Among the patients with inflammation at baseline, the mean percent reductions in MRI scores for inflammation from week 0 to 12 were greater in the adalimumab group compared with the placebo group (Berlin method, -62% versus -5%; SPARCC method, -58% versus -12% [both P < 0.04]). Furthermore, the mean SPARCC erosion score decreased (-0.6) and the SPARCC backfill score increased (+0.8) in the adalimumab group from week 0 to week 12. From week 12 to week 24, larger absolute reductions in the Berlin/SPARCC inflammation scores and the SPARCC erosion score and larger increases in the Berlin/SPARCC fatty lesion scores were seen in the placebo group compared with the adalimumab group. In univariate regression analyses (analysis of covariance) and multivariate stepwise regression analyses, treatment with adalimumab was independently associated with regression of the SPARCC erosion score from week 0 to 12 but not with changes in the other types of MRI lesions., Conclusion: Significant changes in the Berlin and SPARCC MRI-assessed inflammation scores and in the SPARCC MRI-assessed erosion scores occurred within 12 weeks after initiation of adalimumab. Tumor necrosis factor inhibitor treatment was associated with resolution of erosions and the development of backfill., (© 2016, American College of Rheumatology.)

Introduction: Rheumatoid arthritis (RA) is often associated with diminished muscle mass, reflecting an imbalance between protein synthesis and protein breakdown. To investigate the anabolic potential of both exercise and nutritional protein intake we investigated the muscle protein synthesis rate and anabolic signaling response in patients with RA compared to healthy controls., Methods: Thirteen RA patients (age range 34-84 years; diagnosed for 1-32 years, median 8 years) were individually matched with 13 healthy controls for gender, age, BMI and activity level (CON). Plasma levels of C-reactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured using enzyme-linked immunosorbent assay (ELISA) in resting blood samples obtained on two separate days. Skeletal muscle myofibrillar and connective tissue protein fractional synthesis rate (FSR) was measured by incorporation of the amino acid (13)C6-phenylalanine tracer in the overnight fasted state for 3 hours (BASAL) and 3 hours after intake of whey protein (0.5 g/kg lean body mass) alone (PROT, 3 hrs) and in combination with knee-extensor exercise (EX) with one leg (8 × 10 reps at 70 % of 1RM; PROT + EX, 3 hrs). Expression of genes related to inflammatory signaling, myogenesis and muscle growth/atrophy were analyzed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR)., Results: CRP was significantly higher in the RA patients (2.25 (0.50) mg/l) than in controls (1.07 (0.25) mg/l; p = 0.038) and so was TNF-α (RA 1.18 (0.30) pg/ml vs. CON 0.64 (0.07) pg/ml; p = 0.008). Muscle myofibrillar protein synthesis in both RA patients and CON increased in response to PROT and PROT + EX, and even more with PROT + EX (p < 0.001), with no difference between groups (p > 0.05). The gene expression response was largely similar in RA vs. CON, however, expression of the genes coding for TNF-α, myogenin and HGF1 were more responsive to exercise in RA patients than in CON., Conclusions: The study demonstrates that muscle protein synthesis rate and muscle gene expression can be stimulated by protein intake alone and in combination with physical exercise in patients with well-treated RA to a similar extent as in healthy individuals. This indicates that moderately inflamed RA patients have maintained their muscle anabolic responsiveness to physical activity and protein intake.

Psoriatic arthritis (PsA) is a chronic systemic, inflammatory disease associated with skin psoriasis. PsA may be difficult to assess with clinical examination and blood tests because of its complex and multifaceted clinical presentation. Magnetic resonance imaging (MRI) can visualise all peripheral and axial joints and entheses involved in PsA, and allow the rheumatologist to assess inflammation and structural damage in detail. In the present paper, we provide a brief overview of MRI to diagnose, monitor and prognosticate in PsA in clinical care.

Objectives: By whole-body MRI (WBMRI), we aimed to examine the frequency and distribution of inflammatory and structural lesions in PsA patients, SpA patients and healthy subjects (HSs), to introduce global WBMRI inflammation/damage scores, and to assess WBMRI's reproducibility and correlation with conventional MRI (convMRI)., Methods: WBMRI (3.0-T) of patients with peripheral PsA (n = 18) or axial SpA (n = 18) and of HS (n = 12) was examined for proportion of evaluable features (readability) and the presence and pattern of lesions in axial and peripheral joints. Furthermore, global WBMRI scores of inflammation and structural damage were constructed, and WBMRI findings were compared with clinical measures and convMRI (SpA/HS: spine and SI joints; PsA/HS: hand)., Results: The readability (92-100%) and reproducibility (intrareader intraclass correlation coefficient: 0.62-1.0) were high in spine/SI joint, but lower in the distal peripheral joints. Wrists, shoulders, knees, ankles and MTP joints were most commonly involved, with frequency of synovitis > bone marrow oedema (BMO) > erosion. WBMRI global BMO scores of peripheral and axial joints were higher in PsA {median 7 [interquartile range (IQR) 3-15]} and SpA [8 (IQR 2-14)] than in HSs [2.5 (IQR 1-4.5)], both P < 0.05. WBMRI global structural damage scores (erosion, fat infiltration and ankylosis) were higher in SpA [7 (IQR 3-12)] than HSs [1.5 (IQR 0-4.5)], P = 0.012. Correlations between WBMRI and convMRI spine and SI joint scores were ρ = 0.20-0.78., Conclusion: WBMRI allows simultaneous assessment of peripheral and axial joints in PsA and SpA, and the distribution of inflammatory and structural lesions and global scores can be determined. The study strongly encourages further development and longitudinal testing of WBMRI techniques and assessment methods in PsA and SpA., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: In a comparative conventional MRI, dynamic contrast-enhanced (DCE)-MRI, CT and radiography study, the authors aimed to monitor whether inflammation is reduced or even eliminated and damage halted in PsA patients receiving anti-TNF therapy., Methods: A 48-week prospective open-label investigator-initiated trial of 41 biologic-naive patients treated with 40 mg adalimumab every other week. Hand CT, MRI (according to the PsA MRI scoring system method) and radiography (Sharp-van der Heijde method) were obtained at weeks 0, 6 (only MRI), 24 and 48. Clinical response was assessed by the PsA Response Criteria (PsARC)., Results: In the 23 PsARC responders at week 48, significant decreases from baseline in MRI synovitis (mean -2.0, P < 0.05), bone marrow oedema (BMO) (-1.3, P < 0.05), flexor tenosynovitis (-2.1, P < 0.05) and total inflammation (-6.0, P < 0.005) were observed. However, MRI signs of inflammation remained present (week 48 total inflammation score median = 9). Several DCE-MRI parameters also decreased (P < 0.05) and were correlated (ρ = 0.62) with conventional MRI total inflammation score. No statistically significant changes in bone erosion or proliferation scores were observed. With CT as the standard reference for detecting bone erosions/proliferations, sensitivity, specificity and accuracy were 100%/40%, 83%/93% and 84%/86%, respectively, for MRI, whereas corresponding values for radiography were 17%/26%, 98%/96%, and 93%/87%, respectively. Erosive progression as assessed by CT was found in 6 of 480 joints and baseline BMO was predictive (relative risk 10, 95% CI 2.1, 49)., Conclusion: MRI signs of inflammation decrease, but do not disappear, during anti-TNF-α therapy. No overall changes in bone erosions or proliferations were observed. On joint-level baseline MRI, BMO was related to subsequent erosive progression detected by CT., Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov/, NCT01465438.

These national clinical guidelines outlining the screening, prophylaxis and critical information required prior to initiating anti-TNF-alpha treatment have been approved by the Danish Society for Gastroenterology. Anti-TNF-alpha therapy is widely used in gastroenterology (for inflammatory bowel disease), rheumatology (for rheumatoid arthritis, psoriatic arthritis and spondyloarthropathies) and dermatology (for psoriasis). With this background, the Danish Society for Gastroenterology established a group of experts to assess evidence for actions recommended before treatment with anti-TNF-alpha agents. Screening should take place for both active tuberculosis and latent tuberculosis. Screening must evaluate the risk of hepatitis B exposure/infection and that of other viral infections such as human immunodeficiency virus (HIV) and varicella zoster virus (VZV). The assessment should include a history of previous malignancies (cases of malignant disease within 5 years of anti-TNF-alpha treatment should be carefully considered). The physical examination should include lung/heart auscultation and lymph node examination, and the paraclinical investigations should include chest X-rays and laboratory tests, including an interferon gamma release assay, a hepatitis B test, an HIV test and, when prior VZV infection is uncertain, a VZV antibody test. Prophylaxis: Isoniazid should be administered in cases of suspected latent TB infection. Antiviral treatment is recommended in HBsAg-positive patients at the start of anti-TNF-alpha treatment. Before anti-TNF-alpha therapy, vaccination with 23-valent pneumococcal vaccine is recommended, and HBV vaccination may be considered in seronegative patients. Annual vaccination against seasonal influenza is recommended. Human papilloma virus vaccination should be administered in accordance with the guidelines of the National Board of Health of Denmark. In patients without a prior VZV infection, VZV vaccination may be considered. Information for patients: Anti-TNF-alpha treatment results in a generally increased risk of infection and latent tuberculosis flare-up. Women are advised to comply with the national guidelines for screening for cervical cancer, and their HPV immunisation status should be clarified. An increased risk of lymphoma with biological therapy in combination with thiopurines should be mentioned. Patients are advised to seek medical advice in case of herpes zoster infection.

Objective: To investigate the relationship of circulating biomarkers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and YKL-40), angiogenesis (vascular endothelial growth factor), cartilage turnover (C-terminal crosslinking telopeptide of type II collagen [CTX-II], total aggrecan, matrix metalloproteinase 3 [MMP-3], and cartilage oligomeric matrix protein [COMP]), and bone turnover (CTX-I and osteocalcin) to inflammation on magnetic resonance imaging (MRI) and radiographic progression in patients with axial spondylarthritis (SpA) beginning tumor necrosis factor α (TNFα) inhibitor therapy., Methods: MRIs were evaluated according to the Berlin sacroiliac (SI) joint and spine inflammation scoring method at baseline, week 22, and week 46. Radiographs were evaluated using the modified Stoke Ankylosing Spondylitis Spine Score at baseline and week 46. Patients with new syndesmophytes were identified. Biomarker levels in patients were compared to levels in healthy subjects., Results: Higher pretreatment MRI inflammation scores for SI joints and/or lumbar spine were associated with higher baseline CTX-II levels, but not with higher levels of biomarkers of inflammation and bone turnover. During treatment with TNFα inhibitors, a decrease in MRI inflammation scores from baseline to week 22 was associated with larger percentage decreases in and a normalization of CRP and IL-6 levels as compared to an increase or no change in MRI scores. Development of new syndesmophytes was associated with larger percentage decreases in CRP and IL-6 levels and an increase in osteocalcin level, and with normalization of CRP and IL-6 levels from baseline to week 22. Persistent systemic inflammation was associated with radiographic nonprogression., Conclusion: Our findings indicate that inflammation on baseline MRI is associated with higher CTX-II levels. Radiographic progression is associated with decreased systemic inflammation, as assessed by IL-6 and CRP levels and MRI, supporting the notion of a link between the resolution of inflammation and new bone formation in SpA patients during anti-TNFα therapy., (Copyright © 2011 by the American College of Rheumatology.)

Treatment with tumour necrosis factor-alpha inhibitors increases the risk of tuberculosis (TB). Screening for latent TB infection (LTBI) and prophylactic treatment has become mandatory. A 79-yr-old female with a history of severe erosive sero-positive rheumatoid arthritis was screened for LTBI before initiation of treatment with infliximab. The tuberculin skin test (TST) was negative, chest radiography was normal and she had no known risk factors for TB. After 4 months of treatment with infliximab, the patient developed ascites caused by Mycobacterium bovis. The TST was repeatedly negative. QuantiFERON-TB (QFT) testing performed during screening and immunosuppressive treatment was indeterminate, whereas the QFT test performed at the time of ascites puncture was positive. The patient history revealed previous work at a dairy, with probable exposure to unpasteurised milk from M. bovis-infected cattle. Re-activation of bovine tuberculosis is a risk in people with recent or previous exposure to unpasteurised dairy products. The QuantiFERON-TB test has the potential to detect Mycobacterium bovis infection. Indeterminate test results reflect either anergy, due to poor immunity, or technical problems and should be cautiously interpreted and as a minimum be repeated. Studies are ongoing to determine the role of QuantiFERON-TB testing in the screening for latent tuberculosis infection.

At least 12 different C4 gene products with a three band pattern have been identified after electrophoresis of sera pretreated with neuraminidase. Segregation analysis showed at least 12 different C4 haplotypes (or supergenes), of which five represent a single gene product and seven are duplications each composed of an F and an S gene. The data analyzed with respect to linkage showed one recombinant between the C4 and HLAB loci in 154 meioses giving a map distance of C4 HLAB of 0.6 cM. Another recombinant between the C4 and the HLAD loci was found in 101 meioses giving a map distance of C4 HLAD of 1.0 cM. Linkage disequilibrium was found between at least eight C4 haplotypes and certain alleles at the HLAB as well as the HLAD loci. Examinations of 15 families selected through a proband with HLAA 25, HLAB 18 and C2Q0 showed that in almost all cases a slight variant of the C4 supergene F3S2 followed the haplotype HLAA25 HLAB18 C2Q0. No associations were found between the two duplications of C4F3 C4S2 and C4F3 C4S1 and the loci. These findings may indicate that these C4 haplotypes were the original ones preceding the other C4 haplotypes.

A C4 variant found in about 5% of the population is described. The fast-moving part of this variant is governed by an allele (Fx) codominant to F. The Fx allele is in very strong linkage disequilibrium with HLA-B17 as the linkage disequilibrium parameter accounted for nearly 100% of the haplotype frequency of B17,Fx. The strong association is also evidenced by the study of 11 families segregating for the Fx allele. There was no instance of recombination between C4 and HLA in 36 informative meioses.