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Objective: To investigate whether adalimumab (ADA) reduces whole-body (WB-) magnetic resonance imaging (MRI) indices for inflammation in the entheses, peripheral joints, sacroiliac joints, spine, and the entire body in patients with axial spondyloarthritis (axSpA)., Methods: An investigator-initiated, randomized, placebo-controlled, double-blinded 48-week followup trial included 49 patients with axSpA, who had Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4.0 despite treatment with nonsteroidal antiinflammatory drugs and a clinical indication for tumor necrosis factor inhibitor treatment. Patients were randomized to subcutaneous ADA 40 mg or placebo every other week for 6 weeks; thereafter, all patients received ADA. Conventional MRI and WBMRI were performed at weeks 0, 6, 24, and 48. The primary WBMRI endpoint was the proportion of patients with an improvement in WBMRI total inflammation index above the smallest detectable change (SDC) at Week 6., Results: The primary WBMRI endpoint (improvement of SDC > 2.3) was met in 11 (44%) patients in the ADA group and 3 (13%) patients in the placebo group (p = 0.025, Fisher's exact test). The primary conventional MRI endpoint, the minimally important change in Spondyloarthritis Research Consortium of Canada Spine MRI Inflammation Index at Week 6, was achieved by 9 (36%) patients in the ADA group and 4 (17%) patients in the placebo group (p = 0.20). The primary clinical endpoint, BASDAI reduction > 50% or 2.0 at Week 24, was attained by 32 (65%) patients., Conclusion: ADA provided significant reductions in WBMRI indices of peripheral, axial, and whole-body inflammation in patients with axSpA. WBMRI is promising for objective assessment and monitoring of peripheral and axial disease activity in future clinical trials.

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.

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: R 2 = 0.93 and 0.88; change: R 2 = 0.82 and 0.87, respectively), while lower for the global method (baseline: R 2 = 0.79; change: R 2 = 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.

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., Competing Interests: Competing interests: BG: AbbVie; IMJH: Roche; AGL, MLH: AbbVie, BMS, MSD, Pfizer, Roche and UCB; the remaining authors: none declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To compare baseline disease activity and treatment effectiveness in biologic-naive patients with nonradiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) who initiate tumor necrosis factor inhibitor (TNFi) treatment and to study the role of potential confounders (e.g., HLA-B27 status)., Methods: Observational cohort study based on prospectively registered data in the nationwide DANBIO registry. We used Kaplan-Meier plots, Cox, and logistic regression analyses to study the effect of diagnosis (nr-axSpA vs AS) and potential confounders (sex/age/start yr/HLA-B27/disease duration/TNFi-type/smoking/baseline disease activity) on TNFi adherence and response [e.g., Bath Ankylosing Spondylitis Activity Index (BASDAI) 50%/20 mm]., Results: The study included 1250 TNFi-naive patients with axSpA (29% nr-axSpA, 50% AS, 21% lacked radiographs of sacroiliac joints). Patients with nr-axSpA were more frequently women (50%/27%) and HLA-B27-negative (85/338 = 25%), compared to AS (81/476 = 17%; p < 0.01). At TNFi start patients with nr-axSpA had higher visual analog scale scores [median (quartiles)] for pain: 72 mm (55-84)/65 mm (48-77); global: 76 mm (62-88)/68 mm (50-80); fatigue: 74 mm (55-85)/67 mm (50-80); and BASDAI: 64 (54-77)/59 (46-71); all p < 0.01. However, patients with nr-axSpA had lower C-reactive protein: 7 mg/l (3-17)/11 mg/l (5-22); and BAS Metrology Index: 20 (10-40)/40 (20-50); all p < 0.01. Median (95% CI) treatment adherence was poorer in nr-axSpA than in AS: 1.59 years (1.15-2.02) versus 3.67 years (2.86-4.49), p < 0.0001; but only in univariate and not confounder-adjusted analyses (p > 0.05). Response rates were similar in AS and nr-axSpA (p > 0.05). HLA-B27 negativity was associated with poorer treatment adherence [HLA-B27 negative/positive, nr-axSpA: HR 1.74 (1.29-2.36), AS: HR 2.04 (1.53-2.71), both p < 0.0001]; and lower response rates (nr-axSpA: 18/61 = 30% vs 93/168 = 55%; AS: 17/59 = 29% vs 157/291 = 54%, both p < 0.05)., Conclusion: In this nationwide cohort, patients with nr-axSpA had higher subjective disease activity at start of first TNFi treatment, but similar outcomes to patients with AS after confounder adjustment. HLA-B27 positivity was associated with better outcomes irrespective of axSpA subdiagnosis.

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 establish the predictive validity of the Assessment of SpondyloArthritis international Society (ASAS) spondyloarthritis (SpA) classification criteria., Methods: 22 centres (N=909 patients) from the initial 29 ASAS centres (N=975) participated in the ASAS-cohort follow-up study. Patients had either chronic (>3 months) back pain of unknown origin and age of onset below 45 years (N=658) or peripheral arthritis and/or enthesitis and/or dactylitis (N=251). At follow-up, information was obtained at a clinic visit or by telephone. The positive predictive value (PPV) of the baseline classification by the ASAS criteria was calculated using rheumatologist's diagnosis at follow-up as external standard., Results: In total, 564 patients were assessed at follow-up (345 visits; 219 telephone) with a mean follow-up of 4.4 years (range: 1.9; 6.8) and 70.2% received a SpA diagnosis by the rheumatologist. 335 patients fulfilled the axial SpA (axSpA) or peripheral SpA (pSpA) criteria at baseline and of these, 309 were diagnosed SpA after follow-up (PPV SpA criteria: 92.2%). The PPV of the axSpA and pSpA criteria was 93.3% and 89.5%, respectively. The PPV for the 'clinical arm only' was 88.0% and for the 'clinical arm'±'imaging arm' 96.0%, for the 'imaging arm only' 86.2% and for the 'imaging arm'+/-'clinical arm' 94.7%. A series of sensitivity analyses yielded similar results (range: 85.1-98.2%)., Conclusions: The PPV of the axSpA and pSpA criteria to forecast an expert's diagnosis of 'SpA' after more than 4 years is excellent. The 'imaging arm' and 'clinical arm' of the axSpA criteria have similar predictive validity and are truly complementary., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

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.)

Objectives: To investigate the ability of whole-body MRI (WBMRI) to detect axial and peripheral enthesitis in patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), and in healthy subjects (HS). Furthermore, to develop MRI enthesitis indices based on WBMRI and validate these by use of clinical measures of disease activity., Methods: Prospective cross-sectional study of patients with PsA (n=18) and axSpA (n=18) with moderate to high disease activity, and HS (n=12). Enthesitis at 35 individual sites located at upper and lower limbs, chest and pelvis were evaluated by WBMRI and clinical examination, and compared. Three new WBMRI enthesitis indices were developed., Results: WBMRI allowed evaluation of 888 (53%) of 1680 sites investigated, and 19 (54%) of 35 entheses had a readability >70%. The percentage agreement between WBMRI and clinical enthesitis was 49-100%, when compared at the level of the individual entheses. Enthesitis on WBMRI was observed in 148 (17%) of the entheseal sites, and was frequently present at greater trochanters (55%) and Achilles (43%) and supraspinate (23%) tendon insertions in patients and HS. At the first mentioned two locations enthesitis often appeared without clinical signs of enthesitis. Patients and HS differed significantly in one of the new WBMRI enthesitis scores. Patients and HS differed significantly in one of the new WBMRI enthesitis scores, and this score correlated weakly with BASDAI question 4 (tenderness in relation to entheses), BASDAI and patient global (ρ=0.29-0.31, p<0.05)., Conclusions: WBMRI is a promising new imaging modality for evaluation of enthesitis in patients with PsA and axSpA, but requires further investigation before clinical use., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Transient osteoporosis of the hip (TOH) affects pregnant women in the third trimester of pregnancy. Magnetic resonance imaging plays an important role in the diagnosis and shows a pattern of bone marrow oedema. We report a case of TOH post-partum with involvement of both hips in a 34-year-old woman. She was known with undifferentiated spondyloartritis since 2004, which posed a diagnostic challenge. The reported patient was treated conservatively avoiding lactation, weight bearing activities, increased intake of calcium and vitamin D and recovered without further medical treatment.

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.)

Objective: To evaluate new classification criteria for peripheral spondyloarthritis (SpA) in patients with SpA with peripheral manifestations only., Methods: In this Assessment of SpondyloArthritis international Society (ASAS) study, two prespecified sets of criteria were compared against the European Spondylarthropathy Study Group (ESSG) and Amor criteria in newly referred consecutive patients with undiagnosed peripheral arthritis, and/or enthesitis, and/or dactylitis that usually began before 45 years of age. The clinical diagnosis (SpA vs no SpA) made by the ASAS rheumatologist served as reference standard., Results: In all, 24 ASAS centres included 266 patients, with a final diagnosis of SpA being made in 66.2%. After adjustments a final set of criteria showed the best balance between sensitivity (77.8%) and specificity (82.9%): arthritis and/or enthesitis and/or dactylitis plus (A) one or more of the following parameters: psoriasis, inflammatory bowel disease, preceding infection, human leucocyte antigen B27, uveitis, sacroiliitis on imaging, or (B) two or more other parameters: arthritis, enthesitis, dactylitis, inflammatory back pain in the past, family history of SpA. The new criteria performed better than modified versions of the ESSG (sensitivity 62.5%, specificity 81.1%) and the Amor criteria (sensitivity 39.8%, specificity 97.8%), particularly regarding sensitivity. In the entire ASAS population of 975 patients the combined use of ASAS criteria for axial SpA and ASAS criteria for peripheral SpA also had a better balance (sensitivity 79.5%, specificity 83.3%) than the modified ESSG (sensitivity 79.1%, specificity 68.8%) and Amor criteria (sensitivity 67.5%, specificity 86.7%), respectively., Conclusions: The new ASAS classification criteria for peripheral SpA performed well in patients presenting with peripheral arthritis, enthesitis and/or dactylitis.

The objectives of the study were to investigate short and long-term changes and relations to treatment response of plasma interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), YKL-40, matrix metalloproteinase-3 (MMP-3), and total aggrecan in patients with spondyloarthritis (SpA) treated with tumor necrosis factor-alpha (TNFα) inhibitors and to compare with levels in healthy subjects. Biomarkers were measured in an observational cohort of 49 SpA patients (ankylosing spondylitis, n=32, and psoriatic arthritis, n=17) initiating TNFα inhibitor therapy (infliximab, n=38; etanercept, n=8; and adalimumab, n=3) and compared with levels in healthy subjects. Clinical parameters and biomarkers were measured at baseline, weeks 2, 6, and every 6-12 weeks for up to 3 years. Patients with co-morbidities (n=4), missing baseline samples (n=3), and adverse events (n=5) were excluded. Patients with SpA had compared with healthy subjects elevated IL-6 (median 8.5 ng/l (range, 0.98-64) vs. 1.3 (0.33-26)), VEGF (105 ng/l (22-752) vs. 45 (12-351)), YKL-40 (74 μg/l (14-572) vs. 43 (20-184)), and MMP-3 (43 μg/l (9.1-401) vs. 16 (2.5-47), p≤0.001), whereas total aggrecan was lower (662 μg/l (223-2,219) vs. 816 (399-2,190), p≤0.001). Two weeks after first treatment, all biomarker levels changed towards normal levels (p≤0.03) in clinical responders (n=24), and persistent reductions over 3 years were found in IL-6, VEGF, YKL-40, and MMP-3. Only MMP-3 decreased (p≤0.02) in non-responders (n=13). The study demonstrated changes of plasma IL-6, VEGF, YKL-40, MMP-3, and total aggrecan and a potential value for monitoring disease activity and treatment response in SpA patients. Larger prospective studies are required to clarify clinical utility of these biomarkers.

Introduction: The aim of this study was to develop 3E (Evidence, Expertise, Exchange) recommendations (RCs) on the use of methotrexate in rheumatic disorders and to assess the agreement among Danish rheumatologists., Material and Methods: Based on a systematic literature review and Delphi votes, national and multinational (MN) RCs were developed by 751 rheumatologists from 17 countries including Denmark, and the degree of agreement among the participants was assessed. Subsequently, a survey regarding the agreement on the MN RCs was sent to all Danish rheumatologists., Results: A total of 24 Danish RCs were elaborated by 43 rheumatologists at a national meeting. 71-100% (median 94%) of the participants agreed with each of the RCs. A total of 73 rheumatologists answered the survey on the ten MN RCs. On numerical rating scales with values ranging from zero to ten, the median agreement score for each of these RCs ranged from eight to ten. The RCs were already applied in daily practice by 70-100% (median 91%) of the specialists. Any direct conflict between the national and MN RCs was not evident., Conclusion: Based on evidence and expert opinion in a MN approach, national and MN RCs on methotrexate therapy were developed and a high level of agreement among Danish rheumatologists was evidenced.

Objective: To validate and refine two sets of candidate criteria for the classification/diagnosis of axial spondyloarthritis (SpA)., Methods: All Assessment of SpondyloArthritis international Society (ASAS) members were invited to include consecutively new patients with chronic (> or =3 months) back pain of unknown origin that began before 45 years of age. The candidate criteria were first tested in the entire cohort of 649 patients from 25 centres, and then refined in a random selection of 40% of cases and thereafter validated in the remaining 60%., Results: Upon diagnostic work-up, axial SpA was diagnosed in 60.2% of the cohort. Of these, 70% did not fulfil modified New York criteria and, therefore, were classified as having "non-radiographic" axial SpA. Refinement of the candidate criteria resulted in new ASAS classification criteria that are defined as: the presence of sacroiliitis by radiography or by magnetic resonance imaging (MRI) plus at least one SpA feature ("imaging arm") or the presence of HLA-B27 plus at least two SpA features ("clinical arm"). The sensitivity and specificity of the entire set of the new criteria were 82.9% and 84.4%, and for the imaging arm alone 66.2% and 97.3%, respectively. The specificity of the new criteria was much better than that of the European Spondylarthropathy Study Group criteria modified for MRI (sensitivity 85.1%, specificity 65.1%) and slightly better than that of the modified Amor criteria (sensitivity 82.9, specificity 77.5%)., Conclusion: The new ASAS classification criteria for axial SpA can reliably classify patients for clinical studies and may help rheumatologists in clinical practice in diagnosing axial SpA in those with chronic back pain., Trial Registration Number: NCT00328068.

Introduction: The multinational initiative "3e Initiative in Rheumatology - Multi-national Recommendations for the Management of Ankylosing Spondylitis 2006-7" served the primary purpose of providing specific recommendations for the management of ankylosing spondylitis and spondyloarthritis patients in daily practice., Material and Methods: The scientific committees from the ten participating countries selected nine clinical questions regarding diagnosis, monitoring and pharmacologic non-biologic treatment, and the Danish group chose 2 additional questions about non-pharmacologic treatment. Systematic literature searches were performed in Medline by 3 international and a Danish bibliographic fellow. Outcome data were extracted and processed by use of routine methods from clinical epidemiology and statistics. The evidence was presented to the Danish rheumatologists. The participants were divided into three groups, which each proposed recommendations. After a final plenary discussion, a voting session took place. Subsequently, agreement was obtained, and the strength of the recommendations was graded., Results: The bibliographic fellows identified 2,709 relevant manuscripts and included 477 of these in the analysis. All 186 Danish rheumatologists were invited, and 26 (14,0%) participated in the meeting held in Copenhagen, December 2006. The individual recommendations were endorsed by 68-100% of the participants., Conclusion: Within the framework of the multinational 3e project, it was possible to develop Danish recommendations for AS patients by combining an evidence-based approach and the experience of clinical rheumatologists.

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.

Serum amyloid P component (SAP) binds in vitro to DNA; based on findings in SAP-deficient mice it was proposed that SAP's role is to handle chromatin and DNA, thereby preventing formation of anti-DNA antibodies. For the first time we have shown the presence of Ca2+-dependent SAP-DNA complexes, measured by ELISA, in sera from both healthy volunteers and systemic lupus erythematosus patients (SLE). The concentration of SAP-DNA complexes in SLE sera was significantly lower than in normal sera and particularly low in sera from patients with anti-DNA titers exceeding 50. The complexes were dissociated by the SAP ligand heparin and were not demonstrable in EDTA plasma. Normal sera showed similar capacity to form SAP-DNA complexes with both thymus and Escherichia coli DNA, whereas significantly lower amounts of complexes, in particular with E. coli DNA, were formed in SLE sera. SLE patients with moderate to high anti-DNA titers showed a significant negative correlation between serum SAP's binding of E. coli DNA and the anti-DNA titer.

Dengue virus infections have increased globally. This results in an increased incidence of patients with dengue fever in Denmark. In order to draw attention to this diagnosis among febrile persons returning from a stay in tropical and subtropical areas, we present two cases of dengue virus infection and describe the symptoms and diagnostic possibilities. Dengue Haemorrhagic Fever (DHF) is supposed to occur only in persons who have previously had dengue virus infection and who acquire a second infection with dengue virus.

Background: Cardiac surgery with cardiopulmonary bypass (CPB) evokes a systemic inflammatory response involving the proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-1, IL-6, IL-8 and anti-inflammatory cytokines such as IL-10. Like IL-10, opioids downregulate the immune responses in vivo and in vitro, including the activity of the cytokine-producing monocytes and granulocytes. The proinflammatory cytokines are potent inducers of the hepatic acute-phase protein synthesis. The aim of the present study was to investigate if choice of anaesthesia, based on high-dose opioids (fentanyl) versus low-dose opioids influenced the release of IL-6, IL-8, and IL-10. Secondly, it was investigated whether serum amyloid P-component (SAP) is an acute-phase protein in man such as C-reactive protein (CRP), with which it is physically and structurally related., Methods: Sixteen patients submitted to elective coronary artery bypass grafting (CABG) surgery were randomized to either low-dose opioid anaesthesia consisting of thoracic epidural analgesia combined with inhalational anaesthesia (group I) or high-dose fentanyl anaesthesia (group II). From each patient 18 blood samples were taken perioperatively. Cytokine analyses were performed with ELISA, CRP and SAP mere measured with rocket immunoelectrophoresis (RIE)., Results: Surgery and CPB elicited a marked, transient and almost simultaneous proinflammatory and anti-inflammatory cytokine response with no differences between the groups. The cytokine levels returned to preoperative levels 1-3 d after operation. Anaesthesia and surgery did not affect SAP plasma levels while patients showed a major increase in CRP concentrations preceding the cytokine responses., Conclusion: CABG performed during two different anaesthetic techniques, high-dose fentanyl versus low-dose opioid anaesthesia, elicited a well-defined cytokine response with minor variation in the time course of each cytokine. The cytokine production was not modified by type of anaesthesia. Finally, SAP is not an acute-phase protein in men.

Serum amyloid P component (SAP), a member of the pentraxin family of proteins, binds calcium-dependently to several ligands including glycosaminoglycans (GAG's). We have investigated the influence of pH on the Ca2(+)-dependent binding of SAP to solid phase GAG's and amyloid fibril proteins (AA and beta2M) by ELISA. An increase in the dose-dependent binding of SAP to heparan sulfate, AA-protein and beta2M was observed as the pH decreased from 8.0 to 5.0. Furthermore, a lower, but significant Ca2(+)-independent binding of SAP to heparan sulfate, dermatan sulfate, AA protein and the amyloid precursor protein beta2M was observed. This binding was also enhanced at slightly acid pH, most pronounced at pH 5.0. The results of this study indicate that SAP can exhibit both Ca2(+)-dependent and -independent binding to ligands involved in amyloid fibril formation and that the binding is enhanced under conditions of slightly lowered pH.

Serum amyloid P component (SAP), a member of the conserved pentraxin family of plasma proteins, binds calcium dependently to its ligands. The authors investigated SAPs interaction with the complement proteins C4b binding protein (C4bp) and C1q by ELISA, immunoelectrophoresis and electron microscopy. Binding of these proteins to SAP was demonstrated when SAP was immobilized using F(ab')2 anti-SAP, but not when SAP reacted with these proteins in liquid phase; thus the binding to human SAP was markedly phase state dependent. Presaturation of solid phase SAP with heparin, which binds SAP with high affinity, did not interfere with the subsequent binding of C4bp or C1q to SAP. In contrast, collagen I and IV showed partial competition with the binding of C1q to SAP. Using fresh serum, immobilized native SAP bound C4bp whereas binding of C1q/C1 could not be demonstrated. Altogether the results indicate that firm binding of C1q and C4bp to SAP requires that SAP is presented on a solid phase, that C1q and C4bp react with sites distinct from the heparin binding site, and that C1q and collagen I share binding sites on SAP. Immobilized native SAP, aggregated SAP and SAP-heparansulphate complexes induced no detectable complement activation.

Serum amyloid P component (SAP) and C-reactive protein (CRP) are members of the pentraxin protein family. SAP is the precursor protein to amyloid P component present in all forms of amyloidosis. The prevailing notion is that SAP in circulation has the form of a double pentameric molecule (decamer) whereas CRP is a single pentameric molecule. We have investigated by gel permeation chromatography the M(r) of SAP in freshly collected human serum and of SAP purified by carbohydrate affinity chromatography and anion exchange chromatography. SAP was monitored by quantitative immunoelectrophoresis and ELISA, and SAP peak fractions were analysed by use of SDS-PAGE, Western blotting, and electron microscopy. The results indicate that native SAP circulates as a single pentamer, a part of which forms complexes with C4b-binding protein. The properties of SAP changed during purification as indicated by rocket immunoelectrophoresis and electron microscopy. Thus, electron micrographs of purified SAP showed a predominance of decamers. However, the decamer form of SAP reversed to single pentamers when purified SAP was incorporated into SAP-depleted serum.

Human serum amyloid P component (SAP) isolated from 20 healthy individuals was analyzed by anion exchange chromatography and isoelectric focusing (IEF) in order to investigate the existence of multiple forms of SAP and interindividual structural differences. Anion exchange chromatography showed one major and several minor subpopulations of SAP. IEF of all SAP isolates showed a previously unreported degree of heterogeneity with six isoelectric forms (pKi range 5.5-6.1) and with minor interindividual differences in respect of isoelectric points. Total enzymatic deglycosylation of SAP reduced the number of bands in IEF to two indicating the existence of two types of polypeptide chains.

Serum amyloid P component (SAP) is a pentraxin found in the circulation and in all forms of amyloid deposits. Its physiological and pathophysiological functions are largely unknown. Electron microscopy showed purified human SAP to consist of double pentameric discs compatible with the results of size chromatography. The formation of double pentamers did not require calcium ions. The outer diameter of the discs arranged face-to-face was 11.6 nm and the inner diameter 3.2 nm. The thickness of single and double pentamers was 4.1 and 8.7 nm, respectively. Quadruple pentamers were occasionally seen. The self-aggregation of human SAP molecules was investigated in the presence and absence of calcium ions at different concentrations. In calcium-free solutions few and mostly small SAP aggregates were seen. After addition of calcium at increasing concentration the aggregates grew in size and crystalline-like structures were formed already at 2 mM calcium. At 25 mM calcium, large aggregates with a crystalline array occasionally exhibiting cylinders predominated. Binding of the ligands heparin and heparan sulphate to SAP completely abolished the calcium-enhanced aggregation, but the distribution of the SAP molecules was affected, resulting in strands or groups of adjacent molecules. The electrophoretic mobility of SAP was moreover significantly altered after its calcium-dependent reaction with these ligands. We conclude that purified SAP has a tendency to double pentamer formation and self-aggregation also in the absence of calcium ions. However, aggregation is greatly enhanced even at low concentrations (2 mM) of calcium. SAP's tendency to self-aggregation is abolished after its binding to heparin or heparin sulphate. Furthermore, our TEM studies indicate that purified human SAP freed of its natural ligands has the double pentameric form, whereas the electrophoretic investigations suggest that SAP's interaction with low-molecular-weight natural ligands in serum prevents homodimerization and self-aggregation.

The distributions of sodium and potassium in the serum on admission, and the types of medicine used were studied retrospectively in hospitalized geriatric patients (n = 1418). Sodium concentrations below 130 mmol/l were found in 7.4% and potassium concentrations below 3.0 mmol/l in 5.0% of patients. Risk factors for low sodium concentrations were treatment with the combination of thiazide+amiloride, potassium-sparing diuretics, thiazides, emergency hospitalization and low body weight. Risk factors for low potassium concentrations were treatment with the combination of thiazide+amiloride, thiazides and female gender. On an average, patients were given two different drugs from specified groups both on admission and on discharge, but changes in medical treatment were often performed during the hospital stay. Prehospital treatment with thiazide diuretics and the combination of thiazide+amiloride was frequently withdrawn. 38% were given benzodiazepines on discharge. In 40.4% of these, treatment had been started during the hospital stay, most often on account of insomnia.

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.