Radiographic progression is associated with resolution of systemic inflammation in patients with axial spondylarthritis treated with tumor necrosis factor α inhibitors: a study of radiographic progression, inflammation on magnetic resonance imaging, and circulating biomarkers of inflammation, angiogenesis, and cartilage and bone turnover.

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.

ASDAS, BASDAI and different treatment responses and their relation to biomarkers of inflammation, cartilage and bone turnover in patients with axial spondyloarthritis treated with TNFα inhibitors.

OBJECTIVES: To investigate the relation between ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis disease activity index (BASDAI) and treatment response and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), YKL-40), angiogenesis (vascular endothelial growth factor (VEGF)), cartilage (C-terminal crosslinking telopeptide of type II collagen (CTX-II), matrix metalloproteinase-3 (MMP-3), total aggrecan, cartilage oligomeric matrix protein) and bone (C-terminal crosslinking telopeptide of type I collagen, osteocalcin) turnover in 60 patients with axial spondyloarthritis initiating tumour necrosis factor alpha (TNFα) inhibitor therapy. METHODS: ASDAS (CRP-based), BASDAI and biomarkers were determined before and seven times during 46 weeks of TNFα inhibitor therapy. RESULTS: Very high ASDAS were associated with high levels of inflammatory biomarkers, while high BASDAI were not related to any biomarkers. Mixed modeling demonstrated significant longitudinal associations between ASDAS and IL-6, VEGF, MMP-3 and osteocalcin and between BASDAI and CRP, IL-6 and VEGF. Major improvement in ASDAS was associated with larger percentage decreases in biomarkers of inflammation, angiogenesis, MMP-3 and increases in aggrecan and osteocalcin. BASDAI response was associated with larger decreases in CRP and IL-6. Biomarkers with moderate/high differences in responsiveness for major versus no/clinically important improvement in ASDAS were CRP, IL-6, VEGF, aggrecan and osteocalcin, and VEGF and CTX-II for BASDAI response versus non-response. CONCLUSION: Levels and changes of 10 biomarkers in patients with axial spondyloarthritis during anti-TNFα therapy were documented. Construct validity and responsiveness of IL-6, VEGF, MMP-3, total aggrecan and osteocalcin were demonstrated. ASDAS was more associated with these biomarkers than BASDAI, and may better reflect the inflammatory disease processes. ClinicalTrials.gov identifier NCT00133315.

Responsiveness of the Ankylosing Spondylitis Disease Activity Score (ASDAS) and clinical and MRI measures of disease activity in a 1-year follow-up study of patients with axial spondyloarthritis treated with tumour necrosis factor alpha inhibitors.

OBJECTIVES: To investigate construct validity and responsiveness of the novel ankylosing spondylitis (AS) disease activity score (ASDAS) in patients with spondyloarthritis (SpA). METHODS: In a 46-week prospective longitudinal multicentre study of 60 patients with SpA (80% men, median age 40 years (range 21-62)) treated with tumour necrosis factor alpha (TNFalpha) inhibitors (infliximab, n=41; etanercept, n=13; adalimumab, n=6), the responsiveness of ASDAS, conventional clinical measures of disease activity and treatment response and the Berlin MRI sacroiliac joint (SIJ) and lumbar spine inflammation scores were compared. RESULTS: After 22 weeks, 58.3% of the patients were clinical responders (50% or 20 mm reduction in the Bath AS Disease Activity Index (BASDAI)). At baseline, clinical responders had significantly higher median (range) ASDAS than non-responders (4.15 (1.98-6.04) vs 2.99 (2.05-6.19), p=0.008). Changes in ASDAS correlated with changes in clinical measures of disease activity (including BASDAI (rho=0.76) and C-reactive protein (CRP) (0.79)), MRI SIJ inflammation (0.46) and MRI total inflammation scores (0.34). Patients with higher BASDAI or Assessment of SpondyloArthritis International Society (ASAS) responses obtained more profound reductions in ASDAS. ASDAS had the highest responsiveness with an effect size of 2.04 and a standardised response mean of 1.45, whereas BASDAI (effect size 1.86; standardised response mean 1.36) and CRP (effect size 0.63; standardised response mean 0.70) were less responsive. Linear regression showed that a change in BASDAI of 20 mm or 50% corresponded to a change in ASDAS of 1.38 and 1.95, respectively. CONCLUSION: ASDAS demonstrates construct validity and high responsiveness during treatment with TNFalpha inhibitors in patients with SpA. The proposed thresholds for disease activity and treatment response need further validation. Trial registration number NCT00133315.

[Danish recommendations on treatment of ankylosing spondylitis and spondyloarthritis based on multinational project initiative]. / Danske anbefalinger for behandling af ankyloserende spondylitis og spondylartritis udarbejdet i et internationalt projektsamarbejde.

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.

Definition of disease duration in ankylosing spondylitis.

Two definitions of the "disease duration" of ankylosing spondylitis (AS) have been used in the literature: (1) duration since first symptoms connected with AS and (2) duration since diagnosis of AS. To investigate how useful these definitions are for research, we reinvestigated the data of four surveys completed by patients with AS in the years since 1996. We found that the majority of the patients remembered the age at first symptoms with an accuracy of

Clinical vertebral fractures in patients with ankylosing spondylitis.

OBJECTIVE: To evaluate the prevalence and characteristics of clinically confirmed vertebral fractures (CVF) in patients with ankylosing spondylitis (AS). METHODS: Coordinated by the Ankylosing Spondylitis International Federation in Germany and in Denmark, a self-administered questionnaire was sent to all their members about age, diagnosis, disease duration, HLA-B27 status, and history of CVF. Patients who were aware of having had a CVF were asked to return the questionnaire with additional specification of the location of CVF, associated trauma, neurological complications, therapy for these complications, and recovery. We also reviewed available radiographs. RESULTS: Out of 15,097 questionnaires, 59 patients (0.4%) reporting 66 CVF returned the complete questionnaire (46 men, 13 women). Mean age at fracture was 50 +/- 9 years, after a mean duration of symptoms of 26 +/- 11 years. CVF with wedging or crush or transverse fracture were reported in the cervical (n = 21, 36%), thoracic (n = 21, 36%), and lumbar spine (n = 16, 27%), with one unspecified. In 37 fractures (56%), patients reported no/low or medium trauma in relation to the fracture. In 31 fractures (47%), patients reported neurological complications, occurring mostly without trauma (n = 11, 35%) or after minimal trauma (n = 7, 23%). Twenty (65%) of these patients did not have full neurological recovery. CONCLUSION: We found that 0.4% of patients with AS reported CVF at a mean age of 50 years, occurring after 2 decades of disease, mainly without trauma or after minimal trauma, with frequent neurological complications mostly followed by incomplete neurological recovery.