Inge Juul Sørensen

The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection

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 (⩾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.

The Assessment of SpondyloArthritis international Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general

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.

Increased morbidity from ischemic heart disease in patients with Wegener's granulomatosis

OBJECTIVE Experimental studies indicate that patients with Wegeners granulomatosis (WG) experience accelerated atherosclerosis. The purpose of this study was to investigate whether the occurrence of overt ischemic heart disease (IHD) is increased in WG. METHODS A total of 293 WG patients were included in the study. Information on all hospitalizations for IHD in Denmark from 1977 to 2006 was obtained from the Danish National Hospital Register. The WG patients were compared with the Danish background population with respect to rates of hospitalization for clinical manifestations of IHD after the date of vasculitis diagnosis by calculating standardized ratios of observed to expected (O:E) events. RESULTS Sixty-three first IHD events were registered in the WG group during the 2,482 patient-years of followup, corresponding to a significantly increased O:E ratio for IHD of 1.9 (95% confidence interval [95% CI] 1.4-2.4). A significantly increased risk was found for acute myocardial infarction (MI) (O:E ratio 2.5 [95% CI 1.6-3.7]), but not for angina pectoris (O:E ratio 1.3 [95% CI 0.7-2.1]). In analyses stratified according to the time between the diagnosis of vasculitis and the cardiovascular event, increased O:E ratios were found for IHD and acute MI occurring <5.0 years after WG diagnosis (2.1 [95% CI 1.4-3.0] for IHD and 3.6 [95% CI 2.0-5.9] for acute MI) and for IHD occurring > or =10.0 years after WG diagnosis (2.2 [95% CI 1.3-3.4]). Significantly increased O:E ratios for IHD and acute MI were found in patients who were > or =50.0 years of age at the time of diagnosis of WG, in male patients, and in patients who received high cumulative doses of cyclophosphamide. CONCLUSION Compared with the background population, WG patients seem to experience an increased number of both early and late cardiovascular events due to IHD.

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 α 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 α (TNFα) 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 (ρ=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 TNFα inhibitors in patients with SpA. The proposed thresholds for disease activity and treatment response need further validation. Trial registration number NCT00133315.

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.

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.

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

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

Enthesitis in patients with psoriatic arthritis, axial spondyloarthritis and healthy subjects assessed by ‘head-to-toe’ whole-body MRI and clinical examination

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.

Predictive validity of the ASAS classification criteria for axial and peripheral spondyloarthritis after follow-up in the ASAS cohort: a final analysis

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 rheumatologists 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 experts 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.

Cancer preceding Wegener's granulomatosis: a case–control study

OBJECTIVE To investigate whether patients with WG have an increased risk of malignancies prior to and/or around the time of the vasculitis diagnosis, as suggested by previous studies. METHODS A total of 293 WG patients were included in the study. Ten gender- and age-matched controls were selected randomly for each patient from the Danish Central Population Register. Information on malignancies was obtained through the Danish Cancer Registry. Occurrence of malignancies before WG diagnosis among patients and before WG diagnosis of their matched case among controls (reference date) was compared by calculation of prevalence odds ratios (OR). RESULTS Twenty-six patients were diagnosed with cancer before WG, while 194 controls were diagnosed with cancer before the reference date (OR 1.4; 95% CI 0.9, 2.2). Among specific malignancies, a significantly increased prevalence was found for testis cancer (OR 6.4; 95% CI 1.1, 38) based on two patients, who developed testis cancer >10 years before WG. The overall prevalence of malignancies diagnosed <2 years before WG was not significantly increased (OR: 1.6; 95% CI: 0.8, 3.4), but non-melanoma skin cancer occurred with an increased prevalence within this time interval (OR 4.0; 95% CI 1.4, 12). CONCLUSIONS We did not find clear evidence of an increased prevalence of preceding cancer in our WG cohort, indicating that shared risk factors are of minor importance for the excess of malignancies that occur in WG patients after the vasculitis diagnosis. Furthermore, our current and previously reported latency analyses do not substantiate that serious malignancies play a significant role in the pathogenic events that trigger development of WG.