Sex differences in patient-reported outcomes and the association with clinical factors in axial spondyloarthritis patients treated with tumour necrosis factor inhibitors.

OBJECTIVES: To investigate sex differences in patient-reported outcome measures (PROMs) among axSpA patients initiating their first TNFi and identify factors contributing to these disparities over the follow-up. METHODS: Data were included from 15 EuroSpA registries and consisted of axSpA patients initiating their first TNFi, with ≥2 measurements for each analysed PROM (BASDAI and BASFI, scale 0-100) taken at any time point. Linear mixed models were employed to analyse sex differences in PROMs over 24 months and to evaluate how baseline characteristics were related to the observed sex differences. RESULTS: We analysed 13 102 (38% women) in the BASDAI analyses and 10 623 (38% women) in the BASFI analyses. At follow-up, mean sex differences in BASDAI increased from 4.3 units at baseline (95% CI, 3.5-5.1)-8.0 (7.2-8.8) at 6 months, and in BASFI from 2.2 (1.4-3.1)-4.6 (3.6-5.5), with consistently worse scores in women. Baseline characteristics could not substantially account for the observed sex differences over time; however, the magnitude of the sex differences was reduced by HLA-B27 positivity, longer disease duration, and increased CRP levels, but increased by TNFi initiation in later years and peripheral arthritis. CONCLUSION: In axSpA patients initiating their first TNFi, baseline sex differences in BASDAI and BASFI increased two-fold after 6 months of treatment and persisted thereafter, with worse scores in women. Several baseline characteristics moderated the sex differences, though none could fully account for them. These findings improve our understanding of sex differences and underscore their importance in axSpA.

Gender-specific differences in patients with psoriatic arthritis receiving ustekinumab or tumour necrosis factor inhibitor: real-world data.

OBJECTIVE: Investigate effects of gender on disease characteristics and treatment impact in patients with PsA. METHODS: PsABio is a non-interventional European study in patients with PsA starting a biological DMARD [bDMARD; ustekinumab or TNF inhibitor (TNFi)]. This post-hoc analysis compared persistence, disease activity, patient-reported outcomes and safety between male and female patients at baseline and 6 and 12 months of treatment. RESULTS: At baseline, disease duration was 6.7 and 6.9 years for 512 females and 417 males respectively. Mean (95% CI) scores for females vs males were: clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA), 32.3 (30.3, 34.2) vs 26.8 (24.8, 28.9); HAQ-Disability Index (HAQ-DI), 1.3 (1.2, 1.4) vs 0.93 (0.86, 0.99); total PsA Impact of Disease-12 (PsAID-12) score, 6.0 (5.8, 6.2) vs 5.1 (4.9, 5.3), respectively. Improvements in scores were smaller in female than male patients. At 12 months, 175/303 (57.8%) female and 212/264 (80.3%) male patients achieved cDAPSA low disease activity, 96/285 (33.7%) and 137/247 (55.5%), achieved minimal disease activity (MDA), respectively. HAQ-DI scores were 0.85 (0.77, 0.92) vs 0.50 (0.43, 0.56), PsAID-12 scores 3.5 (3.3, 3.8) vs 2.4 (2.2, 2.6), respectively. Treatment persistence was lower in females than males (P ≤ 0.001). Lack of effectiveness was the predominant reason to stop, irrespective of gender and bDMARD. CONCLUSIONS: Before starting bDMARDs, females had more severe disease than males and a lower percentage reached favourable disease states, with lower persistence of treatment after 12 months. A better understanding of the mechanisms underlying these differences may improve therapeutic management in females with PsA. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02627768.

[18F]Fluoride PET provides distinct information on disease activity in ankylosing spondylitis as compared to MRI and conventional radiography.

PURPOSE: To relate [18F]fluoride uptake on PET with abnormalities on magnetic resonance imaging (MRI) and conventional radiography (CR) in ankylosing spondylitis (AS) patients. METHODS: Ten clinically active AS patients (female 6/10, age 38 ± 11 years) were included, and both spine and SI-joints were examined. PET scans were dichotomously scored for enhanced [18F]fluoride uptake, MRI scans were scored for fatty lesions, erosions, ankylosis, and bone marrow edema (BME), and CR was scored for erosions, syndesmophytes, and ankylosis. The overlap of lesions across all modalities was evaluated through univariate and multivariate analyses using a generalized mixed model. RESULTS: In the spine, 69 lesions with enhanced [18F]fluoride uptake, 257 MRI lesions, and 88 CR lesions were observed. PET lesions were mostly located in costovertebral and facet joints, outside the field of view (FOV) of the MRI and CR. However, PET lesions inside the FOV of MRI and CR partially showed no abnormality on MRI and CR. In lesions with abnormalities on multiple modalities, both univariate and multivariate analysis showed that PET activity had the strongest association with BME on MRI and ankylosis on CR. In the SI joints, 15 lesions (75%) with PET uptake were found, with 87% showing abnormalities on MRI and CR. CONCLUSION: [18F]fluoride PET lesions are often found outside the scope of MRI and CR, and even in the same location show only partial overlap with abnormalities on MRI (especially BME) and CR (especially ankylosis). This suggests that [18F]fluoride PET partially visualizes aspects of AS separate from MRI and CR, providing novel information. CLINICAL TRIAL REGISTRATION: NL43223.029.13 registered at 02-05-2013.  https://www.toetsingonline.nl/to/ccmo_search.nsf/fABRpop?readform&unids=C1257BA2002CC066C1257B4E0049A65A.

18F-sodium fluoride PET-CT visualizes both axial and peripheral new bone formation in psoriatic arthritis patients.

PURPOSE: As bone formation is associated with psoriatic arthritis (PsA), positron emission tomography (PET) using a 18F-Fluoride tracer may enable sensitive detection of disease activity. Our primary aim was to determine the feasibility of whole-body 18F-sodium fluoride PET-CT in clinically active PsA patients to depict new bone formation (as a reflection of disease activity) at peripheral joints and entheses. Our secondary aim was to describe 18F-sodium fluoride findings in the axial skeleton. METHODS: Sixteen patients (female 10/16, age 50.6 ± 8.9 years) with PsA fulfilling CASPAR criteria or with a clinical diagnosis of PsA according to the treating rheumatologist and with ≥ 1 clinically active enthesitis site were included. Of each patient, a whole-body 18F-sodium fluoride PET-CT scan was performed. All scans were scored for PET-positive lesions at peripheral joints, enthesis sites and the spine. Clinical disease activity was assessed by swollen/tender joint count 44, enthesitis according to MASES and SPARCC scores. RESULTS: Out of 1088 evaluated joints, 109 joints showed PET enhancement, mainly in the interphalangeal and metatarsal joints of the feet (14/109, 12.9%) and the distal interphalangeal joints of the hands (14/109, 12.9%). PET positivity was found at 44/464 enthesis sites, mainly at the patella tendon insertion (11/44, 25%) and quadriceps tendon insertion (10/44, 22.7%). Of the PET-positive joints and enthesis sites, respectively 18.2% and 29.5% were clinically positive; 81.8% and 70.5% of the PET-positive joints and entheses respectively were clinically asymptomatic. In 11 patients, ≥ 1 axial PET-positive lesion was observed, mainly in the cervical spine. CONCLUSIONS: New molecular bone formation was observed on 18F-sodium fluoride PET-CT scans, in all domains in which PsA disease activity can be observed, with a substantial part showing no clinical symptoms. CLINICAL TRIAL REGISTRATION: EudraCT: 2017-004,850-40, registered on 13 December 2017.

Sex and gender differences in axial spondyloarthritis: myths and truths.

Mounting evidence reveals evident sex differences in physiology, disease presentation and response to medication in axial SpA (axSpA). Unfortunately these data are often neglected in clinical practice and research. In this review, myths that still exist on diagnosis, disease manifestation and drug effectiveness were argued against data of the most recent literature. The aim is to increase awareness of sex differences in the clinical aspects of axSpA.

MRI lesions in the sacroiliac joints of patients with spondyloarthritis: an update of definitions and validation by the ASAS MRI working group.

OBJECTIVES: The Assessment of SpondyloArthritis international Society (ASAS) MRI working group (WG) was convened to generate a consensus update on standardised definitions for MRI lesions in the sacroiliac joint (SIJ) of patients with spondyloarthritis (SpA), and to conduct preliminary validation. METHODS: The literature pertaining to these MRI lesion definitions was discussed at three meetings of the group. 25 investigators (20 rheumatologists, 5 radiologists) determined which definitions should be retained or required revision, and which required a new definition. Lesion definitions were assessed in a multi-reader validation exercise using 278 MRI scans from the ASAS classification cohort by global assessment (lesion present/absent) and detailed scoring (inflammation and structural). Reliability of detection of lesions was analysed using kappa statistics and the intraclass correlation coefficient (ICC). RESULTS: No revisions were made to the current ASAS definition of a positive SIJ MRI or definitions for subchondral inflammation and sclerosis. The following definitions were revised: capsulitis, enthesitis, fat lesion and erosion. New definitions were developed for joint space enhancement, joint space fluid, fat metaplasia in an erosion cavity, ankylosis and bone bud. The most frequently detected structural lesion, erosion, was detected almost as reliably as subchondral inflammation (κappa/ICC:0.61/0.54 and 0.60/0.83) . Fat metaplasia in an erosion cavity and ankylosis were also reliably detected despite their low frequency (κappa/ICC:0.50/0.37 and 0.58/0.97). CONCLUSION: The ASAS-MRI WG concluded that several definitions required revision and some new definitions were necessary. Multi-reader validation demonstrated substantial reliability for the most frequently detected lesions and comparable reliability between active and structural lesions.

Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39.

OBJECTIVES: We sought to investigate whether genetic effects on response to TNF inhibitors (TNFi) in rheumatoid arthritis (RA) could be localised by considering known genetic susceptibility loci for relevant traits and to evaluate the usefulness of these genetic loci for stratifying drug response. METHODS: We studied the relation of TNFi response, quantified by change in swollen joint counts ( Δ SJC) and erythrocyte sedimentation rate ( Δ ESR) with locus-specific scores constructed from genome-wide assocation study summary statistics in 2938 genotyped individuals: 37 scores for RA; scores for 19 immune cell traits; scores for expression or methylation of 93 genes with previously reported associations between transcript level and drug response. Multivariate associations were evaluated in penalised regression models by cross-validation. RESULTS: We detected a statistically significant association between Δ SJC and the RA score at the CD40 locus (p=0.0004) and an inverse association between Δ SJC and the score for expression of CD39 on CD4 T cells (p=0.00005). A previously reported association between CD39 expression on regulatory T cells and response to methotrexate was in the opposite direction. In stratified analysis by concomitant methotrexate treatment, the inverse association was stronger in the combination therapy group and dissipated in the TNFi monotherapy group. Overall, ability to predict TNFi response from genotypic scores was limited, with models explaining less than 1% of phenotypic variance. CONCLUSIONS: The association with the CD39 trait is difficult to interpret because patients with RA are often prescribed TNFi after failing to respond to methotrexate. The CD39 and CD40 pathways could be relevant for targeting drug therapy.

Antidrug antibody detection for adalimumab depends on the type of assay used: an experimental approach to help clinicians interpret diagnostic data.

OBJECTIVES: To compare different methods of antidrug antibody (ADA) against adalimumab detection in ankylosing spondylitis (AS) patients and the impact of ADA on adalimumab drug levels and mean ASDAS-CRP. METHODS: We used the acid-dissociation-radioimmunoassay (ARIA), antidrug-binding-test (ABT) and a bridging Enzyme-linked Immunosorbent Assay (ELISA) to detect ADA at 4, 12 and 24 weeks of treatment. Patients were divided into groups; all assays negative (All-neg), only ARIA positive (ARIA-only-pos), ARIA and ABT positive, bridging ELISA negative (ARIA/ABT-double-pos) and all assays positive (All-pos). RESULTS: Eighty-three consecutive AS patient were included. At week 4, 18% compared to 11% and 0% of the patients tested positive for ADA in the ARIA, ABT and bridging ELISA, respectively. At week 12 and 24, cumulative 52% and 69% patients tested positive in the ARIA, compared to 27% and 30% patients in the ABT and 2% patients in the bridging ELISA. Adalimumab levels between All-neg and ARIA-only-pos were 9.1 (5.5-12.5) and 8.5 (5.7-12.3). Drug levels differed between ARIA/ABT-double-pos (2.7 (1.3-4.4)) and All-neg (9.1 (5.5-12.5)). All-pos patients had undetectable drug levels. Mean ASDAS-CRP at week 24 differs between All-neg (1.9 (±1.2)), and All-pos (3.8 (±1.9)) and ARIA/ABT-double-pos (2.0 (±1.1)) and All-pos. CONCLUSIONS: The majority of AS patients had detectable ADA against adalimumab in the ARIA. The ARIA detects more ADA compared to the less drug tolerant ABT and bridging ELISA. The clinical relevance depends on the impact on the bio-availability of the drug. A drug level measurement therefore helps to interpret ADA data regardless of type of assay used.

Simultaneous occurrence of ankylosing spondylitis and diffuse idiopathic skeletal hyperostosis: a systematic review.

Objectives: AS and DISH are both spinal ankylosing conditions with a 4-fold increased risk of spinal fractures. The most commonly used criteria for DISH were designed to exclude radiographic signs of spondyloarthritis. However, case reports describing the presence of both conditions exist. In this study, the co-occurrence of AS and DISH were reviewed in the literature to explore the potential need to revise the criteria for DISH. Methods: A search was conducted in Pubmed, Embase, Web of Science and the Cochrane library using the terms 'spondyloarthritis' and 'DISH' and their matching synonyms. Full-text articles describing the coexistence of both conditions in the same patient were included. A quality assessment was performed, and the case descriptions were extracted. Results: Twenty articles describing simultaneous occurrence of AS and DISH in 39 cases were retrieved. All articles were case reports or series of moderate quality. Back or neck pain was present in 97% of the patients (mean age 61.2 years, 90% male) and HLA-B27 was positive in 9/27 documented measurements. Radiographic abnormalities were described in the SI joint (82% AS, 13% DISH) and in the spine (49% AS, 100% DISH). Conclusion: Simultaneous occurrence of AS and DISH has been reported in the literature in at least 39 cases. AS and DISH should not be seen as mutually exclusive. If the results of the current study are confirmed in a large observational study, revision of the current criteria to include the co-existence of both conditions should be considered.

Bone formation in ankylosing spondylitis during anti-tumour necrosis factor therapy imaged by 18F-fluoride positron emission tomography.

Objectives: Excessive bone formation is an important hallmark of AS. Recently it has been demonstrated that axial bony lesions in AS patients can be visualized using 18F-fluoride PET-CT. The aim of this study was to assess whether 18F-fluoride uptake in clinically active AS patients is related to focal bone formation in spine biopsies and is sensitive to change during anti-TNF treatment. Methods: Twelve anti-TNF-naïve AS patients [female 7/12; age 39 years (SD 11); BASDAI 5.5 ± 1.1] were included. 18 F-fluoride PET-CT scans were performed at baseline and in two patients, biopsies were obtained from PET-positive and PET-negative spine lesions. The remaining 10 patients underwent a second 18F-fluoride PET-CT scan after 12 weeks of anti-TNF treatment. PET scans were scored visually by two blinded expert readers. In addition, 18F-fluoride uptake was quantified using the standardized uptake value corrected for individual integrated whole blood activity concentration (SUVAUC). Clinical response to anti-TNF was defined according to a ⩾ 20% improvement in Assessment of SpondyloArthritis international Society criteria at 24 weeks. Results: At baseline, all patients showed at least one axial PET-positive lesion. Histological analysis of PET-positive lesions in the spine confirmed local osteoid formation. PET-positive lesions were found in the costovertebral joints (43%), facet joints (23%), bridging syndesmophytes (20%) and non-bridging vertebral lesions (14%) and in SI joints (75%). After 12 weeks of anti-TNF treatment, 18F-fluoride uptake in clinical responders decreased significantly in the costovertebral (mean SUVAUC -1.0; P < 0.001) and SI joints (mean SUVAUC -1.2; P = 0.03) in contrast to non-responders. Conclusions: 18F-fluoride PET-CT identified bone formation, confirmed by histology, in the spine and SI joints of AS patients and demonstrated alterations in bone formation during anti-TNF treatment.

Muscle wasting in male TNF-α blocker naïve ankylosing spondylitis patients: a comparison of gender differences in body composition.

Objective: To assess gender differences in body composition (BC) in a cohort of AS patients naïve to TNF-α blockers. Methods: Patients included fulfilled the Modified New York criteria for AS. Demographic information and disease activity measures (ASDAS and BASDAI) were reported. BC was measured by whole body DXA. Body fat percentage (BF%), fat mass index (FMI), fat free mass index (FFMI) and android/gynoid fat ratio were reported and compared between men and women and with the reference population (percentiles). Results: Seventy consecutive patients were included; 60% were men. Demographic variables were similar, except for dyslipidaemia (57.1% of men; 14.3% of women). Women had significantly more fat (BF%, FMI), and less muscle (FFMI) than men, but below the median of the reference population. Male AS patients had a markedly low FFMI (31.7th percentile) compared with the reference population. In the whole group, after multivariate analysis, an ASDAS CRP >3.5 was related to lower fat free mass content. In men, a significant relationship between having a high disease activity (ASDAS, BASDAI) and lower BF% or FMI percentile was found, but in women it was the opposite. Conclusion: Muscle wasting, measured as low FFMI compared with the reference population, was found in male TNF-α blocker naïve AS patients, especially in those with active disease. Women had higher volumes of body fat than men, but near the median of the reference population. The relationships between fat content and disease activity support the complex association between adipose tissue and inflammation.

Clinical experience with the European Ankylosing Spondylitis Infliximab Cohort (EASIC): long-term extension over 7 years with focus on clinical efficacy and safety.

OBJECTIVES: Knowledge on the long-term effects of anti-TNF therapy in patients with ankylosing spondylitis (AS) is still limited. Our objective was to study the long-term efficacy and safety of anti-TNF therapy in AS. METHODS: After having completed the first part of the EASIC trial a total of 71 patients were enrolled into this 96-week extension study. Patients were treated with the same dosages and dosing intervals of infliximab as in the EASIC core study. Efficacy was assessed by using standardised assessment tools such as BASDAI, BASFI, BASMI, patient global assessment, CRP levels and the proportion of patients without any sign of enthesitis or arthritis. Long-term safety was assessed by documenting adverse events (AE), serious adverse events (SAE) and reasons for dropping out. RESULTS: Of the 71 patients included, 64 (90.1%) completed the trial , and 7 discontinued: one was lost to follow-up, 3 withdrew informed consent and in 3 patients therapy was stopped for different reasons: secondary loss of response, recurrent infections and basal cell carcinoma of the skin. The completers showed rather stable low scores of BASDAI (mean 2.4, median 2.52), BASFI (mean 3.1, median 2.76) and BASMI (mean 3.2, median 3) as well as patients global assessment and CRP. The vast majority of patients did not have enthesitis or arthritis. A total of 476 AE were observed, 13 of which were SAE. The majority of these were infections and most of them affected the respiratory tract. Two malignancies occurred: one basal cell carcinoma and one malignant melanoma. These were the only SAE judged to be possibly related to the study drug. CONCLUSIONS: Anti-TNF treatment with infliximab is efficacious over long periods of time in patients with AS. The observation of two skin related malignancies, including one melanoma, during the whole study period of 7 years is in line with reports from previous large AS data sets.

Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.

Immunogenicity, adalimumab levels and clinical response in ankylosing spondylitis patients during 24†weeks of follow-up.

BACKGROUND: Immunogenicity influences adalimumab levels and therefore clinical response in patients with rheumatic diseases. OBJECTIVES: To study the relationship between clinical response, adalimumab levels and antidrug antibodies (ADAb) in ankylosing spondylitis (AS). METHODS: Observational cohort study of 115 consecutive AS patients treated with adalimumab in the Netherlands (n=85) and Taiwan (n=30), monitored during 24 weeks. Adalimumab levels and ADAb titres were determined using an ELISA and an antigen binding test (ABT), respectively, designed by Sanquin Research, Amsterdam. Response to adalimumab treatment was defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) response, and disease activity was measured using the Ankylosing Spondylitis Disease Activity Score using C-reactive protein (CRP) (ASDAS). RESULTS: At baseline, median BASDAI (IQR) was 6.4 (4.5-7.6) and mean ASDAS (SD) was 3.5 (1.0). After 24 weeks, 49 (42.6%) patients were BASDAI50 responders and mean ASDAS (SD) for responders was 1.5 (1.0) vs 2.6 (1.0) for non-responders (p<0.001). Thirty-one (27.0%) patients had detectable ADAb. After 24 weeks, adalimumab levels (mg/L) (IQR) were significantly higher in ADAb-negative patients than in ADAb-positive patients (12.7 (8.2-18.0) vs 1.2 (0.0-2.0), (p<0.001)). A significant association was demonstrated between adalimumab levels and ASDAS (p=0.02; RC -1.1; 95% CI -2.0 to -0.2). Eleven (9.6%) patients had no detectable adalimumab levels and high detectable ADAb titres (>100 AU/mL). In these patients, CRP and erythrocyte sedimentation rate remained elevated during treatment. CONCLUSIONS: Adalimumab levels are related to clinical response in AS patients measured with ASDAS and are influenced by ADAb detectable with an ABT.

Tumour necrosis factor blocking agents and progression of subclinical atherosclerosis in patients with ankylosing spondylitis.

BACKGROUND: Ankylosing spondylitis (AS) is associated with an increased cardiovascular risk that might be due to the chronic underlying inflammatory process. We investigated whether subclinical atherosclerosis of the carotid artery in patients with AS was reduced after anti-inflammatory treatment with tumour necrosis factor (TNF) inhibitors in a prospective observational cohort study. METHODS: 67 out of 81 AS patients who used TNF inhibitors and underwent ultrasonography at baseline returned for follow-up after 4.9 years. Of all patients, 12 (15%) discontinued the use of TNF inhibitors. Assessments of medication use, AS-related factors and cardiovascular risk factors were measured at baseline and repeated at follow-up. B-mode carotid ultrasonography was used to investigate arterial wall parameters, including carotid intima-media thickness (cIMT) and Young's elastic modulus (YEM). RESULTS: After a median 4.9 years of follow-up, cIMT did not change significantly (paired t test +0.011 mm, p=0.561) in those who continued the use of TNF inhibitors, while cIMT increased substantially (+0.057 mm, p=0.069) in those who did not continue their use of TNF inhibitors. The effect of TNF inhibitors was mainly mediated by a subsequent decrease in AS disease activity. Vascular elasticity (as measured with YEM) did not change significantly in patients who discontinued TNF inhibitors or those who continued TNF inhibitors. CONCLUSIONS: The use of TNF inhibitors might stabilise or slow down the progression of subclinical atherosclerosis in AS patients, reflecting a decreased cardiovascular risk in these patients.

C-reactive protein polymorphisms influence serum CRP-levels independent of disease activity in ankylosing spondylitis.

OBJECTIVES: C-reactive protein (CRP) levels are frequently used to determine disease activity in patients with ankylosing spondylitis (AS), but these levels may not reflect disease activity. We therefore investigated the influence of common single-nucleotide polymorphisms (SNPs) in the CRP gene on CRP levels in AS patients. Additionally, the relation between CRP levels and BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) was examined. METHODS: This exploratory cross-sectional study included 189 Dutch AS patients. CRP SNPs rs2794521, rs3091244, rs1800947 and rs876538 were genotyped and haplotypes constructed. Linear regression analysis was used for the association between SNPs and CRP levels, with correction for confounders non-steroidal anti-inflammatory drugs use, body mass index, smoking, age, gender and disease activity (BASDAI). RESULTS: Only 52% of AS patients with a high disease activity (BASDAI ≥4) showed a high CRP level (≥10mg/L), whereas the others did not. In AS patients, CRP levels changed with different genotypes, with genotype CA of tri-allelic (C>T>A) SNP rs3091244 showing higher CRP levels in comparison with genotype CC (CA: 18.6 mg/L vs. CC: 8.3 mg/L; p=0.02). Carriers of haplotype 5 (tagged by allele A of rs3091244) had a higher risk to express a CRP ≥10 mg/L (OR=2.9, 95%CI 1.0-8.3; p=0.05) when compared with non-carriers. CONCLUSIONS: In AS, patients with high disease activity often do not show corresponding high CRP levels. We found that CRP levels vary with different CRP genotype in AS patients. Carrying distinct genetic variants might play a role in certain AS patients who show low CRP levels despite high disease activity (as well as high CRP levels with low disease activity). This observation may be important for the interpretation of disease activity scores that incorporate CRP levels, like the ASDAS.

Cardiovascular risk management in patients with active ankylosing spondylitis: a detailed evaluation.

BACKGROUND: Ankylosing spondylitis (AS) is an inflammatory disease with documented elevated cardiovascular (CV) risk due to systemic inflammation and a higher prevalence of CV risk factors. CV risk management (CV-RM) could be an effective method to reduce CV mortality and morbidity in AS patients. We assessed CV risk and evaluated guideline adherence according to the Dutch CV-RM guideline. METHODS: This study was conducted with a cohort of consecutive AS patients eligible for treatment with a tumor necrosis factor (TNF) -α inhibitor. Data from the Dutch National Institute for Public Health and Environment was used to compare the prevalence of CV risk factors in AS patients with the Dutch background population. RESULTS: In total, 254 consecutive AS patients were included. The prevalences of hypertension (41% vs 31%) and smoking (43% vs 27%) were substantially higher in AS patients as compared to the general Dutch background population. Of 138 AS patients older than 40 years the 10-years CV risk could be calculated. Fifty-one of these 138 patients (37%) had an indication for CV risk treatment. CV risk treatment was initiated in 42 of the 51 (82%), however, in only 12 of the 51 (24%) patients treatment targets for either hypertension or hypercholesterolemia were reached. CONCLUSION: The increased rates of hypertension and smoking illustrate the importance of CV-RM in AS patients. Although the majority of all AS patients eligible for CV-RM received CV risk medication, CV-RM remains a challenge for treating physicians, as treatment targets were not achieved in three-quarter of the eligible patients.

Pulmonary, renal and neurological comorbidities in patients with ankylosing spondylitis; implications for clinical practice.

Ankylosing spondylitis (AS) is associated with several comorbidities which contribute significantly to morbidity and mortality and add to the complexity of management. In addition to the well known extra-articular manifestations and increased cardiovascular risk, several pulmonary, renal, and neurological complications which have been associated with AS deserve equal attention. Whereas a clear link has been established for some manifestations, the evidence for other associations is less clear. Interstitial lung disease, apical fibrosis, secondary infection, and ventilatory restriction from reduced chest wall movement are well known pulmonary complications; more recently an association with sleep apnoea has been suggested. Renal amyloidosis and IgA nephropathy remain a treatment challenge which may respond to anti-TNF therapy. Atlanto axial subluxation and vertebral fractures can result in serious neurological complications and are notoriously difficult to diagnose unless a high level of suspicion is maintained. Despite several reports linking AS with demyelination a true link remains to be proved. This review discusses the prevalence, pathophysiology, and management of pulmonary, renal, and neurological complications, and implications for clinical practice.

The prevalence of vertebral fractures in diffuse idiopathic skeletal hyperostosis and ankylosing spondylitis: A systematic review and meta-analysis.

Background: Subjects with ankylosing spinal disorders, including diffuse idiopathic skeletal hyperostosis (DISH) and ankylosing spondylitis (AS) are more prone to vertebral fractures and frequently present with neurological deficit compared to the patients without an ankylosed spine. Moreover, prevalent vertebral fractures are an important predictor for subsequent fracture risk. However, the pooled fracture prevalence for DISH is unknown and less recent for AS. We aimed to systematically investigate the prevalence and risk of vertebral fractures in DISH and AS populations. Methods: Publications in Medline and EMBASE were searched from January 1980 until July 2023 for cohort studies reporting vertebral fractures in AS and DISH. Data on prevalence were pooled with random effects modeling after double arcsine transformation. Heterogeneity was assessed with I2 statistics and we performed subgroup analysis and meta-regression to explore sources of heterogeneity. Results: We included 7 studies on DISH (n = 1,193, total fractures = 231) with a pooled vertebral fracture prevalence of 22.6% (95%CI: 13.4%-33.4%). For AS, 26 studies were included (n = 2,875, total fractures = 460) with a pooled vertebral fracture prevalence of 15.2% (95%CI: 11.6%-19.1%). In general, fracture prevalence for AS remained similar for several study-level and clinically relevant characteristics, including study design, diagnostic criteria, spine level, and patient characteristics in subgroup analysis. AS publications from 2010 to 2020 showed higher fracture prevalence compared to 1990 to 2010 (18.6% vs. 11.6%). Fractures in DISH were most common at the thoracolumbar junction, whereas for AS, the most common location was the mid-thoracic spine. Conclusions: Vertebral fractures are prevalent in AS and DISH populations. Differences in fracture distribution along the spinal axis exist between the 2 disorders. Additional longitudinal studies are needed for incident fracture assessment in patients with ankylosing spinal disorders.

Sex Differences in the Effectiveness of First-Line Tumor Necrosis Factor Inhibitors in Psoriatic Arthritis: Results From the European Spondyloarthritis Research Collaboration Network.

OBJECTIVE: Women with psoriatic arthritis (PsA) may have reduced tumor necrosis factor inhibitor (TNFi) effectiveness compared to men. We examined sex differences in treatment response and retention rates during 24 months of follow-up among patients with PsA initiating their first TNFi. METHODS: Data from patients with PsA across 13 European Spondyloarthritis Research Collaboration Network registries starting their first TNFi were pooled. Logistic regression was used to analyze the association between sex and treatment response using low disease activity (LDA) according to the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) (<3.2) at six months as the primary outcome. Analyses were adjusted for age, country, conventional synthetic disease-modifying antirheumatic drug treatment, and TNFi start year. Retention rates were explored using the Kaplan-Meier estimator. RESULTS: We analyzed the treatment response of 7,679 patients with PsA (50% women) with available data on LDA at six months. At baseline, women and men had similar characteristics, including mean DAS28-CRP (women vs men, 4.4 [SD 1.2] vs 4.2 [SD 1.2]), though patient-reported outcome measures were worse in women. At six months, 64% of women and 78% of men had LDA (relative risk [RR] 0.82; 95% confidence interval [CI] 0.80-0.84). This difference was similar after adjustment (RR 0.83; 95% CI 0.81-0.85). TNFi retention rates were evaluated in 17,842 patients with PsA. Women had significantly lower retention rates than men at all time points (women 79%, 64%, and 50% vs men 88%, 77%, and 64% at 6, 12, and 24 months, respectively). CONCLUSION: Despite comparable disease characteristics at baseline, women with PsA have reduced treatment response and retention rates to their first TNFi, highlighting the need to consider sex differences in PsA research and management.