Drug effectiveness of 2nd and 3rd TNF inhibitors in psoriatic arthritis - relationship with the reason for withdrawal from the previous treatment.

OBJECTIVE: To investigate real-world retention and remission rates in PsA patients initiating a 2nd or 3rd TNFi and the association with reason for discontinuation from the previous TNFi-treatment. METHODS: Prospectively collected routine care data from 12 European registries were pooled. Retention rates (Kaplan-Meier estimation) and crude/LUNDEX-adjusted rates of Disease Activity Score 28 and Disease Activity index for PSoriatic Arthritis (DAS28 and DAPSA28) remission were calculated and compared with adjusted Cox regression analyses and Chi-squared test, respectively). RESULTS: We included 5233 (2nd TNFi) and 1906 (3rd TNFi) patients. Twelve-month retention rates for the 2nd and 3rd TNFi were 68% (95%CI: 67-70%) and 66% (64-68%), respectively. Patients who stopped the previous TNFi due to AE/LOE had 12-month retention rates of 66%/65% (2nd TNFi), and 65%/63% (3rd TNFi), respectively. Patients who stopped the previous TNFi due to LOE after less vs more than 24 weeks had 12-month retention rates of 54%/69% (2nd TNFi), and 58%/65% (3rd TNFi). Six-month crude/LUNDEX-adjusted DAS28 remission rates were 48%/35% and 38%/27%, and DAPSA28 remission rates were 19%/14% and 14%/10%, for the 2nd and 3rd TNFi. CONCLUSION: Two-thirds of patients remained on TNFi at 12months for both the 2nd and 3rd TNFi, while one-third and one-quarter of patients were in DAS28 remission after 6months on the 2nd and 3rd TNFi. While drug effectiveness was similar in patients who stopped the previous TNFi due to AE compared to overall LOE, drug effectiveness was better in patients who had stopped the previous TNF due to secondary LOE compared to primary LOE.

Does a short course of etanercept influence disease progression and radiographic changes in patients suspected of non-radiographic axial spondyloarthritis? Three -years follow- up of a placebo-controlled trial.

OBJECTIVE: To study the long-term effect of 16 weeks of etanercept treatment on disease activity and radiographic changes in patients with suspected non-radiographic axial spondyloarthritis (nr-axSpA). METHOD: Eighty patients with inflammatory back pain and suspected nr-axSpA, with a Bath Ankylosing Disease Activity Index (BASDAI) ≥ 4, received etanercept (n = 40) 25 mg twice weekly or placebo (n = 40) for 16 weeks. They were followed without treatment restrictions after 24 weeks, for up to 3 years. Comparisons were made between patients who received etanercept or placebo in the first period, and changes in BASDAI, Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Metrology Index (BASMI), function, and radiographic changes in the spine [according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS)] and sacroiliac joints (Bath Ankylosing Spondylitis Radiology Index (BASRI). RESULTS: After 3 years of follow-up, 84% of the patients were diagnosed with SpA, predominantly axSpA. Biological treatment was started after 24 weeks in 30% of patients. Disease activity scores after 3 years did not reveal significant differences between the initial randomization groups in mean BASDAI scores (mean difference 0.9, 95% CI -1.1;0.7, p = 0.6) and ASDAS (mean ASDAS 0.3, 95% CI 0.6;3.1, p = 0.5). BASMI and function scores remained stable over 3 years. No differences in radiographic changes of the sacroiliac joints or spine were observed over 3 years between the two groups. CONCLUSION: A short course of etanercept in patients with suspected nr-axSpA did not affect disease activity, the chance of biological treatment, or radiographic progression after 3 years of follow-up.

The effect of anti-TNF on renal function in patients with ankylosing spondylitis: a prospective cohort study.

BACKGROUND: Biologicals, such as anti-tumor necrosis factor (anti-TNF), reduce cardiovascular disease (CVD) in patients with inflammatory rheumatic diseases. Impaired renal function is a known predictor of CVD and elevated in ankylosing spondylitis (AS). OBJECTIVE: To assess the effect of anti-TNF on renal function in patients with AS and whether anti-TNF use is safe in AS patients with pre-existing risk factors for renal decline. METHOD: Biological-naïve consecutive AS patients treated with etanercept or adalimumab were prospectively followed from 2005 to 2014. Renal function was determined by calculation of the estimated glomerular filtration rate (eGFR), estimated with the abbreviated modification of diet in renal disease (MDRD) formula. The effect of anti-TNF on eGFR was analyzed using mixed model analysis. RESULTS: 211 AS patients were followed for a median of 156 (36-286) weeks. Overall mixed model analyses showed a significant decrease of eGFR over time (ß = - 0.040, p = 0.000), although this association did not remain significant after adjustment for responding to anti-TNF, alcohol use, disease duration, body mass index (BMI), C-reactive protein (CRP), and disease activity (ß = - 0.018, p = 0.094). However, patients with pre-existing risk factors for renal decline did have a significant change in eGFR over time (ß = - 0.029, p = 0.006). CONCLUSIONS: We found a significant change in eGFR over time, although this small decrease was not clinically relevant. This study further demonstrates that anti-TNF does not affect renal function in AS patients with and without existing risk factors for renal decline, which means that use of anti-TNF is safe concerning renal function in patients with AS. Key Points • Previous studies showed that biologicals, such as anti-tumor necrosis factor (anti-TNF), reduce cardiovascular disease (CVD) in patients with inflammatory rheumatic diseases, such as ankylosing spondylitis (AS). • Impaired renal function is a known predictor of CVD, and also a known concern for many AS patients. • Use of anti-TNF is safe with regard to renal function in patients with AS. • The effect of anti-TNF on CVD in AS patients does not seem to be mediated by changes in renal function.

Disease activity in women with ankylosing spondylitis remains higher under Tumour Necrosis Factor inhibitor treatment than in men: a five-year observational study.

OBJECTIVE: To assess sex differences in response, level of disease activity, and drug survival in tumour necrosis factor inhibitor (TNFi)-naïve ankylosing spondylitis (AS) patients. METHOD: Consecutive AS patients, fulfilling the modified New York criteria, were included in a prospective cohort study at initiation of the first TNFi and followed until this medication was stopped (drug survival). Disease activity scores [AS Disease Activity Score using C-reactive protein (ASDAS-CRP), Bath AS Disease Activity Index (BASDAI), and CRP] were measured at 3, 6, and 12 months, and every subsequent year, up to 5 years. The response was defined by the ASDAS-CRP response criteria (clinically important improvement: ASDAS-CRP decrease ≥ 1.1). Analyses included regression methods for repeated measurements and survival analyses. RESULTS: Overall, 356 patients were included (34% women, mean ± sd age 46 ± 12 years), with a median disease duration of 12 (interquartile range 6;20) years. Women were less likely than men to achieve a clinically important response after 6 months of TNFi treatment (47% vs 64%; relative risk 1.4, 95% confidence interval (CI) 1.1;1.9, p = 0.02], despite a lack of sex differences in mean ASDAS-CRP levels over 5 year follow-up. Adjusted models for BASDAI over 5 years showed that women had a 0.6 point higher BASDAI score than men (ß = 0.6 0.1;1.1 <0.02). Numerically, more women than men discontinued treatment over a period of 5 years (hazard ratio = 1.5, 95% CI 0.9;2.5, p = 0.15). CONCLUSION: Female AS patients show a lower response to TNFi and a higher disease activity compared to men.

Aortic root diameter is associated with HLA-B27: identifying the patient with ankylosing spondylitis at risk for aortic valve regurgitation.

To assess the association between the aortic root diameter in HLA-B27 positive (+) and HLA-B27 negative (-) ankylosing spondylitis (AS) patients from the CARDAS cohort. The CARDAS study is a cross-sectional study in AS patients between 50 and 75 years who were recruited from a large rheumatology outpatient clinic. Patients underwent cardiovascular screening including echocardiography, with 2D, spectral, and color flow Doppler measurements. The aortic root was measured at sinuses of Valsalva during diastole. The aortic root diameter was adjusted for body surface area (BSA) (aortic root index, cm/m2). 193 Consecutive AS patients were included of whom 158 (82%) were HLA-B27 positive. The aortic root index was significantly higher in HLA-B27 + patients compared to HLA-B27- patients, respectively, 1.76 cm ± 0.21 vs. 1.64 cm ± 0.14, p < 0.001. No difference was seen in the prevalence of aortic valve regurgitation (AVR), p = 0.8. Regression analysis showed a significant association between HLA-B27 and aortic root index corrected for age, sex and cardiovascular risk factors (ß 0.091, 95% CI 0.015-0.168, p = 0.02). Especially, male HLA-B27 + patients had a significantly increased aortic root index compared to male HLA-B27- AS patients, respectively, 1.76 cm (1.63-1.88) and 1.59 cm (1.53-1.68), p < 0.001. We found an increased aortic root index in elderly HLA-B27 + AS patients compared to HLA-B27- AS patients, especially in male patients. No difference was seen in the prevalence of AVR. However, as AVR can be progressive, echocardiographic monitoring in elderly male HLA-B27 + AS might be considered.

The effect of anti-TNF treatment on body composition and insulin resistance in patients with rheumatoid arthritis.

Given the link between systemic inflammation, body composition and insulin resistance (IR), anti-inflammatory therapy may improve IR and body composition in inflammatory joint diseases. This study assesses the IR and beta cell function in rheumatoid arthritis (RA) patients with active disease compared to osteoarthritis (OA) patients and investigates the effect of anti-TNF treatment on IR, beta cell function and body composition in RA. 28 Consecutive RA patients starting anti-TNF treatment (adalimumab), and 28 age, and sex-matched patients with OA were followed for 6 months. Exclusion criteria were use of statins, corticosteroids, and cardiovascular or endocrine co-morbidity. Pancreatic beta cell function and IR, using the homeostasis model assessment (HOMA2), and body composition, using dual-energy X-ray absorptiometry (DXA) were measured at baseline and 6 months. At baseline, IR [1.5 (1.1-1.8) vs. 0.7 (0.6-0.9), 100/%S] and beta cell function (133% vs. 102%) were significantly (p < 0.05) higher in RA patients with active disease as compared to OA patients. After 6 months of anti-TNF treatment, IR [1.5 (1.1-1.8) to 1.4 (1.1-1.7), p = 0.17] slightly improved and beta cell function [133% (115-151) to 118% (109-130), p <0.05] significantly improved. Improvement in IR and beta cell function was most pronounced in RA patients with highest decrease in CRP and ESR. Our observations indicate that IR and increased beta cell function are more common in RA patients with active disease. Anti-TNF reduced IR and beta cell function especially in RA patients with highest decrease in systemic inflammation and this effect was not explained by changes in body composition.

Microvascular changes of the retina in ankylosing spondylitis, and the association with cardiovascular disease - the eye for a heart study.

OBJECTIVE: Ankylosing spondylitis (AS) is associated with an increased risk of cardiovascular disease (CVD). Microvasculature changes can precede overt CVD, but have been studied poorly in AS. The retinal vasculature is easily accessible and changes are associated with CVD (e.g. arteriolar narrowing, venular widening, loss of tortuosity). This proof of concept study compared the retinal microvasculature of AS patients with healthy controls, and the influence of gender. METHODS: Cross-sectional case-control study comparing AS patients with healthy controls. Main inclusion criteria were: age 50-75 years, no diabetes mellitus and, for AS, fulfillment of the modified New York criteria. All subjects underwent fundus photography, analyzed with Singapore I Vessel Assessment software, and Optical Coherence Tomography Angiography (OCTA). Subjects were compared with generalized estimating equations (GEE). Multivariable analyses were adjusted for demographics and cardiovascular risk, and stratified for gender. RESULTS: Fifty-nine AS patients and 105 controls were included (50% women). Controls were significantly older than patients (68 versus 60, p<0.01), but did not differ in cardiovascular profile. Patients had a lower retinal arteriolar tortuosity (ß Ì¶-0.1, 95%CI [-0.2; -0.01], p = 0.02), and higher vessel density (ß 0.5, 95% CI [0.1; 0.9], p = 0.02). In addition, male AS patients showed a lower arteriovenular ratio compared to male controls (ß -0.03, p = 0.04, 95%CI [-0.05; -0.001]). There were no differences found between women with and without AS. CONCLUSION: This study detected several retinal microvascular changes, in AS patients compared to controls, which have been associated with CVD. Retinal imaging might be an interesting tool for future CVD screening.

Impact of discordance between patient's and evaluator's global assessment on treatment outcomes in 14 868 patients with spondyloarthritis.

OBJECTIVES: To assess the impact of 'patient's minus evaluator's global assessment of disease activity' (ΔPEG) at treatment initiation on retention and remission rates of TNF inhibitors (TNFi) in psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) patients across Europe. METHODS: Real-life data from PsA and axSpA patients starting their first TNFi from 11 countries in the European Spondyloarthritis Research Collaboration Network were pooled. Retention rates were compared by Kaplan-Meier analyses with log-rank test and by Cox regression, and remission rates by χ2 test and by logistic regression across quartiles of baseline ΔPEG, separately in female and male PsA and axSpA patients. RESULTS: We included 14 868 spondyloarthritis (5855 PsA, 9013 axSpA) patients. Baseline ΔPEG was negatively associated with 6/12/24-months' TNFi retention rates in female and male PsA and axSpA patients (P <0.001), with 6/12/24-months' BASDAI < 2 (P ≤0.002) and ASDAS < 1.3 (P ≤0.005) in axSpA patients, and with DAS28CRP(4)<2.6 (P ≤0.04) and DAPSA28 ≤ 4 (P ≤0.01), but not DAS28CRP(3)<2.6 (P ≥0.13) in PsA patients, with few exceptions on remission rates. Retention and remission rates were overall lower in female than male patients. CONCLUSION: High baseline patient's compared with evaluator's global assessment was associated with lower 6/12/24-months' remission as well as retention rates of first TNFi in both PsA and axSpA patients. These results highlight the importance of discordance between patient's and evaluator's perspective on disease outcomes.

Retention and response rates in 14 261 PsA patients starting TNF inhibitor treatment-results from 12 countries in EuroSpA.

OBJECTIVE: To investigate TNF inhibitor (TNFi) retention and response rates in European biologic-naïve patients with PsA. METHODS: Prospectively collected data on PsA patients in routine care from 12 European registries were pooled. Heterogeneity in baseline characteristics between registries were explored (analysis of variance and pairwise comparison). Retention rates (Kaplan-Meier), clinical remission [28-joint count DAS (DAS28) <2.6; 28 joint Disease Activity index for Psoriatic Arthritis ⩽4] and ACR criteria for 20% improvement (ACR20)/ACR50/ACR70 were calculated, including LUNDEX adjustment. RESULTS: Overall, 14 261 patients with PsA initiated a first TNFi. Considerable heterogeneity of baseline characteristics between registries was observed. The median 12-month retention rate (95% CI) was 77% (76, 78%), ranging from 68 to 90% across registries. Overall, DAS28/28 joint Disease Activity index for Psoriatic Arthritis remission rates at 6 months were 56%/27% (LUNDEX: 45%/22%). Six-month ACR20/50/70 responses were 53%/38%/22%, respectively. In patients initiating a first TNFi after 2009 with registered fulfilment of ClASsification for Psoriatic ARthritis (CASPAR) criteria (n = 1980) or registered one or more swollen joint at baseline (n = 5803), the retention rates and response rates were similar to those found overall. CONCLUSION: Approximately half of >14 000 patients with PsA who initiated first TNFi treatment in routine care were in DAS28 remission after 6 months, and three-quarters were still on the drug after 1 year. Considerable heterogeneity in baseline characteristics and outcomes across registries was observed. The feasibility of creating a large European database of PsA patients treated in routine care was demonstrated, offering unique opportunities for research with real-world data.

The effects of golimumab treatment on systolic and diastolic left ventricular function in ankylosing spondylitis.

BACKGROUND: Diastolic left ventricular (LV) dysfunction appears more prevalent in ankylosing spondylitis (AS). The effects of tumor necrosis factor alpha (TNF-α) blocking therapy, a strong and effective anti-inflammatory drug, on diastolic LV function in AS are unknown. The objective of the study was to find the effects of 1-year treatment with golimumab 50 mg subcutaneously once per month on systolic and diastolic LV dysfunction in AS patients. METHODS: Forty consecutive AS patients were treated with TNF-α blocking therapy for 1 year. Transthoracic echocardiography was performed in all patients at baseline and after 1 year of treatment. RESULTS: Diastolic LV function improved after treatment in four out of six (67%) AS patients who completed follow-up (P=0.125), and did not develop or worsen in any of the other patients. Treatment with TNF-α blocking therapy had no effect on systolic LV function. CONCLUSION: These findings give support to the hypothesis that diastolic LV dysfunction improves during treatment with TNF-α blocking therapy.

Gender Differences in Axial Spondyloarthritis: Women Are Not So Lucky.

PURPOSE OF REVIEW: Ankylosing spondylitis (AS) was historically seen as a predominantly male disease. However, more recent data showed a more homogenous sex prevalence. Unfortunately, in many studies in axial spondyloarthritis (axSpA), the number of women included is low and the analyses are often not stratified for gender distribution. The purpose of this review is to aggregate the existing data on gender differences in axSpA in order to increase the awareness that female axSpA patients are still under-recognized. RECENT FINDINGS: Several studies considering gender differences revealed that female axSpA patients had different disease manifestations due to different immunological, hormonal, and genetic responses. For instance, allelic frequencies of the AHNK-gene and tissue non-specific alkaline phosphatase (TNAP) haplotypes differed between men and women with ankylosing spondylitis (AS). In addition, different levels of tumor necrosis factor (TNF), interleukins IL-6, IL-17, and IL-18, were found between the two sexes. Furthermore, female patients show a higher diagnostic delay compared to males. Several studies indicate a higher frequency of extra-articular manifestations (EAM) in female axSpA patients, such as enthesitis, psoriasis, and inflammatory bowel disease (IBD), whereas acute anterior uveitis is more prevalent in male patients. Male AS patients more frequently show a higher Bath Ankylosing Spondylitis Radiology Index (BASRI) scores and modified Stoke Ankylosing Spondylitis Spine Scores (mSASSS) than females, which indicates that males have higher radiological damage and radiographic progression. However, disease activity (BASDAI) and quality of life (AsQol) scores are significantly higher in women, and more importantly, they have significantly lower response rates to treatment with TNF inhibitors (TNFi) and a significantly lower drug adherence. Despite the fact that men with axial SpA have a worse radiologic prognosis, women have a high disease burden, in part because they have a longer delay in diagnosis, higher disease activity, and significantly less responsiveness to treatment with TNFi.

Comparison of drug survival and clinical outcome in patients with ankylosing spondylitis treated with etanercept or adalimumab.

OBJECTIVE: To compare rates of drug survival and clinical response during 2 years of follow-up in ankylosing spondylitis (AS) patients treated with etanercept or adalimumab in routine care. METHOD: Biological-naïve consecutive AS patients treated with etanercept (n = 163) or adalimumab (n = 82) were followed. Treatment discontinuation was due to inefficacy, adverse events, loss to follow-up, planning a pregnancy, or uveitis. Disease activity was assessed by the Ankylosing Spondylitis Disease Activity Score using C-reactive protein (ASDAS-CRP). Moderate disease activity was defined as an ASDAS-CRP < 2.1. RESULTS: Twenty-seven patients (32.9%) treated with adalimumab and 30 (18.4%) with etanercept discontinued treatment. Cox regression analysis demonstrated a significant difference in survival rate between discontinuation of the drug in adalimumab patients compared with etanercept patients [hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.3-4.5, p = 0.005; corrected for confounding factors: HR 2.5, 95% CI 1.3-4.5, p = 0.006]. There was no significant difference at 2 years of follow-up between the adalimumab- and the etanercept-treated patients in mean ± sd ASDAS-CRP (1.9 ± 1.1 and 2.0 ± 0.9, respectively, p = 0.624), and 23 out of 34 (67.6%) compared to 71 out of 117 (60.7%) reached ASDAS-CRP moderate disease activity (odds ratio 0.738, 95% CI 0.329-1.657, p = 0.530). CONCLUSION: No significant difference was found between AS patients treated with etanercept and those treated with adalimumab in mean ASDAS-CRP and reaching ASDAS-CRP minimal disease activity at 2 year follow-up. Drug survival rate was higher in etanercept- compared to adalimumab-treated patients. However, this should be interpreted cautiously as the risk of allocation bias cannot be excluded.

Long-term efficiency of infliximab in patients with ankylosing spondylitis: real life data confirm the potential for dose reduction.

OBJECTIVE: To analyse the treatment outcome of patients with ankylosing spondylitis (AS) in the European AS infliximab cohort (EASIC) study after a total period of 8 years with specific focus on dosage and the duration of intervals between infliximab infusions. METHODS: EASIC included patients with AS who had received infliximab for 2 years as part of the ASSERT trial. After that period, rheumatologists were free to change the dose or the intervals of infliximab. Clinical data were status at baseline, end of ASSERT and for a total of 8 years of follow-up. RESULTS: Of the initially 71 patients with AS from EASIC, 55 patients (77.5%) had completed the 8th year of anti-tumour necrosis factor (TNF) treatment. Of those, 48 patients (87.3%) still continued on infliximab. The mean infusion interval increased slightly from 6 to 7.1±1.5 weeks, while 45.8% patients had increased the intervals up to a maximum of 12 weeks. The mean infliximab dose remained stable over time, with a minimum of 3.1 mg/kg and a maximum of 6.4 mg/kg. In patients receiving <5 mg/kg infliximab, the mean infusion interval increased to 7.0±1.2 weeks. In total, the mean cumulative dose per patient and per year decreased from 3566.30 to 2973.60 mg. CONCLUSIONS: We could observe that over a follow-up of 8 years of treatment with infliximab, >85% patients still remained on the same treatment, without any major safety events. Furthermore, both the infusion intervals and also the mean infliximab dose were modestly reduced in ≥70% of the patients without the loss of clinical efficiency.

Study on the protective effect of the KIR3DL1 gene in ankylosing spondylitis.

OBJECTIVE: Ankylosing spondylitis (AS) is an autoimmune disease that mainly affects the sacroiliac joints and the spine of the lower back. The disease is strongly associated with HLA-B27. Additional genes, single-nucleotide polymorphisms, and molecular components have been identified to be associated with AS, but the exact mechanism that drives disease development remains poorly understood. The killer cell immunoglobulin-like receptors (KIRs) are regulators of cytotoxicity of natural killer cells and T cell subsets and may be relevant in binding to HLA-B27 and the development of AS. We undertook this study to identify possible associations of KIR genotype with susceptibility to AS and disease characteristics including the presence of the HLA-B27 allele, disease severity, and uveitis. METHODS: We performed complete genotyping of the KIR locus in 303 Caucasian AS patients, 119 randomly selected healthy Caucasian controls, and 50 HLA-B27-positive healthy Caucasian controls by multiplex ligation-dependent probe amplification assay for detection of gene presence and copy number. RESULTS: We did not observe a significant association of any specific KIR gene or haplotype with susceptibility to AS or any other clinical manifestation. Disease severity, as measured by fulfilling the criteria for treatment with tumor necrosis factor blocking therapy, was linked to a lower number of genes for the functional variant of KIR3DL1 (P = 0.007). CONCLUSION: Our exploratory study indicates that KIR genes are not a major risk factor for susceptibility to AS. However, the data do suggest a role for KIRs in progression of the disease, whereby KIR3DL1 has a protective effect against the more severe manifestations of AS.

Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of follow-up.

BACKGROUND: Previous data have shown that etanercept levels are associated with clinical response in rheumatoid arthritis. However, for ankylosing spondylitis (AS), data regarding this topic are inconclusive. OBJECTIVES: To investigate the relationship between etanercept levels and clinical response in patients with AS. METHODS: Observational prospective cohort study of 162 patients with AS =treated with etanercept, monitored during 24 weeks of treatment. Etanercept trough levels were determined, retrospectively, using an ELISA. Disease activity was measured using AS Disease Activity Score (ASDAS), including C-reactive protein (CRP) and Bath AS Disease Activity index (BASDAI). Active disease was defined as ASDAS≥2.1. Since etanercept is a drug administered at home there might have been some variation in trough level sampling. RESULTS: At 24 weeks etanercept levels were significantly higher in patients with ASDAS<2.1, (3.8 mg/L; IQR 2.5-5.2) compared with patients with ASDAS≥2.1 (2.3 mg/L; IQR 1.2-3.4; p≤0.001). Generalised estimating equation analysis demonstrated a statistically significant association between etanercept levels and ASDAS, BASDAI, CRP and erythrocyte sedimentation rate (all p<0.001). When patients were categorised into quartiles according to etanercept levels, the lowest quartile (etanercept<1.80 mg/L) comprised 35% of all patients with ASDAS≥2.1 while the highest quartile comprised only 14%. CONCLUSIONS: Disease activity and inflammation are associated with etanercept levels in patients with AS at 24 weeks of treatment. Measuring etanercept levels might help in identifying overtreatment and undertreatment and optimise etanercept therapy in AS.

Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? A long-term observational study using MRI and conventional radiography.

OBJECTIVE: To study the relationship of spinal inflammation and fatty degeneration (FD) as detected by MRI and new bone formation seen on conventional radiographs (CRs) in ankylosing spondylitis (AS). METHODS: CRs at baseline, 2 years and 5 years and spinal MRIs at baseline and 2 years of 73 AS patients treated with infliximab in European AS Infliximab Cohort were available. Relative risks (RR) were calculated with a general linear model after adjustment for within-patient variation. RESULTS: In a total of 1466 vertebral edges (VEs) without baseline syndesmophytes, 61 syndesmophytes developed at 5 years, the majority of which (57.4%) had no corresponding detectable MRI lesions at baseline. VEs with both inflammation and FD at baseline had the highest risk (RR 3.3, p=0.009) for syndesmophyte formation at 5 years, followed by VEs that developed new FD or did not resolve FD at 2 years (RR=2.3, p=0.034), while inflammation at baseline with no FD at 2 years had the lowest risk for syndesmophyte formation at 5 years (RR=0.8). Of the VEs with inflammation at baseline, >70% resolved completely, 28.8% turned into FD after 2 years, but only 1 syndesmophyte developed within 5 years. CONCLUSIONS: Parallel occurrence of inflammation and FD at baseline and development of FD without prior inflammation after 2 years were significantly associated with syndesmophyte formation after 5 years of anti-tumour necrosis factor (TNF) therapy. However, the sequence 'inflammation-FD-new bone formation' was rarely observed, an argument against the TNF-brake hypothesis. Whether an early suppression of inflammation leads to a decrease of the risk for new bone formation remains to be demonstrated.

Elevated liver enzymes in patients with ankylosing spondylitis treated with etanercept.

TNF-alpha blocking agents are very effective in patients with ankylosing spondylitis (AS), but several cases of liver problems have been published. We systematically studied the frequency of this potential side effect in our AS patients treated with etanercept. Consecutive AS patients treated with etanercept for at least 3 months were included. Liver disease was defined as elevated liver enzymes more than 1.5 times the upper normal limit (UNL) and was categorised as probably, possibly, probably not or not related to etanercept treatment. Patients with and without raised liver enzymes were compared for prognostic factors. A total of 105 patients were included. Fifteen patients had elevated liver enzymes more than once. In nine cases, the liver disease was probably (five) or possibly (four) related to etanercept treatment. The liver enzyme elevations were serious (>3× UNL) in six cases and resulted in permanent cessation of etanercept in two cases. The nine patients with liver disease were compared with patients without elevated liver enzymes. No differences were found in age or use of alcohol; however, in patients with liver disease, a higher body mass index and a trend for a higher atherogenic index were observed. Hepatic steatosis was observed in five of six patients with elevated liver enzymes. Elevated serum aminotransferases, probably or possibly related to etanercept treatment, were observed in 9 % of the AS patients. An increased risk for the elevation of liver enzymes was found in patients with a higher body mass index. We recommend regular testing of liver enzymes in patients treated with etanercept.

High prevalence of low bone mineral density in patients within 10 years of onset of ankylosing spondylitis: a systematic review.

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease. Decreased bone mineral density (BMD) is a common complication of AS, with a prevalence range of 19 to 62 %. Many studies have shown decreased BMD in AS with long disease duration, but only a few studies investigated BMD in early AS. The prevalence of decreased BMD in early disease stages of AS has not yet been clearly described, and for that reason, we reviewed the literature which describes the prevalence of decreased BMD in AS patients with a short disease duration (<10 years). In this review, we included articles which used the modified New York criteria for the diagnosis of AS, included patients with a disease duration of less than 10 years, and used the WHO criteria for osteopenia and osteoporosis. Decreased BMD was defined as a T score < -1.0, including both osteopenia and osteoporosis. For this review, only articles that acquired BMD data of lumbar spine and femoral neck by DXA were used. The literature search provided us 35 articles of which 7 matched all our criteria, and they will be further outlined in this review. The overall prevalence of decreased BMD of the articles reviewed is 54 % (n = 229/424) for lumbar spine and 51 % (n = 224/443) for femoral neck. The prevalence of osteopenia vs. osteoporosis for lumbar spine is 39 vs. 16 % and for femoral neck, 38 vs. 13 %. This review showed a high total prevalence of 51-54 % decreased BMD and 13-16 % osteoporosis in AS with a short disease duration. This high prevalence was not to be expected in a relatively young and predominantly male population. Further research is needed to determine the clinical relevance of this low BMD by investigating the relation between low BMD and vertebral and nonvertebral fractures at this early stage in AS.

High frequency of vertebral fractures in early spondylarthropathies.

UNLABELLED: We demonstrated that vertebral fractures (VF) are commonly found in early SpA. Patients with VF had lower lumbar BMD than patients without VF. VF remained frequently 'unrecognized' and untreated. VF have been associated with more back pain, reduced Qol, and increased risk of future fractures which stresses the importance of recognition also in early stage SpA. INTRODUCTION: VF are a common complication of long-standing ankylosing spondylitis (AS). However, data of VF in early AS patients and in other spondylarthropathies (SpA) are scarce. Therefore we examined the prevalence of VF in early SpA patients and investigated the associations between VF and demographic and disease-related variables. METHODS: SpA patients were included consecutively and radiographs of the spine were made. VF were assessed according to the method of Genant et al.: fractures were defined as reduction of ≥20% of the vertebrae. Descriptive statistics, t-tests and logistic regression analyses were used to study the relationship between VF and demographic and disease-related variables, radiographic damage and BMD. RESULTS: A total of 113 early SpA patients were included with a disease duration of 7 months, a mean age of 37 years. Seventeen patients (15%) had at least one VF. Fourteen patients had one VF, three patients had two VF. Most VF were located at Th6-Th8. In patients with VF, bone mineral density (BMD) of lumbar spine was lower than BMD of patients without VF (t-test: p = 0.043). Axial Psoriatic Arthritis (PsA) was significantly associated with a higher risk for VF (odds ratio [OR]: 4.62, 95% confidence interval [CI] 1.15-18.58, p = 0.031). No significant associations were found with disease activity variables nor with radiographic severity. CONCLUSION: In a group of 113 early, young SpA patients, 15% already had at least one VF. Most VF were asymptomatic, undetected by routine diagnostic procedures and located at the mid-thoracic spine. The VF were associated with low BMD of the lumbar spine and with axial PsA.