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.

Long-term treatment response in rheumatoid arthritis patients starting adalimumab or etanercept with or without concomitant methotrexate.

OBJECTIVES: To observe long-term clinical response and drug survival in a prospective two-year cohort study in rheumatoid arthritis (RA) patients starting adalimumab or etanercept treatment, with or without methotrexate (MTX), after failure of conventional DMARD therapy, including MTX. METHODS: Disease activity score of 28 joints (DAS28) and Health Assessment Questionnaire (HAQ) were collected of 873 consecutive RA patients, treated with adalimumab or etanercept, prospectively at baseline, 4, 16, 28, 40, 52, 78 and 104 weeks of biological therapy. Sustained minimal disease activity (MDA), DAS28 <2.6 for at least 24 consecutive weeks, biological discontinuation, ΔHAQ and ΔDAS28 were compared between patients treated with or without concomitant MTX for etanercept and adalimumab separately. RESULTS: More patients treated with adalimumab and MTX (42%) achieved sustained MDA than patients without MTX (18%). The hazard ratio (HR) was 2.3 [1.4-3.9]. No significant difference was found in etanercept treatment (with MTX 33% vs. 28% without MTX), HR 1.1 [0.8-1.6]. More patients treated without MTX discontinued treatment than patients with MTX co-treatment in adalimumab (HR 2.1 [1.5-3.0]) and etanercept (HR 1.9 [1.0-3.4]). The mean decrease in DAS28 over time was higher for patients treated with MTX in adalimumab (regression coefficient (RC): 0.57, p<0.001), but was not significantly different in etanercept treatment (RC 0.05, p=0.427). No significant differences were found in ΔHAQ. CONCLUSIONS: Treatment discontinuation is lower in patients treated with MTX in both adalimumab and etanercept treatment. However, considering good clinical response, in contrast to etanercept, a synergetic effect of MTX is observed only in adalimumab treatment.

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.

Changes in Tumor Necrosis Factor Inhibitor Drug Survival in Patients With Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis Over 15 Years.

OBJECTIVE: To study changes in retention of first biologic disease-modifying antirheumatic drug (DMARD) therapy over a period of 15 years in an inception cohort of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). METHODS: We assessed patient and disease characteristics and drug survival of patients starting a biologic (tumor necrosis factor inhibitor [TNFi]) therapy between 2004 and 2019 in routine care at the Amsterdam Rheumatology and Immunology Center, Reade, the Netherlands. Starts were classified as early (2004-2008), intermediate (2009-2013), and recent (2014-2018). Kaplan-Meier plots and log-rank tests assessed the overall difference in drug survival between the 3 observation groups and between diagnoses, followed by Cox regression to estimate hazard ratios (HRs). RESULTS: We included 1938 consecutive patients starting TNFi therapy, 63% with RA, 19% with PsA, and 19% with AS; 65% were female. Drug survival decreased significantly over time (overall P < 0.001), mostly caused by decreases in the most recent 4-year period. The HR for drug continuation was 2.04 (95% CI 1.71-2.43, P < 0.001) for the early vs the recent group and 1.92 (95% CI 1.58-2.35, P < 0.001) for the intermediate vs the recent group. Drug survival time was significantly different between diseases (overall P < 0.001), mostly caused by shorter survival in RA. The HR for drug continuation was 0.58 (95% CI 0.47-0.73, P < 0.001) for RA vs PsA and 0.63 (95% CI 0.51-0.78, P < 0.001) for RA vs AS. CONCLUSION: Patients with RA, PsA, and AS currently initiating biologic (TNFi) therapy discontinue the drug much sooner than those starting shortly after the drugs were introduced. This is most likely because of the availability of alternative novel biologic and targeted synthetic DMARD treatments and treat-to-target protocols enabling and necessitating earlier switching.

Fat Mass Lowers the Response to Tumor Necrosis Factor-α Blockers in Patients with Ankylosing Spondylitis.

OBJECTIVE: Our main objective was to assess the relationship between body composition (BC) and response to tumor necrosis factor-α (TNF-α) blocker treatment in patients with ankylosing spondylitis (AS). Our secondary objective was to evaluate the change of BC after treatment, accounting for sex and age. METHODS: All included patients fulfilled the modified New York criteria for AS and were naive to TNF-α blocker. They were followed for at least 6 months after the start of etanercept or adalimumab. The Ankylosing Spondylitis Disease Activity Score containing C-reactive protein (ASDAS-CRP) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were reported. BC was assessed by whole body dual-energy X-ray absorptiometry. Body fat percentage (BF%), fat mass index (FMI), and fat free mass index (FFMI) were reported as absolute values and as percentiles. RESULTS: Forty-one patients were included (61% men). The median followup was 14.3 months (interquartile range 8.4-19.4). After multivariate regression analysis, more fat at baseline (BF%, FMI, or FMI percentile) was significantly related with a lower chance of achieving a clinically important improvement of the ASDAS-CRP or BASDAI after treatment. The body composition did not change significantly after treatment, but there was a trend toward muscle recovery in men (FFMI change from 34.0th to 37.4th percentile). CONCLUSION: Higher body fat content at baseline was independently associated with a worse response to treatment with TNF-α blockers, measured by ASDAS-CRP and BASDAI change, and might contribute to the lower response rates in female patients. Also, there is a trend toward muscle mass recovery in male patients after treatment.

Adalimumab significantly reduces the recurrence rate of anterior uveitis in patients with ankylosing spondylitis.

OBJECTIVE: To investigate whether use of adalimumab decreases the frequency of attacks of anterior uveitis (AU) in patients with ankylosing spondylitis (AS). METHODS: Consecutive patients with AS, visiting an outpatient clinic and treated for at least 12 weeks with adalimumab, were enrolled. The number of attacks of AU in the year before start and during treatment were assessed by patient history and ophthalmological controls. RESULTS: In the 77 patients a total of 52 AU attacks occurred in the year before baseline (68 attacks per 100 patient-yrs), whereas during adalimumab treatment 19 attacks were seen (14 per 100 patient-yrs; reduction rate 80%). Twenty-six patients with AU in the year before start of adalimumab treatment had recurrent attacks, with a median number of 2.0 AU attacks per year [interquartile range (IQR) 1.00-3.00], whereas during treatment this decreased to 10 patients with a median number of 0.56 attacks per year (IQR 0.30-0.75). Hence, the number of attacks per year decreased by 72% (p = 0.000). CONCLUSION: In patients with AS, a significant reduction in the number of AU attacks, as well as in the number of attacks per patient, was observed during adalimumab treatment.

Effect of the application of trial inclusion criteria on the efficacy of adalimumab therapy in a rheumatoid arthritis cohort.

OBJECTIVE: To evaluate the influence of inclusion criteria used in rheumatoid arthritis (RA) trials with adalimumab on clinical outcome and response. METHODS: The different inclusion criteria of published trials of adalimumab in RA were separately applied to a large prospective cohort of patients with RA treated with adalimumab (AdRA cohort), thereby mimicking patient selection for a clinical trial. Clinical response and outcome in the resulting 11 projection groups were compared using the 28-joint Disease Activity Score (DAS28) and time-averaged DAS28 as outcome measures of efficacy. RESULTS: Thirteen trials (n = 54-799) with 11 different sets of entry criteria were identified, resulting in 11 projection groups (n = 22-168). The DAS28 at baseline was similar in the original trial and each projection group based on this trial (5.1-6.4, total AdRA cohort 5.1). After 28 weeks, the efficacy varied substantially among the 11 projected groups (change from baseline DAS28: -1.65 to -2.65, time-averaged DAS28 3.67-4.53). Expressed as outcome (DAS28 at 28 weeks), the efficacy was much more similar for almost all projection groups (3.5-4.0) and thus appeared to be mostly independent of disease activity at baseline. CONCLUSION: We observed that different inclusion criteria for clinical trials can have a marked effect on the expected response, i.e., improvement from baseline. A novel finding is that final disease activity appeared much less dependent on initial disease activity. Our study suggests that for daily practice, one can assume that adalimumab treatment will on average result in a DAS28 between 3.5 and 4.0 after 28 weeks of treatment, regardless of baseline disease activity.