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This study aimed at exploring the concentration-effect relationship of adalimumab and early adalimumab and anti-adalimumab antibody (AAA) levels in predicting primary nonresponse in a real-world pilot cohort of patients with ankylosing spondylitis. Thirty-one patients were included. The Ankylosing Spondylitis Disease Activity Score improved with increasing adalimumab trough level at week 12 and reached a major improvement with levels between 8 and 12 μg/mL. Moreover, weeks 4 and 2 adalimumab levels below 4.28 and 3.37 μg/mL were predictive of primary nonresponse (area under the curve (AUC) = 0.89, 0.88; P = 0.0003, P = 0.034, respectively). Week 4 AAA signal-to-noise levels were significantly higher among primary nonresponders, and the cutoff for primary nonresponse prediction was above 5.31 (AUC = 0.81; P = 0.004). Adalimumab trough levels in a range of 8-12 μg/mL are optimum to reach major improvement, and lower adalimumab with higher AAA levels at the early stage (week 4) predict primary nonresponse by supporting proactive monitoring to optimize adalimumab therapy., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Infliximab (INX) and other tumour necrosis factor inhibitors (TNFi) have revolutionised the treatment of several immune mediated inflammatory diseases. Still, many patients do not respond sufficiently to therapy or lose efficacy over time. The large interindividual variation in serum drug concentrations on standard doses and the development of anti-drug antibodies are thought to be major reasons for treatment failures. Therapeutic drug monitoring (TDM), an individualised treatment strategy based on systematic assessments of serum drug concentrations, has been proposed as a clinical tool to optimise efficacy of INX treatment. TDM seems reasonable both from a clinical and an economical point of view, but the effectiveness of this treatment strategy has not yet been demonstrated in randomised clinical trials. The NORwegian DRUg Monitoring study (NOR-DRUM) aims to assess the effectiveness of TDM, both with regard to the achievement of remission in patients starting INX treatment (part A) as well as to maintain disease control in patients on INX treatment (part B)., Methods: The NOR-DRUM study is a randomised, open, controlled, parallel-group, comparative, multi-centre, national, superiority, phase IV study with two separate parts, NOR-DRUM A and NOR-DRUM B. Patients with rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, ulcerative colitis, Crohn's disease and psoriasis are included. In both study parts participants are randomised 1:1 to either TDM of infliximab (intervention group) or to standard treatment with infliximab without knowledge of drug levels or ADAb status (control group). NOR-DRUM A will include 400 patients starting INX therapy. The primary outcome is remission at 30 weeks. In NOR-DRUM B, 450 patients on maintenance treatment with INX will be included. The primary endpoint is occurrence of disease worsening during the 52-week study period., Discussion: As the first trial to assess the effectiveness, safety and cost-effectiveness of TDM in patients receiving TNFi for a range of immune mediated inflammatory diseases, we hope that the NOR-DRUM study will contribute to the advancement of evidence based personalised treatment with biological medicines., Trial Registration: Clinicaltrials.gov, NCT03074656. Registered on 090317.

Objectives: This study aimed to compare comorbidities and biologic DMARD (bDMARD) use between AS and non-radiographic axial SpA (nr-axSpA) patients, using a large cohort of patients from routine clinical practice in the United States., Methods: We performed a cross-sectional study using electronic medical records from two academic hospitals in the United States. Data were extracted using automated searches (⩾3 ICD codes combined with text searches) and supplemented with manual chart review. Patients were categorized into AS or nr-axSpA according to classification criteria. Disease features, comorbidities (from a list of 39 chronic conditions) and history of bDMARD prescription were compared using descriptive statistics., Results: Among 965 patients identified, 775 (80%) were classified as having axSpA. The cohort was predominantly male (74%) with a mean age of 52.5 years (s.d. 16.8). AS patients were significantly older (54 vs 46 years), more frequently male (77% vs 64%) and had higher serum inflammatory markers than those with nr-axSpA (median CRP 3.4 vs 2.2 mg/dl). Half of all patients had at least one comorbidity. The mean number of comorbidities was 1.5 (s.d. 2.2) and similar between AS and nr-axSpA groups. A history of bDMARD-use was seen in 55% of patients with no difference between groups. The most commonly prescribed bDMARDs were adalimumab (31%) and etanercept (29%). Ever-prescriptions of individual bDMARDs were similar between AS and nr-axSpA., Conclusion: Despite age differences, nr-axSpA patients had similar comorbidity burdens as those with AS. Both groups received comparable bDMARD treatment in this United States clinic-based cohort., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To investigate the effective serum level of etanercept biosimilar in Chinese patients with ankylosing spondylitis (AS) who achieve AS Disease Activity Score-C-reactive protein (ASDAS-CRP) < 2.1, and the effect of antidrug antibodies on drug levels and clinical efficacy., Methods: Our study enrolled 60 patients with AS who were treated with etanercept biosimilar. Serum and clinical data were collected at baseline and treatment weeks 4, 12, and 24. Drug levels and antidrug antibody levels were measured using an enzyme-linked immunosorbent assay while tumour necrosis factor (TNF)-α levels were measured using cytometric bead array. A receiver operating characteristic (ROC) curve was used to analyse effective serum level of etanercept biosimilar., Results: Patients with ASDAS-CRP ≥ 2.1 exhibited significantly lower drug levels than those with ASDAS-CRP < 2.1 did. The cut-off values of effective serum level of patients with AS who achieved ASDAS-CRP < 2.1 at weeks 4, 12, and 24 were 2.32, 2.12, and 2.36 μg/mL, respectively. Patients with drug levels above the cut-off value had lower Bath AS Disease Activity Index (BASDAI) and TNF-α levels. Antidrug antibodies had no effect on the Assessment of Spondylosis Arthritis International Society (ASAS) remission rates, but patients with antidrug antibodies had lower drug levels and higher TNF-α levels., Conclusions: Detecting serum drug levels and antidrug antibody levels might facilitate estimation of the clinical efficacy and adjustment of medication regimen during etanercept biosimilar therapy in Chinese patients with AS.

The purpose of this study was to investigate the correlation of bone marrow edema (BME) in sacroiliac joint (SIJ) with clinical characteristics and clinical response, and whether the quick decrease of BME could be served as a novel marker for dose tapering of etanercept in ankylosing spondylitis (AS) patients.Ninety active AS patients underwent etanercept treatment for 6 months were enrolled consecutively and classified into standard dose group (n = 37) and dose tapering group (n = 53). BME in SIJ and clinical response were assessed by SPARCC criteria and ASAS 40 response criteria, respectively. "Quick decrease of BME in SIJ" was defined as the decrease of SPARCC score≥50% from M0 to M1.BME in SIJ was positively correlated with pain VAS score, BASDAI score, CRP, IL-1β, IL-17, and TNF-α levels. ASAS 40 response rate at M6 was lower in dose tapering group than standard dose group, while higher in patients with a quick decrease of BME in SIJ than other patients. Besides, the ASAS 40 response rate in dose tapering group was similar to standard dose group in patients with a quick decrease of BME in SIJ but was lower than standard dose group in patients without a quick decrease of BME in SIJ at M6.A quick decrease of BME in SIJ predicts better treatment response to etanercept, and it might be served as a novel marker for dose tapering initiation of etanercept in AS patients.

In this study, we analysed the expression level of sera circulating miRNA-5196 in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients before and after tumor necrosis factor (TNF)-α therapy as biomarkers predicting positive treatment outcome. We enrolled 10 RA patients, 13 AS patients, and 12 healthy individuals in the study. The expression of miRNA-5196 was measured by real-time polymerase chain reaction before and after anti-TNF-α therapy. Disease activity of RA patients was assessed using disease activity score 28 (DAS28), whereas ankylosing spondylitis DAS (ASDAS) was used in AS patients. MiRNA-5196 expression was significantly higher in patients with RA and AS before TNF-α therapy than in those following anti-TNF-α therapy and healthy controls. Changes in miRNA-5196 expression positively correlated with delta DAS28 or delta ASDAS, respectively, following TNF-α therapy. In contrast, changes in C-reactive protein (CRP) levels in RA and AS patients did not positively correlate with DAS28 or ASDAS changes. Receiver-operating characteristic analysis showed better diagnostic accuracy of miRNA-5196 expression both in RA (area under curve (AUC) = 0.87, p = 0.055) and AS patients (AUC = 0.90, p = 0.050) compared to CRP levels in RA (AUC = 0.75, p = 0.201) and AS patients (AUC = 0.85, p = 0.086) upon biologic therapy treatment. Finding novel biomarkers, including miRNA-5196 which allow to predict and monitor anti-TNF-α response, would be of clinical value especially during the early phase of RA or AS development.

Objectives: The reason for increased cardiovascular risk in inflammatory arthritis (IA) is unclear. Interestingly, selenium-deficiency is suspected to contribute to the development of cardiovascular disease (CVD) in the general population. Although the reference range of serum selenium (s-selenium) is 50-120 μg/L, there are indications that levels up to 85 μg/L might not be sufficient for optimal cardioprotection. Our aim was to examine s-selenium levels in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), to evaluate the effect of anti-rheumatic treatment on s-selenium levels, and to assess relationships between s-selenium levels and clinical and laboratory parameters including markers of disease activity and CVD risk., Methods: We examined 64 patients with RA, 40 with PsA and 26 with AS starting with methotrexate (MTX) monotherapy or anti-tumor necrosis factor therapy (anti-TNF) with or without methotrexate (anti-TNF ± MTX) due to active disease. S-selenium, inflammatory biomarkers, endothelial function (EF) and other variables were examined at baseline and after 6 weeks and 6 months of treatment., Results: In the total IA group, s-selenium increased within 6 weeks of anti-rheumatic treatment, and thereafter the levels remained stable until the end of the 6 months follow-up period. There were no significant differences in s-selenium changes between the three diagnostic groups and between the two treatment regimens. Changes in s-selenium were negatively related to changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), but there were no significant relationships to any other of the examined risk parameters for CVD including EF., Conclusion: IA patients had s-selenium within the reference range, but below the level that might be necessary for optimal CVD protection. Anti-rheumatic treatment had a relatively rapid and sustained effect on s-selenium levels. The increase in s-selenium was related to reduction in inflammatory activity. In theory, anti-rheumatic drugs might improve s-selenium levels through inhibition of pro-inflammatory processes or through other mechanisms. Although we have not revealed any significant relationships between s-selenium and CVD risk parameters, the role of suboptimal s-selenium levels in pathogenesis of premature CVD in IA cannot be ruled out., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Objectives: To investigate the association between serum golimumab (GLM) trough levels, clinical disease activity and treatment response during the first year of therapy in patients with axial spondyloarthritis (axSpA), as well as determining an optimal concentration range of GLM in axSpA., Methods: This was an observational prospective study including 49 patients with axSpA monitored during 52 weeks (W52). Serum GLM trough levels were measured by capture ELISA and antidrug antibodies by bridging ELISA at baseline, W24 and W52. Disease activity was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) and clinical improvement by ΔASDAS. The association between serum GLM trough levels and disease activity was assessed using univariable and multivariable regression. In case of drop-out or missing data before W52, the last observation carried forward (LOCF) was performed. ASDAS values and GLM levels at W24 were available for 42 patients and 38 patients at W52., Results: In the univariable analyses, serum GLM trough levels were inversely associated with ASDAS at W24 (n=42, r =-0.445; p<0.01), at W52 (n=38, r=-0.330; p<0.05) and W52LOCF (n=49, r=-0.309; p<0.05). In the multivariable analysis, this significant association remained. Serum trough GLM levels above the 0.7-1.4mg/L range did not contribute to additional clinical improvement., Conclusions: In patients with axSpA, serum GLM trough levels are associated with disease activity during the first year of treatment. A concentration range of 0.7-1.4mg/L appears to be useful to achieve clinical response to GLM.

The studies aimed to assess a set of biomarkers for their correlations with disease activity/severity of patients with ankylosing spondylitis (AS). A total of 24 AS patients were treated with etanercept and prospectively followed for 12 weeks. Serum levels of TNF-α, IFN-γ, TGF-β, IL6, IL15, IL17, MMP3, and MICA were measured at baseline and after treatment. The change of these biomarkers was analyzed for correlations with MRI indices for joint inflammation, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, AS Disease Activity Score, serum CRP, and ESR. The Wilcoxon rank sum test was used to compare the biomarker levels between pre- and post-treatment and between pre-treatment and controls. Both step-wise procedures based on the Akaike information criterion (AIC) and least absolute shrinkage and selection operator with fivefold cross-validation were used to select the best model for pairwise correlations between the above clinical measures and the serum biomarkers. Serum levels of both MMP3 and IL6 were significantly higher in AS patients at baseline. After treatment, the levels of MMP3 decreased, but TGF-β and TNF-α increased significantly. The changes of serum MMP3 and MICA were significantly associated with MRI sacroiliac joint (SIJ) scores. CRP was positively correlated with serum MMP3 and IL6. The pattern of combined changes of serum MICA, MMP3, TGF-β, IL17, TNF-α, and IFN-γ predicted the MRI score of SIJ by logistic regression analysis. Specific serum biomarkers were significantly associated with clinical measures of AS. Most prominently, serum MMP3 level was found to have a positive correlation with the MRI score of SIJ and CRP. Serum MICA level negatively correlated with disease remission.

Background: The tumor necrosis factor alpha (TNF-α) inhibitor etanercept has been proven to be effective in the treatment of ankylosing spondylitis (AS), while genetic polymorphism may affect drug metabolism or drug receptor, resulting in interindividual variability in drug disposition and efficacy. The purpose of this study is to investigate the correlations between CYP2C9*3/CYP2D6*10/CYP3A5*3 gene polymorphisms and the efficacy of etanercept treatment for patients with AS., Methods: From March 2012 to June 2015, 312 AS patients (174 males and 138 females, mean age: 35.2 ± 5.83 years) from 18 to 56 years old were enrolled in this study. Polymerase chain reaction-restriction fragment length polymorphism was applied to detect the allele and genotype frequencies of CYP2C93, CYP2D610, and CYP3A53 gene polymorphisms. The joint swelling score, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level of AS patients were compared before and after 24-week etanercept treatment. Assessment in Ankylosing Spondylitis (ASAS) and bath ankylosing spondylitis disease activity index (BASDAI) scores were recorded to assess the efficacy of etanercept treatment., Results: The AS patients with wild-type 1/1 and heterozygous 1/3 genotypes of CYP2C93 polymorphism accounted for 93.59% and 6.41%, respectively, without 3/3 genotype. The AS patients with wild-type CC, heterozygous CT, and mutation homozygous TT genotypes of CYP2D610 polymorphism accounted for 19.23%, 39.10%, and 41.67%, respectively. The AS patients with wild-type 1/1, heterozygous 1/3, and mutation homozygous 3/3 genotypes of CYP3A53 polymorphism accounted for 7.69%, 36.22%, and 56.09%, respectively. After 24-week treatment, AS patients with wild-type 1/1 genotype of CYP2C93, CC genotype of CYP2D610, and 3/3 genotype of CYP3A53 polymorphisms had lower joint swelling score, ESR, and CRP level. The joint swelling score, ESR, and CRP levels were significantly lower in the patients with CC genotype of CYP2D610 polymorphism than in CT and TT genotype patients, and they were lower in patients with 3/3 genotype of CYP3A53 polymorphism compared to those with 1/1 and 1/3 genotypes. Average visual analog scale scores of 4 ASAS20 indexes were decreased after treatment. The patients with CC genotype of CYP2D610 polymorphism and 3/3 genotype of CYP3A53 polymorphism exhibited higher scores of >ASAS20, >BASDAI50%, and effective rate., Conclusion: Our results indicate that CC genotype of CYP2D610 polymorphism and 33 genotype of CYP3A53 polymorphism are correlated with the efficacy of etanercept treatment for AS patients.

Background: Pentraxin 3 is proposed to be a marker of inflammation and cardiovascular risk, but its role in inflammatory rheumatic diseases (IRDs) is still uncertain. Therefore, we wanted to examine if anti-rheumatic treatment reduced serum PTX3 (s-PTX3) levels in IRDs, and if s-PTX3 levels were related to other markers of inflammation and to endothelial function (EF)., Methods: We examined s-PTX3, EF and established inflammatory biomarkers in 114 IRD patients from the PSARA study before and after 6 weeks and 6 months of treatment with methotrexate (MTX) or anti-tumor necrosis factor alpha (anti-TNF) therapy with or without MTX co-medication., Results: s-PTX3 levels in all IRD diagnoses were above the upper limit of the reference range. In contrast to established inflammatory markers, in particular CRP and ESR, s-PTX3 levels did not change significantly after 6 weeks and 6 months of anti-rheumatic therapy. There was no difference in change in s-PTX3 levels from baseline to 6 weeks and 6 months between MTX monotherapy and anti-TNF regimens. CRP, ESR and EF were not related to changes in s-PTX3 neither in crude nor adjusted analyses., Conclusion: IRD patients have increased s-PTX3 levels, which, in contrast to other inflammatory markers, do not seem to improve within 6 months of therapy with MTX and/or anti-TNF. Thus, s-PTX3 might reflect a persisting immune process, even a causal factor of inflammation, not inhibited by the standard anti-rheumatic treatment. Furthermore, even though s-PTX3 is thought to be a strong predictor of cardiovascular prognosis, it was not related to EF.

Objective: To compare baseline disease activity and treatment effectiveness in biologic-naive patients with nonradiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) who initiate tumor necrosis factor inhibitor (TNFi) treatment and to study the role of potential confounders (e.g., HLA-B27 status)., Methods: Observational cohort study based on prospectively registered data in the nationwide DANBIO registry. We used Kaplan-Meier plots, Cox, and logistic regression analyses to study the effect of diagnosis (nr-axSpA vs AS) and potential confounders (sex/age/start yr/HLA-B27/disease duration/TNFi-type/smoking/baseline disease activity) on TNFi adherence and response [e.g., Bath Ankylosing Spondylitis Activity Index (BASDAI) 50%/20 mm]., Results: The study included 1250 TNFi-naive patients with axSpA (29% nr-axSpA, 50% AS, 21% lacked radiographs of sacroiliac joints). Patients with nr-axSpA were more frequently women (50%/27%) and HLA-B27-negative (85/338 = 25%), compared to AS (81/476 = 17%; p < 0.01). At TNFi start patients with nr-axSpA had higher visual analog scale scores [median (quartiles)] for pain: 72 mm (55-84)/65 mm (48-77); global: 76 mm (62-88)/68 mm (50-80); fatigue: 74 mm (55-85)/67 mm (50-80); and BASDAI: 64 (54-77)/59 (46-71); all p < 0.01. However, patients with nr-axSpA had lower C-reactive protein: 7 mg/l (3-17)/11 mg/l (5-22); and BAS Metrology Index: 20 (10-40)/40 (20-50); all p < 0.01. Median (95% CI) treatment adherence was poorer in nr-axSpA than in AS: 1.59 years (1.15-2.02) versus 3.67 years (2.86-4.49), p < 0.0001; but only in univariate and not confounder-adjusted analyses (p > 0.05). Response rates were similar in AS and nr-axSpA (p > 0.05). HLA-B27 negativity was associated with poorer treatment adherence [HLA-B27 negative/positive, nr-axSpA: HR 1.74 (1.29-2.36), AS: HR 2.04 (1.53-2.71), both p < 0.0001]; and lower response rates (nr-axSpA: 18/61 = 30% vs 93/168 = 55%; AS: 17/59 = 29% vs 157/291 = 54%, both p < 0.05)., Conclusion: In this nationwide cohort, patients with nr-axSpA had higher subjective disease activity at start of first TNFi treatment, but similar outcomes to patients with AS after confounder adjustment. HLA-B27 positivity was associated with better outcomes irrespective of axSpA subdiagnosis.

Background: In the present study, we evaluated relationships between serum biomarkers and clinical/magnetic resonance imaging (MRI) findings in golimumab-treated patients with ankylosing spondylitis., Methods: In the GO-RAISE study, 356 patients with ankylosing spondylitis randomly received either placebo (n = 78) or golimumab 50 mg or 100 mg (n = 278) injections every 4 weeks through week 24 (placebo-controlled); patients continuing GO-RAISE received golimumab through week 252. Up to 139/125 patients had sera collected for biomarkers/serial spine MRI scans (sagittal plane, 1.5-T scanner). Two blinded readers employed modified ankylosing spondylitis spine magnetic resonance imaging score for activity (ASspiMRI-a) and ankylosing spondylitis spine magnetic resonance imaging score for chronicity. Spearman correlations (r s ) were assessed between serum biomarkers (n = 73) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), C-reactive-protein (CRP)-based Ankylosing Spondylitis Disease Activity Score (ASDAS), modified Stokes Ankylosing Spondylitis Spine Score (mSASSS), and ASspiMRI scores. Serum biomarkers predicting postbaseline spinal fatty lesion development and inflammation were analyzed by logistic regression., Results: Significant, moderately strong correlations were observed between baseline inflammatory markers interleukin (IL)-6, intracellular adhesion molecule-1, complement component 3 (C3), CRP, haptoglobin, and serum amyloid-P and baseline ASDAS (r s  = 0.39-0.66, p ≤ 0.01). Only baseline leptin significantly correlated with ASDAS improvement at week 104 (r s  = 0.55, p = 0.040), and only baseline IL-6 significantly predicted mSASSS week 104 change (β = 0.236, SE = 0.073, p = 0.002, model R 2  = 0.093). By logistic regression, baseline leptin, C3, and tissue inhibitor of metalloproteinase (TIMP)-1 correlated with new fatty lesions per spinal MRI at week 14 and week 104 (both p < 0.01). Changes in serum C3 levels at week 4 (r s  = 0.55, p = 0.001) and week 14 (r s  = 0.49, p = 0.040) significantly correlated with BASDAI improvement at week 14. Baseline IL-6 and TIMP-1 (r s  = -0.63, -0.67; p < 0.05) and reductions at week 4 in IL-6 (r s  = 0.61, p < 0.05) and C3 (r s  = 0.72; p < 0.05) significantly correlated with week 14 ASspiMRI-a improvement., Conclusions: Extensive serum biomarker multiparametric analyses in golimumab-treated patients with ankylosing spondylitis demonstrated few correlations with disease activity or MRI changes; IL-6 weakly correlated with radiographic progression., Trial Registration: ClinicalTrials.gov identifier: NCT00265083 . Registered on 12 December 2005.

Objective: Serum C-reactive protein (CRP) associates with radiographic progression in patients with ankylosing spondylitis (AS) untreated with tumor necrosis factor (TNF) antagonists. We assessed correlations between serum CRP and radiographic progression/magnetic resonance imaging (MRI)-detected inflammation after 2 years of anti-TNF therapy., Methods: Patients with active AS receiving golimumab (GOL)/placebo through Week 16 (early escape) or Week 24 (crossover by design), followed by GOL through 4 years, had sera/images obtained through Week 208. Lateral spinal radiographs and spinal MRI were scored with the modified Stoke AS Spine Score (mSASSS) and the AS spine MRI activity (ASspiMRI-a) score, respectively. ANOVA assessed differences based on CRP levels and mSASSS progression. The relationships between CRP levels and mSASSS/ASspiMRI-a were assessed by Spearman correlation and logistic regression., Results: Of the randomized GO-RAISE patients, 299 (84.0%) had pre- and posttreatment spinal radiographs. Larger proportions of patients with Week 104 CRP ≥ 0.5 mg/dl (n = 47) versus < 0.5 mg/dl (n = 236, 40.4% vs 22.9%, p = 0.0121) had mSASSS changes ≥ 2 at Week 104. Across several visits, serum CRP demonstrated weak associations with mSASSS change (rs ≤ 0.21, p < 0.05, n = 262-293) and moderate associations with ASspiMRI-a change (rs = -0.33 to 0.54, p < 0.05, n = 65-89). Higher baseline CRP was associated with increased risk for syndesmophytes at Week 104/Week 208, and large, short-term decreases in CRP from baseline to Week 14/Week 24 also yielded increased syndesmophyte formation risk., Conclusion: Elevated CRP after 2 years of anti-TNF treatment correlated with greater radiographic progression risk at 4 years. Elevated CRP at baseline or Week 14/Week 24 of anti-TNF treatment weakly predicted subsequent radiographic progression and modestly predicted residual spinal inflammation in patients with AS treated with anti-TNF. Findings are useful regarding new treatment options in patients treated with anti-TNF. ClinicalTrials.gov: NCT00265083.

Objective: To assess vascular endothelial growth factor (VEGF) correlations with new bone formation and bone marrow edema in patients with ankylosing spondylitis (AS) treated with golimumab (GOL)., Methods: Following placebo control (through weeks 16 and 24), GO-RAISE (A Multicenter Randomized, Double-blind, Placebo-controlled Trial of Golimumab, a Fully Human Anti-TNF-α Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Ankylosing Spondylitis; ClinicalTrials.gov: NCT00265083) all patients received GOL; sera/images were available at weeks 0, 104, and 208. Lateral spinal radiographs and magnetic resonance imaging (MRI) were scored using the modified Stokes Ankylosing Spondylitis Spine Score (mSASSS) and the Ankylosing Spondylitis Spinal MRI activity score, respectively., Results: VEGF levels and the mSASSS did not significantly correlate. Logistic regression analyses showed no association between VEGF levels and an increased risk of syndesmophyte formation at weeks 104 and 208. Pretreatment/Week 14 VEGF did not predict MRI scores/changes at Week 104., Conclusion: Serum VEGF did not predict radiographic progression/spinal inflammation in patients receiving antitumor necrosis factor.

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.

Objectives: To investigate the impact of smoking on the response to treatment with a first tumour necrosis factor inhibitor (TNFi) in patients with axial spondyloarthritis (axSpA) in a real-life cohort., Methods: Patients fulfilling the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA in the Swiss Clinical Quality Management Cohort were included in this study. The potential association between smoking status and differential response to TNFi in terms of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS) was analysed using multiple adjusted longitudinal mixed effect models. Binary response rates at 1 year were assessed with multiple adjusted logistic analyses., Results: A first TNFi was initiated in 698 patients with axSpA with available smoking status and a baseline or follow-up BASDAI assessment, of which 490 (70%) had complete covariate data. In comparison to non-smokers, current smokers demonstrated significantly smaller reductions in BASDAI and ASDAS scores upon treatment with TNFi (0.75 BASDAI units and 0.69 ASDAS units less, p=0.005 and 0.001, respectively) for patients with elevated baseline C-reactive protein (CRP) level. This effect was numerically smaller in patients with normal CRP. The odds for reaching a 50% improvement in BASDAI response or the ASAS criteria for 40% improvement after 1 year were significantly lower in current smokers than in non-smokers (0.54, 95% CI 0.31 to 0.95, p=0.03 and 0.43, 95% CI 0.24 to 0.76, p=0.004, respectively)., Conclusions: Current smoking is associated with an impaired response to TNFi in axSpA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

We investigated changes in circulating T helper type 17 (Th17) cells following anti-tumour necrosis factor (TNF) in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) patients. Peripheral blood mononuclear cells (PBMC) were isolated from 25 RA, 15 AS and eight PsA patients at baseline 4 and 12 weeks after treatment, and Th17 cell frequencies were analysed using interleukin (IL)-17 enzyme-linked immunospot (ELISPOT) and flow cytometry. A significant increase in IL-17-producing cells was observed by ELISPOT in RA and AS patients at 12 weeks. Flow cytometry confirmed significant increases in CD4(+) IL-17(+) cells at 12 weeks in RA and AS and 4 weeks in PsA patients. Anti-TNF treatment increases circulating Th17 cells in three different diseases., (© 2015 British Society for Immunology.)

Objective: Indian Hedgehog (Ihh) is the ligand that activates the Hedgehog pathway (HH) in the skeleton-the main controller of endochondral ossification. We aimed at assessing serum levels of Ihh in patients with ankylosing spondylitis (AS) and the effect of serum from patients with AS on HH pathway activation., Methods: Serum Ihh levels were measured in 59 patients with AS, 70 patients with rheumatoid arthritis (RA), and 53 healthy subjects. The effect of serum from patients with AS on HH pathway activation was evaluated using an osteoblast-like cell line model., Results: Patients with AS not on anti-TNFα treatment had significantly higher Ihh levels compared to patients with RA not on anti-TNFα treatment (mean ± SEM of OD: 0.370 ± 0.025 vs. 0.279 ± 0.026 for patients with AS and RA, respectively, p = 0.027) and healthy subjects (p = 0.031). Patients with AS on anti-TNFα treatment had significantly lower Ihh levels compared to patients with AS not on such treatment (p = 0.028). Patients with RA on anti-TNF treatment had higher levels of Ihh compared to patients not on such treatment (p = 0.013). PTHrP levels were similar in patients with RA, AS, and healthy subjects and were not affected by anti-TNFα treatment. We next assessed HH pathway activation in Saos2 cells following incubation with serum from AS patients prior to and following anti-TNF treatment. The HH pathway was downregulated following treatment., Conclusions: Ihh levels are increased in patients with AS and decrease following anti-TNFα treatment; this finding may have pathogenic and clinical implications., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Biosimilars are biologic medical products whose active drug substance is made by a living organism or derived from it. The term is used to describe a subsequent version of an innovator biopharmaceutical product aiming at approval following patent expiry on the reference product. Biosimilars of monoclonal need to demonstrate similar but not identical quality of nonclinical and clinical attributes. Not all data of the originator product need to be recapitulated, as large numbers of patient-years of exposure data are already available. Thus, biosimilar development is largely based on the safety profiles of the originator product. The evaluation of biosimilarity includes immunogenicity attributed risks. CT-P13 (Remsima™/Inflectra™, Celltrion/Hospira), a biosimilar of the innovator drug infliximab (INF), was the first approved complex biosimilar monoclonal antibody in the EU, within the framework of WHO, EMA and US FDA biosimilar guidelines. CT-P13 has shown analytical and nonclinical features highly similar to INF including pharmacokinetics, efficacy, safety and immunogenicity profiles in ankylosing spondylitis and rheumatoid arthritis. The objective of this article is to highlight the recent biosimilar development and to review the results from the studies PLANETRA and PLANETAS, which have supported the approval of CT-P13 for several indications.

Objective: The aim of this study was to assess the efficacy and safety of golimumab in Chinese patients with active AS., Methods: Two hundred and thirteen patients were randomized in a 1:1 ratio to receive either s.c. injections of placebo from weeks 0 to 20 followed by golimumab 50 mg from weeks 24 to 48 (group 1, n = 105) or golimumab 50 mg from weeks 0 to 48 (group 2, n = 108), both every 4 weeks. Placebo crossover occurred at week 24, while early escape was at week 16. The primary endpoint was an improvement of at least 20% in the Assessment of SpondyloArthritis international Society (ASAS20) criteria at week 14. Major secondary endpoints included week 24 ASAS20 response and week 14 change scores for BASFI and BASMI., Results: Golimumab treatment elicited significantly better responses than placebo in week 14 ASAS20 response [49.1% (53/108) vs 24.8% (26/105), respectively, P < 0.001], week 24 ASAS20 response (50.0% vs 22.9%, P < 0.001) and mean improvements in BASFI (-1.26 vs 0.11, P < 0.001) and BASMI (-0.42 vs -0.19, P = 0.021) scores at week 14. Additionally, golimumab treatment led to significant improvements in the mental and physical components of health-related quality of life (HRQoL) and sleep problems at week 24, all of which were further improved through week 52. During the 16-week placebo-controlled study period, 31.4% and 30.6% of patients had adverse events (AEs) in groups 1 and 2, respectively; similar AE reporting rates were observed through week 24 (34.3% and 32.0%) and among the golimumab-treated patients through week 56 (41.2%)., Conclusion: Golimumab significantly reduced clinical symptoms/signs and improved physical function, range of motion and HRQoL in Chinese patients with active AS without unexpected safety concerns., Trial Registration: ClinicalTrials.gov, NCT01248793., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Despite the clinical efficacy of tumor necrosis factor inhibitors (TNFi), the manner in which TNF-α contributes to disease in patients with ankylosing spondylitis (AS) remains unresolved. We investigated the relationship between TNF-α gene promoter region polymorphism, serum TNF-α levels, and clinical phenotype., Methods: We did a cross-sectional and longitudinal cohort study in TNFi-naive patients with AS (n = 335). Clinical data and biological samples were collected during a research visit with genotyping for TNF-α -238 A/G and -308 A/G performed by Taqman RT-PCR and TNF levels determined by sandwich ELISA. Longitudinal TNF levels were monitored in unselected patients (n = 61)., Results: TNF-α -308 GA/AA genotype was present in 14% and TNF-α -238 GA/AA genotype in 1% of patients. TNF-α -308 GA/AA genotype was associated with a reduced risk of uveitis and better spinal function, while TNF-α -238 GA/AA genotype was associated with later age of onset and lower erythrocyte sedimentation rate (ESR). Serum TNF-α level was lower in patients with AS (151 pg/ml) than in controls (263 pg/ml), because more patients with AS had undetectable serum TNF-α (66 vs 25%, p < 0.001). TNFi treatment did not influence serum TNF-α. There was no effect of TNF-α -308/-238 or HLA-B27 genotype on serum TNF-α or subsequent initiation of TNFi., Conclusion: TNF-α -238 or -308 GA/AA genotypes in patients with AS are associated with signs of less severe disease. Serum TNF-α is, however, undetectable in two-thirds of patients with AS and is not influenced by TNF-α promoter genotype or TNFi therapy. These data suggest a more significant role for TNF-α at local sites of inflammation in AS than through systemic effects.

Introduction: In this study, we evaluated the clinical relevance of serum drug levels and antidrug antibodies (ADAbs) with regard to response to treatment, as well as to relapse upon treatment discontinuation, in peripheral spondyloarthritis (pSpA) patients treated with adalimumab., Methods: The study included 26 pSpA patients treated with adalimumab for either 12 weeks (n = 12) or 24 weeks (n = 14) in a randomized controlled trial. Patients achieving inactive disease measured by Ankylosing Spondylitis Disease Activity Score (ASDAS) at the end of the treatment period were classified as responders. Clinical characteristics, serum trough adalimumab levels and ADAbs were assessed at the end of the treatment period and at follow-up (upon relapse or, in absence of relapse, at 16 weeks after discontinuation)., Results: Serum adalimumab levels measured 2 weeks after the last adalimumab administration ranged from <0.002 to 23.0 μg/ml, with a median of 11.5 μg/ml. These levels were associated with neither response to treatment or disease activity measurements at the end of treatment nor with the occurrence of relapse and time to relapse after discontinuation of treatment. Antiadalimumab ADAbs were present in 23% of the patients at end of treatment and in 35% at follow-up after treatment discontinuation, indicating that ADAbs were masked by the presence of the drug in some patients. However, ADAbs at the end of treatment and at follow-up were not different between responders and nonresponders and were not associated with relapse upon discontinuation of treatment., Conclusions: There is no clear association between adalimumab serum levels or antiadalimumab ADAbs with clinical response to treatment or with relapse upon treatment discontinuation in pSpA., Trial Registration: Netherlands Trial Register ID: NTR1806 (registered 7 May 2009).

Objective: Our aim was to ascertain the efficacy of golimumab compared with placebo in the prevention of atherosclerosis and arterial stiffness in AS., Methods: A randomized, double-blind, placebo-controlled pilot study was performed in which AS patients were treated with golimumab (n = 20) and placebo (n = 21) for 12 months. Patients from the placebo group who failed to achieve a 20% response to Assessment of SpondyloArthritis international Society criteria (ASAS20) at 6 months received open-label golimumab. Intima-media thickness (IMT), pulse wave velocity (PWV) and augmentation index (AIx) were measured at baseline, 6 and 12 months., Results: At 6 months, 11/20 (55%) and 3/21 (14%) patients from the golimumab and placebo groups achieved an ASAS20 response, respectively (P = 0.006). There was no significant difference in the change of the vascular parameters between the two groups. In the placebo group, significantly greater progression of the mean IMT [from 0.51 mm (S.D. 0.07) at baseline to 0.53 mm (S.D. 0.08) at 6 months, P = 0.044] and PWV (from 12.2 m/s (S.D. 1.6) at baseline to 12.6 m/s (S.D. 1.3), P = 0.028] were observed. There was a trend towards progression of the mean IMT in the golimumab group (P = 0.099) but the maximum IMT, PWV and AIx remained unchanged. At 12 months the changes in vascular parameters were similar between the early and delayed (or no) golimumab groups., Conclusion: Uncontrolled inflammation may result in a significant progression in IMT and PWV in patients with AS. Arterial dysfunction may be prevented by golimumab over a period of 6 months, probably because of effective suppression of inflammation., Trial Registration: clinicaltrials.gov (NCT01212653)

The effects of the TNF- α blockers infliximab or etanercept on the levels of TNF- α , TNF-receptor 1 (TNF-R1), and TNF-receptor 2 (TNF-R2), as well as the levels of the inflammation markers CRP and IL-6, were measured in ankylosing spondylitis (AS) and rheumatoid arthritis (RA) patients receiving treatment with either compound. We found that RA patients tend to have higher levels of TNF- α than both healthy individuals and AS patients prior to treatment (P < 0.05). We measured greatly increased levels of TNF- α in both the AS and RA etanercept patient groups during the course of treatment, while in the infliximab treated patients, the amount of TNF- α measured remained unchanged. Elevated TNF- α in the etanercept treated patients does not appear to be a significant risk factor for the spontaneous development of further autoimmune diseases in our study group. Increased levels of TNF-R1 were determined in both AS (P < 0.05) and RA (P < 0.001) patients when compared to healthy controls. In AS patients, the levels of TNF-R1 dropped significantly when treated with either infliximab (P < 0.01) or etanercept (P < 0.001). In contrast, the levels of this receptor remained unchanged in RA patients treated with either compound.

Objectives: To examine changes in serum levels of the bone remodelling molecules dickkopf-1 (Dkk-1), sclerostin, wingless-type protein-3a (Wnt-3a), and bone morphogenetic protein-7 (BMP-7) during 6 months of anti-tumour necrosis factor (anti-TNF) treatment in ankylosing spondylitis (AS) patients with high disease activity., Method: We included 40 patients with axial AS: 20 patients with high disease activity were assigned to treatment with TNF inhibitor and 20 with low disease activity were assigned to non-steroidal anti-inflammatory drug (NSAID) treatment. Markers of bone remodelling and inflammation were assessed at baseline and after 6 months., Results: In the TNF inhibitor-treated group Dkk-1 decreased significantly from 196.8 pg/mL [95% confidence interval (CI) 94.1-399.0] to 116.3 pg/mL (95% CI 38.0-301.6) and BMP-7 increased significantly from 1.4 pg/mL (95% CI 0-23.0) to 20.3 pg/mL (95% CI 4.9-41.3). There was a significant negative correlation between Dkk-1 and BMP-7 at 6 months (r = -0.64, p = 0.004) in this group. Non-parametric regression analysis adjusted for disease duration, age, sex, baseline modified Stoke's Ankylosing Spondylitis Spine Score (mSASSS), and baseline C-reactive protein (CRP) confirmed a statistically significant effect of treatment on time-related changes of Dkk-1 and BMP-7. Erythrocyte sedimentation rate (ESR), CRP, and also the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score decreased significantly in the anti-TNF-treated group., Conclusions: Among the potential biomarkers of bone remodelling in AS, Dkk-1 and BMP-7 displayed significant time alterations and correlative interactions during anti-TNF treatment.

Objective: To study the effect of tumor necrosis factor α (TNFα) inhibitors on progressive spinal damage in patients with ankylosing spondylitis (AS)., Methods: All AS patients meeting the modified New York criteria who had been monitored prospectively and had at least 2 sets of spinal radiographs a minimum of 1.5 years apart were included in the study (n=334). The patients received standard therapy, which included nonsteroidal antiinflammatory drugs and TNFα inhibitors. Radiographic severity was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Patients with a rate of AS progression that was ≥1 mSASSS unit/year were considered progressors. Univariable and multivariable regression analyses were done. Propensity score matching and sensitivity analysis were performed. A zero-inflated negative binomial (ZINB) model was used to analyze the effect of TNFα inhibitors on the change in the mSASSS with varying followup periods. Potential confounders, such as disease activity (as assessed by the Bath Ankylosing Spondylitis Disease Activity Index), the erythrocyte sedimentation rate, C-reactive protein level, HLA-B27 positivity, sex, age at onset, smoking burden (number of pack-years), and baseline damage, were included in the model., Results: TNFα inhibitor treatment was associated with a 50% reduction in the odds of progression, with an odds ratio (OR) of 0.52 (95% confidence interval [95% CI] 0.30-0.88, P=0.02). Patients with a delay of >10 years in starting therapy were more likely to experience progression as compared to those who started earlier (OR 2.4 [95% CI 1.09-5.3], P=0.03). In the ZINB model, the use of TNFα inhibitors significantly reduced disease progression when the gap between radiographs was >3.9 years. The protective effect of TNFα inhibitors was stronger after propensity score matching., Conclusion: Treatment with TNFα inhibitors appears to reduce radiographic progression in AS patients, especially with early initiation and with longer duration of followup., (Copyright © 2013 by the American College of Rheumatology.)

Objectives: To compare the pharmacokinetics (PK), safety and efficacy of innovator infliximab (INX) and CT-P13, a biosimilar to INX, in patients with active ankylosing spondylitis (AS)., Methods: Phase 1 randomised, double-blind, multicentre, multinational, parallel-group study. Patients were randomised to receive 5 mg/kg of CT-P13 (n=125) or INX (n=125). Primary endpoints were area under the concentration-time curve (AUC) at steady state and observed maximum steady state serum concentration (Cmax,ss) between weeks 22 and 30. Additional PK, efficacy endpoints, including 20% and 40% improvement response according to Assessment in Ankylosing Spondylitis International Working Group criteria (ASAS20 and ASAS40), and safety outcomes were also assessed., Results: Geometric mean AUC was 32 765.8 μgh/ml for CT-P13 and 31 359.3 μgh/ml for INX. Geometric mean Cmax,ss was 147.0 μg/ml for CT-P13 and 144.8 μg/ml for INX. The ratio of geometric means was 104.5% (90% CI 94% to 116%) for AUC and 101.5% (90% CI 95% to 109%) for Cmax,ss. ASAS20 and ASAS40 responses at week 30 were 70.5% and 51.8% for CT-P13 and 72.4% and 47.4% for INX, respectively. In the CT-P13 and INX groups more than one adverse event occurred in 64.8% and 63.9% of patients, infusion reactions occurred in 3.9% and 4.9%, active tuberculosis occurred in 1.6% and 0.8%, and 27.4% and 22.5% of patients tested positive for anti-drug antibodies, respectively., Conclusions: The PK profiles of CT-P13 and INX were equivalent in patients with active AS. CT-P13 was well tolerated, with an efficacy and safety profile comparable to that of INX up to week 30.

Objective: The primary objective of this retrospective study was to investigate the possibility of achieving partial remission (PR) in AS patients treated with anti-TNF-α antagonists, such as adalimumab (ADA), etanercept (ETA) and infliximab (INF), in a real clinical practice setting. Predictors of PR were also evaluated., Methods: A retrospective study was conducted in patients with AS treated with ADA, ETA and INF from 2000 to 2012. Kaplan-Meier survival curves were plotted to determine the rates of PR during the treatment with anti-TNF-α drugs., Results: A total of 283 patients with AS were treated with ADA (18.7%), ETA (26.8%) and INF (54.4%) as first anti-TNF-α drugs, with a PR rate of 57.6%. The probability of obtaining PR with ADA, ETA or INF was not significantly different among all anti-TNF-α patients. AS patients treated with a second anti-TNF-α drug had a PR rate of 40.5%, but after switching for lack of response, the probability of obtaining PR with a second anti-TNF-α drug was significantly lower from that of the first anti-TNF-α drug (P = 0.0039). The probability of obtaining PR in patients with enthesitis (P = 0.04) or psoriasis (P = 0.0016) or low levels of CRP (P = 0.0225) was significantly lower compared with that of patients without these manifestations at baseline., Conclusion: Our real-life study on PR confirmed the effectiveness of ADA, ETA or INF as first or second anti-TNF-α drugs. The presence at baseline of enthesitis or psoriasis or low CRP values yielded a lower probability of obtaining PR.

Objective: To evaluate the effect of golimumab on haemoglobin levels in patients with RA, PsA or AS., Methods: Secondary analysis was performed on integrated data from five randomized controlled studies: three RA, one PsA and one AS (2303 patients total). Golimumab 50 or 100 mg was injected s.c. every 4 weeks with or without MTX. Control groups received placebo injections plus MTX or background therapy. Patients with haemoglobin levels below the age- and sex-specific normal ranges were considered to have anaemia. Ferritin levels were used to distinguish anaemia of mixed aetiology (≥ 15 and <60 ng/ml) and anaemia of inflammation (≥ 60 ng/ml). Changes from baseline to weeks 14 and 24 in haemoglobin level were compared between treatment groups using an analysis of variance on the van der Waerden normal scores., Results: At baseline, 21% of RA patients, 9% of PsA patients and 15% of AS patients had anaemia. Of these, 24%, 57% and 25%, respectively, had anaemia of inflammation. The median increase from baseline to week 14 in the haemoglobin level of anaemic patients was 0.3 g/dl in the control group and 0.9 g/dl in the golimumab group (P < 0.001). Haemoglobin levels improved within the subgroups of patients with anaemia of mixed aetiology (control, 0.4 g/dl vs golimumab, 0.7 g/dl) (P = 0.305) and with anaemia of inflammation (0.2 vs 1.4 g/dl, respectively) (P < 0.001)., Conclusion: Compared with the control group, patients receiving golimumab treatment had significantly improved haemoglobin levels, particularly among patients with anaemia of inflammation.

Unlabelled: Anemia is one of the extra-articular findings of ankylosing spondylitis (AS), and anti-TNF therapy has been shown benefit in patients with anemia associated AS. In this study, we aimed to evaluate and compare the effects of biological and non-biological agents on hemoglobin levels in AS patients. One hundred consecutive patients who fulfilled ASAS criteria for AS were included in the study. Fifty-four of the patients treated with anti-TNF agents (20 patients treated with infliximab, 20 patients with adalimumab, and 14 patients with etanercept), and 46 patients treated with non-steroidal anti-inflammatory drugs and/or other disease modifying anti-rheumatic drugs. The C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), hemoglobin (HGB), hematocrit (HCT) counts, and BASDAI scores were compared before starting therapy and at 52 weeks. There was no statistically significant difference between patients about demographical data (age, sex) and disease age (p > 0.05 for all). Significant difference was determined between HGB, HCT, CRP, ESR, and BASDAI values before and after therapy (for infliximab p: 0.001; 0.000; 0.000; 0.000; 0.000, respectively, and for adalimumab p: 0.017; 0.03; 0.001; 0.002; 0.000, respectively). In etanercept group, there was no significant difference in HGB values, when compared with before starting therapy and at 52 weeks (p > 0.05). In the group of treated with non-biological agents, ESR values and BASDAİ scores showed distinctive improvement after 52 weeks of therapy, but was not a significant difference in hemoglobin and hematocrit values., Conclusion: Anti-TNF-alpha therapy with monoclonal antibodies (adalimumab and infliximab) did not only suppress disease activity but also provided a significant improvement in HGB levels. In the groups of treated with a TNF-alpha receptor antagonist (ETA) and non-biological agents, disease activity was suppressed, but there was not founded significant improvement in HGB levels after 52 weeks. Different outcomes of anti-TNF agents may be associated with their different effect mechanisms.

Objectives: The objective of this paper is to assess if disease activity, systemic inflammation and metabolic syndrome are potential determinants of circulating adiponectin and resistin levels in ankylosing spondylitis (AS) patients undergoing TNF-α antagonist therapy., Methods: We investigated adiponectin and resistin serum concentrations in a series of 29 non-diabetic AS patients without history of cardiovascular (CV) events that were treated with the TNF-α antagonist infliximab, immediately prior to an infliximab infusion. Adipokine levels were also determined immediately after administration of an infliximab dose., Results: A significant correlation between adiponectin concentrations and insulin sensitivity (QUICKI at the time of the study) was seen (r=0.384; p=0.05). Also, a marginally significant negative correlation between adiponectin serum levels and the body mass index was observed (r=-0.367; p=0.07). Circulating adiponectin and resistin concentrations did not correlate with disease duration, erythrocyte sedimentation rate, C-reactive protein, BASDAI or VAS at the time of the study. However, AS patients with hip involvement or synovitis and/or enthesitis in other peripheral joints had higher adiponectin concentrations than those who did not have these complications (p-value for both comparisons =0.01). Adiponectin and resistin levels did not change upon infliximab administration., Conclusions: The present study shows that in non-diabetic patients with AS on treatment with infliximab adiponectin and resistin serum levels do not correlate with disease activity. Nevertheless, adiponectin concentration correlates with insulin sensitivity. This finding raises the possibility that low circulating adiponectin concentrations may be involved in the pathogenesis of the CV disease in AS.

Objective: The increased cardiovascular risk associated with AS is attributable to multiple factors: disease activity, systemic inflammation, traditional risk factors and NSAIDs. This study aimed to investigate the effects of 24 and 52 weeks of TNF-α inhibitor treatment on arterial stiffness and cardiovascular risk factors., Methods: Arterial stiffness was measured using the augmentation index (AIx) and pulse wave velocity (PWV), while other cardiovascular risk factors [lipid profile, blood pressure (BP) and BMI] were collected for active AS patients., Results: In total, 49 patients, comprising 30 men, were included in the study, with a mean age of 46.9 (12.1) years. Of these, 20 (40.8%) patients were current smokers, while 10 were treated for hypertension. Patients had long-standing [11.9 (9.2) years] and active AS, with a high initial BASDAI [55.0 (18.2)]. Regarding treatment, 26 patients received etanercept, 17 adalimumab and 6 infliximab. No changes were observed in PWV and AIx after 6 or 12 months following TNF-α blockade [PWV 6.97 (2.03) m/s, 6.92 (1.81) m/s and 7.10 (1.95) m/s at baseline, 6 months and 1 year, respectively, P = 0.64; AIx 19.5 (13.1%), 20.2 (12.8%), 18.3 (13.5%), respectively, P = 0.87]. Lipid profiles and other cardiovascular risk factors were unchanged. However, BASDAI, BASFI and biological inflammation were significantly improved., Conclusion: Arterial stiffness was not improved after 6 and 12 months of anti-TNF-α therapy. However, treatment decreased biological inflammation and disease activity without causing any changes in lipid profiles and other traditional cardiovascular risk factors.

Tumor necrosis factor alpha (TNF-alpha) plays an important role in the pathogenesis of chronic inflammatory diseases, i.e., rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn's disease (CD), and ulcerative colitis (UC). Anti-TNF-alpha strategies are successfully used in their treatment. However, their effect on heart function is still uncertain. The objectives of the study were to examine the acute and long-term effect of infliximab on the heart morphology and function in patients with chronic inflammatory disorders. Thirty-one patients (21 men and 10 women) were included. Ten percent of them were diagnosed with RA, 22.5 % with AS, 22.5 % with CD, and 45 % with UC, respectively. N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) was measured before and immediately after infliximab administration at the beginning of the study and in the sixth and 12th months. Echocardiography was performed at baseline and in the sixth and 12th months. There was a significant increase in NT-proBNP after the first infliximab infusion (88.40 ± 14.09 vs. 95.24 ± 14.28 pg/ml, p = 0.0046) and similar response was detected after each infusion in the sixth and 12th months. Plasma NT-proBNP slightly but not significantly decreased (88.40 ± 14.09 vs. 81.74 ± 23.14 pg/ml, p = 0.583, and 88.40 ± 14.09 vs. 56.83 ± 17.77 pg/ml, p = 0.0576, in the sixth and 12th months, respectively). There were no significant changes in echocardiographic structural and functional parameters of the left ventricle during follow-up. Plasma NT-proBNP mildly but significantly increases immediately after infliximab infusion. However, long-term infliximab administration does not deteriorate both cardiac morphology and function.

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.

Introduction: While adalimumab is licensed for ankylosing spondylitis (AS), open uncontrolled studies suggest therapeutic efficacy of TNF-inhibitors in juvenile onset AS (JoAS)., Methods: A total of 32 patients aged 12 to 17 years with severe, active and refractory JoAS were enrolled in a multicenter, randomized, double-blind, placebo-controlled parallel study of 12 weeks, followed by open-label adalimumab until week 24 for all patients. ASAS40 was used as the primary, and ASAS20, PedACR and single items were used as the secondary outcome measures for the intention to treat population., Results: A total of 17 patients were randomized to receive adalimumab 40 mg/2 weeks and 15 patients received placebo. Two patients (one of each group) discontinued prematurely due to insufficient efficacy and were labeled as non-responders. In the double-blind part, more patients on adalimumab achieved an ASAS40 at week 4 (41%), week 8 (53%) and week 12 (53%) than on placebo (20%, 33%, 33%), while differences at week 8 only reached borderline significance (P = 0.05). Also, at 4, 8 and 12 weeks ASAS20/PedACR30/70 response rates were higher in the adalimumab group (53%/53%/29%; 59%/76%/41%; 53%/65%/53%) compared to placebo (27%/27%/7%; 27%/33%/13%; 33%/40%/27%). In the adalimumab group a significant decrease of all disease activity parameters was noted at week 12 and was even more pronounced at week 24. At week 12 the Bath Ankylosing Spondylitis Disease activity spinal inflammation score decreased by 65% (P <0.001), the back pain score decreased by 50% (P <0.005), the Bath AS Functional Index (BASFI) score decreased by 47% (P <0.02), while the Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI) score improved by 65% (P <0.005). ANCOVA analysis demonstrated superiority of adalimumab over placebo for the physician global assessment of disease activity, parents' global assessment of subject's overall well-being, active joint count (all P <0.05) and erythrocyte sedimentation rate (ESR) (P <0.01)., Conclusions: Adalimumab was well tolerated and highly effective in a double-blind randomized trial in patients with JoAS. Treatment effects rapidly occurred and persisted for at least 24 weeks of treatment., Trial Registration: EudraCT 2007-003358-27.

Introduction: Sclerostin levels have been reported to be low in ankylosing spondylitis (AS), but there is no data regarding the possible role of this Wnt inhibitor during anti-tumor necrosis factor (TNF) therapy. The present study longitudinally evaluated sclerostin levels, inflammatory markers and bone mineral density (BMD) in AS patients under anti-TNF therapy., Methods: Thirty active AS patients were assessed at baseline, 6 and 12 months after anti-TNF therapy regarding clinical parameters, inflammatory markers, BMD and baseline radiographic damage (mSASSS). Thirty age- and sex-matched healthy individuals comprised the control group. Patients' sclerostin levels, sclerostin binding low-density lipoprotein receptor-related protein 6 (LRP6) and BMD were evaluated at the same time points and compared to controls., Results: At baseline, AS patients had lower sclerostin levels (60.5 ± 32.7 vs. 96.7 ± 52.9 pmol/L, P = 0.002) and comparable sclerostin binding to LRP6 (P = 0.387) than controls. Improvement of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Ankylosing Spondylitis quality of life (ASQoL) was observed at baseline vs. 6 vs. 12 months (P < 0.01). Concomitantly, a gradual increase in spine BMD (P < 0.001) and a positive correlation between baseline mSASSS and spine BMD was found (r = 0.468, P < 0.01). Inflammatory parameters reduction was observed comparing baseline vs. 6 vs. 12 months (P <0.01). Sclerostin levels progressively increased [baseline (60.5 ± 32.7) vs. 6 months (67.1 ± 31.9) vs. 12 months (72.7 ± 32.3) pmol/L, P <0.001]. At 12 months, the sclerostin levels remained significantly lower in patients compared to controls (72.7 ± 32.3 vs. 96.70 ± 52.85 pmol/L, P = 0.038). Moreover, sclerostin serum levels at 12 months were lower in the 10 patients with high C reactive protein (CRP) (≥ 5 mg/l) compared to the other 20 patients with normal CRP (P = 0.004). Of note, these 10 patients with persistent inflammation also had lower sclerostin serum levels at baseline compared to the other patients (P = 0.023). Univariate logistic regression analysis demonstrated that AS patients with lower sclerostin serum levels had an increased risk to have high CRP at 12 months (odds ratio = 7.43, 95% CI 1.23 to 45.01, P = 0.020) than those with higher sclerostin values., Conclusions: Persistent low sclerostin levels may underlie continuous inflammation in AS patients under anti-TNF therapy.

To determine plasma homocysteine levels in ankylosing spondylitis (AS) and their correlation with disease activity measurements. To examine the effects of different treatment modalities on homocysteine levels. One hundred eight patients diagnosed with AS according to New York criteria and 65 healthy individuals matched in terms of age and gender were enrolled in the study. Patients were given detailed physical examinations. The Bath AS Disease Activity Index (BASDAI) was used for disease activity, the Bath AS Metrology Index (BASMI) for spinal mobility, the Bath AS Functional Index (BASFI) to determine functional status and the Bath AS Radiological Index (BASRI) for radiological analysis. Sedimentation rate (ESR) and C reactive protein (CRP) levels, acute phase reactants, were measured. Plasma homocysteine levels, serum interleukin (IL) -6 and serum tumor necrosis factor- α (TNF- α) levels were investigated using the enzyme-linked immunosorbent assay (ELISA) method. Plasma homocysteine levels in AS patients were statistically significantly lower compared with those in the healthy control group (P = 0.0001). There was no significant difference among sub-groups established on the basis of medical treatments and disease activity (BASDAI ≤4 and >4). No statistically significant correlation was determined between homocysteine level and disease activity parameters, radiological score and functional indices. A significant negative correlation was, however, established between age and homocysteine level in the AS group (P < 0.05, r = -0.426). Plasma homocysteine was lower in AS patients compared with the control group. This is not correlated with disease activation and medical treatment employed.

During recent decades, biological medications play a crucial role for treating rheumatologic disorders and thus are strongly recommended for initial treatment of ankylosing spondylitis. However, because of high cost of biological drugs, the use of these drugs has been limited. In current series, we tried to assess safety of low-dose etanercept as a common usable biological drug in patients with ankylosing spondylitis. In a case-series study, 4 men with ankylosing spondylitis were treated with low-dose etanercept (25 mg/2 weeks) plus methotrexate (10 mg/week). Safety was assessed by measuring rate of differences in severity of clinical manifestations and level of C-reactive protein (CRP). After the completion of treatment with low-dose etanercept, inflammatory low back pain and morning stiffness was reduced lower than 30 min in all patients. Only one patient had baseline high serum ESR and positive CRP that was changed to negative following treatment protocol. At one-year follow-up, all participants continued their regular treatment regimen with the etanercept survival rate 100%. Neither side effects related to drug nor clinical complications were observed within the follow-up period. Our findings suggest that low-dose etanercept (25 mg/2 weeks) has an acceptable safety and effectiveness profile in individuals with ankylosing spondylitis and can be good alternative instead of conventional therapy with etanercept (25 mg two times per week).

Objective: To investigate whether level of serum matrix metalloproteinase-3 (MMP-3) can serve as a biomarker for monitoring and predicting response to etanercept treatment in patients with ankylosing spondylitis (AS) in daily clinical practice., Methods: Ninety-two consecutive AS outpatients with active disease who started etanercept treatment were included in this longitudinal observational study. Clinical data were collected prospectively at baseline and after 3 and 12 months of treatment. At the same timepoints, serum MMP-3 levels were measured retrospectively by ELISA., Results: Since baseline serum MMP-3 levels were significantly higher in male compared to female patients with AS, data analysis was split for gender. Changes in serum MMP-3 levels after etanercept treatment correlated positively with changes in clinical assessments of disease activity and physical function in both male and female patients. Receiver operating characteristic analysis in male patients showed that baseline serum MMP-3 levels had poor accuracy (AUC < 0.7) to discriminate between Assessments in Ankylosing Spondylitis 20 (ASAS20) or ASAS40 responders and nonresponders after 3 or 12 months of treatment. The accuracy of change in serum MMP-3 levels from baseline to 3 months in predicting response after 3 or 12 months of treatment was poor for ASAS40 (AUC < 0.7) or moderate for ASAS20 (AUC = 0.752 and 0.744, respectively), and was not superior to the accuracy of change in the currently used objective biomarkers, erythrocyte sedimentation rate and C-reactive protein., Conclusion: Although significant changes in serum MMP-3 levels were found after etanercept treatment, data analysis indicates that serum MMP-3 levels are not very useful for monitoring and predicting response to etanercept treatment in patients with AS in daily clinical practice.

Objectives: To create a model that provides a potential basis for candidate selection for anti-tumour necrosis factor (TNF) treatment by predicting future outcomes relative to the current disease profile of individual patients with ankylosing spondylitis (AS)., Methods: ASSERT and GO-RAISE trial data (n=635) were analysed to identify baseline predictors for various disease-state and disease-activity outcome instruments in AS. Univariate, multivariate, receiver operator characteristic and correlation analyses were performed to select final predictors. Their associations with outcomes were explored. Matrix and algorithm-based prediction models were created using logistic and linear regression, and their accuracies were compared. Numbers needed to treat were calculated to compare the effect size of anti-TNF therapy between the AS matrix subpopulations. Data from registry populations were applied to study how a daily practice AS population is distributed over the prediction model., Results: Age, Bath ankylosing spondylitis functional index (BASFI) score, enthesitis, therapy, C-reactive protein (CRP) and HLA-B27 genotype were identified as predictors. Their associations with each outcome instrument varied. However, the combination of these factors enabled adequate prediction of each outcome studied. The matrix model predicted outcomes as well as algorithm-based models and enabled direct comparison of the effect size of anti-TNF treatment outcome in various subpopulations. The trial populations reflected the daily practice AS population., Conclusion: Age, BASFI, enthesitis, therapy, CRP and HLA-B27 were associated with outcomes in AS. Their combined use enables adequate prediction of outcome resulting from anti-TNF and conventional therapy in various AS subpopulations. This may help guide clinicians in making treatment decisions in daily practice.

Background: Adipose tissue-derived leptin and adiponectin control hunger, energy expenditure, insulin sensitivity, endothelial function, reproduction and immunity and are thought to play a role in autoimmune diseases. However, their role in ankylosing spondylitis (AS) is not clearly defined. Tumour necrosis factor ΤNF-α is a potential modulator of adipocytokines. The effect of longterm anti-TNF-α treatment on plasma levels of leptin and adiponectin has not been assessed so far., Objectives: To assess the effect of a 6-month anti-TNF-α treatment on serum leptin and adiponectin levels in AS patients., Methods: Thirty men with AS were included in the study. Thirty age- and weight-matched men served as controls. Clinical and biochemical parameters were assessed and serum levels of leptin and adiponectin were measured with enzyme immunoassay methods prior to and after the 6-month treatment with infliximab., Results: Mean age and disease duration of AS patients were 40.6±13.7 and 13.4±8.4 years, respectively. At baseline, AS patients exhibited significantly higher adiponectin (15.4±8.3 vs. 8.6±4.2 μg/ml, p<0.05), but no difference in leptin levels (7.2±2.9 vs. 8.9±6.4 ng/ml, p=NS). Adipocytokines did not correlate with any disease parameter. Body weight of the patients did not change significantly over the 6-month period. Serum levels of leptin and adiponectin did not change significantly after the 6-month treatment., Conclusions: Adiponectin levels were significantly higher in AS patients compared with controls. Infliximab treatment did not change serum levels of leptin and adiponectin suggesting that the anti-TNF-α treatment may not modulate significantly their levels.

Aim: To investigate the population pharmacokinetics of recombinant human tumor necrosis factor receptor-Fc fusion protein (rhTNFR-Fc) administered via subcutaneous (SC) injection in healthy Chinese volunteers and in Chinese patients with ankylosing spondylitis (AS)., Methods: Thirty-two healthy volunteers were randomly assigned to receive a single SC injection of 12.5, 25, 37.5, or 50 mg of rhTNFR-Fc. Twenty male patients with moderate AS were randomly assigned to receive seven consecutive SC injections of rhTNFR-Fc at either 25 mg twice a week (BIW) or 50 mg once a week (QW). Population pharmacokinetic (PK) analysis was applied to obtain PK parameters of rhTNFR-Fc by the NONMEM method., Results: The data were best described by a one-compartment model with lag time. We found that gender had a significant effect on the apparent clearance (CL/F), with the male CL/F ratio being only 0.665 times the female ratio; the absorption coefficient (F) of multiple dosages of rhTNFR-Fc was only 0.674 times that of a single dosage. The outcome parameters were CL/F (female: 0.168 L/h, male: 0.110 L/h), the apparent volume of distribution (Vd/F: 15.5 L), the absorption rate constant (Ka) (single dosage: 0.0605 h⁻¹, multiple dosage: 0.0408 h⁻¹), and the lag time (T(lag): 1.03 h). The inter-individual variability in the CL/F, Vd/F, Ka, and T(lag) were 33.3%, 42.7%, 55.6%, and 81.8%, respectively., Conclusion: Chinese females have a higher CL/F than Chinese males, and multiple dosings can significantly decrease the absorption of rhTNFR-Fc (SC). The population PK parameters of rhTNFR-Fc in healthy Chinese volunteers and patients with AS were similar to those reported for subjects in published American studies.

The objective of this study was to evaluate the influence of anti-tumor necrosis factor (anti-TNF) in juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS) or psoriatic arthritis (PsA). Sixty-two patients were investigated: 7 JIA; 37 AS; and 18 PsA. Caucasian race accounted for 79% and 29% were female. Mean age was 40.4 +/- 12.6 years. None of the patients had a history of diabetes, and none had used oral hypoglycemic agents or insulin. Treatment was with adalimumab, infliximab and etanercept. Glucose, inflammatory markers and prednisone dose were assessed at baseline, as well as after three and six months of treatment. The mean erythrocyte sedimentation rate was significantly lower at three months and six months than at baseline (13.7 +/- 18.0 and 18 +/- 22.5 vs. 27.9 +/- 23.4 mm; p = 0.001). At baseline, three months and six months, we found the following: mean C-reactive protein levels were comparable (22.1 +/- 22.7, 14.5 +/- 30.7 and 16.0 +/- 23.8 mg/L, respectively; p = 0.26); mean glucose levels remained unchanged (90.8 +/- 22.2 mg/dl, 89.5 +/- 14.6 mg/dl and 89.8 +/- 13.6 mg/dl, respectively; p = 0.91); and mean prednisone doses were low and stable (3.9 +/- 4.9 mg/day, 3.7 +/- 4.8 mg/day and 2.6 +/- 4.0 mg/day, respectively; p = 0.23). During the first six months of treatment, anti-TNF therapy does not seem to influence glucose metabolism in JIA, AS or PsA., (Copyright 2010 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved.)