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Objectives: Risankizumab is an interleukin-23 inhibitor under study for the treatment of patients with psoriatic arthritis (PsA). The phase 3 KEEPsAKE 2 trial investigated the efficacy and safety of risankizumab versus placebo in patients with active PsA who had previous inadequate response or intolerance to ≤2 biological therapies (Bio-IR) and/or ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR). Results through week 24 are reported here., Methods: Adults with PsA who were Bio-IR and/or csDMARD-IR were randomised to receive subcutaneously administered risankizumab 150 mg or placebo at weeks 0, 4 and 16 during a 24-week, double-blind treatment period. The primary endpoint was the proportion of patients who achieved ≥20% improvement in American College of Rheumatology score (ACR20) at week 24. Secondary endpoints assessed key domains of PsA and patient-reported outcomes., Results: A total of 444 patients (median age 53 years, range 23-84 years) were randomised to risankizumab (n=224) or placebo (n=220); 206 patients (46.5%) were Bio-IR. At week 24, a significantly greater proportion of patients receiving risankizumab achieved the primary endpoint of ACR20 (51.3% vs 26.5%, p<0.001) and all secondary endpoints (p<0.05) compared with placebo. Serious adverse events were reported for 4.0% and 5.5% of risankizumab-treated and placebo-treated patients, respectively; serious infections were reported for 0.9% and 2.3%, respectively., Conclusion: Treatment with risankizumab resulted in significant improvements versus placebo in key disease outcomes and was well tolerated in patients with PsA who were Bio-IR and/or csDMARD-IR., Trial Registration Number: NCT03671148., Competing Interests: Competing interests: AO received speaker or consulting fees and/or research grants from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi and UCB. FEVdB received speaker and/or consulting fees from AbbVie, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer and UCB. KP received honoraria or fees for serving on advisory boards, as a speaker and as a consultant. He has received grants for services as principal investigator from AbbVie, Amgen, Astellas, Bausch Health (Valeant), Baxalta, Baxter, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, EMD Serono, Forward Pharma, Galderma, Genentech, GlaxoSmithKline, Janssen, Kyowa Kirin, LEO Pharma, Lilly, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Stiefel, Sun Pharma, Takeda and UCB. CA received research support and honoraria or fees for serving on advisory boards or as a speaker from AbbVie, Amgen, Genentech, Janssen, Lilly, Pfizer and Roche. RB received grants or research support from AbbVie, Merck and Roche. He has received consultation fees or honoraria for serving as a speaker for AbbVie, Bristol-Myers Squibb, Janssen, Lilly, Merck, Pfizer and Roche. JA received honoraria as a consultant, speaker or expert witness. He has received research support from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Galapagos/Gilead, Genentech, GlaxoSmithKline, Lilly, Mallinckrodt, Nektar Therapeutics, Nichi-Iko, Novartis, Pfizer, Regeneron, Roche, Sanofi, Selecta Biosciences and UCB. WL, ZW, AMS, AE and LB are full-time employees of AbbVie, and may hold AbbVie stock or stock options. AMS is listed as an inventor on some AbbVie patents. GA was a full-time employee of AbbVie at the time of this study and may hold AbbVie stock or stock options. AK is a shareholder of Amgen, Gilead, GlaxoSmithKline, Novartis, Pfizer and Sanofi. He received consulting fees from AbbVie, Boehringer Ingleheim, Flexion, Gilead, Janssen, Pfizer, Regeneron, Sanofi and SUN Pharma, and has received speaker’s fees or honoraria from AbbVie, Celgene, Flexion, Genzyme, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, Sanofi and UCB., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Treatment with golimumab monotherapy in early peripheral SpA (pSpA) results in higher rates of clinical remission compared with treatment in more longstanding disease. When reaching remission, treat-to-target recommendations suggest tapering of treatment. We therefore explored whether addition of MTX would permit discontinuation of golimumab in patients with pSpA in sustained clinical remission., Methods: After a 2-year extension phase with golimumab treatment, patients with pSpA reaching clinical remission in the CRESPA trial were offered a tapering strategy leading to discontinuation of golimumab and replacement by MTX monotherapy. Patients were prospectively followed to assess the rate of sustained biologic-free clinical remission. In case of relapse of arthritis, enthesitis or dactylitis under MTX monotherapy, golimumab was restarted., Results: Of the original 60 pSpA patients, 25 entered the step-down strategy. Currently, only 4 patients (16%) are still in sustained remission under MTX monotherapy. In 21 patients (84%), golimumab was reinstalled because of relapse of disease activity (n = 19) or development of adverse events related to MTX (n = 2). Restarting golimumab treatment promptly restored clinical remission in all patients within 12 weeks., Conclusion: In patients with early pSpA achieving clinical remission after 2 years of golimumab treatment, step-down therapy to monotherapy with MTX led to high rates of clinical relapse. This underscores the overall weak efficacy of MTX in maintaining clinical remission in pSpA., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01426815., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aim: We evaluated the effects of anti-tumor necrosis factor (TNF) agents on health economics in ankylosing spondylitis (AS) patients., Methods: QUality of Life as Outcomes and its VAriation with DIsease States (QUO-VADIS) was a prospective observational study following bio-naïve AS patients (modified New York criteria) newly treated with golimumab (GLM) or infliximab (IFX; originator) in a clinical practice setting over 6 months. We evaluated use of concomitant medications, hospitalizations (in-patient care or acute care) and visits in day care and out-patient settings for the assessment of healthcare resource utilization (HCRU). Work productivity and activity impairment (WPAI) was assessed by the number of work days missed and quantifying absenteeism, presenteeism, work impairment, and activity using the WPAI instrument adapted to spondyloarthritis (WPAI-SpA)., Results: Nine hundred and sixty-three patients received ≥1 dose of medication (78%, n = 751 GLM; 22%, n = 221 IFX). Mean age was 42.7 years; 61.4% were male. At baseline, the percentage of patients who reported hospitalizations (in-patient care) was 13.6%, which decreased to 3.1% at 6 months, while out-patient care at baseline was reported by 39.4% of patients, which decreased to 19.0% at 6 months. The percentage of patients receiving acute emergency at baseline reduced from 1.6% to 0.3% at 6 months. The mean (SD) number of days of work missed due to AS, was reduced from 6.3 (31.1) days at baseline to 2.7 (12.3) days at 6 months., Conclusion: In patients with AS newly treated with GLM or IFX for 6 months, HCRU was reduced and work productivity and activity increased., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objectives: The QUO VADIS study evaluated disease activity and health-related quality-of-life (HRQoL) in ankylosing spondylitis (AS) patients treated with golimumab (GLM) or infliximab (IFX, originator) during routine clinical care., Methods: This prospective observational study followed biologics-naïve AS patients newly treated with GLM or IFX for 6 months. Disease activity (BASDAI, BASFI, ASAS, and ASDAS) and HRQoL improvement (≥5 points of SF-36 Physical Component Summary [PCS] score; PCS response) were measured. A Classification and Regression Trees (CART) analysis evaluated association of baseline parameters with PCS response at 6 months., Results: 963 patients (mean age 43 years, 61% male, 64% HLA-B27 positive) received ≥1 dose of medication (78% GLM; 22% IFX). Disease activity was reduced; mean (SD) changes from baseline at month 6 of -2.7 (BASDAI) and -2.1 (BASFI) and 40% and 35% achievement of BASDAI50 and ASAS40 response, respectively, were observed. PCS response was achieved at month 6 in 52% of patients. Using CART analysis, baseline parameters (cut-off values) associated with HRQoL improvement were ASDAS (≥3.48), C-reactive protein (≥8.55 mg/L), age (≤35.5 years), and BASFI (≥1.15). This algorithm correctly identified 57.5% (sensitivity) of PCS responders (≥5 points) and 61.0% (specificity) of PCS non-responders (<5points) with ROC-AUC=0.61. Serious adverse events (AEs) occurred in 1.8% of patients; the most common AEs were infections (7.7%)., Conclusions: We demonstrated clinical and HRQoL improvements over 6 months in a large, real-world population of AS patients newly treated with GLM or IFX; higher ASDAS, elevated CRP, and younger age were associated with improvements in HRQoL and an overall more robust response.

Objective: New treatment algorithms using tumor necrosis factor (TNF) blockers in early stages of spondyloarthritis (SpA) induce high rates of clinical remission or low disease activity. It could be anticipated that such early intervention strategies in peripheral SpA may induce drug-free remission. We undertook this study to evaluate drug-free clinical remission after induction therapy with golimumab in patients with very early active peripheral SpA, and to identify patient characteristics that predict sustained drug-free remission., Methods: Eligible patients were age ≥18 years and fulfilled the Assessment of SpondyloArthritis international Society criteria for peripheral SpA. All patients had symptom duration of <12 weeks. Sustained clinical remission was defined as the absence of arthritis, enthesitis, and dactylitis at 2 consecutive major visits, after which treatment was withdrawn. Patients were prospectively followed up to assess the rate of sustained drug-free clinical remission and clinical relapse., Results: Eighty-two percent of patients (49 of 60) fulfilled sustained clinical remission criteria after a regimen of induction therapy with golimumab. The majority of patients already reached this status at week 24 (n = 30), with an additional 11 and 8 patients at weeks 36 and 48, respectively. All patients had a follow-up period of at least 18 months after drug withdrawal. Fifty-three percent of patients (26 of 49) still have drug-free remission of their disease. Inability to sustain drug-free remission was associated with the presence of psoriasis and polyarticular disease (swollen joint count >5)., Conclusion: Anti-TNF treatment in very early peripheral SpA results in a remarkably high rate of sustained clinical remission. More than 50% of patients continue to have remission of their disease after withdrawal of therapy, which highlights a defined window of opportunity permitting induction of drug-free remission., (© 2018, American College of Rheumatology.)

Objective: To evaluate the efficacy and safety of golimumab to induce clinical remission in patients with very early, active peripheral spondyloarthritis (pSpA)., Methods: Clinical REmission in peripheral SPondyloArthritis is a monocentric study of golimumab treatment in patients with pSpA. All patients fulfilled the Assessment of SpondyloArthritis international Society classification criteria for pSpA, with a symptom duration ≤12 weeks. Patients were randomised 2:1 to receive golimumab 50 mg every 4 weeks or matching placebo for 24 weeks. The primary end point was the percentage of patients achieving clinical remission at week 24, defined as absence of arthritis, enthesitis and dactylitis. Secondary end points included joint and enthesis counts, patient-reported outcomes, erythrocyte sedimentation rate and C reactive protein. From week 12, non-responders were allowed to receive rescue medication with golimumab. Adverse events were recorded., Results: 60 patients were randomised with similar baseline characteristics. At week 24, a significantly higher percentage of patients receiving golimumab achieved clinical remission compared with placebo (75% (30/40) vs 20% (4/20); p<0.001). At week 12, similar results were observed (70% (28/40) vs 15% (3/20); p<0.001). All secondary end points were met at week 24. Rescue medication was necessary in 50% in the placebo group opposed to only 10% in the golimumab arm. Rates of adverse events were low and similar in both groups., Conclusions: Markedly high remission induction rates were noted with golimumab in very early pSpA. Of interest, in placebo-treated patients, very low spontaneous remission rates were observed., Trial Registration Number: NCT01426815; Results., Competing Interests: Ackowledgements: We thank all referring rheumatologist for the help in recruiting patients. Competing interests: None declared., (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/.)

Objective: To evaluate the effect of secukinumab on patient-reported outcomes (PROs) in subjects with active psoriatic arthritis (PsA) in the FUTURE 1 study., Methods: Subjects were randomised 1:1:1 to receive intravenous (i.v.) secukinumab 10 mg/kg at weeks 0, 2 and 4 followed by subcutaneous secukinumab 150 or 75 mg every 4 weeks or matching placebo until week 24., Results: At week 24, subjects receiving secukinumab i.v.→150 mg or i.v.→75 mg reported greater least squares mean changes from baseline than those receiving placebo in patient global assessment of disease activity (-20.6 and -20.0 vs -7.4, respectively), patient assessment of pain (-20.8 and -20.4 vs -6.7), psoriatic arthritis quality of life (-3.5 and -3.2 vs -0.4), Dermatology Life Quality Index (-8.8 and -7.9 vs 0.7); p<0.0001 vs placebo for both secukinumab groups for above PROs and Functional Assessment of Chronic Illness Therapy-Fatigue (6.74 (p<0.05 vs placebo) and 6.03 vs 4.00); all of which well exceeded minimum clinically important differences., Conclusions: In subjects with PsA, secukinumab treatment resulted in clinically meaningful improvements in global disease activity, pain, generic and disease-specific measures of health-related quality of life and fatigue., Trial Registration Number: NCT01392326; Results., (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/.)

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

Aim: It is well established that tumor necrosis factor (TNF) inhibitors help control disease activity, limit radiographic progression and preserve function in patients with rheumatoid arthritis. However, not all patients respond adequately to initial anti-TNF treatment and some patients lose response over time. Possible treatment modifications include optimizing concomitant disease-modifying antirheumatic drugs, switching to another anti-TNF biologic or another class of agent, or optimizing the dose of the anti-TNF agent. Here we review data on dose optimization of infliximab, with emphasis on dose changes to address inadequate response, nonresponse and loss of response., Method: The authors conducted a literature review to identify studies that evaluated the effect of dose optimization on clinical response in infliximab-treated patients with rheumatoid arthritis., Results: Few well-controlled studies of dose optimization of infliximab have been completed for patients with rheumatoid arthritis, and the evidence supporting efficacy and safety after dose adjustment can be difficult to interpret. Studies of dose optimization in infliximab-treated patients who fail to show initial response, have an inadequate response, or lose response over time are not entirely consistent, but tend to show a pattern of improvement after a dose increase., Conclusion: Dose optimization involves a balance of risks and benefits, and future research should seek to clarify which patients are most likely to benefit from dose optimization without undue increase in risk., (© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Spondyloarthritis can be considered one of the prototypes (besides rheumatoid arthritis) of an inflammatory rheumatic disease. The locomotor system is prominently involved with arthritis, enthesitis, dactylitis, sacroiliitis, and/or axial disease; but besides the rheumatologic component, other body systems are frequently affected. Extra-articular manifestations are all the medical conditions and symptoms that are not directly related to the locomotor system. Besides inflammatory bowel diseases, the major concept-related extra-articular manifestations are located in the eye (acute anterior uveitis) and the skin (psoriasis). This review focuses on the possible implications of these nonrheumatologic manifestations regarding the treatment of spondyloarthritis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: To study the long-term efficacy and safety of treatment with infliximab in patients with ankylosing spondylitis (AS) in a real life setting., Methods: AS patients from 6 European countries who had finished the 2-year trial ASSERT were invited to participate in the open- label investigator-driven study EASIC. At baseline, 2 groups were formed: patients of group 1 had not been treated with infliximab after ASSERT, while those of group 2 had continuously received it. Patients of group 1 were further subdivided in group 1a: patients with a relapse and 1b: in remission. All patients of group 1a and 2 continuously received infliximab for 96 weeks, mean dose 5 mg/kg, intervals 6-8 weeks. Patients of group 1b were also treated in case of relapse., Results: A total of 103/149 patients (69%) were included in EASIC, 1.3 ± 0.9 years after the end of ASSERT: 9 in group 1a, 5 in group 1b and 89 in group 2. Most patients were male (83%), mean age 44 years. Most patients of group 2 completed the trial (86%) vs. only 5 of group 1 (33%) - mostly due to allergic reactions after readministration of infliximab. In total, there were 22 drop-outs due to 6 adverse events, 4 lack of efficacy, 3 planned pregnancy. All standard assessments indicated beneficial values over time, at week 96 significantly better than at baseline of ASSERT., Conclusions: The majority of patients were continuously and successfully treated with infliximab for 5 years, whereas discontinuation and reintroduction of therapy was less satisfactory due to the frequent occurrence of hypersensitivity reactions. Anti-TNF therapy with infliximab proved to be effective and safe on a long-term basis.

Objective: We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti-interleukin-17 (anti-IL-17) monoclonal antibody, in a first in-human trial in rheumatoid arthritis (RA) patients taking oral disease-modifying antirheumatic drugs (DMARDs)., Methods: This randomized, double-blind, placebo-controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10., Results: Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-LY2439821-combined groups (-2.3, -2.4, and -2.3, respectively) than in the placebo group (-1.7) at week 10 (P < or = 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821-treated patients than in placebo-treated patients at multiple time points. There was no apparent dose-response relationship in treatment-emergent adverse events., Conclusion: LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL-17 as a potential novel goal for the treatment of RA.

Objectives: To evaluate the effectiveness of adalimumab in patients with psoriatic arthritis (PsA) and identify predictors of good clinical response for joint and skin lesions., Methods: Patients received adalimumab 40 mg every other week in addition to standard therapy in this prospective, 12-week, open-label, uncontrolled study. Four definitions of good clinical response were used: > or =50% improvement in American College of Rheumatology response criteria (ACR50), good response according to European League Against Rheumatism (EULAR) guidelines, a > or =3-grade improvement in Physician Global Assessment of psoriasis (PGA) and a > or =50% improvement in the Nail Psoriasis Severity Index (NAPSI). Response predictors were determined by logistic regression with backward elimination (selection level was 5%)., Results: Of 442 patients, 94% completed 12 weeks of treatment. At week 12, 74%, 51% and 32% of the patients had achieved ACR20, 50 and 70, respectively; 87% and 61% experienced moderate and good responses according to EULAR criteria, respectively. The percentage of patients with PGA results of "clear/almost clear" increased from 34% (baseline) to 68%. The mean NAPSI score was reduced by 44%. No new safety signals were detected. A lower Health Assessment Questionnaire Disability Index (HAQ-DI) score, greater pain assessment, male sex and absence of systemic glucocorticoid therapy were strongly associated with achievement of ACR50 and good response according to EULAR criteria. In addition, greater C-reactive protein concentration and polyarthritis predicted ACR50, and non-involvement of large joints predicted a good response according to EULAR criteria., Conclusions: Adalimumab was effective in patients with PsA. Lower impairment of physical function, greater pain, male sex and no systemic treatment with glucocorticoids were factors that increased the chance of achieving a good clinical response.

Introduction: Tumor necrosis factor (TNF) antagonists reduce the signs and symptoms of spondyloarthritides, including ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Our objective was to evaluate the effectiveness and safety of adalimumab, 40 mg every other week, for patients with AS or PsA and prior treatment with infliximab (IFX) and/or etanercept (ETN)., Methods: Both trials were 12-week, open-label studies with an optional extension period up to week 20. Patients were stratified by history of anti-TNF treatment, prior anti-TNF therapy received (IFX, ETN, or both), and reason for discontinuation of prior TNF antagonist. ETN was discontinued>or=3 weeks, and IFX was discontinued>or=2 months before the first adalimumab administration. Effectiveness at week 12 was evaluated by using observed standard-outcome measurements for AS and PsA., Results: At week 12 of adalimumab treatment, Bath Ankylosing Spondylitis Disease Activity Index 50 responses were achieved by 40.8% of 326 patients with AS who had received prior anti-TNF therapy and by 63.0% of 924 patients with AS who were naive to TNF antagonist. Observed response rates were generally greater for patients who discontinued the prior anti-TNF therapy because of loss of response or intolerance than for patients who discontinued because of lack of response. Median changes in swollen-joint count and in enthesitis score were similar in patients with and without prior TNF-antagonist treatment. Modified PsA response criteria were fulfilled by 71.2% of 66 patients with PsA, with prior exposure to TNF antagonists, and by 78.8% of 376 patients with no history of anti-TNF therapy. The percentages of patients with PsA attaining a Physician's Global Assessment of psoriasis of "Clear/Almost clear" increased from 33.3% to 61.0% for patients with prior IFX and/or ETN treatment and from 34.6% to 69.7% for patients without anti-TNF therapy. The median change in the Nail Psoriasis Severity Index was -6 for both groups. In both studies, patterns of adverse events were similar for patients with and without prior anti-TNF therapy and were consistent with the known safety profile of adalimumab., Conclusions: Patients with AS or PsA previously treated with IFX and/or ETN experienced clinically relevant improvements of their diseases after 12 weeks of adalimumab., Trial Registrations: ClinicalTrials.gov NCT00478660 and NCT00235885.

Objective: Anemia is a common complication in patients with inflammatory diseases such as ankylosing spondylitis (AS). This post hoc analysis of a large, randomized, placebo-controlled trial examined the effect of infliximab on hemoglobin levels, physical function, and fatigue in patients with AS., Methods: Patients received infliximab 5 mg/kg (n = 188) or placebo (n = 68) at weeks 0, 2, 6, 12, and 18. Hemoglobin, interleukin-6 (IL-6), and C-reactive protein (CRP) levels, fatigue (visual analog scale [VAS]), physical function (Bath Ankylosing Spondylitis Functional Index [BASFI]), and disease activity were evaluated at baseline and week 24. Anemia was defined as a hemoglobin level <12 gm/dl for women and <13 gm/dl for men., Results: At baseline, 11 placebo group patients (16.2%) and 37 infliximab group patients (19.7%) had anemia. Of these, more infliximab-treated patients achieved normal hemoglobin levels at week 24 compared with patients receiving placebo (70.3% versus 27.3%; P = 0.0155). Infliximab-treated patients had significant improvements in mean hemoglobin concentration (0.7 gm/dl versus -0.3 gm/dl), BASFI score (-2.1 versus -0.2), and fatigue VAS score (-2.4 versus -0.4) compared with placebo patients (P < 0.001). Multiple regression analyses showed that improvements in hemoglobin level were significantly and independently associated with improvements in physical function and fatigue. Infliximab-treated patients with elevated CRP or IL-6 levels at baseline were more likely than those with low levels to have improvement in hemoglobin levels., Conclusion: Infliximab treatment significantly decreased the proportion of AS patients with anemia and improved hemoglobin levels compared with placebo. Improvement in hemoglobin level was independently associated with improvements in physical function and fatigue.

Objective: To evaluate the long-term effectiveness and tolerability of adalimumab in the treatment of psoriatic arthritis (PsA)., Methods: Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks. At the time of this analysis, available efficacy evaluations throughout 2 years of treatment (n = 245) included American College of Rheumatology (ACR) 20%, 50% and 70% improvement scores, measures of joint disease and skin disease, disability and quality of life; modified total Sharp scores (mTSS) were available for 2.75 years of treatment for patients who received adalimumab in the 24-week study., Results: After 24 weeks of double-blind treatment, the mean change in mTSS was -0.2 for the adalimumab group (N = 144) and 1.0 for the placebo group (N = 152; p<0.001), and outcomes for all individual ACR component variables were significantly improved in adalimumab compared with placebo-treated patients. Compared with 24-week responses, inhibition of radiographic progression and improvements in joint disease were maintained in most patients during long-term, open-label adalimumab treatment. Also, improvements in skin disease were maintained, with >20% of patients achieving the strict criterion of psoriasis area and severity index 100. The nature and frequency of adverse events during long-term adalimumab treatment were consistent with the safety profile during short-term treatment., Conclusions: The clinical and radiographic efficacy of adalimumab demonstrated during short-term treatment was sustained during long-term treatment. Adalimumab has a favourable risk-benefit profile in patients with PsA., Trial Registration Number: NCT00195689.

Objective: CCR2 is a chemokine receptor expressed by monocytes, macrophages, and a subset of T cells. Its ligand, CCL2 (monocyte chemotactic protein 1), is abundantly present in the synovium of patients with rheumatoid arthritis (RA). Blocking CCR2 prevents CCL2-mediated chemotaxis in vitro and modulates arthritis in animal models of RA. In this study we examined the effects of CCR2 blockade on synovial inflammation in RA., Methods: The study was designed as a phase IIa clinical trial with a human CCR2 blocking antibody (MLN1202) in patients with active RA. Thirty-two patients received 3 infusions, over a period of 6 weeks, with either placebo (n = 9) or anti-CCR2 monoclonal antibody at 0.5 mg/kg (n = 7), 1.5 mg/kg (n = 7), or 4.0 mg/kg (n = 9). Safety was monitored with laboratory tests, immunotoxicity assessments, and documenting of adverse events, and European League Against Rheumatism and American College of Rheumatology response criteria were used to assess clinical improvement. Synovial tissue was obtained at baseline and after 43 days of treatment, for pharmacodynamic analysis using immunohistochemistry and digital image analysis. The Kruskal-Wallis test was used to compare groups, and the Wilcoxon signed rank test was used to assess changes within the groups., Results: All patients completed the study. Treatment with CCR2 blocking antibody reduced the levels of free CCR2 on CD14+ monocytes by at least 57% and up to 94% (P < 0.001), demonstrating the biologic activity of the compound. However, there was no reduction in the levels or expression of any of the synovial biomarkers. Accordingly, no clinical improvement was observed., Conclusion: Treatment with anti-CCR2 blocking antibody did not result in amelioration of synovial inflammation in active RA. The results do not support the notion that blockade of CCR2 may be sufficient to induce clinical improvement in RA.

Objective: To examine whether clinical benefits observed after treatment with infliximab were accompanied by improvement in productivity and reduction in time lost from work in a randomized, double-blind, placebo-controlled, multicenter trial of patients with ankylosing spondylitis (AS)., Methods: Adults with active AS receiving standard antiinflammatory treatment were randomly assigned in a 3:8 ratio to receive infusions of placebo or 5 mg/kg infliximab at weeks 0, 2, 6, and every 6 weeks thereafter through week 24. Physical function was measured using the Bath Ankylosing Spondylitis Functional Index. The impact of disease on productivity was measured using a visual analog scale (range 0-10). Self-reported employment status and time lost at work before and during the trial were collected. Spearman's correlation coefficient was used to examine factors associated with productivity., Results: Patients treated with infliximab had a more significant reduction in limitations of work and daily activity due to physical or emotional problems than patients treated with placebo. Of the subset of patients employed full time, patients in the infliximab group had a significantly greater improvement in productivity as early as week 6 compared with the placebo group. The median change from baseline in the productivity score at week 24 was 0.7 (median percent change 11%) in the placebo group compared with 2.1 (62%) in the infliximab group (P < 0.05). Daily productivity was significantly correlated with physical function and disease activity at baseline and week 24., Conclusion: The daily productivity of patients with active AS was significantly associated with functional impairment and disease activity. Infliximab treatment significantly improved productivity and reduced workday loss among employed patients with AS.

Objective: Chemokines such as CCL2/monocyte chemotactic protein 1 (MCP-1) play a key role in leukocyte migration and are potential targets in the treatment of chronic inflammatory disorders. The objective of this study was to evaluate the effects of human anti-CCL2/MCP-1 monoclonal antibody (ABN912) treatment in patients with rheumatoid arthritis (RA)., Methods: Patients with active RA were enrolled in a randomized, placebo-controlled, dose-escalation study of ABN912. Infusions were administered on day 1 and day 15. In the dose-escalation phase, 4 cohorts of 8 patients each underwent serial arthroscopic biopsy of synovial tissue. Immunohistochemistry and digital image analysis were used to characterize biomarkers in synovial tissue. Laboratory evaluation included pharmacokinetic analysis and immunotypic studies of peripheral blood mononuclear cells. To assess the clinical effects of treatment with ABN912, an additional 21 patients were treated with the highest dose tolerated., Results: The total study population comprised 45 patients: 33 patients received ABN912, and 12 patients received placebo. ABN912 treatment was well tolerated. Unexpectedly, there was a dose-related increase in ABN912-complexed total CCL2/MCP-1 levels in peripheral blood, up to 2,000-fold. There was no detectable clinical benefit of ABN912 compared with placebo, nor did treatment with the study drug result in a significant change in the levels of biomarkers in synovial tissue and peripheral blood., Conclusion: ABN912 treatment did not result in clinical or immunohistologic improvement and may have been associated with worsening of RA in patients treated with the highest dose. The results might be related to the greatly increased level of total CCL2/MCP-1 in serum that was observed following treatment with ABN912. This observation may be relevant for a variety of antibody-based therapies.

Although there is strong evidence supporting the short-term efficacy and safety of anti-tumour necrosis factor-alpha agents, few studies have examined the long-term effects. We evaluated 511 patients with long-standing refractory rheumatoid arthritis treated with intravenous infusions of infliximab 3 mg/kg at weeks 0, 2, 6, and 14 and every 8 weeks thereafter for 4 years. Among the initial 511 patients included in the study, 479 could be evaluated; of these, 295 (61.6%) were still receiving infliximab treatment at year 4 of follow-up. The most common reasons for treatment discontinuation were lack of efficacy (65 patients, 13.6%), safety (81 patients, 16.9%), and elective change (38 patients, 7.9%). Analysis of disease activity scores (DAS28 [disease activity score based on the 28-joint count]) over time showed that, after the initial rapid improvement during the first 6 to 22 weeks of therapy, a further decrease in disease activity of 0.2 units in the DAS28 score per year was observed. DAS28 scores, measured at week 14 or 22, were found to predict subsequent discontinuation due to lack of efficacy. In conclusion, long-term maintenance therapy with infliximab 3 mg/kg is effective in producing further reductions in disease activity. Disease activity measured by the DAS28 at week 14 or 22 of infliximab therapy was the best predictor of long-term attrition.

Objective: To analyze the clinical and biologic correlates of autoantibody induction during longer-term tumor necrosis factor alpha (TNFalpha) blockade with either the monoclonal antibody infliximab or the soluble receptor etanercept., Methods: Thirty-four patients with spondylarthropathy (SpA) and 59 patients with rheumatoid arthritis (RA) were treated with infliximab for 2 years. Additionally, 20 patients with SpA were treated with etanercept for 1 year. Sera were blindly analyzed for antinuclear antibodies (ANAs), anti-double-stranded DNA (anti-dsDNA) antibodies, anti-extractable nuclear antigen (anti-ENA) antibodies, and antihistone, anti-nucleosome, and anticardiolipin antibodies (aCL). The anti-dsDNA antibodies were isotyped., Results: High numbers of infliximab-treated patients with SpA or RA had newly induced ANAs (61.8% and 40.7%, respectively) and anti-dsDNA antibodies (70.6% and 49.2%, respectively) after 1 year, but no further increase between year 1 and year 2 was observed. In contrast, induction of ANAs and anti-dsDNA antibodies was observed only occasionally in the etanercept-treated patients with SpA (10% of patients each). Isotyping revealed almost exclusively IgM or IgM/IgA anti-dsDNA antibodies, which disappeared upon interruption of treatment. Neither infliximab nor etanercept induced other lupus-related reactivities such as anti-ENA antibodies, antihistone antibodies, or anti-nucleosome antibodies, and no clinically relevant lupus-like symptoms were observed. Similarly, infliximab but not etanercept selectively increased IgM but not IgG aCL titers., Conclusion: The prominent ANA and anti-dsDNA autoantibody response is not a pure class effect of TNFalpha blockers, is largely restricted to short-term IgM responses, and is not associated with other serologic or clinical signs of lupus. Similar findings with aCL suggest that modulation of humoral immunity may be a more general feature of infliximab treatment.

Objectives: To analyse the effect of a dose increase in patients with severe rheumatoid arthritis (RA) with insufficient clinical response to 3 mg/kg infliximab every 8 weeks., Methods: Patients suffering from active refractory RA despite methotrexate, were treated with i.v. infusions of infliximab (3 mg/kg) on week 0, 2, 6 and every 8 weeks thereafter. Based on the clinical judgement at week 22, patients received a dose increase of 100 mg from week 30 on. The American College of Rheumatology (ACR) core set for disease activity measures was regularly assessed., Results: Five hundred and eleven RA patients were included. At week 22, 61.4, 34 and 14.1% of all patients met ACR 20, ACR 50 and ACR 70 criteria, respectively, and 6.1% of patients were in remission. A low swollen joint count at baseline was correlated with improvement at week 22 for ACR 20 (P < 0.06), ACR 50 (P < 0.06) and ACR 70 (P < 0.005). The change in HAQ score between weeks 0 and 22 was predictive for response at week 54 (P < 0.01). The dose of infliximab was increased by 100 mg in 22% of the patients. Most baseline values of patients requiring dose increase were higher (P < or = 0.001) than the baseline values of the remaining patients. Increasing the dose of infliximab by one vial from week 30 on could circumvent the partial loss of response in these patients., Conclusion: Infliximab use in this large out-patient cohort resulted in a significant clinical improvement. A subgroup that partially lost response during the first 22 weeks could regain response by adding 100 mg of infliximab to the subsequent doses. Due to the current study design, however, a regression to the mean like effect could not be ruled out.

Objective: To confirm and extend the immunopathological evidence of effects of infliximab on the synovium in active spondyloarthropathy., Methods: Synovial biopsies obtained in patients with spondyloarthropathy at baseline and week 12 were stained and scored by two independent observers. Two study populations were evaluated: I, a cohort of 10 patients treated with 5 mg/kg infliximab at week 0, 2, and 6, plus three placebo treated patients; and II, a pooled cohort of 20 patients fulfilling identical inclusion and exclusion criteria and treated with the same loading dose regimen., Results: In study population I, treatment with infliximab induced reduction in synovial lining layer thickness (p = 0.015), endothelial activation (E-selectin, p = 0.034), and inflammatory cell infiltration with neutrophils (p = 0.041), macrophages (p = 0.034), and T cells (p = 0.026), but not with B cells and plasma cells; no such trends were observed in the placebo treated patients. Besides confirming the highly significant downregulation of inflammation, analysis of cohort II showed structural changes such as normalisation of lining layer thickness (p = 0.030), reduction in the number of blood vessels (p = 0.039), and downregulation of follicular organisation (p = 0.050). No differences in histopathological response were observed between spondyloarthropathy subtypes., Conclusions: Profound immunomodulatory changes in the synovium parallel the clinical benefit in patients with spondyloarthropathy treated with infliximab, independently of the subtype. The study provides histological evidence that TNF alpha blockade not only downregulates inflammation but also leads to tissue remodelling.

Objectives: To analyse the effect of infliximab on IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies, and determine whether baseline autoantibody titres (IgM RF and anti-CCP antibodies) are associated with changes in acute phase reactants., Patients and Methods: 62 patients with refractory RA were treated with infliximab combined with methotrexate. At baseline and week 30, serum samples were tested for IgM RF by two agglutination assays, and for anti-CCP antibodies by an ELISA. Percentage change in C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) was calculated., Results: At baseline and week 30 RF titres were reduced significantly during infliximab treatment (p<0.001 and p = 0.038, respectively), whereas anti-CCP antibodies were unchanged (p = 0.240). Baseline IgM RF titres, but not anti-CCP antibodies, correlated inversely with changes in CRP and ESR during treatment. Patients with a marked decrease in acute phase reactants had lower IgM RF titres than those with a smaller decrease in CRP and ESR; no significant differences were found for anti-CCP antibodies., Conclusion: The differential effect of infliximab treatment on IgM RF and anti-CCP antibodies, and the different predictive value on changes in acute phase reactants during infliximab treatment support the existing evidence that RF and anti-CCP antibodies are independent autoantibody systems in RA.

This study is based on an expanded access program in which 511 patients suffering from active refractory rheumatoid arthritis (RA) were treated with intravenous infusions of infliximab (3 mg/kg+methotrexate (MTX)) at weeks 0, 2, 6 and every 8 weeks thereafter. At week 22, 474 patients were still in follow-up, of whom 102 (21.5%), who were not optimally responding to treatment, received a dose increase from week 30 onward. We aimed to build a model to discriminate the decision to give a dose increase. This decision was based on the treating rheumatologist's clinical judgment and therefore can be considered as a clinical measure of insufficient response. Different single and composite measures at weeks 0, 6, 14 and 22, and their differences over time were taken into account for the model building. Ranking of the continuous variables based on areas under the curve of receiver-operating characteristic (ROC) curve analysis, displayed the momentary DAS28 (Disease Activity Score including a 28-joint count) as the most important discriminating variable. Subsequently, we proved that the response scores and the changes over time were less important than the momentary evaluations to discriminate the physician's decision. The final model we thus obtained was a model with only slightly better discriminative characteristics than the DAS28. Finally, we fitted a discriminant function using the single variables of the DAS28. This displayed similar scores and coefficients as the DAS28. In conclusion, we evaluated different variables and models to discriminate the treating rheumatologist's decision to increase the dose of infliximab (+MTX), which indicates an insufficient response to infliximab at 3 mg/kg in patients with RA. We proved that the momentary DAS28 score correlates best with this decision and demonstrated the robustness of the score and the coefficients of the DAS28 in a cohort of RA patients under infliximab therapy.

Background: Recent studies with infliximab indicate the therapeutic potential of tumour necrosis factor alpha blockade in spondyloarthropathy (SpA). Because defective host defence is implicated in the pathogenesis of SpA, the potential side effects of this treatment due to impact on the antimicrobial defence are a major concern., Objective: To report systematically the adverse events seen in a large cohort of patients with SpA treated with infliximab, with special attention to bacterial infections., Patients and Methods: 107 patients with SpA were treated with infliximab for a total of 191.5 patient years. All serious and/or treatment related adverse events were reported., Results: Eight severe infections occurred, including two reactivations of tuberculosis and three retropharyngeal abscesses, and six minor infections with clear bacterial focus. One patient developed a spinocellular carcinoma of the skin. No cases of demyelinating disease or lupus-like syndrome were seen. Two patients had an infusion reaction, which, however, did not relapse during the next infusion. Finally, three patients with ankylosing spondylitis developed palmoplantar pustulosis. All patients recovered completely with adequate treatment, and infliximab treatment had to be stopped in only five patients with severe infections., Conclusions: Although the global safety of infliximab in SpA is good compared with previous reports in rheumatoid arthritis and Crohn's disease, the occurrence of infections such as tuberculosis and retropharyngeal abscesses highlights the importance of careful screening and follow up. Focal nasopharyngeal infections and infection related symptoms, possibly induced by streptococci, occurred frequently, suggesting an impairment of specific host defence mechanisms in SpA.

A major breakthrough has been achieved in the treatment of patients who have AS and other types of SpA. The identification of the expression and role of TNF-alpha in patients who have these diseases and the recognition of their relation with gut inflammation (where infliximab therapy has proven efficacious already) has led to the successful use of TNF-alpha blockade in SpA, establishing a new indication for this type of anticytokine therapy. Evidence supports equal response in cases of axial or peripheral disease. Infliximab therapy has been most extensively documented in this new indication for anti-TNF-alpha therapy, but other compounds are also in the field. Gorman et al reported on 40 patients who had active AS who were randomly assigned to receive twice-weekly subcutaneous injections of etanercept (25 mg) or placebo for 4 months [65]. The primary endpoint was a composite of improvements. Treatment with etanercept resulted in significant and sustained improvement (treatment response in 80% in the etanercept group versus 30% in the placebo). Data regarding the human anti-TNF-alpha monoclonal antibody adalimumab in SpA are not yet available. Different questions remain open, including optimal dosing, long-term safety, and effects of this new treatment on the structural articular level; however, a therapeutic breakthrough like the one currently reviewed has seldom occurred in arthritis care.

Objective: To investigate the effect of infliximab treatment on antinuclear antibodies (ANAs), anti-double-stranded DNA (anti-dsDNA), antinucleosome, antihistone, and anti-extractable nuclear antigen (anti-ENA) antibodies in rheumatoid arthritis (RA) and spondylarthropathy (SpA) patients., Methods: Sera from 62 RA and 35 SpA patients treated with infliximab were tested at baseline and week 30 (RA group) or week 34 (SpA group). ANAs were tested by indirect immunofluorescence (IIF) on HEp-2 cells. Anti-dsDNA antibodies were detected by IIF on Crithidia luciliae and by enzyme-linked immunosorbent assay (ELISA) and were further isotyped with gamma, mu, and alpha chain-specific conjugates at various time points. Antinucleosome antibodies were tested by ELISA. Antihistone and anti-ENA antibodies were detected by line immunoassay., Results: Initially, 32 of 62 RA patients and 6 of 35 SpA patients tested positive for ANAs. After infliximab treatment, these numbers shifted to 51 of 62 (P < 0.001) and 31 of 35 (P < 0.001), respectively. At baseline, none of the RA or SpA patients had anti-dsDNA antibodies. After infliximab treatment, 7 RA patients (P = 0.016) and 6 SpA patients (P = 0.031) became positive for anti-dsDNA antibodies. All 7 anti-dsDNA-positive RA patients had IgM and IgA anti-dsDNA antibodies. Three of the 6 anti-dsDNA-positive SpA patients had IgM and IgA anti-dsDNA antibodies, and 2 had IgM anti-dsDNA antibodies alone. In both diseases, the IgM anti-dsDNA antibodies appeared before the IgA anti-dsDNA antibodies. During the observation period, no IgG anti-dsDNA antibodies or lupus symptoms were observed. The development of antinucleosome, antihistone, or anti-ENA antibodies following infliximab treatment was observed in some patients, but the numbers were not statistically significant., Conclusion: Infliximab treatment may induce ANAs, and especially IgM and IgA anti-dsDNA antibodies, in RA and SpA patients. However, no anti-dsDNA IgG antibodies or lupus symptoms were observed during the period of observation in this study, and the development of antinucleosome, antihistone, or anti-ENA antibodies was not statistically significant. These observations do not exclude potential induction of clinically significant lupus in the long term, and further followup is therefore mandatory.

Spondyloarthropathies (SpA) are a group of related disorders with common clinical and genetic characteristics. The prototype disease in this group is ankylosing spondylitis; other entities include reactive arthritis, psoriatic arthritis, and arthritis in patients with inflammatory bowel disease. Over recent years, there has been a special interest in the relation between spondylitis/synovitis and gut inflammation in patients with SpA. Two thirds of patients with undifferentiated SpA show histologic signs of gut inflammation, and a fraction of these patients go on to develop clinically overt Crohn's disease. In this review, the authors will focus on 1) the growing evidence that has been provided that gut inflammation in SpA is immunologically related to Crohn's disease, based on the molecular characterization of the inflammation (lymphocyte homing markers and ligands, T cell cytokines, macrophage markers, and serology); and 2) on the therapeutic implications resulting from this concept. The recent introduction and positioning of anti-tumor necrosis factor-alpha therapy in patients with ankylosing spondylitis and other types of SpA is, in large part, based on this concept.

Background: In a pilot study, the anti-tumour necrosis factor alpha monoclonal antibody, infliximab, induced a rapid and significant improvement in global, peripheral, and axial disease manifestations of patients with active spondyloarthropathy., Objective: To determine whether repeated infusions of infliximab would effectively and safely maintain the observed effect., Methods: Safety and efficacy of a maintenance regimen (5 mg/kg infliximab every 14 weeks) was evaluated using the measurements reported in the pilot study. Of the 21 patients, 19 completed the one year follow up for efficacy; two patients changed to another dosing regimen after week 12 owing to partial lack of efficacy. However, they are still being followed up for safety analysis., Results: After each re-treatment a sustained significant decrease of all disease manifestations was observed. Before re-treatment, symptoms recurred in 3/19 (16%) at week 20, in 13/19 (68%) at week 34, and in 15/19 (79%) at week 48. No withdrawals due to adverse events occurred. Twelve minor infectious episodes were observed. Twelve patients (57%) developed antinuclear antibodies; in four of them (19%) anti-dsDNA antibodies were detected. However, no lupus-like symptoms occurred., Conclusion: In this open study of infliximab in patients with active spondyloarthropathy, the significant improvement of all disease manifestations was maintained over a one year follow up period without major adverse events. Although recurrence of symptoms was noted in a rising number of patients before each re-treatment, no loss of efficacy was observed after re-treatment.

Objective: To confirm in a placebo-controlled trial the safety and efficacy profile of infliximab in short-term treatment of patients with active spondylarthropathy (SpA)., Methods: Forty patients with active SpA were randomly assigned to receive an intravenous loading dose (weeks 0, 2, and 6) of 5 mg/kg infliximab or placebo. Evaluations for efficacy and safety were performed at weeks 1, 2, 6, 8, and 12. The primary end points of this study were the improvements in patient and physician global assessments of disease activity on a 100-mm visual analog scale., Results: Both primary end points improved significantly in the infliximab group compared with the baseline value, with no improvement in the placebo group. As early as week 2 and sustained up to week 12, there was a highly statistically significant difference between the values for these 2 end points in the infliximab versus the placebo group. In most of the other assessments of disease activity (laboratory measures, assessments of specific peripheral and/or axial disease), significant improvements were observed in the infliximab group compared with the baseline value and compared with placebo. Minor adverse events not causing discontinuation were equally observed in both treatment groups. There was one severe drug-related adverse event, in which a patient developed disseminated tuberculosis., Conclusion: Tumor necrosis factor alpha blockade with infliximab in patients with active SpA was well tolerated and resulted in significant clinical and laboratory improvements in this short-term, placebo-controlled study. However, the occurrence of tuberculosis in one patient necessitates strict inclusion criteria and long-term followup.

Objectives: To evaluate the effect of anti-TNFalpha on the Th1 and Th2 cytokines in patients with spondyloarthropathy (SpA)., Methods: Peripheral blood mononuclear cells (PBMC) were obtained from 20 patients with active SpA treated with infliximab (5 mg/kg). For comparison, PBMC were also obtained from 15 healthy controls and 19 patients with active rheumatoid arthritis (RA). After stimulation with PMA/ionomycin, the intracellular cytokines interleukin (IL)2, IL4, IL10, and interferon (IFN)gamma were determined in CD3+ T cells and in CD3+/CD56+ natural killer (NK) T cells by flow cytometry., Results: At baseline the percentage of T cells positive for IFNgamma (p=0.020) and IL2 (p=0.046) was decreased in patients with SpA compared with healthy controls, while IL10 (p=0.001) was increased. This cytokine profile, confirmed by the mean fluorescence intensities (MFI), was more pronounced in CD3+/CD8- cells and contrasted with higher IL2 production in RA. NK T cells, characterised by high IL4 and IL10 numbers, were also increased in patients with SpA (p=0.017). Treatment with infliximab induced a significant and persistent increase in IFNgamma and IL2 in patients with SpA. Moreover, there was a transient decrease in IL10 and NK T cells in patients with high baseline values, resulting in values comparable with those of healthy controls. This switch in cytokine profile was seen in both the CD3+/CD8- and CD3+/CD8+ subsets., Conclusions: Before treatment patients with SpA had an impaired Th1 cytokine profile compared with healthy controls and patients with RA. TNFalpha blockade induced restoration of the Th1 cytokines, resulting in a normal cytokine balance. These data confirm the effect of anti-TNFalpha on the immune changes in SpA, and provide insights into the mechanisms involved in TNFalpha blockade.

Objective: To evaluate the efficacy and safety of a loading dose regimen of three intravenous infusions with infliximab in patients with active spondyloarthropathy., Methods: A monocentre, open-label pilot study of 21 patients with different subtypes of spondyloarthropathy was conducted. Treatment resistant patients with active disease (fulfilling inclusion criteria) received three infusions of 5 mg/kg infliximab (at weeks 0, 2, and 6). Standard clinical assessments were performed at baseline, and on days 3, 7, and 14, and from then on every two weeks. In patients who fulfilled criteria for ankylosing spondylitis, axial assessment was performed at baseline and on days 14, 42, and 84., Results: In all global assessments (visual analogue scale of patient global assessment, patient pain assessment, doctor global assessment), erythrocyte sedimentation rate, and C reactive protein, a highly significant decrease could be seen already at day 3 (compared with baseline), which was maintained up to day 84. In patients with peripheral disease (n=18), tender and swollen joint count significantly decreased. In patients with axial disease (n=11), functional and disease activity indices significantly improved. Moreover in eight patients with psoriatic arthritis a significant decrease of the psoriasis area and severity index was observed. The treatment was well tolerated in all patients; no significant adverse events were seen., Conclusion: In this open-label pilot study of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor alpha in patients with active spondyloarthropathy, there was a fast and significant improvement of axial and peripheral articular manifestations, without major adverse experiences.