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1.  Effectiveness and safety of adalimumab in patients with ankylosing spondylitis or psoriatic arthritis and history of anti-tumor necrosis factor therapy 
Arthritis Research & Therapy  2010;12(3):R117.
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).
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 ≥ 3 weeks, and IFX was discontinued ≥ 2 months before the first adalimumab administration. Effectiveness at week 12 was evaluated by using observed standard-outcome measurements for AS and PsA.
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.
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 NCT00478660 and NCT00235885.
PMCID: PMC2911911  PMID: 20553600
2.  Safety and effectiveness of switching from infliximab to etanercept in patients with rheumatoid arthritis: results from a large Japanese postmarketing surveillance study 
Rheumatology International  2011;32(6):1617-1624.
Finding an effective treatment strategy for rheumatoid arthritis (RA) patients who have not benefited from previous tumor necrosis factor–α antagonist treatment is important for minimizing RA disease activity and improving patient outcomes. The aim of this study was to compare the safety and effectiveness of etanercept in patients with and without infliximab (IFX) treatment experience. Patients (n = 7,099) from a large postmarketing observational study of etanercept use in Japan were divided into 2 cohorts based on previous IFX use (pre-IFX and non-IFX). Baseline characteristics were assessed in each cohort. Adverse events (AEs) and European League Against Rheumatism (EULAR) responses were monitored every 4 weeks for 24 weeks. At baseline, pre-IFX patients were younger and had fewer comorbidities and a shorter RA duration than non-IFX patients. During the study, pre-IFX patients received concomitant methotrexate more often than non-IFX patients. The incidence of AEs and serious AEs were significantly lower in pre-IFX patients, as was the percentage of patients who discontinued treatment. Both cohorts had significant improvement (P < 0.001) in EULAR responses at the end of the treatment period. This study demonstrated that etanercept was effective and well tolerated in active RA patients with and without prior IFX treatment.
PMCID: PMC3364424  PMID: 21331576
Etanercept; Infliximab; Postmarketing surveillance study; Rheumatoid arthritis; TNF-α antagonists
3.  The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT): results of radiographic analyses after 1 year 
Annals of the Rheumatic Diseases  2006;65(8):1038-1043.
Infliximab is effective in improving signs and symptoms of joint/skin involvement, functional status, and quality of life in patients with psoriatic arthritis (PsA). Using IMPACT trial data, we assessed the effect of infliximab (IFX) on structural damage in PsA.
Patients with active PsA were randomly assigned to receive placebo (PBO/IFX) or infliximab 5 mg/kg (IFX/IFX) at weeks 0, 2, 6, and 14, with the primary endpoint at week 16. The PBO group received infliximab loading doses at weeks 16, 18, and 22. Thereafter, all patients received infliximab 5 mg/kg every 8 weeks through week 50. Hand/feet radiographs were obtained at weeks 0 and 50. Total radiographic scores were determined using the PsA modified van der Heijde‐Sharp (vdH‐S) score. Projected annual rate of progression was calculated by dividing x ray score by disease duration (years).
As reported previously, 65% of infliximab treated patients versus 10% of PBO treated patients achieved an ACR20 response at week 16 (p<0.001). At week 50, 69% of patients achieved an ACR20 response. Radiographs (baseline and week 50) were available for 72/104 patients. At baseline, estimated mean annual rate of progression was 5.8 modified vdH‐S points/year. Mean (median) changes from baseline to week 50 in the total modified vdH‐S score were −1.95 (−0.50) for PBO/IFX and −1.52 (−0.50) for IFX/IFX patients (p = NS). At week 50, 85% and 84% of patients in the PBO/IFX and IFX/IFX groups had no worsening in the total modified vdH‐S score.
Infliximab inhibits radiographic progression in patients with PsA through week 50.
PMCID: PMC1798249  PMID: 16439444
infliximab; psoriasis; psoriatic arthritis; structural damage; tumour necrosis factor α
4.  Correlation of antinuclear antibody and anti-double-stranded DNA antibody with clinical response to infliximab in patients with rheumatoid arthritis: a retrospective clinical study 
Arthritis Research & Therapy  2011;13(6):R213.
The induction of antinuclear antibodies (ANAs) or anti-double-stranded (ds) -DNA antibodies (Abs) after infliximab (IFX) therapy in rheumatoid arthritis (RA) is a well-known phenomenon, but the correlation of such Abs with the clinical response to IFX has not yet been determined. The aims of this retrospective observational study were to examine the prevalence of positive ANA and anti-ds-DNA Abs before and after IFX therapy in patients with RA and to investigate whether an increased titer of such Abs is associated with the clinical efficacy of IFX.
One hundred eleven RA patients who had received IFX were studied. ANA (indirect immunofluorescence with HEp-2 cells) and anti-ds-DNA Abs (Farr assay) results were examined before and after IFX therapy.
The overall clinical response assessed by EULAR response criteria was as follows: good response in 55%, including remission in 38%; moderate response in 18%; and no response (NOR) in 27%. The positivity of ANA (≥ 1:160) and anti-ds-DNA Abs significantly increased from 25% to 40% (P = 0.03) and from 3% to 26% (P < 0.001) after IFX, respectively. EULAR response differed significantly according to the ANA titer before IFX (P = 0.001), and the efficacy of IFX became worse as the ANA titer before starting IFX increased. Furthermore, the differences in the clinical response of the ANA titer before IFX ≤ 1:80 and ≥ 1:160 were significant (good, moderate, and no response were 66%, 9%, and 25% in ≤ 1:80 group versus 26%, 33%, 41% in ≥ 1:160 group, respectively; P < 0.001). In 13 patients whose ANA had increased after IFX, 10 showed NOR, only one showed a good response, and none reached remission. These clinical responses were significantly different from ANA no-change patients. In 21 patients with positive anti-ds-DNA Abs after IFX, 16 showed NOR, only two showed a good response, and none reached remission.
The present study suggests that the ANA titer before starting IFX predicts the clinical response to IFX. The increased titers of ANA or anti-ds-DNA Abs after IFX may be useful markers of NOR.
PMCID: PMC3334666  PMID: 22192852
5.  Antidrug antibodies against TNF-blocking agents: correlations between disease activity, hypersensitivity reactions, and different classes of immunoglobulins 
Although anti-TNF drugs have changed the clinical course of rheumatoid arthritis (RA), survival rates and resistance-to-therapy data confirm that about 30% of RA patients fail to respond. The aim of this study was to evaluate the correlations between the development of antidrug antibodies, specific IgG4 antibodies against TNF inhibitors, and resistance to therapy in RA patients. This retrospective study involved 129 patients with established RA naïve to biological agents (98 females and 32 males, mean age 56.7±12.3 years, disease duration 6.3±1.2 years, baseline Disease Activity Score [DAS]-28 3.2–5.6) who received treatment with anti-TNF agents after the failure of conventional disease-modifying antirheumatic drugs (32 received infliximab [IFX], 58 etanercept [ETN], and 39 adalimumab [ADA]). After 6 months of treatment, the patients were classified as being in remission (DAS28 <2.6), having low disease activity (LDA; DAS28 2.6–3.2), or not responding (NR: DAS28 >3.2). The patients were also tested for serum antidrug antibodies and IgG4 antibodies against TNF inhibitors. After 24 weeks of treatment, 38% of the ETN-treated patients and 28% of those treated with ADA had injection-site reactions; the rate of systemic reactions in the IFX group was 25%. The differences among the three groups were not statistically significant (P=0.382; ETN versus ADA P=0.319). The percentages of patients with adverse events stratified by drug response were: LDA 8% and NR 18% in the ADA group; in remission 3%, LDA 22%, and NR 10% in the ETN group; and LDA 6% and NR 16% in the IFX group (P=0.051). The percentages of patients with antidrug antibodies were: ADA 33.3%, ETN 11.5%, and IFX 10.3% (P=0.025; ADA versus ETN P=0.015). The percentages of patients with IgG4 antibodies were: ADA 6%, ETN 13%, and IFX 26% (P=0.017; ADA versus ETN P=0.437). Associations between antidrug antibodies, specific IgG4 antibodies, and adverse reactions were not significant for any of the three drugs. IgG4 levels were higher in the ADA group than in the other two groups, and higher in the patients with worse DAS28 (NR) and in those experiencing adverse events. These data suggest a possible association between IgG4 levels and worse DAS28 (r2=5.8%, P=0.011). The presence of specific IgG4 antibodies against TNF blockers in patients with RA might affect the drugs’ activity. Patients with injection-site reactions and IgG4 against ETN may show a decreased response.
PMCID: PMC4337417  PMID: 25733803
antidrug antibodies; TNF-blocking agents; IgG4 antibodies
6.  A systematic review of infliximab in the treatment of early rheumatoid arthritis 
Several health authorities have recently revised the indication of infliximab (IFX) to include the treatment of early rheumatoid arthritis (RA). The aim of this systematic review of the literature was to appraise the efficacy, safety, and cost-effectiveness of early therapy with IFX.
We identified published clinical trials from 1966 to May 2006. We included randomized clinical trials (RCTs) in RA with disease duration of less than 3 years comparing the treatment of methotrexate-IFX (MTX-IFX) with methotrexate-placebo (MTX-placebo).
A total of 8 studies met inclusion criteria. Three studies reported redundant data regarding the vdH Sharp Score. Out of the 5 remaining studies, 4 analyzed structural joint destruction (vdH Sharp Score) and demonstrated a significant reduction in radiographic damage progression in favor of the combination of MTX-IFX compared with MTX-placebo (−4.1 vdH Sharp Score units (95% CI: 3.5; 4.6). Three studies also displayed a benefit of MTX-IFX on functional outcomes of RA (HAQ score) and disease activity measures (DAS, ACR response criteria), although less markedly.
Although data might be skewed because of only 2 existing large studies with concordant data, results from RCTs demonstrate improved efficacy of the combination MTX-IFX compared with MTX-placebo in early RA. However, many early RA patients probably do not require the addition of IFX to achieve a satisfying clinical and radiological course. So far, no evidence has established the superiority of MTX-IFX over MTX-prednisone or other combinations of traditional disease-modifying anti-rheumatic agents.
PMCID: PMC2376089  PMID: 18473014
rheumatoid arthritis; antirheumatic agents; infliximab
7.  Efficacy and Safety of Adalimumab in Crohn's Disease 
Adalimumab (ADA) is a subcutaneously (SC) self-administered fully human Ig G1 monoclonal antibody directed against tumor necrosis factor alpha (TNFce). In the CLASSIC dose-ranging trial, ADA was superior to placebo for inducing remission in patients with moderate-to-severe Crohn's disease (CD) naive to TNFa inhibitor therapy. In CLASSIC II, patients in remission following CLASSIC I maintained remission for up to 56 weeks while on ADA. In CHARM, approximately 40% of the 499 patients with moderate-to-severe CD who responded to ADA, maintained remission at 26 and 52 weeks, thus confirming long-term efficacy. ADA demonstrated steroid-sparing properties, beneficial effects in patients with perianal fistulas, and decreases in rates of hospitalization and surgery. Sub-group analyses demonstrated similar remission rates irrespective of concomitant immunosuppressive use or previous exposure to other TNFa inhibitor therapy. In the GAIN trial, 325 patients who had either lost response or become intolerant to infliximab (IFX) were randomized to recieve ADA induction therapy or placebo. In this difficult-to-treat patient population, 21% achieved remission and half demonstrated clinical benefit from ADA induction therapy. Injection site reactions may occur with SC ADA (2-5% of patients), which are generally less dramatic in nature than infusion reactions experienced with intravenous IFX. Immunogenicity occurs with all monoclonal antibodies; however, in the CD development program anti-ADA antibodies were detected at low rates (0.7 and 2.6% of patients in the CLASSIC I and CLASSIC II studies, respectively). Based on robust short- and long-term efficacy data from large randomized controlled trials and a favorable safety signal, ADA has become a key addition to the therapeutic armamentarium in the treatment of moderate-to-severe CD.
PMCID: PMC3002485  PMID: 21180513
Crohn's disease; TNFα inhibitors; adalimumab; infliximab
8.  Clinical Course of Infliximab Treatment in Korean Pediatric Ulcerative Colitis Patients: A Single Center Experience 
Infliximab (IFX) is considered safe and effective for the treatment of ulcerative colitis (UC) in both adults and children. The aim of this study was to evaluate the short- and long-term clinical course of IFX in Korean children with UC.
Pediatric patients with UC who had received IFX infusions between November 2007 and May 2013 at Samsung Medical Center were retrospectively investigated. The clinical efficacy of IFX treatment was evaluated at 8 weeks (short term) and 54 weeks (long term) after the initiation of IFX treatment using the Pediatric Ulcerative Colitis Activity Index (PUCAI). The degree of response to IFX treatment was defined as complete response (PUCAI score=0), partial response (decrement of PUCAI score≥20 points), and non-response (decrement of PUCAI score <20 points). Adverse events associated with IFX treatment were also investigated.
Eleven pediatric patients with moderate to severe UC had received IFX. The remission rate after IFX treatment was 46% (5/11) and 82% (9/11) at 8 weeks and 54 weeks after IFX treatment, respectively. All patients who were steroid-dependent before treatment with IFX achieved remission at 54 weeks and were able to stop treatment with corticosteroids, while all steroid-refractory patients failed to achieve remission at 54 weeks after treatment with IFX.
Response to IFX treatment after 8 weeks may predict a favorable long-term response to IFX treatment in Korean pediatric UC patients.
PMCID: PMC3990780  PMID: 24749085
Inflammatory bowel diseases; Ulcerative colitis; Infliximab; Child; Korea
9.  Long-term efficacy of infliximab for refractory ulcerative colitis: results from a single center experience 
BMC Gastroenterology  2014;14:80.
The long-term efficacy of infliximab (IFX) for patients with refractory ulcerative colitis (UC) is unclear. The aim of this study was to assess the long-term outcomes of IFX treatment in patients with refractory UC.
Thirty-three patients with refractory UC who received IFX treatment at Kyoto University Hospital between 2003 and 2013 were retrospectively evaluated. IFX intensification was defined as a dose escalation (up to 10 mg/kg) and/or shorter intervals between infusions (every 4–6 weeks).
Of the 33 patients who received scheduled infusions of IFX, 24 (72.7%) achieved clinical remission within 8 weeks after initiating IFX treatment. Of these 24 responders, 17 (70.8%) experienced a relapse of UC and required IFX intensification, and 16 (66.7%) eventually maintained clinical remission with IFX treatment, including IFX intensification. Of the 33 patients, 6 (18.2%) underwent colectomy during IFX treatment. Multivariate regression analysis showed that a serum C-reactive protein (CRP) concentration <5 mg/L two weeks after starting IFX was a predictor of a positive clinical response to IFX induction therapy. No severe adverse events occurred in UC patients treated with IFX.
IFX intensification was necessary for long-term maintenance of remission and to prevent colectomy in patients with refractory UC.
PMCID: PMC4012244  PMID: 24758588
Ulcerative colitis; Infliximab; Immunomodulator; Infliximab intensification
10.  Monitoring Drug and Antidrug Levels: A Rational Approach in Rheumatoid Arthritis Patients Treated with Biologic Agents Who Experience Inadequate Response While Being on a Stable Biologic Treatment 
BioMed Research International  2014;2014:702701.
Clinical response in patients with rheumatoid arthritis (RA) treated with biologic agents can be influenced by their pharmacokinetics and immunogenicity. The present study evaluated the concordance between serum drug and antidrug levels as well as the clinical response in RA patients treated with biological agents who experience their first disease exacerbation while being on a stable biologic treatment. 154 RA patients treated with rituximab (RTX), infliximab (IFX), adalimumab (ADL), or etanercept (ETN) were included. DAS28, SDAI, and EULAR response were assessed at baseline and reevaluated at precise time intervals. At the time of their first sign of inadequate response, patients were tested for both serum drug level and antidrug antibodies level. At the next reevaluation, patients retreated with RTX that had detectable drug level had a better EULAR response (P = 0.038) with lower DAS28 and SDAI scores (P = 0.01 and P = 0.03). The same tendency was observed in patients treated with IFX and ETN regarding EULAR response (P = 0.002 and P = 0.023), DAS28 score (P = 0.002 and P = 0.003), and SDAI score (P = 0.001 and P = 0.026). Detectable biologic drug levels correlated with a better clinical response in patients experiencing their first RA inadequate response while being on a stable biologic treatment with RTX, IFX, and ETN.
PMCID: PMC4054977  PMID: 24982902
11.  Safety and effectiveness of adalimumab in a clinical setting that reflects Canadian standard of care for the treatment of rheumatoid arthritis (RA): Results from the CanACT study 
This multicenter, open-label, prospective, single cohort study evaluated the effectiveness and safety of adalimumab in a clinical setting reflecting the Canadian standard of care for the treatment of patients with rheumatoid arthritis (RA).
Patients ≥ 18 years of age with a history of active RA ≥ 3 months and fulfilling Canadian requirements for biological therapy received adalimumab 40 mg subcutaneously every other week for 12 weeks. Pre-study DMARD treatment regimens, corticosteroids, or NSAIDs were allowed throughout the study. The primary effectiveness outcome measure was the mean change in 28-joint disease activity score (DAS28) from baseline to Week 12. Secondary measures included the proportion of patients achieving joint remission (DAS28 < 2.6) and low-disease activity (DAS28 < 3.2) at Week 12, and European League Against Rheumatism (EULAR: moderate and good) and American College of Rheumatology (ACR: ACR20, 50, and 70) responses, as well as responses in ACR core components at Weeks 4, 8, and 12. Subgroup analysis included a comparison of patients naïve to biological DMARD (BDMARD) therapy versus BDMARD-experienced patients. Safety was assessed in terms of adverse and serious adverse events.
A total of 879 patients (mean disease duration > 12 years) were enrolled; 772 (87.9%) completed the 12-week period. Adalimumab treatment was associated with rapid and sustained improvements in the signs and symptoms of RA. Significant improvements in mean DAS28 score were observed as early as Week 4. After 12 weeks of adalimumab treatment, 15.3% and 28.9% of patients achieved clinical remission and low-disease activity, respectively. Similarly, significant improvements in ACR core components were observed as early as Week 4, with continued improvements occurring through 12 weeks. Patients naïve to BDMARD therapy demonstrated numerically greater clinical responses when compared with patients who had experienced prior BDMARD therapy, although both subgroups were associated with significant improvements from baseline. The rates and types of adverse events, as well as the results of laboratory measures, demonstrated that adalimumab was generally safe and well-tolerated.
This study demonstrated that, under conditions reflective of the normal clinical practice in Canada, adalimumab is an effective and safe treatment for patients with RA.
Trial registration
PMCID: PMC3226526  PMID: 22093579
12.  Discontinuation of infliximab therapy in patients with Crohn's disease in sustained complete remission (the STOP IT study): protocol for a double-blind, randomised, placebo-controlled, multicentre trial 
BMJ Open  2014;4(12):e005887.
Infliximab (IFX), a monoclonal chimeric antibody against tumour necrosis factor (TNF) α, is effective for induction and maintenance of remission in moderate to severe Crohn's disease. Discontinuation of IFX maintenance therapy in patients in remission should be considered in order to reduce the potential long-term side effects and lower costs.
Methods and analysis
This is a prospective, double-blind, randomised, placebo-controlled, multicentre study of patients with luminal Crohn’s disease who have been treated with IFX for at least 1 year and are in sustained complete clinical, biochemical and endoscopic remission (ie, Crohn's Disease Activity Index (CDAI) score <150, complete mucosal healing and biochemical markers of inflammation within the normal range). These patients are randomised to receive placebo infusions or continue IFX maintenance therapy. The primary end point is the proportion of patients in maintained remission after 48 weeks (def. CDAI <150).
Ethics and dissemination
It is estimated that the knowledge gained about how to optimally handle patients with Crohn’s disease in complete long-term sustained remission on IFX is proportionate to the risks and inconveniences related to participation in this study. Prolonged exposure to IFX may cause severe side effects and increased risk of malignancies. Conversely, IFX discontinuation should not unnecessarily create a high risk of relapse. Thus, empirical evidence is needed concerning the safety of discontinuing IFX once a patient exhibits sustained remission. Study results will be published in an English language scientific medical journal. The study is approved by the Danish Medicines Agency (EudraCT-number: 2012-002702-51) and the Regional Ethics Committee of Region Hovedstaden Denmark (Approval-number: H-4-2012-099). The project is reported to the Danish Data Protection Agency (ID-number: 2007-58-0015/HEH.750.89-27), registered at, and monitored by independent GCP units for the University of Copenhagen, Odense and Aarhus. The current approved protocol is V.3.2, dated 1 June 2014.
Trial registration number
PMCID: PMC4275671  PMID: 25524543
13.  Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease 
Gut  2007;56(9):1226-1231.
Episodic infliximab (IFX) treatment is associated with the formation of antibodies to IFX (ATIs) in the majority of patients, which can lead to infusion reactions and a shorter duration of response. Concomitant use of immunosuppressives (IS) reduces the risk of ATI formation.
Aims and methods
To investigate which of the IS—that is, methotrexate (MTX) or azathioprine (AZA)—is most effective at reducing the risk of ATI formation, a multicentre cohort of 174 patients with Crohn's disease, treated with IFX in an on‐demand schedule, was prospectively studied. Three groups were studied: no IS (n = 59), concomitant MTX (n = 50) and concomitant AZA (n = 65). ATI and IFX concentrations were measured in a blinded manner at Prometheus Laboratories before and 4 weeks after each infusion.
ATIs were detected in 55% (96/174) of the patients. The concomitant use of IS therapy (AZA or MTX) was associated with a lower incidence of ATIs (53/115; 46%) compared with patients not taking concomitant IS therapy (43/59; 73%; p<0.001). The incidence of ATIs was not different for the MTX group (44%) compared with the AZA group (48%). Patients not taking IS therapy had lower IFX levels (median 2.42 μg/ml (interquartile range (IQR) 1–10.8), maximum 21 μg/ml) 4 weeks after any follow‐up infusion than patients taking concomitant IS therapy (median 6.45 μg/ml (IQR 3–11.6), maximum 21 μg/ml; p = 0.065), but there was no difference between MTX or AZA. In patients who developed significant ATIs >8 μg/ml during follow‐up, the IFX levels 4 weeks after the first infusion were retrospectively found to be significantly lower than in patients who did not develop ATIs on follow‐up or had inconclusive ATIs.
Concomitant IS therapy reduces ATI formation associated with IFX treatment and improves the pharmacokinetics of IFX. There is no difference between MTX and AZA in reducing these risks. ATI profoundly influences the pharmacokinetics of IFX. The formation of ATIs >8 μg/ml is associated with lower serum levels of IFX already at 4 weeks after its first administration.
PMCID: PMC1954977  PMID: 17229796
14.  A randomised comparative study of the short term clinical and biological effects of intravenous pulse methylprednisolone and infliximab in patients with active rheumatoid arthritis despite methotrexate treatment 
Annals of the Rheumatic Diseases  2004;63(9):1069-1074.
Objectives: To compare the short term clinical and biological effects of intravenous (IV) pulse methylprednisolone (MP) and infliximab (IFX) in patients with severe active rheumatoid arthritis (RA) despite methotrexate (MTX) treatment.
Methods: Patients with active RA despite MTX treatment were randomly allocated to receive a single IV infusion of MP (1 g) or three IV infusions of IFX (3 mg/kg) on weeks 0, 2, and 6. Patients were "blindly" evaluated for disease activity measures. Quality of life (QoL) was evaluated through the SF-36 health survey. Serum matrix metalloproteinase-3 (MMP-3) titres were measured at baseline, weeks 2 and 6.
Results: Compared with baseline, significant improvement was noted in all activity measures, including serum C reactive protein (CRP) titres, in the IFX group only. At week 14, 6/9 (67%) and 4/9 (44%) IFX patients met the ACR20 and 50 response criteria, while this was the case in only 1/12 (8%) and 0/12 (0%) MP patients, respectively (p<0.05). None of the QoL scales improved with MP treatment, whereas some did so in the IFX group. Serum MMP-3 titres significantly decreased (41% drop) at week 6 in the IFX group, while no changes were seen in patients given MP.
Conclusion: This short term randomised comparative study demonstrates that TNF blockade is better than MP pulse therapy in a subset of patients with severe refractory RA, with improvement in not only clinical parameters of disease activity but also biological inflammatory indices, such as serum CRP and MMP-3 titres.
PMCID: PMC1755125  PMID: 15308515
15.  Adalimumab for the treatment of Crohn’s disease 
Biologics : Targets & Therapy  2008;2(4):763-777.
Crohn’s disease (CD) is a chronic inflammatory bowel disease characterized by a relapsing-remitting course with trans-mural inflammation of potentially any section of the digestive tract. Adalimumab (ADA) is a subcutaneously administered, recombinant, fully human, IgG1 monoclonal antibody that binds with high affinity and specificity to human TNF-alpha, thus modulating its biologic functions and its proinflammatory effects.
To review the available data on ADA in CD for biological properties, efficacy, and safety.
Electronic searches were conducted using the Pubmed and SCOPUS databases from the earliest records to April 2008. The search terms used were “adalimumab”, “anti-TNF”, “TNF-alpha”, “biologicals”, “inflammatory bowel disease”, and “Crohn’s disease”. Reference lists of all relevant articles were searched for further studies.
Available studies suggest that ADA has the potential to induce and maintain clinical response and remission in moderate-severe CD, both in anti-TNF-naïve patients and in subjects who lost their response and/or became intolerant to infliximab (IFX). ADA seems also effective in maintaining corticosteroid-free remission and obtaining complete fistula closure (although no specific randomized trials are available). No concomitant immunosuppressors seem to be necessary. Side effects appear similar to IFX, while site-injection reactions are frequent and specific. Data on immunogenicity and its clinical impact are uncertain.
ADA appears to be effective in inducing and maintain clinical remission in CD, including patients not manageable with IFX. Successive clinical practice and further on going trials will confirm a positive role for ADA as a new anti-TNF treatment in CD. The impact on clinical management or on resources should be more studied.
PMCID: PMC2727899  PMID: 19707457
Crohn’s disease; adalimumab; anti-TNF; treatment; biologics
16.  Safety of Ferric Carboxymaltose Immediately after Infliximab Administration, in a Single Session, in Inflammatory Bowel Disease Patients with Iron Deficiency: A Pilot Study 
PLoS ONE  2015;10(5):e0128156.
To obtain preliminary safety and efficacy data on intravenous (IV) administration of infliximab (IFX) and ferric carboxymaltose (FCM) to inflammatory bowel disease (IBD) patients in a single treatment session.
A two-phase non-interventional, observational, prospective pilot study was performed to evaluate safety and efficacy of FCM given immediately after IFX. IBD patients were recruited consecutively in the outpatient clinic in two groups. Control group patients (n = 12) received FCM on a separate day from IFX. Subsequently, single-session group patients (n = 33) received FCM after IFX on the same day. All patients received 5mg/kg IFX and 1000mg FCM for iron-restricted anemia (IRA) or 500mg FCM for iron deficiency without anemia. Safety assessment was performed by recording adverse events (AEs) during and immediately after infusion, 30 minutes afterwards, and via follow-up at 7 days and 8 weeks. For efficacy assessment, hematological parameters were assessed prior to FCM infusion (pre-FCM) and after 8 weeks. Economic impact of FCM given immediately after IFX was assessed.
All 45 patients (35 Crohn´s disease, 10 ulcerative colitis) received IFX 5mg/kg. 21 patients received 500mg FCM and 24 received 1000mg. FCM administration immediately after IFX corrected iron deficiency or IRA as shown by increases in hematological parameters. No AEs were reported during the safety evaluation at the end of FCM or IFX administration, 30 minutes, 7 days and 8 weeks afterwards, in either control or single-session groups. Total cost per patient for single-session administration was 354.63€; for patients receiving IFX and FCM on separate days, it was 531.94€, giving a 177.31€ per-patient cost saving.
Single-session administration of FCM after IFX was safe and effective in IBD patients and can offer a good cost-benefit ratio and improve treatment adherence. To our knowledge, this study is the first to evaluate FCM and IFX administration in a single treatment session.
PMCID: PMC4443970  PMID: 26011514
17.  Efficacy of mizoribine pulse therapy in patients with rheumatoid arthritis who show a reduced or insufficient response to infliximab 
Modern Rheumatology  2009;19(3):229-234.
The efficacy of infliximab, a chimeric antibody against tumor necrosis factor-α used to treat patients with rheumatoid arthritis (RA), tends to decrease as patients develop human antichimeric antibody against infliximab (HACA). The clinical study reported here was designed to evaluate the efficacy of mizoribine (MZR) pulse therapy in patients who show a reduced or insufficient response to infliximab. Ten RA patients who had active arthritis despite infliximab therapy were treated with MZR pulse therapy at a dose of 100 mg MZR and methotrexate (MTX) and the disease activity assessed at baseline and at weeks 4–8, 12–16, and 20–24. The dose was increased to 150 mg in those patients who showed an insufficient response to MZR. The mean 28-joint disease activity score (DAS28) at weeks 12–16 and 20–24 of therapy was significantly lower than that at baseline. A moderate or good European League against Rheumatism (EULAR) response was achieved in seven patients (70%) at weeks 12–16 and in five patients (50%) at weeks 20–24. The dose of 150 mg MZR was effective in one of the three patients who showed an insufficient response to pulse therapy with 100 mg MZR. Based on these results, we propose that MZR pulse therapy should be attempted before the patient is switched to other biologics.
PMCID: PMC2689357  PMID: 19326186
Infliximab; Mizoribine; Rheumatoid arthritis
18.  Utility of serum TNF-α, infliximab trough level, and antibody titers in inflammatory bowel disease 
AIM: To assess tumor necrosis factor-α (TNF-α), infliximab (IFX) concentrations, and antibodies against IFX molecules in patients with inflammatory bowel disease (IBD) who develop loss of response, side effects, or allergic reaction during anti TNF-α therapy.
METHODS: Blood samples of 36 patients with response loss, side effects, or hypersensitivity to IFX therapy (Group I) and 31 patients in complete clinical remission (Group II) selected as a control group were collected to measure trough serum TNF-α level, IFX, and anti-IFX antibody (ATI) concentration. We examined the correlation between loss of response, the development of side effects or hypersensitivity, and serum TNF-α, IFX trough levels, and ATI concentrations.
RESULTS: The serum TNF-α level was shown to be correlated with the presence of ATI; ATI positivity was significantly correlated with low trough levels of IFX. ATIs were detected in 25% of IBD patients with loss of response, side effects, or hypersensitivity, however no association was revealed between these patients and antibody positivity or lower serum IFX levels. Previous use of IFX correlated with the development of ATI, although concomitant immunosuppression did not have any impact on them.
CONCLUSION: On the basis of the present study, we suggest that the simultaneous measurement of serum TNF-α level, serum anti TNF-α concentration, and antibodies against anti TNF-α may further help to optimize the therapy in critical situations.
PMCID: PMC4009537  PMID: 24833846
Tumor necrosis factor-α; Infliximab; Antibody; Inflammatory bowel disease
19.  Adalimumab alone and in combination with disease‐modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial 
Annals of the Rheumatic Diseases  2007;66(6):732-739.
To evaluate the safety and effectiveness of adalimumab alone or in combination with standard disease‐modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA).
Patients with active RA despite treatment with DMARDs or prior treatment with a tumour necrosis factor antagonist participated in a multicentre, open‐label clinical study of adalimumab 40 mg every other week for 12 weeks with an optional extension phase. Patients were allowed to continue with pre‐existing traditional DMARDs. Long‐term safety results are reported for all patients (4210 patient‐years (PYs) of adalimumab exposure). The observed effectiveness results at week 12 are reported using American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria.
Among the 6610 treated patients, adalimumab was generally well tolerated. Serious infections occurred in 3.1% of patients (5.5/100 PYs, including active tuberculosis, 0.5/100 PYs). Demyelinating disease (0.06%) and systemic lupus erythematosus (0.03%) were rare serious adverse events. The standardised incidence ratio of malignancy was 0.71 (95% CI 0.49 to 1.01). The standardised mortality ratio was 1.07 (95% CI 0.75 to 1.49). At week 12, 69% of patients achieved an ACR20 response, 83% a moderate, and 33% a good EULAR response. Adalimumab was effective in combination with a variety of DMARDs. The addition of adalimumab to antimalarials was comparably effective to the combination of adalimumab and methotrexate.
Considering the limitations of an open‐label study, adalimumab alone or in combination with standard DMARDs appeared to be well tolerated and effective in 6610 difficult‐to‐treat patients with active RA treated in clinical practice.
PMCID: PMC1954645  PMID: 17329305
adalimumab; rheumatoid arthritis; tumour necrosis factor; monoclonal antibody; antirheumatic agents
20.  Impact of adalimumab on work participation in rheumatoid arthritis: comparison of an open-label extension study and a registry-based control group 
Annals of the Rheumatic Diseases  2008;68(6):930-937.
Background and objectives:
Rheumatoid arthritis (RA) causes considerable disability and often results in loss of work capacity and productivity. This study evaluated the impact of adalimumab, a tumour necrosis factor antagonist with demonstrated efficacy in RA, on long-term employment.
Data from an open-label extension study (DE033) of 486 RA patients receiving adalimumab monotherapy who previously did not respond to at least one disease-modifying antirheumatic drug (DMARD) and had baseline work status information were compared with data from 747 RA patients receiving DMARD treatment in a Norway-based longitudinal registry. Primary outcomes included the time patients continued working at least part time and the likelihood of stopping work. Secondary outcomes included American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) responses and disease remission. Outcomes were compared 6, 12 and 24 months after enrolment.
During a 24-month period, the 158 patients who received adalimumab and were working at baseline worked 7.32 months longer (95% CI 4.8 to 9.1) than did the 180 patients treated with DMARDs, controlling for differences in baseline characteristics. Regardless of baseline work status, patients receiving adalimumab worked 2.0 months longer (95% CI 1.3 to 2.6) and were significantly less likely to stop working than those receiving DMARDs (HR 0.36 (95% CI −0.30 to 0.42) for all patients and 0.36 (95% CI 0.15 to 0.85) for patients working at baseline, respectively). The patients who received adalimumab were also considerably more likely to achieve ACR responses and disease remission than DMARD-treated patients. Patients who achieved EULAR good response and remission were less likely to stop working, but this relationship was only seen in patients receiving DMARDs.
Patients with RA who received adalimumab experienced considerably longer periods of work and continuous employment, and greater rates of clinical responses, than patients receiving DMARDs. The mechanism by which adalimumab decreases likelihood of stopping work seems to be different from that of DMARD treatment and independent of clinical responses.
PMCID: PMC2674552  PMID: 18829616
21.  The efficiency of biologic therapy in a group of patients with rheumatoid arthritis 
Journal of Medicine and Life  2015;8(1):79-84.
Objectives. The following study aims to evaluate the monotherapy with biologic agents: Infliximab (IFX), Etanercept (ETA), Adalimumab (ADA) and Rituximab (RTX) in patients diagnosed with rheumatoid arthritis (RA).
Methods. To achieve these objectives, the database of “Dr. I. Cantacuzino” Clinical Hospital, Department of Internal Medicine and Rheumatology, was used.
The study was retrospective and descriptive, covering 168 patients with RA, followed for 12 months, from January 2012 to January 2013.
Admission criteria for the study were the following: patients diagnosed with RA according to ACR 1987/ EULAR 2010 criteria, disease activity score (DAS 28)> 5.1, positive inflammation tests, presence of RA refractory to classic remitting treatment administered at least 6 months prior to the initiation of biological therapy, on patients treated with RTX. They were considered non-responders after 6 months of treatment with anti tumor necrosis factor alpha (anti-TNF) and decided to switch agents with anti CD-20.
Results . Comparing values between any two points in time (baseline - 6 months -12 months) for any type of therapy, there were significant decreases in the values of erythrocyte sedimentation rate (ESR), reactive C protein (CRP) and disease activity score (DAS 28).
There were no significant differences between therapies regarding ESR at 6 months (p = 0.070, ANOVA) and 12 months (p = 0.375, Kruskal-Wallis), significant differences were regarding CRP at 6 and 12 months (p = 0.000, Kruskal-Wallis) and DAS 28 at 6 months (p = 0.000, Kruskal- Wallis) and 12 months (p = 0.018, Kruskal-Wallis).
Conclusion . All 4 therapies have proven efficient, prognostic markers decreasing gradually at 6 and 12 months.
Abbreviations: RA = rheumatoid arthritis, IFX = Infliximab, ETA = Etanercept, ADA = Adalimumab, RTX = Rituximab, ESR = erythrocyte sedimentation rate, CRP = reactive C protein, DAS 28 = disease activity score, anti TNF = inhibitor of tumor necrosis factor
PMCID: PMC4397527  PMID: 25914745
rheumatoid arthritis; biologic therapy
22.  Significance of low level infliximab in the absence of anti-infliximab antibodies 
AIM: To evaluate the prevalence of double negative (DN) sera and the mechanisms responsible for DN status.
METHODS: Sera of inflammatory bowel disease patients treated with infliximab (IFX) were tested for drug/antibodies to infliximab (ATI) trough levels and the proportion of DN results was compared between a commercially available double antigen ELISA (with labeled IFX as the detection antibody) and an anti-lambda ELISA (with anti-human lambda chain detection antibody). Repeat testing with lower than customary serum dilution (1:10) was performed. Patients with DN status were matched with IFX+/ATI- controls and were followed-up for subsequent development of non-transient ATI to investigate if DN status precedes ATI.
RESULTS: Of 67 sera obtained at time of loss of response, only 6/67 (9%) were DN by anti-lambda ELISA compared to 27/67 (40%) with double antigen ELISA (P < 0.001, Fisher’s Exact test). Of the latter 27 sera, 22% were also DN by anti-lambda ELISA, whereas 44% were actually IFX positive (IFX+ATI-), 30% were ATI positive (IFX-ATI+) and 4% were double positive (IFX+ATI+). Re-testing using a 1:10 dilution converted most DN results into IFX+ and /or ATI+ status. Patients with DN status had shorter survival free of non-transient ATI compared with matched controls (log rank test, P < 0.001). In 9/30 (30%) of these patients, non transient ATI occurred before and after the event at which the DN serum was obtained, supporting the view that a DN result may represent a particular time-point along the two curves of ATI titer rise and infliximab drug level decline.
CONCLUSION: DN status may result from false negative detection of IFX or ATI by double antigen ELISA, suggesting a transitional state of low-level immunogenicity, rather than non-immunological clearance.
PMCID: PMC4323470  PMID: 25684959
Inflammatory bowel disease; Biological therapy; Infliximab; Immunology; Drug response
23.  Impact of Antibodies to Infliximab on Clinical Outcomes and Serum Infliximab Levels in Patients With Inflammatory Bowel Disease (IBD): A Meta-Analysis 
Antibodies to infliximab (ATIs) have been associated with loss of clinical response and lower serum infliximab (IFX) levels in some studies of patients with inflammatory bowel disease (IBD). This has important implications for patient management and development of novel biologic therapies. The objective of this study was to perform a systematic review and meta-analysis of studies that reported clinical outcomes and IFX levels according to patients’ ATI status.
MEDLINE, Web of Science, CINAHL, Scopus, and EMBASE were searched for eligible studies. Quality assessment was undertaken using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. Raw data from studies meeting inclusion criteria was pooled for meta-analysis of effect estimates. Sensitivity analysis was performed for all outcomes. Funnel plot was performed to assess for publication bias.
Thirteen studies met the inclusion criteria, and reported results in 1,378 patients with IBD. All included studies had a high risk of bias in at least one quality domain. The pooled risk ratio (RR) of loss of clinical response to IFX in patients with IBD who had ATIs was 3.2 (95 % confidence interval (CI): 2.0–4.9, P < 0.0001), when compared with patients without ATIs. This effect estimate was predominantly based on data from patients (N = 494) with Crohn’s disease (RR: 3.2, 95 % CI: 1.9–5.5, P < 0.0001). Data only from patients with ulcerative colitis (n = 86) exhibited a non-significant RR of loss of response of 2.2 (95 % CI: 0.5–9.0, P = 0.3) in those with ATIs. Heterogeneity existed between studies, in both methods of ATI detection, and clinical outcomes reported. Three studies (n = 243) reported trough serum IFX levels according to ATI status; the standardized mean difference in trough serum IFX levels between groups was −0.8 (95 % CI −1.2, −0.4, P < 0.0001). A funnel plot suggested the presence of publication bias.
The presence of ATIs is associated with a significantly higher risk of loss of clinical response to IFX and lower serum IFX levels in patients with IBD. Published studies on this topic lack uniform reporting of outcomes. High risk of bias was present in all the included studies.
PMCID: PMC3561464  PMID: 23147525
24.  Effectiveness of adalimumab in treating patients with active psoriatic arthritis and predictors of good clinical responses for arthritis, skin and nail lesions 
Annals of the Rheumatic Diseases  2009;69(2):394-399.
To evaluate the effectiveness of adalimumab in patients with psoriatic arthritis (PsA) and identify predictors of good clinical response for joint and skin lesions.
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: ⩾50% improvement in American College of Rheumatology response criteria (ACR50), good response according to European League Against Rheumatism (EULAR) guidelines, a ⩾3-grade improvement in Physician Global Assessment of psoriasis (PGA) and a ⩾50% improvement in the Nail Psoriasis Severity Index (NAPSI). Response predictors were determined by logistic regression with backward elimination (selection level was 5%).
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.
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.
PMCID: PMC2800202  PMID: 19815494
25.  Efficacy of infliximab in acute severe ulcerative colitis: A single-centre experience 
AIM: To suggest infliximab (IFX) is effective for acute severe ulcerative colitis, from real-life clinical practice.
METHODS: All patients receiving IFX for the treatment of acute severe ulcerative colitis in a single centre were included. Data were extracted from clinical records in order to assess response to IFX therapy. The primary endpoint was colectomy-free survival, and secondary outcomes included glucocorticosteroid-free remission and safety, which was evaluated by recording deaths and adverse events. Demographic and clinical characteristics of those who underwent colectomy and those who were colectomy-free, both at discharge from their index admission, and during follow-up after an initial response to IFX were compared.
RESULTS: Forty-four patients (16 females, mean age 36 years) received IFX between May 2006 and January 2012 for acute severe ulcerative colitis. The median duration of follow-up post-first infusion was 396 d (interquartile range = 173-828 d). There were 21 (47.7%) patients with < 1 year of follow-up, 10 (22.7%) with 1 years to 2 years of follow-up, and 13 (29.5%) with > 2 years of follow-up post-first infusion of IFX. Overall, 35 (79.5%) responded to IFX, avoiding colectomy during their index admission, 29 (65.9%) were colectomy-free at last point of follow-up (median follow-up 396 d), and 25 (56.8%) were in glucocorticosteroid-free remission at end of follow-up. There was one death from post-operative sepsis, 20 d after a single IFX infusion. Colectomy rates were generally lower among those “bridging” to thiopurine. Of 18 patients “bridged” to thiopurine therapy, 17 (94.4%) were colectomy-free, and 15 (83.3%) were in glucocorticosteroid-free remission at study end. No predictors of response were identified.
CONCLUSION: IFX is effective for acute severe ulcerative colitis in real-life clinical practice. Two-thirds of patients avoided colectomy, and more than 50% were in glucocorticosteroid-free remission.
PMCID: PMC3581997  PMID: 23467174
Ulcerative colitis; Severe; Azathioprine; Infliximab; Remission

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