0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Immunogenicity of Monoclonal Antibodies Against Tumor Necrosis Factor Used in Chronic Immune-Mediated Inflammatory Conditions:  Systematic Review and Meta-analysis FREE

Jose Ramon Maneiro, MD1; Eva Salgado, MD1; Juan Jesus Gomez-Reino, PhD1,2
[+] Author Affiliations
1Rheumatology Unit, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago, Spain
2Department of Medicine, Medical School, Universidad de Santiago, Santiago, Spain
JAMA Intern Med. 2013;173(15):1416-1428. doi:10.1001/jamainternmed.2013.7430.
Text Size: A A A
Published online

Importance  Knowledge of the immunogenicity of biologic agents may be helpful for the development of strategies for treatment of chronic immune-mediated inflammatory diseases.

Objective  To summarize the influence of antibodies against biologic agents (AABs [seropositivity]) on efficacy and safety in immune-mediated inflammatory diseases.

Data Sources  MEDLINE, EMBASE, Cochrane Library, and the Web of Knowledge were searched for articles published in English, Spanish, French, Italian, or Portuguese between 2000 and March 2012. The search strategy focused on synonyms of diseases, immunogenicity, and biologic agents. Abstracts from 2001 to 2011 of the European League Against Rheumatism and American College of Rheumatology congresses were also included.

Study Selection  The selection criteria were (1) observational or interventional studies in rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, spondyloarthritis, and psoriasis; (2) studies including patients who received biologic agents; and (3) studies collecting data on AABs.

Data Extraction and Synthesis  Data collected included publication details, study design, characteristics of patients and treatments, presence of antibodies, and definition of response.

Main Outcomes and Measures  The primary end point was the association of AABs with response to treatment. Secondary end points were the association of AABs with safety, the association of AABs with concentration of the drug, and the influence of use of concomitant immunosuppressive therapy in the formation of AABs.

Results  The search captured 10 728 articles and abstracts. By hand and reverse search, 31 articles were additionally included. After evaluation of the full reports, 60 references were selected. They included 59 studies of anti–tumor necrosis factor monoclonal antibodies: 1 with etanercept, 2 with rituximab, and 2 with abatacept. In rheumatoid arthritis but not in inflammatory bowel disease or spondyloarthritis, seropositive patients presented worse clinical response at 6 months or less (odds ratio [OR], 0.03; 95% CI, 0.01-0.21), and at 6 months or more (0.03; 0.00-0.30) by meta-analysis. In rheumatoid arthritis, discontinuation of the biologic agent for all reasons was more common in seropositive patients (OR, 3.53; 95% CI, 1.60-7.82). In all conditions, seropositive patients had a higher risk of hypersensitivity reactions (OR, 3.97; 95% CI, 2.36-6.67). Overall, concomitant treatment with disease-modifying antirheumatic drugs, including azathioprine, decreased the risk of seropositivity (OR, 0.32; 95% CI, 0.25-0.42).

Conclusions and Relevance  Presence of antibodies against anti–tumor necrosis factor monoclonal antibodies confers a risk of discontinuation of treatment in rheumatoid arthritis and a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases. The combined use of anti–tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks. Information on other biologic agents is fragmentary.

Figures in this Article

The development of biological therapies signified an advance in the treatment of immune-mediated chronic inflammatory diseases (IMIDs).13 Nevertheless, several patients initially responding to a biologic agent develop acquired drug resistance or gradual drug failure, and some have to discontinue treatment with the biologic agent because of adverse events. In recent years, the immunogenicity related to these drugs, especially with monoclonal antibody as the cause of these unfavorable outcomes, has been studied. Results suggested that antibodies against biological therapies (AABs) affect the efficacy48 and safety of the biologic agents.810 Primarily, immunogenicity against anti–tumor necrosis factor (TNF) monoclonal antibodies has been extensively studied but also has been described against the TNF receptor etanercept, rituximab,11 tocilizumab,12 and abatacept.13,14 In contrast with anti-TNF monoclonal antibodies, the incidence of antibodies against etanercept is low,15 and the AABs are not neutralizing.16,17 A significant amount of information is available on rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) but is scarce for other IMIDs. Overall, data regarding the presence of AABs and safety and efficacy are fragmentary. Knowledge of factors affecting the immunogenicity of biologic agents could help in the development of treatment strategies to prevent loss of efficacy and improved safety. The main objective of this study was to summarize the data on the presence of AABs and their relationship with the efficacy and safety of biological therapies in IMIDs.

A systematic literature review was performed to identify all publications that analyzed the immunogenicity of biological therapies in IMIDs. Data regarding the use of biologic agents in nonapproved indications were dismissed. The protocol of this review is available from the corresponding author; the Preferred Reporting Items for Systematic Reviews and Meta-analyses consensus was followed for the systematic review and meta-analysis.18

Systematic Literature Research

MEDLINE, EMBASE, Cochrane Library, and the Web of Knowledge were searched for articles published between 2000 and March 2012. The search strategy focused on synonyms of diseases, biologic agents, and immunogenicity, and was limited to articles published in English, Spanish, French, Italian, or Portuguese. We also included abstracts online from 2001 to 2011 from the European League Against Rheumatism (EULAR) and the American College of Rheumatology congresses.

Selection of Articles

The selection criteria were (1) studies in patients with RA, juvenile idiopathic arthritis, IBD, ankylosing spondylitis, psoriasis, psoriatic arthritis, or other spondyloarthropathies; (2) studies in patients receiving at least 1 biological drug; (3) studies collecting data on antibodies against biologic agents using some method of measurement; and (4) retrospective or prospective observational studies or intervention studies. Two reviewers (J.R.M. and E.S.) screened articles and abstracts for selection criteria independently. Once unrelated articles were excluded, the full report of selected studies was reviewed. Subsequently, articles not fulfilling all selection criteria were excluded. A table with reasons for exclusion was constructed (eTable 1 in the Supplement). For completeness, a reverse search of included articles and a hand search of published clinical trials of biological therapies were performed.

Data Extraction

Data collected included publication details, study design, AABs status and method of measurement, definition of response, and characteristics of patients and treatments. The primary end point was the association of AABs with response to treatment. Secondary end points were the association of AABs with safety, the association of AABs with concentration of the drug, and the influence of use of concomitant immunosuppressive therapy in the formation of AABs.

Risk of Bias

We created an ad hoc checklist to analyze the risk of bias of the included studies in the meta-analysis. The checklist contains 30 items with a score range of 0 to 100, with 100 indicating the absence of risk of bias. This checklist (available from the authors on request) was based on the guidelines for assessing quality in prognostic studies on the basis of framework of potential biases proposed by Hayden et al.19 The level of evidence of the studies was assessed using the levels of evidence of the Oxford Centre for Evidence-Based Medicine.20

Statistical Analysis

Meta-analyses were performed when at least 3 studies had comparable outcome measures using the random-effects method for computing odds ratios (ORs) of DerSimonian and Laird.21 For each available analysis, the effect was plotted by the inverse of its standard error to identify the risk of publication bias by visually assessing the symmetry of such funnel plots. Statistical significance was determined using the Egger test.22 Heterogeneity was tested as proposed by Higgins and Thompson23 and Higgins et al24 using I2. An I2 value greater than 40% was arbitrarily considered a high level of heterogeneity. If high statistical heterogeneity was present, possible explanations were investigated using sensitivity analysis and meta-regression. Meta-regression was aimed to determine the contribution of time to assess response, number of participants, quality of the data, time of disease duration, method of measurement of antibodies, design of the study, and levels of evidence. P < .10 was considered significant in meta-regression. Statistical analysis was conducted using commercial software (Stata, version 11.1for Windows (StataCorp LP) was used in all statistical analyses.

The search captured 10 728 articles and abstracts. After title and abstract screening, 95 articles were retrieved for full-text review. By hand search and reverse search, 31 articles were added.2555 A total of 66 articles were excluded after detailed review; 60 articles and abstracts were included in the present analysis (eFigure 1 in the Supplement).

In 64 studies from 60 articles, 13 982 patients were included. Thirty studies were randomized clinical trials and 34 were observational studies. Characteristics of the selected articles, including the demographics of patients, duration of disease, treatment, and treatment response definition, are presented in the Table. 48,13,14,2545,4756,5878 Forty-two studies analyzed the association of AABs with clinical response. In 50 articles (78%), secondary end points, such as the association of AABs with safety, association of AABs with concentration of the drug, and influence of concomitant treatment in AABs formation, were reported.

Table Graphic Jump LocationTable.  Evidence and Characteristics of Studies Included in the Review

The quality of data was higher than 70% in 37 of the studies (60%). The level of evidence was 4 in 10 studies and 3 in the other 54 studies. Individual results of studies are presented according to outcome in eTables 2 through 5 in the Supplement. Only data on anti-TNF monoclonal antibodies were sufficient to perform a meta-analysis; data on other biologic agents were insufficient.

Association of AABs With Efficacy
Response in RA

The measures to evaluate efficacy in RA are the EULAR response criteria and the rate of improvement in the American College of Rheumatology criteria of response79,80 (eTable 6 in the Supplement).

Five studies with data on infliximab and adalimumab analyzed EULAR responses from 12 to 192 weeks.8,60,62,63,72 Significantly better response in seronegative patients was reported in most studies. In the meta-analysis of EULAR responses at 6 months, the OR of response for seropositive patients was 0.03 (95% CI, 0.01-0.21) with heterogeneity (I2 = 49.6%; P = .11) (Figure 1).8,49,53,60,62,63,6567,75,78 The type of biologic agent, design of the study, and level of evidence of the studies were identified by meta-regression as the sources of the heterogeneity. No asymmetries were found in a funnel-plot evaluation (Egger test P = .055). In the meta-analysis of EULAR response between month 6 and month 12, the OR for seropositive patients was 0.03 (95% CI, 0.00-0.30) with heterogeneity (I2 = 71%; P = .02). Only the length of follow-up was identified as a source of heterogeneity. The Egger test was significant for publication bias (P = .02).

Place holder to copy figure label and caption
Figure 1.
Meta-analysis of Association of Antibodies Against Biological Therapies (AABs) With Efficacy

Size of the data marker corresponds to the relative weight assigned in the pooled analysis using random-effects analysis. A, Association with European League Against Rheumatism (EULAR) response at 6 months or less. B, Association with EULAR response at 6 months or more. C, Association with Assessment in AS International Working Group response. D, Association with clinical response in inflammatory bowel disease. AAB– indicates seronegative patients; AAB+, seropositive patients; ACT, Active Ulcerative Colitis Trial; ADA, adalimumab; IFX, infliximab; OR, odds ratio.

Graphic Jump Location

Five studies with infliximab, adalimumab, golimumab, abatacept, and rituximab reported the association of AABs with the American College of Rheumatology 20 response.14,28,39,42,45 Only one study45 with adalimumab showed a significant difference in American College of Rheumatology 20 response comparing seropositive and seronegative patients. The meta-analysis included 3 studies with an OR of 0.57 (95% CI, 0.25-1.28) and heterogeneity (I2 = 62.8%; P = .07). No factors accounting for heterogeneity were found, and the funnel plot did not show publication bias (Egger test P = .24).

Response in Spondyloarthropathies

Efficacy in spondyloarthropathies was evaluated using the criteria response of Assessment in the Ankylosing Spondylitis International Working Group (ASAS)81 (eTables 2-5 in the Supplement). Four studies reported the association of AABs with ASAS response in spondyloarthropathies.6568 Two studies included data on adalimumab and 2 reported results on infliximab. Individual studies suggested that seronegative patients presented a better ASAS response than did seropositive patients. Three studies6567 were included in this meta-analysis, with an OR of 0.28 (95% CI, 0.08-1.03) (Figure 1). The heterogeneity was I2 = 52.9% (P = .12). No factor was identified as a source of heterogeneity. The funnel plot did not show publication bias (Egger test P = .13).

Clinical Response in IBD

Data were extracted from 11 studies.4,30,49,53,74,75,77,78 All but one included studies with infliximab. A significantly better clinical response in seronegative patients than in seropositive patients was reported in most studies. Five studies49,53,75,78 were included in the meta-analysis, resulting in an OR of 0.53 (95% CI, 0.16-1.72) with heterogeneity of I2 = 74.1% (P = .004) (Figure 1). The meta-regression identified quality of data and design, and level of evidence of studies as sources of heterogeneity. No asymmetries were found in funnel-plot analysis (Egger test P = .87). Meta-analysis was also performed after removing the retrospective studies,75,78 and no significant result with absence of heterogeneity was found (OR, 1.08; 95% CI, 0.78-1.50; I2 = 0.0%; P = .50).

Data on remission in IBD were reported in 3 studies; 2 studies with infliximab27,30 and one with certolizumab pegol.52 In one with infliximab and another with certolizumab, no seropositive patients achieved remission.30,52 The meta-analysis with these 3 studies showed a relative risk of 0.27 (95% CI, 0.04-1.80) with a heterogeneity of I2 = 63.4% (P = .06). The age and sex of patients, length of follow-up, design of studies, and quality of data were identified as sources of heterogeneity. No asymmetries were found in funnel-plot analysis (Egger test P = .25).

Loss of Response in RA, Psoriasis, and IBD

Loss of response was reported in 4 studies44,57,59,75 with anti-TNF monoclonal antibodies. Seropositive patients presented numerically higher rates of loss of response than did seronegative patients. Meta-analysis showed an OR of 3.0 (95% CI, 0.99-9.09) for loss of response for seropositive patients, with I2 = 31.8% (P = .22). No asymmetries were found in funnel-plot analysis (Egger test P = .90).

Association of AABs With Safety

Significantly higher concentrations of AABs in patients with infusion reaction were reported in 2 observational studies.4,62 Seventeen studies reported data on serologic status of AABs (positive/negative) and risk of hypersensitivity reactions.4,8,25,26,3033,43,48,49,53,56,57,62,6668,75 Seropositive patients presented more hypersensitivity reactions than did seronegative patients treated with anti-TNF monoclonal antibodies irrespective of the diagnosis. One study43 with rituximab in patients with RA showed similar results. Meta-analysis was performed grouping patients treated with anti-TNF monoclonal antibodies for RA, IBD, and spondyloarthropathies (Figure 2).8,25,26,3033,48,49,53,56,57,6668,75 The resulting OR was 3.97 (95% CI, 2.36-6.67), with I2 = 62.5% (P < .001). The length of follow-up, prior use of TNF inhibitors, quality of data and design, and level of evidence of studies were identified as possible sources of heterogeneity in meta-regression. Analysis stratified by these factors was conducted. Studies with lower quality of data (≤0.60) presented nonsignificant results (OR, 6.97; 95% CI, 0.97-50.35; I2 = 62.2%). However, studies of moderate (0.61-0.79) or high (≥0.80) quality reported significant ORs of 3.97 (95% CI, 2.36-6.67) and 1.96 (95% CI, 1.36-2.84), with I2 = 0.0% and 14.2%, respectively. No publication bias was shown in funnel-plot analysis (Egger test P = .23).

Place holder to copy figure label and caption
Figure 2.
Meta-analysis of Association of Antibodies Against Biological Therapies (AABs) With Hypersensitivity Reactions

Size of the data marker corresponds to the relative weight assigned in the pooled analysis using random-effects analysis. AAB– indicates seronegative patients; AAB+, seropositive patients; ACT, Active Ulcerative Colitis Trial; OBS, observational study; OR, odds ratio.

Graphic Jump Location

Three studies5,57,62 reported data on discontinuation of treatment for all reasons in patients with RA. Data suggested that seropositive patients discontinued treatment more frequently than did seronegative patients. In meta-analysis, the OR for discontinuation of treatment in seropositive patients was 3.53 (95% CI, 1.60-7.82), with I2 = 34.5% (P = .22). No publication bias was found in funnel-plot analysis (Egger test P = .95).

Concomitant Treatment and Development of AABs

Thirty studies analyzed the use of concomitant treatment and development of AABs. These studies suggested that patients who received concomitant anti-TNF monoclonal antibodies and nonbiological disease-modifying antirheumatic drugs experienced less immunogenicity than did patients who received only anti-TNF monoclonal antibodies. One study13 reported no significant difference in the rate of seropositivity comparing patients receiving abatacept and concomitant disease-modifying antirheumatic drugs and patients who received abatacept monotherapy. Eighteen studies on patients with different diseases receiving different anti-TNF monoclonal antibodies were included in the meta-analysis (Figure 3).4,27,30,32,40,51,5355,73,75,77,78 The resulting OR was 0.32 (95% CI, 0.25-0.42) without heterogeneity (I2 = 0.0%, P = .71). Funnel-plot analysis did not show risk of publication bias (Egger test P = .08).

Place holder to copy figure label and caption
Figure 3.
Meta-analysis of Concomitant Treatment Influence in Development of Antibodies Against Biological Therapies

Size of the data marker corresponds to the relative weight assigned in the pooled analysis using random-effects analysis. ACT indicates Active Ulcerative Colitis Trial; ADA, adalimumab; CTZ, certolizumab; INF, infliximab; OR, odds ratio.

Graphic Jump Location

The specific effect of different drugs in AABs immunogenicity was also investigated. In observational studies7 in IBD, patients who received azathioprine combined with anti-TNF monoclonal antibodies developed fewer AABs than did patients with anti-TNF monoclonal antibody monotherapy. Meta-analysis was not performed because of insufficient data. In the meta-analysis of the influence of concomitant methotrexate in AABs development, 13 studies7,29,3436,38,39,41,57,58,62,65 were included. The resulting OR was 0.31 (95% CI, 0.18-0.54), with an I2 of 44.3% (P = .04). The diagnosis of the disease was reported as a possible factor of heterogeneity in meta-regression. Stratified analysis was conducted after removing one study41 in patients with juvenile idiopathic arthritis and merging psoriasis/psoriatic arthritis, IBD, and ankylosing spondylitis as spondyloarthropathies. In patients with RA, the resulting OR for the presence of AABs in combined therapy was 0.15 (95% CI, 0.06-0.35), with I2 = 10.6% (P = .35). In patients with spondyloarthropathy, OR was 0.52 (95% CI, 0.28-0.95), with I2 of 33.3% (P = .12). The funnel plot did not show risk of publication bias (Egger test P = .50).

Four studies32,53,58 reported the effect of concomitant use of oral corticosteroids and AABs. No significant differences were found comparing monotherapy with combined therapy. Meta-analysis of these 4 studies was performed with a resulting OR of 0.73 (95% CI, 0.43-1.17) without heterogeneity (I2 = 0.0%; P = .41). Funnel-plot analysis did not show risk of publication bias (Egger test P = .455).

Association of AABs With the Concentration of Drug

Nine studies5,7,8,37,58,64,66,76 analyzed the association of AABs with concentrations of infliximab, adalimumab, and golimumab in patients with RA, spondyloarthropathies, and IBD. Drug concentrations were lower in patients with higher titers of AABs, with a significant difference in most studies. Meta-analysis was not performed because of insufficient analogous comparisons.

In our review, we investigated the association of AABs with the efficacy and safety of biological drugs, as well as the role of concomitant therapy in the development of these antibodies. Main limitations of the study were the diversity in methods of determination of AABs and inconsistency in the time of antibody investigation and at assessing response. Other weaknesses were related to the variance of the design of studies included in the analysis (clinical trials as well as prospective and retrospective observational studies). To minimize this issue, our analysis of heterogeneity included not only quality of data but design and level of evidence of the studies. For completeness, diagnosis of disease as a putative heterogeneity factor was included in the meta-regression. Although OR is not the best estimate of association, we used it because OR was the most frequently provided measure in the different studies. Finally, this review focused mainly on the immunogenicity of anti-TNF monoclonal antibodies (infliximab and adalimumab) that have the highest rate of immunogenicity among biologic agents; therefore, conclusions may not be extended to other drugs because of the absence of information.

One of the benefits of meta-analysis is to extend conclusions beyond the populations that are included in a single study. However, meta-analysis can be limited by sampling bias, inadequate data, and biased outcome interpretation.

There is some disagreement on restriction of the analysis to randomized clinical trials. However, observational studies often represent the best available evidence. Observational studies are thought to overestimate treatment or exposure effects. Nevertheless, meta-analyses of observational studies continue to be valuable and common in assessing efficacy and effectiveness, and they are being published in increasing numbers.82

Heterogeneity may help to identify factors that influence the results of the outcomes that were not observable in individual trials.83,84 Our statistics included analysis of heterogeneity, risk of bias, and quality of data with stringent predefined criteria. Sensitivity analysis was performed by stratification of meta-analyses by variables causing heterogeneity. That was the case in the analysis of association of AABs with hypersensitivity reactions or in the analysis of influence of methotrexate in the development of AABs. Risk of publication bias was predefined as a significant result in the Egger test, and this occurred in the meta-analysis of the EULAR response between month 6 and month 12. Finally, the quality of data was more than 70% in 37 studies (60%).

It has been reported10 that AABs produce a decrease in drug concentration and a parallel reduction in efficacy. This could be the result of clearance of free drug by immune-complex formation. Herein, the greater response was greater in seronegative than in seropositive patients regardless of the type of anti-TNF monoclonal antibodies or type of disease. In contrast, analysis of the association of AABs with efficacy produced highly variable results. This could have several explanations. First, studies on different anti-TNF monoclonal antibodies were included in the meta-analysis. Dissimilar immunogenicity of chimeric and human monoclonal antibodies has been reported.85 However, the type of the anti-TNF monoclonal antibody was taken into account in the meta-regression and type was not identified as a heterogeneity factor. Second, different immunogenicity with different prevalence in AABs formation in diseases included in this review has been documented.86 In agreement, the association of AABs with efficacy was relevant in RA but not in spondyloarthropathies or IBD. In RA, the disease activity score reflects absolute values. It is used to determine and evaluate the status and course of disease activity in individual patients.87,88 The EULAR criteria are based on a significant change in disease activity score in relationship to the level of disease activity attained, whereas the American College of Rheumatology criteria are based only on change and do not consider the actual disease activity at the end point.79 Of relevance in clinical practice, the disease activity score at the time of evaluation correlates best with the decision to change medication therapy.89 Thus, our results concerning the effect of AABs on the EULAR response could be of clinical relevance. These results should be interpreted with caution because of the presence of publication bias and heterogeneity. The presence of AABs did not have a detectable effect on efficacy in patients with IBD. This may be the result of variability in the definition of response. Nonetheless, difference in the immunogenicity profile of IMID as discussed above could account for the result. The results of the effect of concomitant medication on the clinical response support the impact of the difference in the immunogenicity profile. Meta-regression to identify factors affecting heterogeneity showed that diagnosis was the cause as confirmed by the stratified analysis. On the whole, discontinuation of the biologic agent for all reasons reflecting effectiveness was affected by the presence of AABs.

Meta-analysis of the association of AABs with safety showed higher risk of hypersensitivity reactions in seropositive than in seronegative patients, yet there was a high level of heterogeneity. Interestingly, one of the factors accounting for the heterogeneity was prior use of TNF inhibitors. However, the stratified analysis did not reveal significant association with prior use of TNF antagonists. A previous article90 reported that development of antibodies against infliximab do not affect a patient’s response to adalimumab.

Biologic agent monotherapy is commonly used in clinical practice. A survey91 of prescribing RA practices found that 28% to 30% of patients with newly diagnosed RA received a biologic agent as monotherapy. Several trials suggest that TNF inhibitors may need to be given in conjunction with methotrexate to improve the clinical efficacy in patients who do not respond to methotrexate therapy.92 In RA, the presence of antibodies against anti-TNF monoclonal antibodies produces significantly worse clinical response and higher risk of discontinuation of treatment and development of hypersensitivity reactions. The use of combined therapy of anti-TNF monoclonal antibodies with disease-modifying antirheumatic drugs reduces the formation of AABs and these risks. Thus, monotherapy with anti-TNF monoclonal antibodies may not be suitable for treatment of RA. Information regarding other biologic agents and IMID is limited.

Accepted for Publication: March 24, 2013.

Corresponding Author: Jose Ramon Maneiro, MD, Rheumatology Department, Complejo Hospitalario Universitario de Santiago de Compostela, C/Choupana s/n, 15701 Santiago de Compostela, Spain (joseramon.maneiro.fernandez@sergas.es).

Published Online: June 24, 2013. doi:10.1001/jamainternmed.2013.7430.

Author Contributions: All authors gave final approval of the version to be published.

Study concept and design: All authors.

Acquisition of data: Maneiro and Salgado.

Analysis and interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Gomez-Reino.

Statistical analysis: Maneiro and Salgado.

Obtained funding: Gomez-Reino.

Study supervision: Gomez-Reino.

Conflict of Interest Disclosures: Drs Maneiro and Salgado have received grants from UCB Pharma. Dr Gomez-Reino is a member of the advisory boards of BMS, Pfizer, Roche, Schering-Plough, and UCB SA; has received lecture fees from BMS, Roche, Schering-Plough, and Wyeth; and has received research grants from Roche and Schering-Plough.

Funding/Support: The study was supported by an unrestricted grant from UCB Pharma, Spain.

Role of the Sponsor: The funding sources had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Baraliakos  X, Listing  J, Fritz  C,  et al.  Persistent clinical efficacy and safety of infliximab in ankylosing spondylitis after 8 years—early clinical response predicts long-term outcome. Rheumatology (Oxford). 2011;50(9):1690-1699.
PubMed   |  Link to Article
Perrier  C, Rutgeerts  P.  Cytokine blockade in inflammatory bowel diseases. Immunotherapy. 2011;3(11):1341-1352.
PubMed   |  Link to Article
Scott  DL.  Biologics-based therapy for the treatment of rheumatoid arthritis. Clin Pharmacol Ther. 2012;91(1):30-43.
PubMed   |  Link to Article
Baert  F, Noman  M, Vermeire  S,  et al.  Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348(7):601-608.
PubMed   |  Link to Article
Bartelds  GM, Krieckaert  CL, Nurmohamed  MT,  et al.  Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305(14):1460-1468.
PubMed   |  Link to Article
Bendtzen  K, Geborek  P, Svenson  M, Larsson  L, Kapetanovic  MC, Saxne  T.  Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor α inhibitor infliximab. Arthritis Rheum. 2006;54(12):3782-3789.
PubMed   |  Link to Article
Vermeire  S, Noman  M, Van Assche  G, Baert  F, D’Haens  G, Rutgeerts  P.  Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut. 2007;56(9):1226-1231.
PubMed   |  Link to Article
Wolbink  GJ, Vis  M, Lems  W,  et al.  Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54(3):711-715.
PubMed   |  Link to Article
Anderson  PJ.  Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. Semin Arthritis Rheum. 2005;34(5)(suppl 1):19-22.
PubMed   |  Link to Article
van der Laken  CJ, Voskuyl  AE, Roos  JC,  et al.  Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis. Ann Rheum Dis. 2007;66(2):253-256.
PubMed   |  Link to Article
Thurlings  RM, Teng  O, Vos  K,  et al.  Clinical response, pharmacokinetics, development of human anti-chimaeric antibodies, and synovial tissue response to rituximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis. 2010;69(2):409-412.
PubMed   |  Link to Article
Stubenrauch  K, Wessels  U, Birnboeck  H, Ramirez  F, Jahreis  A, Schleypen  J.  Subset analysis of patients experiencing clinical events of a potentially immunogenic nature in the pivotal clinical trials of tocilizumab for rheumatoid arthritis: evaluation of an antidrug antibody ELISA using clinical adverse event–driven immunogenicity testing. Clin Ther. 2010;32(9):1597-1609.
PubMed   |  Link to Article
Haggerty  HG, Abbott  MA, Reilly  TP,  et al.  Evaluation of immunogenicity of the T cell costimulation modulator abatacept in patients treated for rheumatoid arthritis. J Rheumatol. 2007;34(12):2365-2373.
PubMed
Weinblatt  ME, Genovese  MC, Schiff  MH,  et al.  Immunogenicity is low and transient with intravenous (IV) abatacept therapy: results from a large pooled analysis of 3985 patients (pts) with rheumatoid arthritis (RA) and up to 8 years' exposure [abstract]. Arthritis Rheum. 2011;63(suppl 10):2191.
de Vries  MK, van der Horst-Bruinsma  IE, Nurmohamed  MT,  et al.  Immunogenicity does not influence treatment with etanercept in patients with ankylosing spondylitis. Ann Rheum Dis. 2009;68(4):531-535.
PubMed   |  Link to Article
Dore  RK, Mathews  S, Schechtman  J,  et al.  The immunogenicity, safety, and efficacy of etanercept liquid administered once weekly in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2007;25(1):40-46.
PubMed
Yount  S, Sorensen  MV, Cella  D, Sengupta  N, Grober  J, Chartash  EK.  Adalimumab plus methotrexate or standard therapy is more effective than methotrexate or standard therapies alone in the treatment of fatigue in patients with active, inadequately treated rheumatoid arthritis. Clin Exp Rheumatol. 2007;25(6):838-846.
PubMed
Liberati  A, Altman  DG, Tetzlaff  J,  et al.  The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. doi:10.1371/journal.pmed.1000100.
PubMed   |  Link to Article
Hayden  JA, Côté  P, Bombardier  C.  Evaluation of the quality of prognosis studies in systematic reviews. Ann Intern Med. 2006;144(6):427-437.
PubMed   |  Link to Article
OCEBM levels of evidence system. CEBM: Centre for Evidence-Based Medicine website. http://www.cebm.net/index.aspx?o=5653. Accessed October 1, 2012.
DerSimonian  R, Laird  N.  Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177-188.
PubMed   |  Link to Article
Egger  M, Davey Smith  G, Schneider  M, Minder  C.  Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-634.
PubMed   |  Link to Article
Higgins  JP, Thompson  SG.  Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539-1558.
PubMed   |  Link to Article
Higgins  JP, Thompson  SG, Deeks  JJ, Altman  DG.  Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560.
PubMed   |  Link to Article
Asahina  A, Nakagawa  H, Etoh  T, Ohtsuki  M; Adalimumab M04-688 Study Group.  Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a phase II/III randomized controlled study. J Dermatol. 2010;37(4):299-310.
PubMed   |  Link to Article
Braun  J, Deodhar  A, Dijkmans  B,  et al; Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy Study Group.  Efficacy and safety of infliximab in patients with ankylosing spondylitis over a two-year period. Arthritis Rheum. 2008;59(9):1270-1278.
PubMed   |  Link to Article
Colombel  JF, Sandborn  WJ, Reinisch  W,  et al; SONIC Study Group.  Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383-1395.
PubMed   |  Link to Article
Emery  P, Fleischmann  R, Filipowicz-Sosnowska  A,  et al; DANCER Study Group.  The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006;54(5):1390-1400.
PubMed   |  Link to Article
Emery  P, Fleischmann  RM, Moreland  LW,  et al.  Golimumab, a human anti–tumor necrosis factor α monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four–week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum. 2009;60(8):2272-2283.
PubMed   |  Link to Article
Farrell  RJ, Alsahli  M, Jeen  YT, Falchuk  KR, Peppercorn  MA, Michetti  P.  Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology. 2003;124(4):917-924.
PubMed   |  Link to Article
Gottlieb  AB, Evans  R, Li  S,  et al.  Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2004;51(4):534-542.
PubMed   |  Link to Article
Hanauer  SB, Feagan  BG, Lichtenstein  GR,  et al; ACCENT I Study Group.  Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359(9317):1541-1549.
PubMed   |  Link to Article
Hyams  J, Crandall  W, Kugathasan  S,  et al; REACH Study Group.  Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007;132(3):863-873, quiz 1165-1166.
PubMed   |  Link to Article
Inman  RD, Davis  JC  Jr, Heijde  Dv,  et al.  Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum. 2008;58(11):3402-3412.
PubMed   |  Link to Article
Kavanaugh  A, Krueger  GG, Beutler  A,  et al; IMPACT 2 Study Group.  Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial. Ann Rheum Dis. 2007;66(4):498-505.
PubMed   |  Link to Article
Kavanaugh  A, McInnes  I, Mease  P,  et al.  Golimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: twenty-four–week efficacy and safety results of a randomized, placebo-controlled study. Arthritis Rheum. 2009;60(4):976-986.
PubMed   |  Link to Article
Kay  J, Matteson  EL, Dasgupta  B,  et al.  Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum. 2008;58(4):964-975.
PubMed   |  Link to Article
Keystone  EC, Genovese  MC, Klareskog  L,  et al; GO-FORWARD Study.  Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis. 2009;68(6):789-796.
PubMed   |  Link to Article
Kremer  J, Ritchlin  C, Mendelsohn  A,  et al.  Golimumab, a new human anti–tumor necrosis factor α antibody, administered intravenously in patients with active rheumatoid arthritis: forty-eight–week efficacy and safety results of a phase III randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2010;62(4):917-928.
PubMed   |  Link to Article
Lichtenstein  GR, Diamond  RH, Wagner  CL,  et al.  Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials. Aliment Pharmacol Ther. 2009;30(3):210-226.
PubMed   |  Link to Article
Lovell  DJ, Ruperto  N, Goodman  S,  et al; Pediatric Rheumatology Collaborative Study Group; Pediatric Rheumatology International Trials Organisation.  Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008;359(8):810-820.
PubMed   |  Link to Article
Maini  RN, Breedveld  FC, Kalden  JR,  et al; Anti–Tumor Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy Study Group.  Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum. 2004;50(4):1051-1065.
PubMed   |  Link to Article
Mease  PJ, Cohen  S, Gaylis  NB,  et al.  Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE trial. J Rheumatol. 2010;37(5):917-927.
PubMed   |  Link to Article
Menter  A, Tyring  SK, Gordon  K,  et al.  Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial. J Am Acad Dermatol. 2008;58(1):106-115.
PubMed   |  Link to Article
Miyasaka  N; CHANGE Study Investigators.  Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study. Mod Rheumatol. 2008;18(3):252-262.
PubMed   |  Link to Article
Papp  K, Crowley  J, Ortonne  JP,  et al.  Adalimumab for moderate to severe chronic plaque psoriasis: efficacy and safety of retreatment and disease recurrence following withdrawal from therapy. Br J Dermatol. 2011;164(2):434-441.
PubMed   |  Link to Article
Ruperto  N, Lovell  DJ, Cuttica  R,  et al; Paediatric Rheumatology International Trials Organisation; Pediatric Rheumatology Collaborative Study Group.  A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 2007;56(9):3096-3106.
PubMed   |  Link to Article
Ruperto  N, Lovell  DJ, Cuttica  R,  et al; Paediatric Rheumatology International Trials Organization (PRINTO); Pediatric Rheumatology Collaborative Study Group (PRCSG).  Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis: findings from an open-label treatment extension. Ann Rheum Dis. 2010;69(4):718-722.
PubMed   |  Link to Article
Rutgeerts  P, Sandborn  WJ, Feagan  BG,  et al.  Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353(23):2462-2476.
PubMed   |  Link to Article
Sandborn  WJ, Feagan  BG, Stoinov  S,  et al; PRECISE 1 Study Investigators.  Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med. 2007;357(3):228-238.
PubMed   |  Link to Article
Sandborn  WJ, Hanauer  SB, Rutgeerts  P,  et al.  Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut. 2007;56(9):1232-1239.
PubMed   |  Link to Article
Sandborn  WJ, Schreiber  S, Feagan  BG,  et al.  Certolizumab pegol for active Crohn’s disease: a placebo-controlled, randomized trial. Clin Gastroenterol Hepatol.2011;9(8):670-678.e3. doi:10.1016/j.cgh.2011.04.031.
PubMed   |  Link to Article
Sands  BE, Anderson  FH, Bernstein  CN,  et al.  Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350(9):876-885.
PubMed   |  Link to Article
Schreiber  S, Khaliq-Kareemi  M, Lawrance  IC,  et al; PRECISE 2 Study Investigators.  Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med. 2007;357(3):239-250.
PubMed   |  Link to Article
van den Bemt  BJ, den Broeder  AA, Wolbink  GJ,  et al.  Anti-infliximab antibodies are already detectable in most patients with rheumatoid arthritis halfway through an infusion cycle: an open-label pharmacokinetic cohort study. BMC Musculoskelet Disord. 2011;12:12.
PubMed   |  Link to Article
Abe  T, Takeuchi  T, Miyasaka  N,  et al.  A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37-44.
PubMed
Bender  NK, Heilig  CE, Dröll  B, Wohlgemuth  J, Armbruster  F-P, Heilig  B.  Immunogenicity, efficacy and adverse events of adalimumab in RA patients. Rheumatol Int. 2007;27(3):269-274.
PubMed   |  Link to Article
Ducourau  E, Mulleman  D, Paintaud  G,  et al.  Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases. Arthritis Res Ther. 2011;13(3):R105. doi:10.1186/ar3386.
PubMed   |  Link to Article
Finckh  A, Dudler  J, Wermelinger  F,  et al; Physicians of SCQM.  Influence of anti-infliximab antibodies and residual infliximab concentrations on the occurrence of acquired drug resistance to infliximab in rheumatoid arthritis patients. Joint Bone Spine. 2010;77(4):313-318.
PubMed   |  Link to Article
Geborek  P, Saxne  T, Kapetanovic  MC, Larsson  L, Svensen  M, Bendtzen  K.  Serum TNF-binding capacity and drug antibody development are useful for monitoring rheumatoid arthritis patients treated with infliximab in clinical practice [abstract]. Ann Rheum Dis. 2005;64(suppl III):414.
Klareskog  L, Wajdula  J, Baker  P, Fatenejad  S.  Low and transient auto- and anti-etanercept antibody formation has no measurable impact on clinical outcomes during 5 years of etanercept (Enbrel) treatment in patients with rheumatoid arthritis [abstract]. Ann Rheum Dis.2006;65(suppl I):325.
Link to Article
Pascual-Salcedo  D, Plasencia  C, Ramiro  S,  et al.  Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. Rheumatology (Oxford). 2011;50(8):1445-1452.
PubMed   |  Link to Article
Radstake  TR, Svenson  M, Eijsbouts  AM,  et al.  Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis. 2009;68(11):1739-1745.
PubMed   |  Link to Article
Arends  S, Lebbink  HR, Spoorenberg  A,  et al.  The formation of autoantibodies and antibodies to TNF-α blocking agents in relation to clinical response in patients with ankylosing spondylitis. Clin Exp Rheumatol. 2010;28(5):661-668.
PubMed
Davis  J, Peng  JZ, Noertersheuser  PA, Paulson  S, Van der Heijde  D, Schiff  D.  Pharmacokinetics of adalimumab in patients with active ankylosing spondylitis (AS)—the Atlas trial [abstract]. Ann Rheum Dis. 2006;65(suppl II):537.
Link to Article
de Vries  MK, Wolbink  GJ, Stapel  SO,  et al.  Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formation. Ann Rheum Dis. 2007;66(9):1252-1254.
PubMed   |  Link to Article
de Vries  MK, Brouwer  E, van der Horst-Bruinsma  IE,  et al.  Decreased clinical response to adalimumab in ankylosing spondylitis is associated with antibody formation. Ann Rheum Dis. 2009;68(11):1787-1788.
PubMed   |  Link to Article
Plasencia  C, Pascual-Salcedo  D, Bonilla  MG,  et al.  Influence of immunogenicity on the efficacy of long-term treatment with infliximab in spondyloarthritis [abstract]. Arthritis Rheum. 2011;63(suppl 10):2636.
Adişen  E, Aral  A, Aybay  C, Gürer  MA.  Anti-infliximab antibody status and its relation to clinical response in psoriatic patients: a pilot study. J Dermatol. 2010;37(8):708-713.
PubMed   |  Link to Article
Lecluse  LLA, Driessen  RJB, Spuls  PI,  et al.  Extent and clinical consequences of antibody formation against adalimumab in patients with plaque psoriasis. Arch Dermatol. 2010;146(2):127-132.
PubMed   |  Link to Article
Hoffmann  JH, Hartmann  M, Enk  AH, Hadaschik  EN.  Autoantibodies in psoriasis as predictors for loss of response and anti-infliximab antibody induction. Br J Dermatol. 2011;165(6):1355-1358.
PubMed   |  Link to Article
van Kuijk  AW, de Groot  M, Stapel  SO, Dijkmans  BA, Wolbink  GJ, Tak  PP.  Relationship between the clinical response to adalimumab treatment and serum levels of adalimumab and anti-adalimumab antibodies in patients with psoriatic arthritis. Ann Rheum Dis. 2010;69(3):624-625.
PubMed   |  Link to Article
Afif  W, Loftus  EV  Jr, Faubion  WA,  et al.  Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol. 2010;105(5):1133-1139.
PubMed   |  Link to Article
Ainsworth  MA, Bendtzen  K, Brynskov  J.  Tumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn’s disease. Am J Gastroenterol. 2008;103(4):944-948.
PubMed   |  Link to Article
Ben-Horin  S, Yavzori  M, Katz  L,  et al.  The immunogenic part of infliximab is the F(ab’)2, but measuring antibodies to the intact infliximab molecule is more clinically useful. Gut. 2011;60(1):41-48.
PubMed   |  Link to Article
Karmiris  K, Paintaud  G, Noman  M,  et al.  Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterology. 2009;137(5):1628-1640.
PubMed   |  Link to Article
Steenholdt  C, Bendtzen  K, Brynskov  J, Thomsen  OO, Ainsworth  MA.  Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn’s disease. Scand J Gastroenterol. 2011;46(3):310-318.
PubMed   |  Link to Article
West  RL, Zelinkova  Z, Wolbink  GJ, Kuipers  EJ, Stokkers  PCF, van der Woude  CJ.  Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn’s disease. Aliment Pharmacol Ther. 2008;28(9):1122-1126.
PubMed   |  Link to Article
Felson  DT, Anderson  JJ, Boers  M,  et al;  American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38(6):727-735.
PubMed   |  Link to Article
Fransen  J, van Riel  PL.  The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol. 2005;23(5)(suppl 39):S93-S99.
PubMed
Anderson  JJ, Baron  G, van der Heijde  D, Felson  DT, Dougados  M.  Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis Rheum. 2001;44(8):1876-1886.
PubMed   |  Link to Article
Stroup  DF, Berlin  JA, Morton  SC,  et al; Meta-analysis of Observational Studies in Epidemiology (MOOSE) group.  Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283(15):2008-2012.
PubMed   |  Link to Article
Dickersin  K, Min  YI, Meinert  CL.  Factors influencing publication of research results: follow-up of applications submitted to two institutional review boards. JAMA. 1992;267(3):374-378.
PubMed   |  Link to Article
Biggerstaff  BJ, Tweedie  RL.  Incorporating variability in estimates of heterogeneity in the random effects model in meta-analysis. Stat Med. 1997;16(7):753-768.
PubMed   |  Link to Article
Hwang  WY, Foote  J.  Immunogenicity of engineered antibodies. Methods. 2005;36(1):3-10.
PubMed   |  Link to Article
Emi Aikawa  N, de Carvalho  JF, Artur Almeida Silva  C, Bonfá  E.  Immunogenicity of anti–TNF-α agents in autoimmune diseases. Clin Rev Allergy Immunol. 2010;38(2-3):82-89.
PubMed   |  Link to Article
Fransen  J, Stucki  G, van Riel  P.  The merits of monitoring: should we follow all our rheumatoid arthritis patients in daily practice? Rheumatology (Oxford). 2002;41(6):601-604.
PubMed   |  Link to Article
Wolfe  F, Cush  JJ, O’Dell  JR,  et al.  Consensus recommendations for the assessment and treatment of rheumatoid arthritis. J Rheumatol. 2001;28(6):1423-1430.
PubMed
Vander Cruyssen  B, Van Looy  S, Wyns  B,  et al.  DAS28 best reflects the physician’s clinical judgment of response to infliximab therapy in rheumatoid arthritis patients: validation of the DAS28 score in patients under infliximab treatment. Arthritis Res Ther. 2005;7(5):R1063-R1071.
PubMed   |  Link to Article
van der Bijl  AE, Breedveld  FC, Antoni  CE,  et al.  An open-label pilot study of the effectiveness of adalimumab in patients with rheumatoid arthritis and previous infliximab treatment: relationship to reasons for failure and anti-infliximab antibody status. Clin Rheumatol. 2008;27(8):1021-1028.
PubMed   |  Link to Article
Yazici  Y, Shi  N, John  A.  Utilization of biologic agents in rheumatoid arthritis in the United States: analysis of prescribing patterns in 16,752 newly diagnosed patients and patients new to biologic therapy. Bull NYU Hosp Jt Dis. 2008;66(2):77-85.
PubMed
Gómez-Reino  J.  Biologic monotherapy as initial treatment in patients with early rheumatoid arthritis. Rheumatology (Oxford). 2012;51(suppl 5):v31-v37.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Meta-analysis of Association of Antibodies Against Biological Therapies (AABs) With Efficacy

Size of the data marker corresponds to the relative weight assigned in the pooled analysis using random-effects analysis. A, Association with European League Against Rheumatism (EULAR) response at 6 months or less. B, Association with EULAR response at 6 months or more. C, Association with Assessment in AS International Working Group response. D, Association with clinical response in inflammatory bowel disease. AAB– indicates seronegative patients; AAB+, seropositive patients; ACT, Active Ulcerative Colitis Trial; ADA, adalimumab; IFX, infliximab; OR, odds ratio.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Meta-analysis of Association of Antibodies Against Biological Therapies (AABs) With Hypersensitivity Reactions

Size of the data marker corresponds to the relative weight assigned in the pooled analysis using random-effects analysis. AAB– indicates seronegative patients; AAB+, seropositive patients; ACT, Active Ulcerative Colitis Trial; OBS, observational study; OR, odds ratio.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Meta-analysis of Concomitant Treatment Influence in Development of Antibodies Against Biological Therapies

Size of the data marker corresponds to the relative weight assigned in the pooled analysis using random-effects analysis. ACT indicates Active Ulcerative Colitis Trial; ADA, adalimumab; CTZ, certolizumab; INF, infliximab; OR, odds ratio.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Evidence and Characteristics of Studies Included in the Review

References

Baraliakos  X, Listing  J, Fritz  C,  et al.  Persistent clinical efficacy and safety of infliximab in ankylosing spondylitis after 8 years—early clinical response predicts long-term outcome. Rheumatology (Oxford). 2011;50(9):1690-1699.
PubMed   |  Link to Article
Perrier  C, Rutgeerts  P.  Cytokine blockade in inflammatory bowel diseases. Immunotherapy. 2011;3(11):1341-1352.
PubMed   |  Link to Article
Scott  DL.  Biologics-based therapy for the treatment of rheumatoid arthritis. Clin Pharmacol Ther. 2012;91(1):30-43.
PubMed   |  Link to Article
Baert  F, Noman  M, Vermeire  S,  et al.  Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348(7):601-608.
PubMed   |  Link to Article
Bartelds  GM, Krieckaert  CL, Nurmohamed  MT,  et al.  Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305(14):1460-1468.
PubMed   |  Link to Article
Bendtzen  K, Geborek  P, Svenson  M, Larsson  L, Kapetanovic  MC, Saxne  T.  Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor α inhibitor infliximab. Arthritis Rheum. 2006;54(12):3782-3789.
PubMed   |  Link to Article
Vermeire  S, Noman  M, Van Assche  G, Baert  F, D’Haens  G, Rutgeerts  P.  Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut. 2007;56(9):1226-1231.
PubMed   |  Link to Article
Wolbink  GJ, Vis  M, Lems  W,  et al.  Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54(3):711-715.
PubMed   |  Link to Article
Anderson  PJ.  Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. Semin Arthritis Rheum. 2005;34(5)(suppl 1):19-22.
PubMed   |  Link to Article
van der Laken  CJ, Voskuyl  AE, Roos  JC,  et al.  Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis. Ann Rheum Dis. 2007;66(2):253-256.
PubMed   |  Link to Article
Thurlings  RM, Teng  O, Vos  K,  et al.  Clinical response, pharmacokinetics, development of human anti-chimaeric antibodies, and synovial tissue response to rituximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis. 2010;69(2):409-412.
PubMed   |  Link to Article
Stubenrauch  K, Wessels  U, Birnboeck  H, Ramirez  F, Jahreis  A, Schleypen  J.  Subset analysis of patients experiencing clinical events of a potentially immunogenic nature in the pivotal clinical trials of tocilizumab for rheumatoid arthritis: evaluation of an antidrug antibody ELISA using clinical adverse event–driven immunogenicity testing. Clin Ther. 2010;32(9):1597-1609.
PubMed   |  Link to Article
Haggerty  HG, Abbott  MA, Reilly  TP,  et al.  Evaluation of immunogenicity of the T cell costimulation modulator abatacept in patients treated for rheumatoid arthritis. J Rheumatol. 2007;34(12):2365-2373.
PubMed
Weinblatt  ME, Genovese  MC, Schiff  MH,  et al.  Immunogenicity is low and transient with intravenous (IV) abatacept therapy: results from a large pooled analysis of 3985 patients (pts) with rheumatoid arthritis (RA) and up to 8 years' exposure [abstract]. Arthritis Rheum. 2011;63(suppl 10):2191.
de Vries  MK, van der Horst-Bruinsma  IE, Nurmohamed  MT,  et al.  Immunogenicity does not influence treatment with etanercept in patients with ankylosing spondylitis. Ann Rheum Dis. 2009;68(4):531-535.
PubMed   |  Link to Article
Dore  RK, Mathews  S, Schechtman  J,  et al.  The immunogenicity, safety, and efficacy of etanercept liquid administered once weekly in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2007;25(1):40-46.
PubMed
Yount  S, Sorensen  MV, Cella  D, Sengupta  N, Grober  J, Chartash  EK.  Adalimumab plus methotrexate or standard therapy is more effective than methotrexate or standard therapies alone in the treatment of fatigue in patients with active, inadequately treated rheumatoid arthritis. Clin Exp Rheumatol. 2007;25(6):838-846.
PubMed
Liberati  A, Altman  DG, Tetzlaff  J,  et al.  The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. doi:10.1371/journal.pmed.1000100.
PubMed   |  Link to Article
Hayden  JA, Côté  P, Bombardier  C.  Evaluation of the quality of prognosis studies in systematic reviews. Ann Intern Med. 2006;144(6):427-437.
PubMed   |  Link to Article
OCEBM levels of evidence system. CEBM: Centre for Evidence-Based Medicine website. http://www.cebm.net/index.aspx?o=5653. Accessed October 1, 2012.
DerSimonian  R, Laird  N.  Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177-188.
PubMed   |  Link to Article
Egger  M, Davey Smith  G, Schneider  M, Minder  C.  Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-634.
PubMed   |  Link to Article
Higgins  JP, Thompson  SG.  Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539-1558.
PubMed   |  Link to Article
Higgins  JP, Thompson  SG, Deeks  JJ, Altman  DG.  Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560.
PubMed   |  Link to Article
Asahina  A, Nakagawa  H, Etoh  T, Ohtsuki  M; Adalimumab M04-688 Study Group.  Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a phase II/III randomized controlled study. J Dermatol. 2010;37(4):299-310.
PubMed   |  Link to Article
Braun  J, Deodhar  A, Dijkmans  B,  et al; Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy Study Group.  Efficacy and safety of infliximab in patients with ankylosing spondylitis over a two-year period. Arthritis Rheum. 2008;59(9):1270-1278.
PubMed   |  Link to Article
Colombel  JF, Sandborn  WJ, Reinisch  W,  et al; SONIC Study Group.  Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383-1395.
PubMed   |  Link to Article
Emery  P, Fleischmann  R, Filipowicz-Sosnowska  A,  et al; DANCER Study Group.  The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006;54(5):1390-1400.
PubMed   |  Link to Article
Emery  P, Fleischmann  RM, Moreland  LW,  et al.  Golimumab, a human anti–tumor necrosis factor α monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four–week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum. 2009;60(8):2272-2283.
PubMed   |  Link to Article
Farrell  RJ, Alsahli  M, Jeen  YT, Falchuk  KR, Peppercorn  MA, Michetti  P.  Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology. 2003;124(4):917-924.
PubMed   |  Link to Article
Gottlieb  AB, Evans  R, Li  S,  et al.  Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2004;51(4):534-542.
PubMed   |  Link to Article
Hanauer  SB, Feagan  BG, Lichtenstein  GR,  et al; ACCENT I Study Group.  Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359(9317):1541-1549.
PubMed   |  Link to Article
Hyams  J, Crandall  W, Kugathasan  S,  et al; REACH Study Group.  Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007;132(3):863-873, quiz 1165-1166.
PubMed   |  Link to Article
Inman  RD, Davis  JC  Jr, Heijde  Dv,  et al.  Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum. 2008;58(11):3402-3412.
PubMed   |  Link to Article
Kavanaugh  A, Krueger  GG, Beutler  A,  et al; IMPACT 2 Study Group.  Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial. Ann Rheum Dis. 2007;66(4):498-505.
PubMed   |  Link to Article
Kavanaugh  A, McInnes  I, Mease  P,  et al.  Golimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: twenty-four–week efficacy and safety results of a randomized, placebo-controlled study. Arthritis Rheum. 2009;60(4):976-986.
PubMed   |  Link to Article
Kay  J, Matteson  EL, Dasgupta  B,  et al.  Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum. 2008;58(4):964-975.
PubMed   |  Link to Article
Keystone  EC, Genovese  MC, Klareskog  L,  et al; GO-FORWARD Study.  Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis. 2009;68(6):789-796.
PubMed   |  Link to Article
Kremer  J, Ritchlin  C, Mendelsohn  A,  et al.  Golimumab, a new human anti–tumor necrosis factor α antibody, administered intravenously in patients with active rheumatoid arthritis: forty-eight–week efficacy and safety results of a phase III randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2010;62(4):917-928.
PubMed   |  Link to Article
Lichtenstein  GR, Diamond  RH, Wagner  CL,  et al.  Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials. Aliment Pharmacol Ther. 2009;30(3):210-226.
PubMed   |  Link to Article
Lovell  DJ, Ruperto  N, Goodman  S,  et al; Pediatric Rheumatology Collaborative Study Group; Pediatric Rheumatology International Trials Organisation.  Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008;359(8):810-820.
PubMed   |  Link to Article
Maini  RN, Breedveld  FC, Kalden  JR,  et al; Anti–Tumor Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy Study Group.  Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum. 2004;50(4):1051-1065.
PubMed   |  Link to Article
Mease  PJ, Cohen  S, Gaylis  NB,  et al.  Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE trial. J Rheumatol. 2010;37(5):917-927.
PubMed   |  Link to Article
Menter  A, Tyring  SK, Gordon  K,  et al.  Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial. J Am Acad Dermatol. 2008;58(1):106-115.
PubMed   |  Link to Article
Miyasaka  N; CHANGE Study Investigators.  Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study. Mod Rheumatol. 2008;18(3):252-262.
PubMed   |  Link to Article
Papp  K, Crowley  J, Ortonne  JP,  et al.  Adalimumab for moderate to severe chronic plaque psoriasis: efficacy and safety of retreatment and disease recurrence following withdrawal from therapy. Br J Dermatol. 2011;164(2):434-441.
PubMed   |  Link to Article
Ruperto  N, Lovell  DJ, Cuttica  R,  et al; Paediatric Rheumatology International Trials Organisation; Pediatric Rheumatology Collaborative Study Group.  A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 2007;56(9):3096-3106.
PubMed   |  Link to Article
Ruperto  N, Lovell  DJ, Cuttica  R,  et al; Paediatric Rheumatology International Trials Organization (PRINTO); Pediatric Rheumatology Collaborative Study Group (PRCSG).  Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis: findings from an open-label treatment extension. Ann Rheum Dis. 2010;69(4):718-722.
PubMed   |  Link to Article
Rutgeerts  P, Sandborn  WJ, Feagan  BG,  et al.  Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353(23):2462-2476.
PubMed   |  Link to Article
Sandborn  WJ, Feagan  BG, Stoinov  S,  et al; PRECISE 1 Study Investigators.  Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med. 2007;357(3):228-238.
PubMed   |  Link to Article
Sandborn  WJ, Hanauer  SB, Rutgeerts  P,  et al.  Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut. 2007;56(9):1232-1239.
PubMed   |  Link to Article
Sandborn  WJ, Schreiber  S, Feagan  BG,  et al.  Certolizumab pegol for active Crohn’s disease: a placebo-controlled, randomized trial. Clin Gastroenterol Hepatol.2011;9(8):670-678.e3. doi:10.1016/j.cgh.2011.04.031.
PubMed   |  Link to Article
Sands  BE, Anderson  FH, Bernstein  CN,  et al.  Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350(9):876-885.
PubMed   |  Link to Article
Schreiber  S, Khaliq-Kareemi  M, Lawrance  IC,  et al; PRECISE 2 Study Investigators.  Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med. 2007;357(3):239-250.
PubMed   |  Link to Article
van den Bemt  BJ, den Broeder  AA, Wolbink  GJ,  et al.  Anti-infliximab antibodies are already detectable in most patients with rheumatoid arthritis halfway through an infusion cycle: an open-label pharmacokinetic cohort study. BMC Musculoskelet Disord. 2011;12:12.
PubMed   |  Link to Article
Abe  T, Takeuchi  T, Miyasaka  N,  et al.  A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37-44.
PubMed
Bender  NK, Heilig  CE, Dröll  B, Wohlgemuth  J, Armbruster  F-P, Heilig  B.  Immunogenicity, efficacy and adverse events of adalimumab in RA patients. Rheumatol Int. 2007;27(3):269-274.
PubMed   |  Link to Article
Ducourau  E, Mulleman  D, Paintaud  G,  et al.  Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases. Arthritis Res Ther. 2011;13(3):R105. doi:10.1186/ar3386.
PubMed   |  Link to Article
Finckh  A, Dudler  J, Wermelinger  F,  et al; Physicians of SCQM.  Influence of anti-infliximab antibodies and residual infliximab concentrations on the occurrence of acquired drug resistance to infliximab in rheumatoid arthritis patients. Joint Bone Spine. 2010;77(4):313-318.
PubMed   |  Link to Article
Geborek  P, Saxne  T, Kapetanovic  MC, Larsson  L, Svensen  M, Bendtzen  K.  Serum TNF-binding capacity and drug antibody development are useful for monitoring rheumatoid arthritis patients treated with infliximab in clinical practice [abstract]. Ann Rheum Dis. 2005;64(suppl III):414.
Klareskog  L, Wajdula  J, Baker  P, Fatenejad  S.  Low and transient auto- and anti-etanercept antibody formation has no measurable impact on clinical outcomes during 5 years of etanercept (Enbrel) treatment in patients with rheumatoid arthritis [abstract]. Ann Rheum Dis.2006;65(suppl I):325.
Link to Article
Pascual-Salcedo  D, Plasencia  C, Ramiro  S,  et al.  Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. Rheumatology (Oxford). 2011;50(8):1445-1452.
PubMed   |  Link to Article
Radstake  TR, Svenson  M, Eijsbouts  AM,  et al.  Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis. 2009;68(11):1739-1745.
PubMed   |  Link to Article
Arends  S, Lebbink  HR, Spoorenberg  A,  et al.  The formation of autoantibodies and antibodies to TNF-α blocking agents in relation to clinical response in patients with ankylosing spondylitis. Clin Exp Rheumatol. 2010;28(5):661-668.
PubMed
Davis  J, Peng  JZ, Noertersheuser  PA, Paulson  S, Van der Heijde  D, Schiff  D.  Pharmacokinetics of adalimumab in patients with active ankylosing spondylitis (AS)—the Atlas trial [abstract]. Ann Rheum Dis. 2006;65(suppl II):537.
Link to Article
de Vries  MK, Wolbink  GJ, Stapel  SO,  et al.  Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formation. Ann Rheum Dis. 2007;66(9):1252-1254.
PubMed   |  Link to Article
de Vries  MK, Brouwer  E, van der Horst-Bruinsma  IE,  et al.  Decreased clinical response to adalimumab in ankylosing spondylitis is associated with antibody formation. Ann Rheum Dis. 2009;68(11):1787-1788.
PubMed   |  Link to Article
Plasencia  C, Pascual-Salcedo  D, Bonilla  MG,  et al.  Influence of immunogenicity on the efficacy of long-term treatment with infliximab in spondyloarthritis [abstract]. Arthritis Rheum. 2011;63(suppl 10):2636.
Adişen  E, Aral  A, Aybay  C, Gürer  MA.  Anti-infliximab antibody status and its relation to clinical response in psoriatic patients: a pilot study. J Dermatol. 2010;37(8):708-713.
PubMed   |  Link to Article
Lecluse  LLA, Driessen  RJB, Spuls  PI,  et al.  Extent and clinical consequences of antibody formation against adalimumab in patients with plaque psoriasis. Arch Dermatol. 2010;146(2):127-132.
PubMed   |  Link to Article
Hoffmann  JH, Hartmann  M, Enk  AH, Hadaschik  EN.  Autoantibodies in psoriasis as predictors for loss of response and anti-infliximab antibody induction. Br J Dermatol. 2011;165(6):1355-1358.
PubMed   |  Link to Article
van Kuijk  AW, de Groot  M, Stapel  SO, Dijkmans  BA, Wolbink  GJ, Tak  PP.  Relationship between the clinical response to adalimumab treatment and serum levels of adalimumab and anti-adalimumab antibodies in patients with psoriatic arthritis. Ann Rheum Dis. 2010;69(3):624-625.
PubMed   |  Link to Article
Afif  W, Loftus  EV  Jr, Faubion  WA,  et al.  Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol. 2010;105(5):1133-1139.
PubMed   |  Link to Article
Ainsworth  MA, Bendtzen  K, Brynskov  J.  Tumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn’s disease. Am J Gastroenterol. 2008;103(4):944-948.
PubMed   |  Link to Article
Ben-Horin  S, Yavzori  M, Katz  L,  et al.  The immunogenic part of infliximab is the F(ab’)2, but measuring antibodies to the intact infliximab molecule is more clinically useful. Gut. 2011;60(1):41-48.
PubMed   |  Link to Article
Karmiris  K, Paintaud  G, Noman  M,  et al.  Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterology. 2009;137(5):1628-1640.
PubMed   |  Link to Article
Steenholdt  C, Bendtzen  K, Brynskov  J, Thomsen  OO, Ainsworth  MA.  Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn’s disease. Scand J Gastroenterol. 2011;46(3):310-318.
PubMed   |  Link to Article
West  RL, Zelinkova  Z, Wolbink  GJ, Kuipers  EJ, Stokkers  PCF, van der Woude  CJ.  Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn’s disease. Aliment Pharmacol Ther. 2008;28(9):1122-1126.
PubMed   |  Link to Article
Felson  DT, Anderson  JJ, Boers  M,  et al;  American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38(6):727-735.
PubMed   |  Link to Article
Fransen  J, van Riel  PL.  The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol. 2005;23(5)(suppl 39):S93-S99.
PubMed
Anderson  JJ, Baron  G, van der Heijde  D, Felson  DT, Dougados  M.  Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis Rheum. 2001;44(8):1876-1886.
PubMed   |  Link to Article
Stroup  DF, Berlin  JA, Morton  SC,  et al; Meta-analysis of Observational Studies in Epidemiology (MOOSE) group.  Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283(15):2008-2012.
PubMed   |  Link to Article
Dickersin  K, Min  YI, Meinert  CL.  Factors influencing publication of research results: follow-up of applications submitted to two institutional review boards. JAMA. 1992;267(3):374-378.
PubMed   |  Link to Article
Biggerstaff  BJ, Tweedie  RL.  Incorporating variability in estimates of heterogeneity in the random effects model in meta-analysis. Stat Med. 1997;16(7):753-768.
PubMed   |  Link to Article
Hwang  WY, Foote  J.  Immunogenicity of engineered antibodies. Methods. 2005;36(1):3-10.
PubMed   |  Link to Article
Emi Aikawa  N, de Carvalho  JF, Artur Almeida Silva  C, Bonfá  E.  Immunogenicity of anti–TNF-α agents in autoimmune diseases. Clin Rev Allergy Immunol. 2010;38(2-3):82-89.
PubMed   |  Link to Article
Fransen  J, Stucki  G, van Riel  P.  The merits of monitoring: should we follow all our rheumatoid arthritis patients in daily practice? Rheumatology (Oxford). 2002;41(6):601-604.
PubMed   |  Link to Article
Wolfe  F, Cush  JJ, O’Dell  JR,  et al.  Consensus recommendations for the assessment and treatment of rheumatoid arthritis. J Rheumatol. 2001;28(6):1423-1430.
PubMed
Vander Cruyssen  B, Van Looy  S, Wyns  B,  et al.  DAS28 best reflects the physician’s clinical judgment of response to infliximab therapy in rheumatoid arthritis patients: validation of the DAS28 score in patients under infliximab treatment. Arthritis Res Ther. 2005;7(5):R1063-R1071.
PubMed   |  Link to Article
van der Bijl  AE, Breedveld  FC, Antoni  CE,  et al.  An open-label pilot study of the effectiveness of adalimumab in patients with rheumatoid arthritis and previous infliximab treatment: relationship to reasons for failure and anti-infliximab antibody status. Clin Rheumatol. 2008;27(8):1021-1028.
PubMed   |  Link to Article
Yazici  Y, Shi  N, John  A.  Utilization of biologic agents in rheumatoid arthritis in the United States: analysis of prescribing patterns in 16,752 newly diagnosed patients and patients new to biologic therapy. Bull NYU Hosp Jt Dis. 2008;66(2):77-85.
PubMed
Gómez-Reino  J.  Biologic monotherapy as initial treatment in patients with early rheumatoid arthritis. Rheumatology (Oxford). 2012;51(suppl 5):v31-v37.
PubMed   |  Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Supplement.

eTable 1. Excluded articles and reasons for exclusion

eTable 2. Individual results of the influence of AAB in efficacy

eTable 3. Individual results of the influence of AAB in hypersensitivity reactions

eTable 4. Individual results of effect of concomitant treatment in development of AAB

eTable 5. Individual results of the influence of AAB on the concentration of biological drugs

eTable 6. Efficacy measures included in the review

eFigure. Results of literature search

eReferences.

Supplemental Content

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 4

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
[Main therapeutic advances in IBD in 2007]. Rev Med Suisse 2008;4(141):200, 202-4, 206-8 passim.