S. Garcês

The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis

Background Immunogenicity of aTNFs is one of the mechanisms behind treatment failure. Objective To assess the effect of anti-drug antibodies (ADA) on drug response to infliximab, adalimumab and etanercept, and the effect of immunosuppression on ADA detection, in patients with Rheumatoid Arthritis, Spondyloarthritis, Psoriasis and Inflammatory Bowel Diseases. Data sources PubMed, EMBASE, Cochrane databases, article reference lists (through August 19 2012). Study selection Out of 2082 studies, 17 were used in the meta-analysis (1RCT; 16 observational studies). Data extraction Two reviewers extracted data. Risk ratios (RR), 95% CI, using random-effect models, sensitivity analysis, meta-regressions and Eggers test were calculated. Data synthesis Of 865 patients, ADA against infliximab or adalimumab reduced drug response rate by 68% (RR=0.68, 95% CI=0.12 to 0.36), an effect attenuated by concomitant methotrexate (MTX): <74% MTX+: RR=0.23, 95% CI=0.15 to 0.36; ≥74% MTX+: RR=0.32, 95% CI=0.22 to 0.48. Anti-etanercept antibodies were not detected. Of 936 patients, concomitant MTX or azathioprine/mercaptopurine reduced ADA frequency by 47% (RR=0.53, 95% CI=0.42 to 0.67), particularly when ADA were assessed by RIA (RR=0.36, 95% CI=0.23 to 0.55) compared with ELISA (RR=0.63, 95% CI=0.53 to 0.74). Conclusions ADA reduces drug response, an effect that can be attenuated by concomitant immunosuppression, which reduces ADA frequency. Drug immunogenicity should be considered for the management of patients receiving biological therapies.

A preliminary algorithm introducing immunogenicity assessment in the management of patients with RA receiving tumour necrosis factor inhibitor therapies

Introduction Clinical remission is today the treatment goal for rheumatoid arthritis (RA), which requires fast and assertive therapeutic decisions for a tight control of disease activity. Few objective parameters are available to guide clinical decisions, particularly in switcher patients. We designed a preliminary algorithm introducing immunogenicity assessment in the current approach to patients with RA receiving tumour necrosis factor inhibitors (TNFi). Objective To evaluate the concordance between the new algorithm and current clinical practice, comparing the effectiveness of ‘immunogenicity-based’ versus ‘empirical-based’ switches in a cohort of patients with established RA receiving biologics. Methods EULAR therapeutic response was evaluated in 105 patients with RA (naive or switchers) over one year, through generalised estimation equation (GEE) analyses. Serum drug trough levels were assessed by ELISA and antidrug antibodies (ADAb) by Bridging ELISA. Results During follow-up, 48.6% of patients had therapeutic decisions concordant with the proposed algorithm (Group A), and 51.4% had discordant decisions (Group B). One year after the therapeutic decision, patients from Group A had a higher probability of achieving response (OR=7.91, p<0.001, 95% CI 3.27 to 19.13) and low disease activity (OR=9.77, p<0.001, 95% CI 4.69 to 20.37) than patients in Group B. Conclusions Immunogenicity assessment might help to optimise therapeutic decisions, leading to a better control of disease activity with significantly better clinical outcomes in patients with RA receiving TNFi.

SAT0479 Clinical impact of immunogenicity of infliximab, adalimumab and etanercept: A systematic review of the literature with a meta-analysis

Background Despite the beneficial effects of aTNF alpha agents on the systemic rheumatic and inflammatory bowel diseases, a significant proportion of patients cannot sustain a therapeutic response over time. An increasing body of literature highlights immunogenicity as one of the main factors behind therapeutic failure and infusion-related adverse events1-5. Given the recent recommendations by the EMA to monitor immunogenicity in clinical practice6, it is important to reevaluate the impact of anti-biologic antibodies on drug efficacy and safety. Objectives We conducted a meta-analysis to assess the influence antibodies against infliximab, adalimumab and etanercept on therapeutic efficacy/effectiveness and the influence of concomitant immunosuppression in anti-biologic antibodies production, in patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease and ulcerative colitis. Methods A systematic literature search of Medline, Embase and Cochrane Library was conducted through Dec 2011, complemented with the reference lists of articles and consultation with experts. We included clinical trials and observational studies. Nineteen studies met our inclusion criteria. Random-effects models according to the Laird method were used for clustering results. Heterogeneity examined by calculating the Qui2 test for heterogeneity and the I2 measure of inconsistency. Meta-regression and sub-group analysis were used to evaluate the effect size modification by: a) type of disease; b) proportion of patients co-treated with Methotrexate (MTX); c) proportion of patients who underwent aTNF dose escalation; d) proportion of patients who started with higher initial doses of aTNF; d) scheduled treatment regimens; e) type of assay for ABAs detection; f) population and individual study characteristics. Results In studies where the proportion of patients co-treated in MTX was less than 79%, the presence of ABAs reduced therapeutic response by 80% (RR 0.20, 95% CI 0.12-0.36), while in studies where that proportion was ≥79%, the effect size reduction of drug response was attenuated to 50% (RR 0.50, 95% CI 0.36 to 0.69). Concomitant immunosuppressive therapy reduced detectable ABAs by 65% (RR 0.35 95% CI 0.24 to 0.51) when RIA was used to detect ABAs, while when ELISA methods were used the effect size reduction of detectable ABAs was attenuated to 36% (RR 0.64, 95% CI 0.54 to 0.75). No definitive conclusions can be drawn regarding the effect size modification by the other evaluated factors. Conclusions There is evidence of an increased risk of therapeutic failure in patients with anti-biologic antibodies. Concomitant immunosuppression reduces but does not abrogate anti-biological antibodies production. The type of assays employed to assess anti-biologic antibodies can influence the results. Routine assessment of immunogenicity may clarify the reason behind therapeutic failure, which might be of high relevance to optimize the use of biologic therapies. References Baert et al. N Engl J Med 2003;348:601-8. Maini et al. Arthritis Rheum 1998;41:1552-63. Pascual-Salcedo et al. Rheumatology 2011;50(8):445-52. Bartelds et al. JAMA 2011;305:1460-8. Jamnistski et al. Ann Rheum Dis 2011;70:284-8. E.M.A. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003946.pdf; Disclosure of Interest None Declared

The Immunogenicity of Biologic Therapies

Virtually all therapeutic proteins (biologics) elicit an immune response with the consequent production of anti-drug antibodies (ADA). The majority of ADA to therapeutic monoclonal antibodies (mAbs) are directed against the antigen-binding site of the therapeutic mAb, and hence are neutralizing. This nature of the ADA response explains why fully human antibodies can still be highly immunogenic. The detection of ADA is technically challenging and all assays have limitations, namely a limited capacity in detecting ADA in the presence of a drug due to immune complex (IC) formation, which may underestimate the ADA incidence. Refined assays, able to disrupt drug-ADA ICs, have revealed the presence of ADA in a higher proportion of patients. The great heterogeneity among ADA assays prevents a direct comparison of immunogenicity between different molecules and across studies. The formation of drug-ADA ICs can significantly alter pharmacokinetics and directly reduce drug efficacy if the ADA titer (i.e., concentration) is sufficiently high and persistent. In patients with low ADA titer, free drug concentrations may remain high enough to be effective, while in patients developing high ADA titer a substantial part of the drug will be neutralized and clinical non-response is likely to occur. ADA can also increase the risk of adverse events, namely hypersensitivity reactions. Several studies have revealed the presence of ADA before a clinically overt adverse reaction, highlighting their predictive value. Algorithms integrating therapeutic drug monitoring and immunogenicity information in the current clinical evaluation of patients receiving biologics are today available to guide therapeutic decisions in clinical practice, helping us to design safer and more cost-effective therapeutic strategies.

OP0008-HPR Challenges with the applicability of the eular recommendations for rheumatology nursing management in portugal

Background Several studies have highlighted the added value of nurses in the management of patients with chronic inflammatory arthritis[1,2], which led the EULAR Nursing Task Force to formulate a set of recommendations for the role of nurses in this particular context[3]. Rheumatology as a nursing specialty does not exist in Portugal, and this may constitute an important barrier for the implementation of these recommendations. Objectives We aimed to evaluate the level of agreement of Portuguese nurses working in rheumatology departments with the EULAR recommendations and the degree of their applicability in routine clinical practice. Methods During January 2012, a questionnaire was sent to all Portuguese Rheumatology centers inviting practicing nurses to answer anonymously to a closed-type set of questions that addressed the level of agreement with each of the recommendations (1 – total disagreement to 5 – total agreement), the recommendations’ application in practice (not applied (0), partly (1) or full applied (2)) and the level of confidence in the applicability of each of the recommendations (0-not at all confident; to 5 totally confident). Chi2 and Mann-Whitney tests were used to plot the results. Results A total of 42 nurses (83% female; 4.8±4.4 years of practice) from 10 rheumatology centers were included. Twenty-eight (67%) worked at the outpatient clinic, 7 at the inpatient clinic and 7 at both places. Only twelve (29%) worked exclusively at rheumatology departments. Although all nurses stated to be interested in getting more training in rheumatology and 67% would like to have the formal specialty in rheumatology, only eleven (45%) had received some type of training. On average, the level of agreement with all the EULAR recommendations was 4.9±0.2 (with averages for the individual recommendations ranging from 4.6±0.7 to 5±0). In the majority of cases (76.2%) these recommendations were partly applied in practice and the level of confidence in their full applicability was 3.7±0.9 (with averages for the individual recommendations ranging from 3.1±1.5 to 4.3±0.9). Comparing nurses with and without specific training in rheumatology, a significantly higher proportion of those who received training totally agreed with providing care based on protocols and guidelines (94% vs 63%, p=0.02) – Recommendation 7. Similar results were found among nurses working at day-care units when compared to the others (87% vs 50%, p=0.03). A significantly higher proportion of nurses from day-care units showed total agreement with Recommendation 9, which states that nurses should be encouraged to undertake extended roles after specialised training, according to national regulations (97% vs 67%, p=0.02). The level of confidence in the applicability of recommendation 7 was also significantly higher in those two subgroups. Conclusions There is a high level of agreement with the EULAR recommendations for rheumatology nursing management in Portugal, despite the fact that most of the nurses are working in partial dedication to rheumatology and without specific training. The highest level of agreement was verified among nurses with specific training and working at day-care units, underlining the importance of specific training for future commitment. References Hill et al. Br J Rheumatol 1994; 33:283-8. Ryan et al, J Adv Nurs 2006;53:277-86. Eijk-Hustings et al. Ann Rheum Dis 2012; 71:13-19. Disclosure of Interest None Declared

FRI0092 New algorithm to approach ra patients receiving biologic therapies: Introducing immunogenicity assessment in the eular guidelines

Background In the last years, the “treat to target” strategy revealed the importance of tight control of disease activity in RA patients1. To reach clinical remission or at least low disease activity as soon as possible, this strategy, now part of the EULAR guidelines, requires therapeutic combinations and/or fast switches between different therapies2. Over the last years it became clear that drug immunogenicity is one of the main mechanism behind biologic therapeutic failure3-4. How to integrate the notion of drug immunogenicity in clinical practice remains to be formally established. We conducted a systematic review of the Literature with a meta-analysis evaluating the clinical implications of drug immunogenicity5. Based on the information retrieved we designed a new algorithm which introduces immunogenicity assessment in the EULAR guidelines for the management of RA patients receiving biologic therapy. Objectives We assessed the influence of adherence to our proposed algorithm on therapeutic responses and low disease activity rates in a prospective cohort of RA patients treated with biologics. Methods We conducted a prospective cohort study over 2-years evolving 106 consecutive RA patients, 92% female, with a mean age of 55±13 yrs and mean disease duration of 6±4 yrs. Patients had been submitted to biologic therapy by a mean period of 4±3 years. Serum drug trough levels were assessed by ELISA and anti-drug antibodies (ADA) by an optimized Bridging ELISA, which we previously compared with a fluid-phase RIA. Clinicians were blind for the tests results. Therapeutic response and low disease activity were defined according to the EULAR guidelines. Results At the study onset 22 patients were receiving Infliximab (36.4% anti-infliximab pos), 33 Adalimumab (27.3% anti-adalimumab pos) and 49 Etanercept (0% anti-etanercept pos). Patients with detectable ADAs had undetectable serum drug trough levels and lower therapeutic responses rates (37.5% vs 76.9%, p=0.001 for Infliximab and 33.3 vs 66.7%, p=0.02 for Adalimumab). Not a single patient with detectable ADAs had low disease activity. During follow-up period, therapeutic decision coincident with our proposed algorithm concerned 48.6% of the patients (Group 1), however with a décalage median (IQR) time of 249 days (116-388). Therapeutic decisions were discordant with our algorithm for 51.4% of the patients (Group 2). A significant higher proportion of patients in Group 1, when compared to Group 2, reached therapeutic response at 3 months (97.9% vs 52.2%, p=0.001) and at 12 months (71.4% vs 13% p=p=0.000). Moreover, a significant higher proportion of patients in Group 1 achieved low disease activity at 3 months (71.4% vs 13%, p=0.000) and at 12 months (58.8% vs 3.8%, p=0.000). Considering drug direct costs only, we evaluated that about 1 million euros were spent inefficiently in this cohort over 2 years. Conclusions Our study strongly suggests that including immunogenicity assessment in EULAR guidelines will allow the design of more cost-effective strategies, tailored to each RA patient receiving biologic therapy. References Schipper LG et al. Ann Rheum Dis 2011;Dec30. Smolen JS et al. Ann Rheum Dis 2010;69:964-75. Bartelds et al. JAMA 2011;305:1460-8. Jamnistski et al. Ann Rheum Dis 2011; 70:284-8. EULAR 2012 Abstract: EULAR12-3348. Disclosure of Interest None Declared