Antonio Martínez

Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis

OBJECTIVEnTo analyse the clinical relevance of the production of anti-infliximab antibodies (anti-infliximab Abs) in patients with RA undergoing infliximab treatment over a prolonged period of time.nnnMETHODSnClinical characteristics, serum trough infliximab and antibody levels were evaluated in 85 RA patients treated with infliximab for a median of 4.42 (interval 0.4-10.2) years. DAS in 28 joints (DAS-28), EULAR response criteria and survival of treatment were assessed at 3 time points (6 months, 12 months and >4 years).nnnRESULTSnAntibodies against infliximab were detected in 28 (32.9%) patients and were present in all EULAR non-responder patients. Antibody levels were higher in EULAR non-responders throughout the study period (Pu2009=u20090.05 at 6 months, Pu2009=u20090.02 at 1 year, Pu2009=u20090.003 at >4 years) compared with EULAR (good and moderate) responders. Nine (10.5%) patients, all of them with high-serum anti-infliximab Ab levels, developed infusion-related reactions. Patients with anti-infliximab Abs more often required increased infliximab doses (51.7%) (Pu2009=u20090.032) and median survival time on treatment was shorter (4.15 vs 8.89 years) (Pu2009=u20090.0006). MTX co-therapy was not associated with lower proportion of anti-infliximab Ab-positive patients, but those receiving both infliximab and MTX had lower levels of anti-infliximab Abs (Pu2009=u20090.073) and longer survival (Pu2009=u20090.015) on treatment.nnnCONCLUSIONnThe formation of anti-infliximab Abs during treatment with infliximab is associated with a loss of clinical response, the appearance of infusion reactions and discontinuation of treatment.

Prediction of functional impairment and remission in rheumatoid arthritis patients by biochemical variables and genetic polymorphisms

OBJECTIVEnTo develop a model to predict RA outcome based on biochemical variables and single nucleotide polymorphisms (SNPs).nnnMETHODSnWe collected baseline data from RA patients. SNP genotyping was performed using an oligonucleotide microarray. Remission and severe disability were investigated as outcomes of the study. Logistic regression models and receiver operating characteristic (ROC) curves were used to determine sensitivity (S), specificity (Sp) and likelihood ratio (LR).nnnRESULTSnSix hundred and thirty-two patients (375 in the study and 257 in the validation) were included. Twenty-two out of 152, and 19 out of 208 patients had an HAQ > 2. The model obtained to predict disability included levels of the anti-cyclic citrullinated peptide (anti-CCP) antibodies, ESR and SNP rs2070874 in the IL-4 gene. Homozygous and heterozygous carriers of the IL-4 33T allele had a decreased risk of severe disability. The discriminative power had an area under the curve (AUC) of 0.792 (95% CI 0.694, 0.889), with S 41%, Sp 95% and LR +7.6. Twenty-one out of 268 and 17 out of 211 patients were in remission in the study and validation cohorts, respectively. The model included absence of anti-CCP antibodies and the SNP rs2476601 on the PTPN22 gene. Homozygous and heterozygous carriers of the PTPN22 1858T allele had a decreased probability of remission. The discriminative power had an AUC of 0.842 (95% CI 0.756, 0.928), with S 76%, Sp 86% and LR + 5.4. Predictive ability was confirmed on the validation cohort.nnnCONCLUSIONSnWe have developed two models based on laboratory variables that are associated with relevant outcomes for RA patients at disease onset.

A New Biomarker Panel in Bronchoalveolar Lavage for an Improved Lung Cancer Diagnosis

Introduction: The enormous biological complexity and high mortality rate of lung cancer highlights the need for new global approaches for the discovery of reliable early diagnostic biomarkers. The study of bronchoalveolar lavage samples by proteomic techniques could identify new lung cancer biomarkers and may provide promising noninvasive diagnostic tools able to enhance the sensitivity of current methods. Methods: First, an observational prospective study was designed to assess protein expression differences in bronchoalveolar lavages from patients with (n = 139) and without (n = 49) lung cancer, using two-dimensional gel electrophoresis and subsequent protein identification by mass spectrometry. Second, validation of candidate biomarkers was performed by bead-based immunoassays with a different patient cohort (204 patients, 48 controls). Results: Thirty-two differentially expressed proteins were identified in bronchoalveolar lavages, 10 of which were confirmed by immunoassays. The expression levels of APOA1, CO4A, CRP, GSTP1, and SAMP led to a lung cancer diagnostic panel that reached 95% sensitivity and 81% specificity, and the quantification of STMN1 and GSTP1 proteins allowed the two main lung cancer subtypes to be discriminated with 90% sensitivity and 57% specificity. Conclusions: Bronchoalveolar lavage represents a promising noninvasive source of lung cancer specific protein biomarkers with high diagnostic accuracy. Measurement of APOA1, CO4A, CRP, GSTP1, SAMP, and STMN1 in this fluid may be a useful tool for lung cancer diagnosis, although a further validation in a larger clinical set is required for early stages.

FRI0204 Comparison the long-term clinical outcomes between nontnf-inhibitors versus tnf-i in ra patients who failed to a first tnf-i

Background There are many biological therapies for Rheumatoid Arthritis (RA) with different mechanisms of action and good efficacy rate; however, up to 40% of patients (pts) fail to respond to the 1st biologic agent, and it is still not clear what strategy to follow after showing inadequate response to tumor necrosis factor α inhibitors (TNF-i) Objectives To assess the clinical response and survival (SVV), in our cohort of RA pts that discontinued the 1st TNF-i, of a 2nd TNF-i vs a nonTNF-i, both in the global cohort and in the subpopulation that dropped out the 1st TNF-I due to inefficacy Methods This observational study included 110 pts in the RA-Paz cohort who previously suspended Ifx (68%) or Ada (32%) between 1999–2016. Two groups were established as they switched to a TNF-i or nonTNF-i. Clinical response was evaluated by DAS28, Delta-DAS28 (ΔDAS28) and EULAR response (E-resp). The assessments were performed at 6 (v-6) and 12 months (v-12) since initiating 2nd biological agent and during the last visit prior to drug discontinuation or ending of the study for those who did not interrupt the drug (v-end). Statistical analysis was performed using SPSS version 20.0 Results Of the 110 pts who had stopped Ifx or Ada as 1st TNF-i, 65% changed to a 2nd TNF-i. The 84% of the overall pts were women. The mean age was 64±14 years and the mean time of 2nd biologic drug was 3.71±3.51 years. 61% associated methotrexate at the beginning of 2nd biologic agent and 56% at the v-end, without differences between those who switched to TNF-i and those who did to nonTNF-i. At v-6 and v-12, there was no difference in ΔDAS28 [at v-6:1.3±1.4 in TNF-i and 1.2±1.2 in nonTNF-i (p=0.919), at v-12: 1.3±1.5 in TNF-I and 1.2±1.1 in nonTNF-i (p=0.852)]. In contrast, at v-end, pts with nonTNF-i showed a higher clinical improvement (ΔDAS28: 0.68±1.7 in TNF-i, 1.8±1.1 in nonTNF-i, p=0.002). At v-6, the TNF-i group achieved higher good E-resp rate (41% vs 18%, p=0.035), but there was no difference at v-12 (36% in TNF-I vs 23% in nonTNF-i, p=0.435). However, at v-end, the nonTNF-I group achieved better E-resp (good resp: 38% in nonTNF-i vs 25% in TNF-I, no resp 18% in nonTNF-i vs 50% in TNF-i, p=0.01). Likewise, 100% (n=7) of the pts that finished 2nd biologic agent by remission, had changed to a nonTNF-i (p<0.00001). There were no differences regarding 2nd biologic drug SVV (mean SVV time of 5.7±0.66 in TNF-I, 4.3±0.59 in nonTNF-i, p=0.797). When analyzing the cohort that discontinued 1st TNF-I because of inefficacy, at v-6 and v-12 there were no differences between switchers to TNF-I and nonTNF-i in ΔDAS28 [v-6: 1.4±1.4 vs 0.9±1 p=0.164); v-12: 1.5±1.4 vs 1±1, p=0.192)], but at v-end, the nonTNF-i group reached a higher ΔDAS28 (0.9±1.5 in TNF-i, 1.6±1 in nonTNF-i, p=0.031) Conclusions In our sample of RA patients who suspended Ifx/Ada as 1st TNF-i, switching to a 2nd biologic agent did not show relevant clinical differences between a TNF-i and a nonTNF-i within the 1st year of treatment. However, in the long-term, switching to a nonTNF-i shows enhanced clinical benefits with no impact on survival vis-à-vis a 2nd TNF-i. Despite the efficacy of TNF-i, new therapeutic targets are needed for those who fail to respond to these biological agents Disclosure of Interest None declared

AB0687 Association between golimumab tapering strategy and drug serum levels in spa-paz spondiloarthritis cohort

Background Golimumab (Glm) is a tumour necrosis factor (TNF) inhibitor used as Spondiloarthritis (SpA) treatment. There is more and more evidence of tapering therapies used in maintained low disease activity patients, avoiding overtreatments and adverse effects. Up to now, there are no studies concerning SpA patients with Glm tapering therapy and serum drug levels measured prior to tapering strategy. Objectives To analyze clinical and analytical course of SpA patients with Glm interval prolongation in SpA-Paz cohort. Associate pre-tapering Glm serum levels with flare occurrence along tapering treatment. Methods Observational prospective SpA-Paz cohort study of 22 patients treated with Glm that remained with low disease activity, so they started tapering strategy (Tap-S). We measured clinical activity with ASDAS and ΔASDAS at baseline, pre-tapering visit (v-pre)and at 6, 12, 18 and 24 months after tapering starting (v-end). All of them had a clinically important improvement determined as ΔASDAS≥11. We registered flares, defined as clinical worsening based on patient anamnesis and physical examination and on diverse activity indexes made from the beginning until the last visit. Drug serum levels in v-pre were measured by ELISA and classified following optimal concentration previously defined in our laboratory: <07 mg/L, 07–14 mg/L, >14 mg/L. We used the software Graph-Pad Prism 6 for statistical analysis. Results 22 of 79 patients from our cohort (28%) initiated Tap-S. The age range was between 25 and 70 years, 73% men and 27% women. 52% were non-smokers. 5 patients (23%) received another antiTNF drug previously (4 Infliximab, 1 Etanercept). All of them had a 6 months visit prior to tapering, 18 patients had 12 months visit, 8 had 18 months visit and 5 had 24 months visit. ASDAS and ΔASDAS were similar in v-pre and v-end (ASDAS: 13±04 v-pre vs 12±07 v-fin, p=03; ΔASDAS: 23±07 v-pre vs 24±09 v-end, p=06). 13 patients (59%) had 1 or 2 flares along tapering therapy. The occurrence of flare average was 14 months. In all the patients with flares, disease activity was controlled returning to previous tapering dose (4/13, 31%), to monthly schedule (6/13, 46%) or remaining tapering dose with symptomatic treatment adjustments (3/13, 23%). None of them discontinued the treatment. At v-end, ASDAS and ΔASDAS were similar between patients with and without flares along Tap-S (ASDAS v-end: 1±07 in patients without flares vs 13±07 in patients with flares, p=04, ΔASDAS v-fin: 27±07 in patients without flares vs 22±1 in patients with flares, p=03). All the patients (4/4, 100%) that were under optimal drug concentration (<07mg/L) had at least one flare along Tap-S; however, only 23% (3/9) of those who were in optimal drug concentration in v-pre (07–14 mg/L) had flares. Conclusions The tapering strategy in our SpA cohort treated with Glm results in similar disease activity control after 24 months of monitoring. The activity disease in patients with flares was controlled with symptomatic or biologic treatment adjustments avoiding therapy discontinuation. Flares incidence was more frequent in patients under optimal drug concentration in v-pre. Disclosure of Interest None declared

SAT0168 Discontinuation of first biologic therapy in rheumatoid arthritis: main causes and correlation between secondary inefficacy and development of immunogenicity

Background Biologic therapy has been a major change in Rheumatoid Arthritis (RA) prognosis, but around 40% of patients (pts) fail to respond. Part of this treatment failure can be explained by the development of anti-drug antibodies (ADA), but the ADA-associated secondary inefficacies rate is currently unclear Objectives To assess in our AR cohort treated with Adalimumab (Ada), Infliximab (Ifx), etanercept (Etn), certolizumab (Czp), Tocilizumab (Tcz) and Abatacept (Abt) as 1st biologic agent, the frequency of drug suspension as well as the main causes for discontinuation and the secondary inefficacy rate associated with the development of immunogenicity Methods From the RA cohort that initiated their 1st biologic agent at Hospital La Paz between 2005 and 2016, only those who had suspended those drugs were included, and causes for suspension were collected. Clinical activity was measured by DAS28 and Delta-DAS28 at 6 months of treatment to classify discontinuation by primary or secondary inefficacy. Drug levels (DL) and/or ADA were also measured by ELISA at 6 months since initiating the biologic agent in 43 pts and at drug discontinuation in 59 pts. Primary inefficacy was defined as DAS28>3.2 and delta-DAS28 <1.2 at 6 months with DL present. Secondary inefficacy was defined both as DAS28>3.2 plus delta-DAS28 <1.2 at 6 months with ADA+ and Delta-DAS28>1.2 or DAS28 <3.2 at 6 months with subsequent loss of efficacy. Statistical analysis was performed using SPSS version 20.0 Results From the 246 pts who started their first biologic therapy, 144 (58%) pts who had definitively discontinued were included. [Ifx (n 35, 24%), Ada (n 40, 28%), Etn (n 30, 21%), Czp (n 23, 16%), Tcz (n 10, 7%) y Abt (n 6, 4%)]. 116 (80,6%) were women. The mean age was 56.3±14.7 years. The mean time of biologic was 2.23±1.96 years. From the global cohort, 18 (12.5%) drop out the treatment due to primary inefficacy, 41 (28.5%) to secondary inefficacy, 57 (39.6%) to adverse effects (AE), 11 (7.6%) to remission and 17 (11.8%) to other causes (surgery, pregnancy, etc.). 12.5% pts who discontinued due to AE or other causes had also a primary or secondary inefficacy; by including those pts in these last causes for suspension, a total of 20 pts (14%) failed due to primary inefficacy and 57 pts (39.6%) to secondary inefficacy. The most frequent AEs were: infections (35%), cutaneous AEs (psoriasis, rash, etc. (10.5%), infusion reactions (9%) and neoplasia (9%). Of the 59 pts who had DL/ADA measured at drug discontinuation, 42.4% were ADA +. Within the group that failed due to secondary inefficacy and had DL/ADA determined, 50% were ADA+; nevertheless this rate was smaller in suspensions due to other causes. Likewise, in the ADA+ pts, 73% suspended due to secondary inefficacy Conclusions In our RA cohort, adverse effects were the main cause for discontinuation, with infections at 1st place. The 2nd cause conditioning interruption was the secondary inefficacy, in which 50% of our pts were ADA+ at drug discontinuation. These data suggest that the development of ADA is a frequent cause of secondary inefficacy in our RA pts Disclosure of Interest None declared

OP0016 Increased Frequency of Anti-Drug Antibodies in Patients Carrying Compatible IGG1 Allotypes and Treated with Anti-TNF Antibodies

Background One of the causes of insufficient response to biological drugs is the production of anti-drug antibodies (ADA) (1). These antibodies can decrease the effectiveness of treatment by altering bioavailability or by neutralizing the drug. In addition, they may contribute to hypersensitivity reactions. Some ADA are directed against IgG allotypes, which are protein polymorphisms able to induce an immune response in incompatible subjects. Infliximab (INX) and adalimumab (ADM) have the G1m17,1 allotypes, while about 50% of the Europeans are homozygous for the incompatible G1m3,n allotypes. Therefore, the allotypes could contribute to ADA and, in this way, explain the recently described loss of efficiency of INX in allotype-incompatible RA patients (2). Objectives We aimed to analyze the usefulness of IgG1 allotypes as biomarker of the development of ADA against INX and ADM. Methods The presence of ADA was determined in 252 consecutive patients with inflammatory arthritis in the Hospital La Paz (116 with rheumatoid arthritis (RA), 74 with ankylosing spondylitis (AS), 26 with psoriatic arthritis, 17 with non-radiographic spondylitis, 11 with spondylitis and inflammatory bowel disease, 3 with uveitis and 5 with other arthropathies). Patients were assessed during INX treatment (151), or with ADM (82), or sequentially during treatment with INX and ADM (19). ADA were determined by two-site bridging ELISA as described (1). Allotypes of IgG1 were determined by genotyping 2 SNPs, rs1071803 (for allotype G1m17/G1m3) and rs11621259 (for allotype G1m1/null) with the SNaPshot Multiplex kit (Applied Biosystems) as reported (2). Results Patients with compatible allotypes (carriers of G1m17,1) showed a larger frequency of ADA (33% vs. 20%, p=0.02) and a trend toward higher titers of these antibodies (18.0x103 vs. 8.3x103 AU, ns) than patients with incompatible allotypes (homozygous for G1m3,n). This association was clearer in patients treated with INX (41% vs. 25%, p=0.03) than in those treated with ADM (18% vs. 12%, ns). ADA were more frequent in patients treated with INX than in those treated with ADM, as already known. Multivariate analysis showed that the frequency of ADA was increased in patients with RA compared to other diseases (OR =7.6, p<0.0001), and decreased in older patients (OR =0.65 per 10 years, p<0.001). Other factors, such as sex, having AS against other diseases, and treatment with methotrexate or corticosteroids, were not associated with ADA. Conclusions Patients with compatible allotypes showed more frequently ADA than patients with incompatible allotypes, showing for the first time this association in patients treated with INX and reinforcing the previously reported association for ADM (3). These results suggest a genetic factor in linkage with the allotype, but different from it, that will predispose to ADA. References Pascual-Salcedo D, et al. Rheumatology (Oxford). 2011;50:1445 Montes A, et al. Arthritis Res Ther. 2015;17:63 Bartelds GM, et al. Arthritis Res Ther. 2010;12:R221 Acknowledgement Funding was provided by the Instituto de Salud Carlos III (Spain) through grants PI12/01909, PI15/01651 and RD12/009/008, which are partially financed by the European Regional Development Fund of the EU. Disclosure of Interest None declared