IL-15 is a proinflammatory cytokine that acts early in the inflammatory response and has been associated with several autoimmune diseases including rheumatoid arthritis, where it had been proposed as a therapeutic target. We recently reported an IL-15 antagonist peptide corresponding to sequence 36-45 of IL-15 (KVTAMKCFLL) named P8, which specifically binds to IL-15Rα and inhibits IL-15 biological activity with a half maximal inhibitory concentration (IC50) of 130 µ m in CTLL-2 proliferation assay. In order to improve binding of peptide P8 to the receptor IL-15Rα, we used an Ala scan strategy to study contribution of each individual amino acid to the peptide's antagonist effect. Here, we found that Phe and Cys are important for peptide binding to IL-15Rα. We also investigated other single site mutations and replaced the second Lys in the sequence by the polar non-charged amino acid threonine. The resulting peptide [K6T]P8 exhibited a higher activity than P8 with an IC50 of 24 µm. We also found that this peptide was more active than peptide P8 in the inhibition of TNFα secretion by synovial cells from rheumatoid arthritis patients. The peptide [K6T]P8 described in this work is a new type of IL-15 antagonist and constitutes a potential therapeutic agent for rheumatoid arthritis.

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BackgroundBIOBADAGUAY is the Paraguayan/Uruguayan registry of adverse events in patients with inflammatory rheumatic conditions under biologic therapy (BT). The registry includes patients with different diagnosis that share similar biological therapies indication. However, different pathogenesis, patients’ characteristics and treatment options can affect the survival of the BT.ObjectivesTo analyze survival of biological therapies among patients with chronic inflammatory arthritis in the BIOBADAGUAY registry.MethodsPatients with chronic inflammatory arthritis (CIA) such us rheumatoid arthritis (RA), spondylarthritis (SpA), psoriatic arthritis (PsA) and juvenile onset arthritis (JIA) enrolled in BIOBADAGUAY where analyzed. Other diseases included in the registry were grouped as others. Drug survival and clinical and epidemiological predictors were studied. Fewer than BT 25 registries were not included in the study. Survival analysis was performed using Kaplan-Meier estimators, and Cox proportional hazard models were used to estimate hazard ratios (HRs).ResultsA total of 1378 treatments (876 RA, 176 SpA, 40 JIA, 88 PsA, 98 others) were included. The mean BT survival according to diagnosis was 300.9 (95%CI, 230.6-444.4) weeks (wks) for RA; 541.6 (95%CI, 409.6-541.6) wks for SpA; 154.1 (95%CI, 125.0-194.7) wks for JIA and 555.3 (95%CI, 282.1-611.6) wks for PsA. In the general analysis, when survival was compared between different diagnosis, it was found that BT survival for SpA patients (p˂0.05; HR=1.23 [95% CI 0.97-1.56]) was higher than other CIA. On the other hand, JIA diagnosis was significantly associated with a lower BT survival (p˂0.05; HR=1.85 [95% CI 1.36–2.52]). In the general analysis, no significant differences between BT were found (p>0.05). When each drug survival was analyzed according to diagnosis, adalimumab showed a significant difference in SpA patients (p˂0,05; HR=0.55 [95% CI, 0.39-0.76]) and JIA patients (p=<0.005; HR=1.8 [95% CI 1.36–2.52]). Etanercept had a significant difference in RA (p <0.005; HR=0.57 [95% CI, 0.40-0.82]) and JIA patients (p=<0.005; HR=2.07 [95% CI, 1.39–3.06]). Following these results we analyzed JIA patients and found that remission was the principal reason of discontinuation in this group of patients (p<0.005, HR=10.700 [95% CI, 5.91–19.36]).Multivariable analysis showed that the number of previous BTs (p=0.01, HR=1.18 [95% CI, 1.03-1.34), corticosteroid treatment (p=0.05; HR=1.18 [95% CI; 0.99–1.40), SpA (p=0.01; HR=0.688 [95% CI 0.51-0.91) and JIA diagnosis (p=0.02; HR=1.4 [95% CI, 1.06-2.02]) where associated with BT survival.ConclusionIn this study we found different survival profiles according to diagnosis. This could be related to different pathogenesis, discontinuation motives and treatment options in different health systems.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsGabriela Avila Grant/research support from: Casa Boller - Roche, Sonia Cabrera-Villalba Grant/research support from: Casa Boller - Roche, Patricia Melgarejo Grant/research support from: Casa Boller - Roche, Lourdes Roman Grant/research support from: Casa Boller - Roche, ZOILO MOREL Grant/research support from: Casa Boller - Roche, Roger Rolón Grant/research support from: Casa Boller - Roche, Mariela Zarza Grant/research support from: Casa Boller - Roche, Macarena Soto Estevez: None declared, Evelyn Leiva Grant/research support from: Casa Boller - Roche, Angelica Amarilla Grant/research support from: Casa Boller - Roche, Paola Pusineri Grant/research support from: Casa Boller - Roche, Clyde PArodi Grant/research support from: Casa Boller - Roche, Carolina Díaz: None declared, Belen Acevedo: None declared, ALEJANDRO FERNANDEZ: None declared, Vannia Valinotti Grant/research support from: Casa Boller - Roche, PALOMA DE ABREU TRIGUEROS Grant/research support from: Casa Boller - Roche.