Secukinumab Loss of Efficacy Is Perfectly Counteracted by the Introduction of Combination Therapy (Rescue Therapy): Data from a Multicenter Real-Life Study in a Cohort of Italian Psoriatic Patients That Avoided Secukinumab Switching

Since psoriasis (PsO) is a chronic inflammatory disease, patients may experience a drug failure also with very effective drugs (i.e., secukinumab) and, consequently, dermatologists have two therapeutic options: switching or perform a combination therapy (rescue therapy) to save the drug that had decreased its efficacy. At the moment no studies focused on combination/rescue therapy of secukinumab, so we performed a 52-weeks multicenter retrospective observational study that involved 40 subjects with plaque psoriasis that experienced a secondary failure and were treated with combination therapy (ciclosporin (n = 11), MTX (n = 15), NB-UVB (n = 7) and apremilast (n = 7)). After 16 weeks of rescue/combination therapy, PASI and a DLQI varied respectively from 8 [7.0–9.0] and 13 [12.0–15.0], to 3 [2.8–4.0] and 3 [2.0–3.3]), suggesting a significant improvement of daily functionality and quality of life. Results were maintained at 52 weeks. No side effects were experienced during the study. Secukinumab remains a safety and effective drug for PsO patients also in the IL-23 and JAK inhibitors era. The rescue therapy is a valid therapeutic option in case of secukinumab secondary failure.

Efficacy of Recombinant Human Thrombopoietin for the Treatment of Secondary Failure of Platelet Recovery After Allogeneic HSCT

Secondary failure of platelet recovery (SFPR) is a life-threatening complication that may affect up to 20% of patients after allogeneic hematopoietic stem cell transplantation (HSCT). In this study, to evaluate the efficacy of recombinant human thrombopoietin (rhTPO), we retrospectively analyzed 29 patients who received continuous rhTPO for the treatment of SFPR. Overall response and complete response were observed in 24 (82.8%) patients and 10 (34.5%) patients, at a median time of 21.5 days (range, 3-41 days) and 39.5 days (range, 7-53 days) after initiation of rhTPO treatment, respectively. Among the responders, the probability of keeping overall response and complete response at 1 year after response was 77.3% and 80.0%, respectively. In multivariate analysis, higher CD34+ cells (≥3 × 106/kg) infused during HSCT (HR: 7.22, 95% CI: 1.53-34.04, P = 0.01) and decreased ferritin after rhTPO treatment (HR: 6.16, 95% CI: 1.18-32.15, P = 0.03) were indicated to associate with complete response to rhTPO. Importantly, rhTPO was well tolerated in all patients without side effects urging withdrawal and clinical intervention. The results of this study suggest that rhTPO may be a safe and effective treatment for SFPR.

Gaps in Material Qualification Requirement and Acceptance for Severe to Extreme Sour-Sweet Corrosive HPHT Environments Impacting Completion Design

Severe to extreme sour-corrosive environment assisted cracking (EAC) phenomenon are complex. Mandatory test qualification requirements and acceptance criteria is non-existent, in relevant API and NACE standards for fracture toughness of the CRA's. This paper, perhaps an industry first, attempts to highlight some of these gaps and how it translates into material strength uncertainties thereby impacting tubing design and risk assessment. The materials in this context are high strength group 1 to 4 corrosion resistant alloys of API 5CRA. Fracture toughness or critical stress intensity factor is a measure of resistance to failure due to crack propagation - a key parameter for HPHT tubing material selection and design. This material aspect of fracture toughness can be influenced by several factors like Microstructure, Strength, Hardness, Heat treatment, Anisotropy etc. Low temperature is generally considered as worst case, nevertheless at higher temperatures, well environment driven embrittlement can have a serious impact on the fracture toughness value. Therefore, with several factors influencing, its characterization is important to define the burst envelope of the tubing when exposed to severe to extreme sour-sweet corrosive environment typical of HPHT wells. A unique approach is followed to determine the brittle burst tri-axial envelope of selected tubing based on minimum fracture toughness value of the CRA material, referred to as KIMAT for SSC (or EAC) as prescribed by the mill. Proportional radial scaling is proposed to generate scaled down von-mises brittle-burst envelope. The tubing loads and the safety factors are analyzed to the shrunken envelope to visualize the risks of tubular failure under sour-sweet corrosive environment. The analysis includes varying crack depths of 5% and 3%. In addition, a minimum KIMAT for SSC (or EAC) value required to achieve full scale VME is investigated to determine specific material property requirements. TM0177 NACE D covers methods to measure fracture toughness KIMAT for sour service at ambient temperature only and does not address the context of EAC exposure at ambient or elevated conditions i.e., KIMAT for EAC.This implies that a methodology for evaluation of EAC risk is not available as yet. Guidance on the potential for corrosion to cause cracking of CRAs is given in Table B.1 of ISO 15156-3 with primary and secondary failure mechanisms. However, a quantitative test to cover the risk of cracking of materials by specifying minimum required KIMAT for EAC for each group type in 5CRA is non-existent. Even KIMAT for sour service minimum requirements with SSC as primary failure mechanism, e.g., group 1 CRA, does not currently exist. Consequently, KIMAT for EAC minimum requirements are considered as far-fetched. Additionally, mills prescribed KIMAT for SSC lacks basis due to gaps in the minimum fracture toughness requirement stipulations for group 1 to 4 CRA materials listed at API 5CRA. Therefore, this paper provides risk insights and potential of tubing failure that can lead to serious integrity issues on a HPHT well. A joint industry program or joint API/NACE task group is proposed as a logical next step.

Characteristics of intramedullary nail breakage in pertrochanteric femur fractures: a summary of 70 cases

Objective To reveal noteworthy characteristics of intramedullary (IM) nail breakage in pertrochanteric femur fractures. Materials and methods The data from 6 patients with IM nail breakage in our hospital between August 2008 and May 2018 were reviewed retrospectively. With an additional 64 cases reported in articles in the PubMed database prior to October 2019, a total of 70 cases were reviewed and analysed; epidemiological patient data and data on the initial trauma, fracture type, nail selected for the original surgery, time from surgery to breakage, mechanism and location of breakage, status of fracture healing, salvage treatment and prognosis were assessed. Results Seventy patients with pertrochanteric fractures, including 2 stable fractures and 68 unstable fractures, experienced IM nail breakage at a mean of 9.4 months after the initial surgery. Among them, 9 (12.9%) occurred within 3 months, 23 (32.9%) between 3 and 6 months and 38 (54.3%) after 6 months. The mean age was 72.3 years, and 16 (22.9%) patients were younger than 65 years old. When nail breakage occurred, 66 fractures (94.3%) exhibited delayed union/non-union. Self-dynamisation was found in 12 cases (17.1%). The salvage procedures included 4 partial/total implant removal procedures, 17 hemi/total hip arthroplasty procedures, 3 conservative treatment procedures, and 46 revised osteosyntheses, of which 7 cases (15.2%) sustained secondary implant failure. No significant differences were found between the failure rates of IM nails and extramedullary(EM) devices (odds ratio [OR], 3.429; 95% confidence interval [CI], 0.632–18.877; p = 0.330). Conclusion IM nail breakage is a rare complication lack of time regularity and mostly occurs in unstable pertrochanteric fractures in the presence of delayed union/non-union. Osteosynthesis revision can be conduct by a new IM nail or EM device but considerable secondary failure rate is noteworthy. Self-dynamisation may be a warning sign of nail breakage.

Golimumab in juvenile idiopathic arthritis-associated uveitis unresponsive to Adalimumab

Objective To assess the efficacy of golimumab (GLM) as a treatment option for juvenile idiopathic arthritis (JIA)-associated uveitis refractory to adalimumab (ADA). Methods Retrospective single-centre study including patients with JIA receiving GLM for active uveitis after failing ADA. JIA- and uveitis-related data, including intraocular inflammation, best-corrected visual acuity, corticosteroid-sparing potential, and ocular complications were evaluated at start of GLM treatment, at 1 month and 3 months, and every 3 months thereafter during GLM administration. We further investigated the association of response to GLM with primary and secondary failure of ADA treatment. Results Ten patients were studied, all female (17 affected eyes, mean age 14.3 + 6.7 yrs., mean follow-up 25.2 + 21.7 mos). Two patients were switched to GLM because of primary non-response to ADA. Eight were switched because of loss of response (LOR). In 5 of the latter LOR was associated with neutralizing anti-ADA-antibodies. Response to GLM was observed in all 8 patients with LOR, while the 2 patients with primary non-response to ADA also did not respond to GLM. Three of the 8 responders experienced LOR. At the end of follow-up 4 of the 5 remaining responders had achieved complete response. One had achieved partial response. Conclusion GLM is an efficacious therapeutic option in patients who experience LOR to ADA. Our data indicate that patients without primary response to ADA should be rather switched to a biologic agent with a different mode of action instead of further blocking the TNF-alpha pathway.

AB0213 SAVING GLUCOCORTICOIDS AFTER RITUXIMAB TREATMENT IN PATIENTS WITH REUMATOID ARTHRITIS. ANALYSIS OF A COMMON CLINICAL PRACTICE COHORT

Background:Rituximab (RTX) is a monoclonal antibody against the CD20 B cell antigen that has been used successfully in recent years for the treatment of rheumatoid arthritis (RA). It is an effective drug that reaches survival rates of 60% at 5 years of treatment as reflected in the British experience. However, survival in Spanish patients is unknown.Objectives:To study the survival of RTX treatment and the characteristics of patients with RA treated with the drug since its commercialization in Spain.Methods:Observational, retrospective and analytical study of a cohort of patients with RA treated with at least one dose of RTX. We reviewed the medical records of all patients with RA from January 2007 to June 2017. A total of 178 previous defined variables were collected, highlighting data about treatment (use of RTX, associated conventional synthetic disease modifying drugs [FAMEsc], doses of corticosteroids [GC] used) and activity indices. Descriptive statistics were performed (median and the 25th and 75th percentiles are shown). The comparative analysis was done with χ2 and U of Mann Whitney for categorical variables and paired sign rank test or Student’s t for continuous. Survival Kaplan Mayer curves were constructed. The study was carried out in accordance with the standards of our Clinical Research Ethics Committee.Results:A total of 54 patients were analyzed. 74% (n = 40) of them were women, the age was 61.2 years (51.0 - 67.4). 74% (n = 40) presented some type of relevant comorbidity. Its RA was FR + in 96% (n = 52) and ACCP + in 78% (n = 42) of the cases, with an evolution time of 9.3 years (3.5-19, 2), and with radiographic erosions in up to 63% (n = 34). At the time of the start of the RTX, 100% of the patients (n = 54) received some FAMEsc, and 33 (61%) were treated with prednisone; the daily dose of prednisone was 9 (6-12) mg. The baseline DAS28-VSG was 5 (4.1 - 6.0). The duration of the follow-up was 56.6 (29.3-92.1) months. Patients received a mean of 5 (1-6) cycles of RTX at a dose of 1000 mg on days 0 and 15 in most cases. The final DAS28-VSG was 2.6 (2.1 - 4.0), p = 0.00001 compared to baseline. The delta between baseline and final DAS was -2.36 (-0.55 - -3.1). At the end of the RTX treatment, the EULAR response rate was good in 64% (n = 25), reaching remission in 17 (31%) of the patients, and moderate response in 21% (n = 8) of them (Figure 1). Only 2 (4%) patients were treated with GCC at the end of the follow-up, p<0,00001 compared to baseline. The daily dose of PDN at the end of follow-up was 6 mg in a case and 12 mg in the other, p=00001 compared to baseline. At the end of the follow-up 24%of the patients (n = 13) changed or discontinued the drug: 9 changed due to secondary failure, 2 suspended due to adverse events, 1 due to death due to prior neoplastic process and 1 due to complete disease remission. Survival at 1, 2, 3, 4, 5, 6 and 7 years was 92%, 92%, 82% 78%, 75%, 75% and 65% respectively; with a mean survival rate of 90 months (Figure 1).Conclusion:The results of our analysis show that patients with RA undergoing RTX treatment have adequate control of disease activity and drug survival rates, like published data. RTX treatment allowed stopped GCC treatment in 31 cases (90%).References:[1]Oldroyd AGS, et al. Rheumatology (Oxford). 2018 Jun 1;57(6):1089-1096.Disclosure of Interests:Gonzalo Jurado Quijano: None declared, Lola Fernández de la Fuente Bursón: None declared, Blanca Hernández-Cruz Speakers bureau: Sociedad Española de Reumatología, Abbvie, Roche, Bristol, MSD, Lilly, Pfizer, Amgen, Sanofi, Consultant of: Abbvie, Lilly, Sanofi, STADA, UCB, Amgen, Grant/research support from: Fundación para la Investigación Sevilla, Junta de Andalucía, Fundación Andaluza de Reumatología, Paloma Muñoz Reinoso: None declared, Vicente Merino Bohóquez: None declared, José Javier Pérez Venegas: None declared

POS0461 RESPONSE TO BIOLOGIC THERAPY IN RHEUMATOID ARTHRITIS: RETHINKING OUR CLASSIFICATION

Background:In rheumatoid arthritis (RA), primary failure with biologic treatment may be understood as lack of initial clinical response, while secondary failure would be loss of effectiveness after an initial response. Despite these clinical concepts, there is no unifying operational definition of primary and secondary non-response to RA treatment in observational studies using real-world data. On top of data-driven challenges, when conceptualizing secondary non-responders, it is unclear if the mechanism behind loss of effectiveness after a brief initial response is similar to loss of effectiveness after previous benefit sustained over time.Objectives:This viewpoint aims to motivate discussion on how to define primary and secondary non-response in observational studies. Ultimately, we aim to trigger expert committees to develop standard terminology for these concepts.Methods:We discuss different methodologies for defining primary and secondary non-response in observational studies. To do so, we shortly overview challenges characteristic of performing observational studies in real-world data, and subsequently, we conceptualize whether treatment response should be a dichotomous classification (Primary response/non-response; Secondary response/non-response), or whether one should consider three response categories (Primary response/non-response; Primary sustained/non-sustained response; Secondary response/non-response).Results:RA or biologic registries are a common data source for studying treatment response in real-world data. While registries include disease-specific variables to assess disease progression, missing data, loss of follow-up, and visits restricted to the year or mid-year visit may present a challenge. We believe there is a general agreement to assess primary response within the first 6 month of treatment. However, conceptualizing secondary non-response, one could wonder if a patient with brief initial response and immediate loss of it should belong to the same response category as a patient who relapses after a period of prior benefit that was sustained over time. Until this concern is clarified, we recommend considering a period of sustained response as a pre-requisite for secondary failure. This would result in the following three categories: a) Primary non-response: Lack of response within the first 6 months of treatment; b) Primary sustained response: Maintenance of a positive effectiveness outcome for at least the first 12 months since treatment start; c) Secondary non-response: Loss of effectiveness after achieved primary sustained response. Figure 1 illustrates this classification through a decision tree. Since the underlying mechanisms for treatment failure may differ among the above-mentioned categories, we recommend to use the three-category classification. However, since this may pose additional methodological challenges in real-world data, optionally, a dichotomous 12-month time-point may be used to assess secondary non-response (unfavourable outcome after 12-months) in comparison to primary non-response or non-sustained response (unfavourable outcome within the first 12-months). Similarly, to study primary response, the solely 6-month timepoint may be used.Conclusion:A unified operational definition of treatment response will minimize heterogeneity among observational studies and help improve the ability to draw cross-study comparisons, which we believe would be of particular interest when identifying predictors of treatment failure. Thus, we hope to open the room for discussion and encourage expert committees to work towards a common approach to assess treatment primary and secondary non-response in RA in observational studies.Disclosure of Interests:Enriqueta Vallejo-Yagüe: None declared, Sreemanjari Kandhasamy: None declared, Edward Keystone Speakers bureau: Amgen, AbbVie, F. Hoffmann-La Roche Inc., Janssen Inc., Merck, Novartis, Pfizer Pharmaceuticals, Sanofi Genzyme, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb Company, Celltrion, Myriad Autoimmune, F. Hoffmann-La Roche Inc, Gilead, Janssen Inc, Lilly Pharmaceuticals, Merck, Pfizer Pharmaceuticals, Sandoz, Sanofi-Genzyme, Samsung Bioepsis, Grant/research support from: Amgen, Merck, Pfizer Pharmaceuticals, PuraPharm, Axel Finckh Speakers bureau: Pfizer, Eli-Lilly, Paid instructor for: Pfizer, Eli-Lilly, Consultant of: AbbVie, AB2Bio, BMS, Gilead, Pfizer, Viatris, Grant/research support from: Pfizer, BMS, Novartis, Raphael Micheroli Consultant of: Gilead, Eli-Lilly, Pfizer and Abbvie, Andrea Michelle Burden: None declared