Observational Study Medicine ® OPEN Effectiveness and persistence of golimumab as a second biological drug in patients with spondyloarthritis Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy A retrospective study wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/08/2023 ∗ Juan J. Alegre-Sancho, MD, PhDa, , Xavier Juanola, MD, PhDb, José M. Rodríguez-Heredia, MDc, Javier Manero, MDd, Ignacio Villa-Blanco, MDe, Ana Laiz, MD, PhDf, María J. Arteaga, MDg, Luis Cea-Calvo, MDg, Carlos M. González, MD, PhDh Abstract This observational, longitudinal retrospective, noncomparative study was designed to assess the persistence and effectiveness of golimumab as a second anti-tumor necrosis factor (TNF) drug in patients with spondyloarthritis requiring discontinuation from a first anti-TNF drug. Data were collected retrospectively for all patients with axial spondyloarthritis or psoriatic arthritis from 20 rheumatology clinics in Spain who started golimumab as a second anti-TNF drug between January 2013 and December 2015. Golimumab persistence was assessed with Kaplan-Meier survival analysis, and associated factors were assessed with Cox regression analysis. 210 patients started golimumab as a second anti-TNF drug: 131 with axial spondyloarthritis and 79 with psoriatic arthritis. In axial spondyloarthritis patients, the mean (standard deviation) Bath Ankylosing Spondylitis Disease Activity Index score at baseline was 5.5 (2.1), decreasing to 3.9 (2.0) at month 3 and 3.5 (2.0) at year 1, and remaining stable thereafter. In psoriatic arthritis patients, mean (standard deviation) baseline Disease Activity Score was 4.0 (1.3), reducing to 2.5 (1.2) at month 3 and to 2.2 (1.3) at year 1. Corresponding improvements were recorded from baseline in C-reactive protein levels and erythrocyte sedimentation rates. The probability of persistence of treatment with golimumab was 80% at year 1, 70% at year 2 and 65% at years 3 and year 4, and was similar in those who had stopped the first anti-TNF due to loss of efficacy or other reasons. Cox regression analysis showed that the probability of survival with golimumab was higher in patients with higher erythrocyte sedimentation rate, in patients with axial spondyloarthritis than with psoriatic arthritis, and in those who had discontinued adalimumab as first anti-TNF. Seventy-two patients (34.3%) discontinued golimumab during follow-up, 50 of them due to lack of efficacy. In patients with spondyloarthritis requiring discontinuation from a first anti-TNF drug, treatment with golimumab was effective and showed a high probability of persistence up to 4 years of treatment. Abbreviations: AS = ankylosing spondylitis, BASDAI = Bath Ankylosing Spondylitis Disease Activity Index, CI = confidence interval, CRP = C-reactive protein, DAS = disease activity score, ESR = erythrocyte sedimentation rate, PsA = psoriatic arthritis, RA = rheumatoid arthritis, SD = standard deviation, SpA = spondyloarthritis, TNF = tumor necrosis factor. Keywords: ankylosing spondylitis, anti- tumor necrosis factor, golimumab, psoriatic arthritis, spondyloarthritis, tumor necrosis factor inhibitor Editor: Raouf Hajji. This study was funded by Merck Sharp & Dohme Spain, a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA. Conflict of interest: Juan J Alegre-Sancho: speaker for MSD; Xavier Juanola: no conflicts of interest; José M Rodríguez-Heredia: board membership for Janssen, Sandoz and Sanofi, and speaker for BMS, UCB, Pfizer, Janssen, Novartis and Celgene; Javier Manero: no conflicts of interest; Ignacio Villa-Blanco: no conflicts of interest; Ana Laiz: board membership for Janssen, Novartis and Celgene, and speaker for Lilly, MSD, Janssen, Novartis and Celgene; María J Arteaga: full-time employee of Merck Sharp & Dohme Spain; Luis Cea-Calvo: full-time employee of Merck Sharp & Dohme Spain; Carlos M González: consultancy for MSD, Gilead, Pfizer, Roche, Novartis and Janssen, speaker for Roche, Novartis and Celgene, and travel and accommodation costs for meetings from Janssen, Pfizer and Roche. Supplemental Digital Content is available for this article. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. a Department of Rheumatology, Hospital Universitario Dr Peset, Valencia, b Rheumatology Unit, Hospital Universitari de Bellvitge, IDIBELL, L’Hospitalet de Llobregat, Barcelona, c Department of Rheumatology, Hospital Universitario de Getafe, Madrid, d Department of Rheumatology, Hospital Miguel Servet, Zaragoza, e Department of Rheumatology, Hospital de Sierrallana, Torrelavega, f Rheumatology Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, g Medical Affairs Department, Merck Sharp & Dohme, Madrid, h Department of Rheumatology, Hospital Universitario Gregorio Marañón, Complutense University, Madrid, Spain. ∗ Correspondence: Juan J. Alegre-Sancho, Department of Rheumatology, Hospital Universitario Dr Peset, Av. de Gaspar Aguilar, 90, 46017 Valencia, Spain (e-mail: txantxo@gmail.com). Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. How to cite this article: Alegre-Sancho JJ, Juanola X, Rodríguez-Heredia JM, Manero J, Villa-Blanco I, Laiz A, Arteaga MJ, Cea-Calvo L, González CM. Effectiveness and persistence of golimumab as a second biological drug in patients with spondyloarthritis: a retrospective study. Medicine 2021;100:13(e25223). Received: 30 March 2020 / Received in final form: 14 September 2020 / Accepted: 20 February 2021 http://dx.doi.org/10.1097/MD.0000000000025223 1 Alegre-Sancho et al. Medicine (2021) 100:13 Medicine 1. Introduction second biological drug (after discontinuation of a first anti-TNF drug), between January 2013 and December 2015, according to Spondyloarthritis (SpA) comprises several rheumatic diseases, standard prescribing information. The diagnosis of axial SpA or among which the most prevalent and studied are axial PsA was made according to clinical practice in Spain, where it is spondyloarthritis (axial SpA) and psoriatic arthritis (PsA). Both recommended to follow the Assessment of SpondyloArthritis diseases impact patient quality of life at an early age and are International Society criteria for classification of axial SpA,[11,12] associated with loss of productivity and sick leave.[1] Biological and the Classification Criteria for Psoriatic Arthritis criteria for drugs – initially inhibitors of tumor necrosis factor (TNF) alpha Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy PsA.[13] For patients presenting with mixed forms involving both and later drugs with other mechanisms of action – have changed axial and peripheral symptoms, investigators assigned them to the course of these diseases and improved patient quality of life. the dominant group fulfilling criteria. wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/08/2023 For patients with ankylosing spondylitis or nonradiographic axial SpA, notwithstanding the use of nonsteroidal antiinflam- matory drugs, the American College of Rheumatology, Spondy- 2.2. Ethics approval and consent to participate litis Association of America, and Spondyloarthritis Research and The study was approved by the Clinical Research Ethics Committee Treatment Network, and the European League Against Rheu- of the Hospital Universitari of Bellvitge, L’Hospitalet de Llobregat, matism, recommend the use of anti-TNF drugs;[2,3] for patients Barcelona, Spain (ref EPA003/17) as reference center, and then by with PsA, biological drugs are recommended when conventional the participating centers. Signed informed consent forms were therapy fails.[4] Whilst anti-TNF drugs are the most frequently obtained from all available patients for whom data were used in the used first biological drugs, the response declines over time in some study. Where patients could not be located to obtain consent, their patients, requiring a switch to another biological.[3,4] retrospective data were anonymized prior to inclusion. This was Most information on the clinical efficacy of anti-TNF drugs is approved by the Clinical Research Ethics Committees. derived from controlled clinical trials or observational studies in patients who failed on conventional non-biological therapy and were naïve to anti-TNF drugs. There is less reported experience of 2.3. Assessment criteria the mid- and long-term effectiveness of biological drugs as second The primary objective was to assess 1-, 2- and 3-year probability biologicals in patients who have discontinued a first anti-TNF of persistence (survival on treatment, or retention rate) on drug. golimumab and to explore possible variables associated with Golimumab is a human anti-TNF monoclonal antibody with longer persistence on treatment with golimumab. high affinity binding to soluble and transmembrane TNF.[5] It The following data were collected for stratified analyses: improves the signs and symptoms of disease in patients with active gender, smoking status, age above/below median, disease rheumatoid arthritis (RA), PsA and axial SpA [either non- duration above/below median, axial SpA compared to PsA radiographic SpA or ankylosing spondylitis (AS)], and in clinical patients, reason for discontinuation of first anti-TNF drug (loss of trials golimumab showed a high retention rate in biological-naïve efficacy versus other reasons), baseline C-reactive protein (CRP), patients with RA, PsA or SpA, with around 70% of patients still on erythrocyte sedimentation rate (ESR), human leukocyte antigen therapy after 5 years of treatment and with sustained efficacy.[6] (HLA) B27 status for axial SpA patients, presence or absence of However, except in RA – where the efficacy of golimumab after the radiographic erosions for PsA patients, prior anti-TNF drug used, failure of other anti-TNF drugs was studied in the prospective, presence or absence of concomitant immune disease and the controlled GO-AFTER study,[7] and a retrospective analysis of nature of concurrent medications. data from the LORHEN registry[8] – information on the The effectiveness of golimumab was assessed at baseline and effectiveness and persistence rate of golimumab as second-line after 3 months and 1 year, using the Bath Ankylosing Spondylitis treatment is scarce. In patients with axial SpA or PsA, information Disease Activity Index (BASDAI) for patients with axial on golimumab retention rates in biological non-naïve patients SpA,[14,15] and Disease Activity Score (DAS28) for patients with (second or further biological drug) comes from subgroups of 2 PsA,[16,17] according to the available information contained in studies in different lines of therapy.[9,10] clinical records. For patients lacking DAS28 assessment, Given the scarce information available, we focused our evolution of painful and swollen joints was recorded. In case research on the specific group of patients with spondyloarthro- patients presented with axial and peripheral symptoms, effec- pathies (axial SpA or PsA) treated with golimumab as a second tiveness was measured using the dominant disease assessment biological agent. Thus, the main objective of this retrospective criterion. Due to the retrospective nature of the study, flexible study was to assess the effectiveness of golimumab as a second windows of +/- 1 month for the 3-month assessment and of +/- 3 anti-TNF drug in patients with SpA (either axial SpA or PsA) who months for the 1-year assessment were permitted. discontinued a first anti-TNF drug. In particular, the study investigated the probability of persistence (retention rate of 2.4. Patient selection treatment with golimumab, or drug survival) over time and variables associated with higher persistence. Patients aged ≥18 years who started golimumab for SpA as a second anti-TNF drug between January 2013 and December 2. Patients and methods 2015 were included in the study if they had been treated successfully with a first anti-TNF drug for at least 3 months (i.e. 2.1. Study design the patient had obtained clinical benefit from a first anti-TNF drug) and discontinued it for 1 of the following reasons: The present study was an observational multicenter, longitudinal retrospective, and noncomparative study undertaken in 20 (1) disease reactivation (loss of response or secondary failure rheumatology clinics in Spain. Data were collected for all SpA after the patient had responded), (axial SpA or PsA) patients who had initiated golimumab as a (2) patient discomfort, poor tolerability or adverse event or 2 Alegre-Sancho et al. Medicine (2021) 100:13 www.md-journal.com (3) physician and patient agreement to substitute for patient tion and each background disease. Patients who were still on convenience or preference, with no therapy failure. golimumab at the study visit and those who had not discontinued Patients considered to have had a primary failure to a first anti- golimumab, but for whom data were not available from a specific TNF drug (patient did not show clinical improvement on the first time point (due to death, emigration to other region or country, anti-TNF) were excluded, as were patients who, during the or end of data availability for other reasons), were right-censored. retrospective study period, participated in a clinical trial with Comparisons of survival between different subgroups were antirheumatic drugs. evaluated with the log-rank test. Cox-regression analyses were Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy Patients were identified in the rheumatology clinic records or performed to identify factors related to the probability of hospital pharmacy registry, and all patients fulfilling the criteria persistence on golimumab. R Software (version 3.4.3, R Core Team, 2017) and the RStudio interface (version 1.1.419) were wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/08/2023 were included in the study. All patients still on golimumab signed informed consent before being enrolled into the study. Patients used for statistical analyses. who had already discontinued golimumab were identified, localized and also invited to participate. For patients unable to 3. Results attend the rheumatology clinic (e.g. due to death, change of address or other reason), anonymized data were recorded from 3.1. Patient demographics and baseline condition their clinical records. This was done to avoid bias in the Between January 2013 and December 2015, 210 patients from 20 evaluation of the primary objective (probability of persistence on hospital rheumatology clinics had initiated golimumab as a second golimumab). For the same reason, it was mandatory that centers anti-TNF drug for the treatment of axial SpA (n = 131; 28 with included all golimumab patients in the study, that is, patients still non-radiographic axial SpA and 103 with ankylosing spondylitis) receiving golimumab and those who had discontinued golimu- or PsA (n = 79). Five patients from 1 center (which failed to include mab. Centers that could not fulfil this commitment were excluded all golimumab patients) were excluded from all analyses. from participation to avoid selection bias. Mean (standard deviation [SD]) age was 49.0 (12.1) years. General demographic data, disease-related data, previous anti- There were 126 men (60.0%) and 84 women (40.0%). Median TNF drug use and reason for discontinuation, and baseline disease duration prior to golimumab initiation was 7 years disease activity (prior to golimumab initiation) were collected (interquartile range: 3–13). Baseline characteristics of the from the clinical records. The first date of golimumab injection population are displayed in Table 1. Previous anti-TNF therapy and last observation date with golimumab were recorded to was etanercept (n = 53, 25.2%), adalimumab (n = 83, 39.5%), assess the primary objective of the study. For patients who infliximab (n = 73, 34.8%) and certolizumab (n = 1, 0.48%) permanently discontinued golimumab, the reason for discontin- (Table 2). Reasons for discontinuation of the first anti-TNF drug uation was classified as: were: loss of efficacy (n = 149, 71.0%), poor tolerability or (1) primary failure (the patient never responded to golimumab), adverse event (n = 24, 11.4%) and patient or physician preference (2) disease reactivation (secondary failure, loss of response after (n = 37, 17.6%). golimumab was initially efficacious), (3) poor tolerability, 3.2. Effect of golimumab on disease activity (4) adverse event, (5) inactive disease or low disease activity or In axial SpA patients, mean (SD) BASDAI at baseline (n = 78) was (6) other reason. 5.5 (2.1). It was rapidly reduced to a mean of 3.9 (2.0) at month 3 and 3.5 (2.0) at year 1, and remained stable thereafter. The Patients who stopped golimumab temporarily (i.e. due to percentage of patients with a BASDAI 50 response was 69.1% at infection, programmed surgery or other reason), but resumed it month 3 and 58.5% at year 1; the percentages with BASDAI 4 successfully later on (grace period, 2 months), were considered as were 53.2% and 60.4%, respectively. Baseline mean (SD) CRP continuing on golimumab. (n = 121) was 0.9 (1.7) mg/dL and was reduced to 0.3 (0.6) mg/dL at month 3 and 0.5 (1.5) mg/dL at year 1. Similarly, ESR (n = 119) decreased from baseline 22.4 (24.8) mm/h to 13.0 (12.2) and 10.8 2.5. Statistical analysis (9.8) mm/h at month 3 and year 1, respectively. The sample size was calculated to assess the primary objective, In PsA patients, mean (SD) DAS28 (n = 28) was 4.0 (1.3) at and due to the lack of information on persistence (retention rate) baseline and was reduced to 2.5 (1.2) at month 3 and to 2.2 (1.3) of a second anti TNF alpha after discontinuation of a first anti at year 1. The mean number of painful joints (n = 59) decreased TNF alpha in spondyloarthropathies at the time of the study from 4.2 (4.7) at baseline to 2.1 (2.2) and 1.1 (1.9) at month 3 and design, a 50% retention rate was selected as the percentage year 1, respectively, and the mean number of swollen joints from requiring the highest sample size. With a confidence level (level 1- 2.4 (2.7) to 1.3 (2.3) and 0.7 (2.0), respectively. Baseline mean alpha) of 95% and 7% precision, the estimated sample size was (SD) CRP (n = 68) was 1.0 (2.1) mg/dL and was reduced to 0.4 196 patients with SpA. The target sample size was increased by (0.6) at month 3 and 0.3 (0.5) mg/dL at year 1. ESR (n = 66) 15% (to 231 patients) to compensate for possible missing data. decreased from 18.9 (20.0) mm/h at baseline to 14.1 (17.7) and No stratification by background disease (axial SpA versus PsA) 12.9 (13.4) mm/h at month 3 and year 1, respectively. was done during recruitment since centers were obliged to recruit all patients, whether or not balanced. 3.3. Probability of persistence of treatment with Summary descriptive statistics are presented as means with golimumab standard deviations, or medians with percentiles and percentages when applicable. The probability of persistence (drug survival) Patients were followed up for a mean (SD) period of 29.8 (16.5) was assessed by Kaplan-Meier analysis, for the overall popula- months: axial SpA patients, 30.2 (17.1) months; PsA patients, 3 Alegre-Sancho et al. Medicine (2021) 100:13 Medicine Table 1 compared with those discontinuing for other reasons (P = .750, General characteristics of patients at golimumab initiation. Fig. 2B; Supplemental Digital Content Table 2, http://links.lww. com/MD/F976). Axial SpA PsA There were no differences in the probability of persistence by (n = 131) (n = 79) gender (P = .313), age above/below the median (49 years, p = Age 1.000), smoking status (P = .381), or disease duration above/ yr, mean (SD) 48.0 (12.3) 50.0 (11.7) below the median (80 months, P = .985). Gender Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy The probability of persistence with golimumab was slightly Male, n (%) 83 (63.4) 43 (54.4) Female, n (%) 48 (36.6) 36 (45.6) higher in patients with CRP values above the median (0.28 mg/ dL) at the time of golimumab initiation compared to those with wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/08/2023 Duration of disease Years, median (IQR) 8.0 (4.0–16.0) 6.0 (3.0–9.5) values below the median (P = .175, Fig. 2C; Supplemental Digital Smoking habit Content Table 3, http://links.lww.com/MD/F977), as well as in Never, n (%) 47 (42.3) 33 (55.9) those with ESR above the median when golimumab was started Current, n (%) 40 (36.0) 9 (15.3) (16 mm/h) compared to those with values below the median Past, n (%) 24 (21.6) 17 (28.8) (P = .011, Fig. 2D; Supplemental Digital Content Table 4, http:// Not available, n 20 20 links.lww.com/MD/F978). HLA B27 status There were no differences in the probability of persistence with Positive, n (%) 95 (76.7) 8 (17.8) regard to the HLA B27 status in patients with axial SpA, or with Negative, n (%) 29 (23.4) 37 (82.2) Not available, n 7 34 regard to the presence or not of radiographic erosions in PsA Concomitant immune-mediated diseases patients. The probability of persistence was higher in those Psoriasis, n (%) 12 (9.2) 38 (48.1) previously treated with adalimumab as first anti-TNF (continua- Inflammatory Bowel Disease, n (%) 6 (4.6) 0 (0.0) tion rate at year 3: 73%) compared to in those who had stopped Uveitis, n (%) 22 (16.8) 1 (1.3) infliximab (63%) or etanercept (55%), but the difference was not Concomitant medication statistically significant (P = .070, Figure 2e; Supplemental Digital NSAIDs 101 (77.1) 45 (57.0) Content Table 5, http://links.lww.com/MD/F979). Steroids, n (%) 13 (9.9) 25 (31.7) Finally, the probability of persistence did not differ between Non-biological DMARD 41 (31.3) 52 (65.8) patients with or without other concomitant immune disease Methotrexate, n 29 36 (P = .731) and was also similar in those who were or were not Sulfasalazine, n 11 6 Leflunomide, n 2 13 treated with glucocorticoids, nonsteroidal anti-inflammatory drugs or non-biological disease-modifying antirheumatic drugs DMARD = disease modifying antirheumatic drug, HLA = human leukocyte antigen, IQR = interquartile (P = .710, .490, and .657, respectively). Persistence was slightly, range, NSAIDs = nonsteroidal antiinflammatory drugs, SD = standard deviation. but non-significantly, higher (69% versus 63% at both year 3 and year 4) in those treated with methotrexate (P = .254; Supplemen- 29.0 (16.5) months. During this period, 72 of 210 patients tal Digital Content Table 6, http://links.lww.com/MD/F980). In a (34.3%) discontinued golimumab: 39 of 131 axial SpA patients post hoc analysis, persistence with/without methotrexate in (29.8%) and 33 of 79 PsA patients (41.8%). The probability of patients with axial SpA or PsA was, in both cases, slightly but persistence of treatment with golimumab (survival of golimumab non-significantly higher in patients treated with methotrexate therapy) since initiation was 80% at year 1 (95% confidence compared to those without methotrexate (P = .202 for axial SpA interval [CI] 75–86), 70% at year 2 (95% CI 64–77), and 65% at patients; P = .313 for PsA patients). year 3 and year 4 (95% CI 59–72) (Fig. 1). The probability of persistence was slightly but non-significantly higher in patients with axial SpA than in those with PsA (P = .121, Fig. 2A; Supplemental Digital Content Table 1, http://links.lww.com/ MD/F975). The probability curves were very similar in patients who discontinued their first anti-TNF due to loss of efficacy Table 2 Characteristics of treatment with the first anti-TNF. Axial SpA PsA (n = 131) (n = 79) First anti-TNF Adalimumab, n (%) 55 (42.0) 28 (35.4) Etanercept, n (%) 26 (19.9) 27 (34.2) Infliximab, n (%) 50 (38.1) 23 (29.1) Certolizumab, n (%) – 1 (1.3) Duration of treatment with the first anti-TNF Months, median (SD) 35.0 (10.0–73.0) 28.0 (10.5–59.0) Reason for discontinuation Loss of efficacy (disease reactivation), n (%) 98 (74.8) 51 (64.5) Adverse event or intolerance, n (%) 11 (8.4) 13 (16.5) Patients and/or physician preference, n (%) 22 (16.8) 15 (19.0) Figure 1. Probability of persistence with golimumab treatment in all patients. SD = standard deviation, TNF = tumor necrosis factor. 4 Alegre-Sancho et al. Medicine (2021) 100:13 www.md-journal.com Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/08/2023 Figure 2. Probability of persistence with golimumab treatment in patients (A) diagnosed with axial SpA (red) or PsA (blue); (B) discontinuing the first anti-TNF drug for loss of efficacy (red) versus for other reasons (blue); (C) whose baseline C-reactive protein (CRP) level was over (red) or under (blue) the median value; (D) whose baseline erythrocyte sedimentation rate (ESR) level was over (red) or under (blue) the median value; (E) treated with adalimumab (red), etanercept (green) or infliximab (blue) as first anti-TNF drug. 3.4. Multivariate analysis non-naïve patients in second or further lines of therapy.[9,10] Our Cox-regression analysis including CRP and ESR showed that study assessed, specifically, the effectiveness and persistence patients with ESR above the median at golimumab initiation were (survival on therapy or retention rate) of golimumab as a second less likely to discontinue golimumab than those below the median anti-TNF drug in patients with SpA (axial SpA or PsA) who had (hazard ratio [HR], 0.59, 95% CI 0.36–0.95; P = .031). CRP was discontinued a first anti-TNF drug, with up to 4 years of follow-up. not statistically related to discontinuation of golimumab in this Golimumab was effective for the treatment of these patients in the model (Table 3). short term, reducing disease activity (BASDAI and DAS28) and A second model, including as predictive variables age, gender, inflammatory markers (CRP and ESR). In the long term, methotrexate use and those variables with P-values .2 in the there was a high rate of retention of golimumab therapy (65%) bivariate analysis (diagnosis, previous anti-TNF drug, CRP and ESR after 3–4 years. Golimumab showed similar short-term effective- when golimumab was started), showed that patients who had stopped treatment with adalimumab had a lower probability of discontinua- tion of golimumab therapy than those previously treated with Table 3 etanercept (HR, 0.28, P= .012). Similarly, patients with axial SpA had Cox-regression analysis. Hazard ratios for risk of discontinuation a lower probability of discontinuation of golimumab therapy of golimumab. compared to PsA patients (HR, 0.44, P= .063) [Table 3, Model 2]. 95% Hazard Confidence 3.5. Reasons for discontinuation of golimumab ratio interval P Model 1 Overall, 72 of 210 patients (34.3%) discontinued golimumab ESR (above vs below the median) 0.59 0.36–0.95 .031 during the follow-up. The reasons for discontinuation were CRP (above vs below the median) 0.74 0.48–1.19 .217 primary failure (n = 21), disease reactivation or secondary failure Model 2 (n = 29), poor tolerability (n = 4), adverse events (n = 10) and Gender (women vs men) 0.58 0.25–1.34 .206 patient-physician agreement due to inactive disease or low Age (above vs below the median) 1.68 0.75–3.76 .208 disease activity (n = 8). Reasons for discontinuation did not differ Diagnosis (axial SpA vs PsA) 0.44 0.18–1.05 .063 between patients with axial SpA or those with PsA. Previous anti-TNF (adalimumab vs etanercept) 0.28 0.10–0.76 .012 Previous anti-TNF (infliximab vs etanercept) 0.45 0.18–1.16 .098 Use of methotrexate (yes vs no) 0.55 0.25–1.23 .145 4. Discussion ESR (above vs below the median) 0.53 0.24–1.19 .123 Previous observational studies have described the golimumab CRP (above vs below the median) 0.60 0.26–1.37 .225 retention rate in SpA patients previously treated with other CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; PsA = psoriatic arthritis; SpA = biological drugs as subgroups of larger cohorts without stratifying spondyloarthritis; TNF = tumor necrosis factor. 5 Alegre-Sancho et al. Medicine (2021) 100:13 Medicine ness in patients with axial SpA or PsA, but long-term persistence patients, reported drug survival rates with golimumab after 3 seemed better in patients with axial SpA. years of 76% in AS patients, 60% in RA patients, and 53% in The clinical development of golimumab comprised clinical PsA patients.[26] Regarding the use of golimumab as a second trials in patients with RA, axial SpA and PsA who had failed anti-TNF, a recent retrospective analysis of data from the conventional non-biological treatment, including disease-modi- LORHEN registry showed that the 2-year retention rate was fying antirheumatic drugs (methotrexate), in RA. For patients higher with golimumab than with etanercept or adalimumab with RA (but not axial SpA or PsA), clinical trials also considered (53.4%, 39.8%, and 31.2%, respectively), and there was a lower Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy patients who had failed on previous biological medication. Thus, discontinuation rate due to adverse events in patients treated with the current study provides specific information on the effective- golimumab.[8] Iannone et al described 2-year persistence rates of ness of golimumab in a subset of patients who had not been 67.3% and 72.2% for the overall naïve and non-naïve arthritis wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/08/2023 included in clinical trials, and suggests that, in patients with population, with no differences for patients with axial SpA or spondyloarthropathies who need to discontinue using a first anti- PsA,[9] and recently Michelsen et al. reported a 4-year retention TNF, switching to golimumab is a suitable option. rate of around 30% in non-naïve golimumab patients,[10] but A review of English-language publications of clinical trials they did not stratify by second or further line of therapy. Finally, a which reported on the efficacy of second-line biologicals retrospective analysis of the Spanish Registry of Biological Drugs concluded that, for PsA and AS patients failing a first anti- in Rheumatic Diseases reported high continuation rates of TNF drug, switching to a second is advisable.[18] Indeed, after the golimumab as a second biological drug in rheumatic diseases up failure of a first anti-TNF, therapeutic guidelines describe the to 4 years of follow-up (up to 59.2% at year 4) including a small option of switching to another biological drug; either another sample of patients with axial SpA (n = 52) or PsA (n = 33).[27] anti-TNF or a drug with a different mechanism of action.[2–4] In Interestingly, in the current study, golimumab seemed to be particular, the recently updated 2019 American College of similarly effective in patients who discontinued the first anti-TNF Rheumatology, Spondylitis Association of America and Spon- drug due to loss of efficacy compared with in those who dyloarthritis Research and Treatment Network guidelines discontinued for other reasons. Others have also reported no conditionally recommend a second anti-TNF after discontinua- difference in survival analysis with a second anti-TNF drug tion of a first anti-TNF due to secondary nonresponse in axial according to reason for discontinuation of the first anti-TNF spondyloarthritis, although with a very low level of evidence.[2] drug.[10] This finding supports the use of golimumab in these For patients with primary nonresponse, the guidelines recom- patients after failure or discontinuation of a first anti-TNF drug mend switching to a drug with another mechanism of action, also independently of the reason, except when discontinuation was with a very low level of evidence.[2] Thus, data on the due to primary nonresponse. Higher retention of golimumab was effectiveness of different biologicals after discontinuation of seen in patients with higher CRP or, significantly, higher ESR one anti-TNF drug are welcome. Recent research indicates that levels. These patients, with higher markers of inflammation at therapeutic drug monitoring (TDM) with serum level measure- baseline, would seem better suited for obtaining clinical benefit ment and antidrug antibody detection could potentially be a from anti-TNF drugs. It has previously been shown that increased useful tool for the individualization of biological therapy[19–21] CRP levels and higher BASDAI scores are valuable predictors of and selection of a second or subsequent biological drug. clinical response to anti-TNF drugs.[28] In the GO-AHEAD study, In the present study, probabilities of persistence with the benefits of golimumab were not apparent in patients with golimumab as a second anti-TNF drug in SpA patients were normal CRP and no inflammatory signs by magnetic resonance high and at least as good as data reported with other anti-TNF imaging.[29] In the present study, mean CRP was relatively low drugs, whether as first-line or subsequent lines of anti-TNF because all patients had been previously treated with a biological therapy. Among 990 anti-TNF treatment courses (with adali- drug and because up to 29% of patients were discontinued for mumab, infliximab, etanercept or golimumab) as first, second or reasons other than disease reactivation. third anti-TNF in 765 patients with PsA treated in Finland The higher probability of continuation with golimumab in between 2004 and 2014, the probability of persistence was 80% patients who had received adalimumab compared with that in at 1 year and 72% at 2 years.[22] The probability of discontinua- patients who had previously received other anti-TNF drugs tion of anti-TNF drug was similar whether it was the first or a requires further investigation with a larger sample of patients. subsequent drug.[22] Similarly, in a review of randomized The slightly better persistence seen with golimumab when used in controlled trials of anti-TNF drugs for axial SpA or AS (but combination with methotrexate is consistent with earlier mostly AS), across all anti-TNF drugs, drug survival was 70% to reports.[30] 80% after 1 year, 65% to 75% after 2 years and 55% at 5 Possible explanations for these high retention rates with years.[23] In AS patients, across all anti-TNF drugs, median drug golimumab as a second anti-TNF could relate to the convenience survival was 3.1 years for a first anti-TNF drug, 1.6 years for a of a once-monthly, self-administered medication,[22] and/or the second and 1.8 years for a third; 2-year drug survival was 58%, fact that the drug was well tolerated (only 6.7% of patients 47%, and 49%, respectively (based on data from the Danish discontinued golimumab for poor tolerability or adverse effects in nationwide DANBIO registry[24]).[23] In contrast, in a longer- the present study). From some studies it appears that, due to the term analysis of patients with axial SpA receiving anti-TNF drugs molecular characteristics of golimumab, there is a lower at 2 specialist centers in the UK, median drug survival was 10.2 frequency of anti-drug antibody formation,[21] and this may years for the first or index anti-TNF drug (n = 651) and 5.5 years also contribute to the good retention rate of golimumab as a for a second anti-TNF drug after switching from the index drug second biological drug. Because persistence with the same anti- (n = 105). Drug survival was not influenced by the choice of anti- TNF drug in second-line treatment decreases the overall disease- TNF drug.[25] associated costs compared with non-persistence, this aspect also With regard to studies which have focused on golimumab, a merits consideration by physicians and payers when choosing a retrospective, observational study in Greece involving 328 biological drug.[31] 6 Alegre-Sancho et al. Medicine (2021) 100:13 www.md-journal.com There were a number of limitations to this study. Because data Río Hortega, Valladolid), Noelia Álvarez and Tomás Ramón were collected retrospectively, disease activity (BASDAI and DAS Vázquez (Hospital Universitario Lucus Agusti, Lugo), César 28) was not reported adequately in the clinical records for all Antonio Egües (Hospital Universitario de Donostia, San patients. Functional and motion activity indexes (Bath Ankylos- Sebastián), Belén Serrano (Hospital Universitario Gregorio ing Spondylitis Functional Index, Bath Ankylosing Spondylitis Marañón, Madrid), Ángel Aragón and Ángel Jaime Zubieta Metrology Index), and other currently important activity indices (Hospital Universitario de Getafe), Ana Milena (Hospital de la like Ankylosing Spondylitis Disease Activity Score or Disease Santa Creu i Sant Pau, Barcelona), Juan Víctor Tovar (Hospital Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy Activity for Psoriatic Arthritis, were not reported in the clinical General Universitario de Elche), Victoria N uñez and Ana Sendra records, so accurate information on disease evolution was (Hospital Universitario Doctor Pesset, Valencia), Enrique Raya limited. Similarly, data to calculate currently used indices, such as and Cristina Cano (Hospital Universitario San Cecilio, Granada), wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/08/2023 minimal disease activity in PsA, were also lacking, and body mass Rosario Ibáñez and Ricardo Gutiérrez (Complejo Hospitalario index data, an important variable, were not collected in many de Navarra, Pamplona), Ches us Beltrán, Álvaro Lesta, Marta clinical records and, therefore, could not be analyzed. Previous Medrano and Carlos Vázquez (Hospital Universitario Miguel studies have shown a relationship between overweight and Servet, Zaragoza), Jordi Pons (Hospital Royo Villanova, obesity with poorer clinical outcomes and lower retention rate of Zaragoza), Rosa Roselló and Blanca García (Hospital General biological drugs,[32,33] but unfortunately we could not analyze San Jorge, Huesca), Emma Beltrán, Carolina Pérez, Jone the impact of body mass index in our study. As real-world data Llorente, Tarek Carlos Salman-Monte, Luciano Polino and are becoming indispensable for understanding the effectiveness of Jordi Monfort (Hospital del Mar, Barcelona), Sara García drugs in different populations and guiding the best therapeutic Carazo, Irene Monjo and Diana Peiteado (Hospital Universitario decisions, standardization of data collection among different La Paz, Madrid). clinics or regions/countries is needed to facilitate obtaining this important information more accurately. The absence of Author contributions radiographic analysis meant that it was not possible to confirm whether the clinical effectiveness of golimumab in these patients Juan J Alegre-Sancho, Xavier Juanola, María J Arteaga, Luis was associated with reduced radiographic damage or progres- Cea-Calvo and Carlos M González designed the study. Juan J sion. Also, whilst we considered some predictive factors, it would Alegre-Sancho, Xavier Juanola, and Carlos M González be interesting for future research to assess other aspects such as interpreted the results. Juan J Alegre-Sancho, Xavier Juanola, the type of arthritis in PsA (e.g. polyarthritis or oligoarthritis, María J Arteaga, Luis Cea-Calvo and Carlos M González drafted enthesitis), psoriasis severity, extra-articular involvement such as the manuscript. José M Rodríguez-Heredia, Javier Manero, uveitis or inflammatory bowel disease, and other comorbidities, Ignacio Villa-Blanco and Ana Laiz made substantial contribu- for which a larger sample size of patients will be needed. In this tions to the draft manuscript. All authors reviewed and approved case, the sample size was limited, precluding the identification of the final version of the manuscript. Authors from the sponsor stronger associations. In particular, the influence of methotrexate (MSD Spain) participated in the study design, statistical analysis on long-term effectiveness cannot be ruled out. planning and in drafting the manuscript. Changing from 1 biological drug to another has been reported Conceptualization: Juan J Alegre-Sancho, Xavier Juanola, José to be associated with an increase in treatment costs.[31,34] M Rodríguez-Heredia, Javier Manero, Ignacio Villa-Blanco, Nonetheless, treatment switching is required (and recommended) Ana Laiz, María J Arteaga, Luis Cea-Calvo, Carlos M where there is treatment failure or intolerance. Except for patients González. with primary nonresponse to anti-TNF drugs, starting a second Data curation: Juan J Alegre-Sancho, Xavier Juanola, María J anti TNF drug is supported by current recommendations.[2–4] Arteaga, Luis Cea-Calvo and Carlos M González. Choosing a subsequent anti-TNF drug with a high survival or Formal analysis: Juan J Alegre-Sancho, Xavier Juanola, María J persistence rate is, therefore, an important factor in the Arteaga, Luis Cea-Calvo and Carlos M González. economics of patient management for patients with rheumatic Funding acquisition: María J Arteaga, Luis Cea-Calvo. disease. Golimumab was effective and showed a high probability Investigation: Juan J Alegre-Sancho, Xavier Juanola, José M of persistence as a second anti-TNF drug in patients with SpA Rodríguez-Heredia, Javier Manero, Ignacio Villa-Blanco, Ana who need to discontinue the use of a first anti-TNF drug for Laiz, María J Arteaga, Luis Cea-Calvo, Carlos M González. reasons other than primary nonresponse. Methodology: Juan J Alegre-Sancho, Xavier Juanola, María J Arteaga, Luis Cea-Calvo and Carlos M González. Project administration: María J Arteaga, Luis Cea-Calvo, Carlos Acknowledgments M González, Laura Perez (on behalf of the authors). Study implementation and statistical analysis were conducted by Resources: María J Arteaga, Luis Cea-Calvo. SERMES CRO, Spain. Medical writing assistance was provided Software: María J Arteaga, Luis Cea-Calvo. by Jon Monk and David P. Figgitt PhD, ISMPP CMPP, Content Supervision: Juan J Alegre-Sancho, Xavier Juanola, María J Ed Net, with funding from Merck Sharp & Dohme Spain. Special Arteaga, Luis Cea-Calvo and Carlos M González. thanks to the study coordinators, Beatriz Ramos, Sabela Validation: Juan J Alegre-Sancho, José M Rodríguez-Heredia, Fernández and Yvonne Mestre, Medical Affairs, Merck Sharp Javier Manero, María J Arteaga, Luis Cea-Calvo, Carlos M & Dohme Spain. González. List of investigators: The authors want to acknowledge the Visualization: Juan J Alegre-Sancho, Xavier Juanola, Ignacio participation of the following investigators in the study: María Villa-Blanco, Ana Laiz, María J Arteaga, Luis Cea-Calvo, Martín (Hospital Universitario 12 de Octubre, Madrid), Miriam Carlos M González. Retuerto, Antía Crespo and Carlota Íñiguez (Hospital Uni- Writing – original draft: Juan J Alegre-Sancho, Xavier Juanola, versitario de León), José Manuel Martín (Hospital Universitario María J Arteaga, Luis Cea-Calvo and Carlos M González. 7 Alegre-Sancho et al. Medicine (2021) 100:13 Medicine Writing – review & editing: Juan J Alegre-Sancho, Xavier tion in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8. Juanola, José M Rodríguez-Heredia, Javier Manero, Ignacio [17] Wells G, Becker JC, Teng J, et al. Validation of the 28-joint Villa-Blanco, Ana Laiz, María J Arteaga, Luis Cea-Calvo, Disease Activity Score (DAS28) and European League Against Carlos M González. Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and compari- son with the DAS28 based on erythrocyte sedimentation rate. Ann References Rheum Dis 2009;68:954–60. [18] Cantini F, Niccoli L, Nannini C, et al. Second-line biologic therapy Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy [1] Garrido-Cumbrera M, Hillmann O, Mahapatra R, et al. Improving the optimization in rheumatoid arthritis, psoriatic arthritis, and ankylosing management of psoriatic arthritis and axial spondyloarthritis: round- spondylitis. Semin Arthritis Rheum 2017;47:183–92. table discussions with healthcare professionals and patients. Rheumatol [19] Balsa A, Sanmarti R, Rosas J, et al. Drug immunogenicity in patients with wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/08/2023 Ther 2017;4:219–31. inflammatory arthritis and secondary failure to tumour necrosis factor [2] Ward MM, Deodhar A, Gensler LS, et al. 2019 Update of the American inhibitor therapies: the REASON study. Rheumatology (Oxford) College of Rheumatology/Spondylitis Association of America/Spondy- 2018;57:688–93. loarthritis Research and Treatment Network Recommendations for the [20] Bornstein G, Lidar M, Langevitz P, et al. The prevalence and clinical Treatment of Ankylosing Spondylitis and Nonradiographic Axial effect of immunogenicity of TNF-(blockers in patients with axial Spondyloarthritis. Arthritis Care Res (Hoboken) 2019;71:1285–99. spondyloarthritis. Clin Exp Rheumatol 2018;36:228–32. [3] Van der Heijde D, Ramiro S, Landewé R, et al. 2016 update of the ASAS- [21] Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of biologics in chronic EULAR management recommendations for axial spondyloarthritis. Ann inflammatory diseases: a systematic review. BioDrugs 2017;31:299–316. Rheum Dis 2017;76:978–91. [22] Aaltonen K, Heinonen A, Joensuu J, et al. Effectiveness and drug survival [4] Gossec L, Smolen JS, Ramiro S, et al. European League Against of TNF-inhibitors in the treatment of psoriatic arthritis: a prospective Rheumatism (EULAR) recommendations for the management of cohort study. Semin Arthritis Rheum 2017;46:732–9. psoriatic arthritis with pharmacological therapies: 2015 update. Ann [23] Corbett M, Soares M, Jhuti G, et al. Tumour necrosis factor-(inhibitors Rheum Dis 2016;75:499–510. for ankylosing spondylitis and non-radiographic axial spondyloarthritis: [5] Zhou H, Jang H, Fleischmann RM, et al. Pharmacokinetics and safety of a systematic review and economic evaluation. Health Technol Assess golimumab, a fully human anti-TNF-alpha monoclonal antibody, in 2016;20:1–334. v-vi. subjects with rheumatoid arthritis. J Clin Pharmacol 2007;47:383–96. [24] Glintborg B, Østergaard M, Krogh NS, et al. Clinical response, drug [6] Tahir Z, Kavanaugh A. The role of golimumab in inflammatory arthritis. survival and predictors thereof in 432 ankylosing spondylitis patients A review of the evidence. Ther Adv Musculoskelet Dis 2018;10:181–94. after switching tumour necrosis factor ( inhibitor therapy: results from [7] Smolen JS, Kay J, Doyle M, et al. Golimumab in patients with active the Danish nationwide DANBIO registry. Ann Rheum Dis rheumatoid arthritis after treatment with tumor necrosis factor ( 2013;72:1149–55. inhibitors: findings with up to five years of treatment in the multicenter, [25] Yahya F, Gaffney K, Hamilton L, et al. Tumour necrosis factor inhibitor randomized, double-blind, placebo-controlled, phase 3 GO-AFTER survival and predictors of response in axial spondyloarthritis-findings from study. Arthritis Res Ther 2015;17:14. a United Kingdom cohort. Rheumatology (Oxford) 2018;57:619–24. [8] Favalli EG, Sinigaglia L, Becciolini A, et al. Two-year persistence of [26] Thomas K, Flouri I, Repa A, et al. High 3-year golimumab survival in golimumab as second-line biologic agent in rheumatoid arthritis as patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic compared to other subcutaneous tumor necrosis factor inhibitors: real- arthritis: real world data from 328 patients. Clin Exp Rheumatol life data from the LORHEN registry. Int J Rheum Dis 2018;21:422–30. 2018;36:254–62. [9] Iannone F, Santo L, Anelli MG, et al. Golimumab in real-life settings: 2 [27] Hernandez MV, Sanchez-Piedra C, Garcia-Magallon B, et al. Factors Years drug survival and predictors of clinical outcomes in rheumatoid associated with long-term retention of treatment with golimumab in a arthritis, spondyloarthritis, and psoriatic arthritis. Semin Arthritis real-world setting: an analysis of the Spanish BIOBADASER registry. Rheum 2017;47:108–14. Rheumatol Int 2019;39:509–15. [10] Michelsen B, Sexton J, Wierød A, et al. Four-year follow-up of [28] Rudwaleit M, Listing J, Brandt J, et al. Prediction of a major clinical inflammatory arthropathy patients treated with golimumab: data from response (BASDAI 50) to tumour necrosis factor alpha blockers in the observational multicentre NOR-DMARD study. Semin Arthritis ankylosing spondylitis. Ann Rheum Dis 2004;63:665–70. Rheum 2020;50:12–6. [29] Sieper J, van der Heijde D, Dougados M, et al. A randomized, double- [11] Rudwaleit M, van der Heijde D, Landewé R, et al. The development of blind, placebo-controlled, sixteen-week study of subcutaneous golimu- Assessment of SpondyloArthritis international Society classification mab in patients with active nonradiographic axial spondyloarthritis. criteria for axial spondyloarthritis (part II): validation and final selection. Arthritis Rheumatol 2015;67:2702–12. Ann Rheum Dis 2009;68:777–83. [30] Behrens F, Cañete JD, Olivieri I, et al. Tumour necrosis factor inhibitor [12] Rudwaleit M, van der Heijde D, Landewé R, et al. The Assessment of monotherapy vs combination with MTX in the treatment of PsA: a SpondyloArthritis International Society classification criteria for periph- systematic review of the literature. Rheumatology (Oxford) 2015;54: eral spondyloarthritis and for spondyloarthritis in general. Ann Rheum 915–26. Dis 2011;70:25–31. [31] Dalén J, Svedbom A, Black CM, et al. Second-line treatment persistence and [13] Taylor W, Gladman D, Helliwell P, et al. Classification criteria for costs among patients with immune-mediated rheumatic diseases treated with psoriatic arthritis: development of new criteria from a large international subcutaneous TNF-alpha inhibitors. Rheumatol Int 2017;37:2049–58. study. Arthritis Rheum 2006;54:2665–73. [32] Lopalco G, Venerito V, Cantarini L, et al. Different drug survival of first [14] Calin A, Garrett S, Whitelock H, et al. A new approach to defining line tumour necrosis factor inhibitors in radiographic and non- functional ability in ankylosing spondylitis: the development of the Bath radiographic axial spondyloarthritis: a multicentre retrospective survey. Ankylosing Spondylitis Functional Index. J Rheumatol 1994;21:2281–5. Clin Exp Rheumatol 2019;37:762–7. [15] Garrett S, Jenkinson T, Kennedy LG, et al. A new approach to defining [33] di Minno MN, Peluso R, Iervolino S, et al. Obesity and the prediction of disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis minimal disease activity: a prospective study in psoriatic arthritis. Disease Activity Index. J Rheumatol 1994;21:2286–91. Arthritis Care Res 2013;65:141–7. [16] Prevoo ML, van ’t Hof MA, Kuper HH, et al. Modified disease activity [34] Gu T, Mutebi A, Stolshek BS, et al. Cost of biologic treatment persistence or scores that include twenty-eight-joint counts. Development and valida- switching in rheumatoid arthritis. Am J Manag Care 2018;24:S338–45. 8