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Predictors of response to etanercept-methotrexate treatment: a post hoc logistic regression analysis of a randomized, open-label study in Latin American patients with rheumatoid arthritis

Predictors of response to etanercept-methotrexate treatment: a post hoc logistic regression... Background: Determining potential predictors of clinical response would allow a more personalized rheumatoid arthritis (RA) treatment approach in heterogeneous populations such as Latin American (LA) patients. Methods: Post hoc analysis to identify baseline characteristics predictive of clinical remission in response to treat‑ ment with etanercept (ETN) plus methotrexate (MTX) in LA patients with moderate to severe MTX‑resistant RA. We report data from the group of patients who received ETN 50 mg/week plus MTX (ETN + MTX, n = 281) in a clinical trial consisting of an initial 24‑ week open‑label phase, followed by a 104‑ week extension. Remission was defined as 28‑joint Disease Activity Score with erythrocyte sedimentation rate (DAS28‑ESR) score < 2.6. Cutoff values to dichoto ‑ mize baseline variables maximizing the detection of remission were obtained from Receiver Operator Curve analyses. Baseline dichotomized and categorical variables were analyzed altogether in a stepwise logistic regression model. Odds of attaining response at Weeks 24 and 128 were estimated for each significant predictor. Results: At Week 24 and Week 128, 27% (66/241) and 42% (91/219) of patients in the ETN + MTX group achieved remission. On average, patients achieving remission were younger and had lower baseline ESR, lower Physician Global Assessment (PGA) scores, lower total Health Assessment Questionnaire (HAQ) scores, and lower visual analog scale ( VAS) Pain scores compared with patients who did not achieve remission. The best subset of baseline variables predicting Week 24 remission in the stepwise regression model were age ≤ 49 years (odds ratio [OR] 2.93), body mass index (BMI) > 28.5 kg/m (OR 3.24), disease duration > 3.7 years (OR 2.22), ESR ≤ 42 mm/h (OR 2.72), PGA ≤ 6 (OR 3.21), tender joint count ≤ 14 (OR 2.25), and total HAQ score ≤ 1.6 (OR 2.86). At Week 128, age ≤ 42 years (OR 2.21), SF‑36 Mental Health Scale score > 39.6 (OR 2.16), White race (OR 4.07), > 18 swollen joints (OR 2.11), and VAS Pain ≤ 41 (OR 6.05) at baseline were the best subset of significant predictors of remission. *Correspondence: mainadelavega.mdlv@gmail.com CEIM Investigaciones Médicas, Laprida 1307, Ciudad De Buenos Aires, 1425 Buenos Aires, Argentina Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. de la Vega et al. Adv Rheumatol (2021) 61:56 Page 2 of 8 Conclusions: In LA patients with RA, younger age, higher BMI, longer disease duration, higher SF‑36 Mental Health Scale score, higher swollen joint count, and overall lower disease activity predicted clinical response to ETN + MTX therapy. Trial registration: ClinicalTrials.gov Identifier: NCT00848354. Background plus MTX (n = 142) for 24  weeks. The second phase Rheumatoid arthritis (RA) is characterized by chronic (104  weeks) was an optional extension period allowing inflammation and joint erosion, often leading to inabil - investigators to select a treatment regimen (ETN, MTX, ity to work and poor quality of life [1]. The prevalence of hydroxychloroquine, or sulfasalazine, in any combination RA in Latin America is estimated to be around 0.4% [2], at the desired dosage) based on the participants’ previ- compared with 0.24–1.0% worldwide [3, 4]. A majority ous response to randomized treatment, their preference, of clinical trials investigating treatments for RA, includ- and local product labeling [9]. Clinical efficacy endpoints ing those of the tumor necrosis factor (TNF) inhibitor at Weeks 24 and 128 included the proportion of partici- etanercept (ETN), have been conducted in patients from pants who achieved response based on the 28-joint Dis- North America and Europe. However, the population of ease Activity Score with erythrocyte sedimentation rate Latin America is highly diverse and differs from West - (DAS28-ESR) consistent with disease remission (< 2.6). ern populations in its racial, ethnic, and socio-economic We report data from a post hoc analysis of predictors of make-up [5], factors that have been associated with the response to treatment in only the group of participants treatment outcomes of RA [6, 7]. randomized to receive ETN + MTX. In a 24-week, randomized open-label study of meth- otrexate (MTX)-resistant patients with moderate or Statistical analysis severe RA, conducted in Latin America (NCT00848354), This observed-cases analysis included participants ETN plus MTX was shown to be superior to MTX plus who were initially randomized to receive ETN + MTX another conventional disease-modifying antirheumatic (Week 24 assessment) and their subset who enrolled drug (DMARD) [8]. During the open-label, 104-week in the extension phase (Week 128 assessment). Clini- extension phase, benefits of ETN plus MTX treatment cal response at both Weeks 24 and 128 was defined as were maintained for up to 2  years [9], and a post hoc DAS28-ESR remission. Differences between Week 24 analysis demonstrated that clinical outcomes at Week 12 (and Week 128) remitters for demographic and base- could be used as predictors of patient-reported outcomes line disease characteristics were analyzed in one-way at Week 24 [10]. analysis of variance (ANOVA) models (for continuous However, as in most RA trials, treatment benefits were characteristics) and in chi-square tests (for categori- not distributed uniformly among the participants [8, 9]. cal characteristics). Each continuous baseline variable Determining potential baseline predictors of clinical was dichotomized twice using the Receiver Operator remission would allow a more personalized approach to Curve approach from logistic regression model of Week the treatment of RA in this heterogeneous patient popu- 24 remission (or Week 128 remission). Variables were lation. The aim of this post hoc analysis of the trial was dichotomized by determining the cutoff values that max - to identify potential baseline characteristics that predict imized the sensitivity (true positive rate) plus specific - which participants were more likely to respond to treat- ity (true negative rate) of detecting Week 24 (and Week ment with ETN plus MTX at Weeks 24 and 128. 128) remission. These dichotomized variables along with other categorical baseline variables were then analyzed Methods altogether in a stepwise logistic regression model, and Study design and patient selection the odds of attaining response in the ETN + MTX group The study design and primary outcomes have been at Weeks 24 and 128 (observed cases) were estimated described in detail previously [8]. Briefly, patients for each significant predictor, with the cutoff p-value to from Argentina, Chile, Colombia, Mexico, and Pan- enter of 0.15 and stay in the model set at 0.05. Baseline ama with moderate to severe active RA and inadequate characteristics used in the stepwise model as dichoto- response to MTX were included in the study. In the ini- mized/categorical variables included: age; body mass tial phase, participants were randomized 2:1 to receive index (BMI); C-reactive protein (CRP); cyclic citrulli- open-label treatment with ETN 50  mg weekly plus nated peptide antibody positive; DAS28; disease dura- MTX (ETN + MTX, n = 281) or an additional conven- tion; ESR; modified total Sharp score; morning stiffness; tional DMARD (hydroxychloroquine or sulfasalazine) prior use of MTX, non-steroidal anti-inflammatory drugs de la  Vega et al. Adv Rheumatol (2021) 61:56 Page 3 of 8 and corticosteroids; Physician Global Assessment (PGA); VAS Pain scores (all p < 0.05 at Week 24), and a lower rate race; rheumatoid factor (RF); sex; Short Form 36 (SF-36) of RF positivity (p < 0.05 at Week 128) compared with physical component summary; SF-36 mental component non-responders. There were no significant differences in summary; SF-36 vitality domain score; subject global terms of baseline CRP (Table 2). assessment; swollen joint count; tender joint count; total Health Assessment Questionnaire (HAQ) score; visual Predictors of response at weeks 24 and 128 analog scale (VAS) General Health; VAS Fatigue; and Baseline factors found to be associated with response VAS Pain. to ETN + MTX at Weeks 24 and 128 in the one-way ANOVA models and in chi-square tests are shown in Results Fig.  1. The subsets of baseline factors that predicted Baseline characteristics response to ETN + MTX therapy at Weeks 24 and 128 Most of the 281 patients assigned to ETN + MTX treat- in the stepwise regression analysis are shown in Fig.  2. ment were women (248; 88%); the average disease dura- Significantly higher odds of attaining remission at tion was 7.9  years (Table  1). A total of 269 participants Week 24 were associated with a younger age (≤ 49  years from the ETN + MTX group completed the initial phase. vs > 49  years; odds ratio [OR] 2.93 [95% CI 5.91–1.45]), 2 2 Of those, 260 participants enrolled in the ETN + MTX higher BMI (> 28.5 kg/m vs ≤ 28.5  kg/m ; OR 3.24 [95% group in the extension phase [9]. DAS28 remission data CI 1.54–6.83]), longer disease duration (> 3.7  years were available for 241 and 219 patients at Weeks 24 and vs ≤ 3.7  years; OR 2.22 [95% CI 1.09–4.52]), lower ESR 128, respectively. (≤ 42.0  mm/h vs > 42.0  mm/h; OR 2.72 [95% CI 1.28– At Week 24, 27% (66/241) of participants in the 5.80]), lower PGA score (≤ 6.0 vs > 6.0; OR 3.21 [95% CI ETN + MTX group achieved DAS28-ESR remission. 1.62–6.35]), lower prorated number of tender joints (≤ 14 This increased to 42% (91/219) of participants at Week vs > 14; OR 2.25 [95% CI 1.01–5.01]), and lower total 128 (Table  2). On average, responders were significantly HAQ score (≤ 1.6 vs > 1.6; OR 2.86 [95% CI 1.40–5.88]) younger than non-responders (p < 0.05 at Weeks 24 and (all p < 0.05). Significantly higher odds of attaining remis - 128). Responders also had, on average, a lower baseline sion at Week 128 were associated with a younger age ESR, lower PGA scores, lower total HAQ scores, lower (≤ 42  years vs > 42  years; OR 2.21 [95% CI 1.16–4.21]), higher SF-36 Mental Health Scale score (> 39.6 vs ≤ 39.6; OR 2.16 [95% CI 1.15–4.05]), White versus other race Table 1 Select Baseline Demographic and Clinical (OR 4.07 [95% CI 1.48–11.11]), higher number of swol- Characteristics of the ETN + MTX Group*. Adapted From [8] len joints (> 18 vs ≤ 18; OR 2.11 [95% CI 1.12–3.97]), and ETN + MTX a lower VAS Pain score (≤ 41  mm vs > 41  mm; OR 6.05 (n = 281) [95% CI 2.37–15.48]) (all p < 0.05). Age, years 48.4 ± 12.0 Women, n (%) 248 (88.3) Discussion and conclusions Race, n (%) To the best of our knowledge, this is the first analysis White 134 (47.7) of baseline predictors of clinical response to treatment Mestizo 60 (21.4) with ETN in Latin American patients with RA. The African‑Latin American 39 (13.9) best subset of factors that predicted clinical response Other 48 (17.1) to ETN + MTX therapy for 24  weeks were younger age, BMI, kg/m 26.4 ± 5.1 higher BMI, longer disease duration, and an overall lower CRP, mg/L 20.7 ± 25.4 disease activity (lower ESR, PGA, and total HAQ scores). ESR, mm/h 43.2 ± 16.6 At 128  weeks, the best subset of factors that predicted Disease duration, years 7.9 ± 7.0 clinical response to ETN + MTX therapy were younger RF positive, n (%) 242 (86.1) age, higher SF-36 score, White race, higher number of DAS28‑ESR 6.6 ± 0.7 swollen joints, and lower pain. In line with our findings, younger age of patients with HAQ total score 1.6 ± 0.7 RA predicted a stronger clinical response in a study of PGA 6.7 ± 1.6 the TNF inhibitor adalimumab [11, 12] and in a study of VAS Pain, mm (0–100 scale) 65.6 ± 21.3 the IL6 inhibitor tocilizumab [13]. However, age did not Data are mean ± SD unless stated otherwise predict clinical response in a British registry study of the BMI body mass index, CRP C-reactive protein, DAS28-ESR 28-joint Disease Activity Score with erythrocyte sedimentation rate, ETN etanercept, HAQ TNF inhibitor infliximab [14]. Health Assessment Questionnaire, MTX methotrexate, PGA Physician Global Although it could be argued that younger age may be a Assessment, RF rheumatoid factor, SD standard deviation, VAS visual analog surrogate marker for shorter disease duration—which has scale de la Vega et al. Adv Rheumatol (2021) 61:56 Page 4 of 8 Table 2 Select Baseline Demographic and Baseline Disease Characteristics of Responders and Non‑Responders (Observed Cases) Baseline Characteristic* Week 24 Week 128 Responders Non-responders p value** Responders Non-responders p value** (n = 66) (n = 175) (n = 91) (n = 128) Age, years 45.4 ± 11.8 49.2 ± 11.7 0.024 45.7 ± 11.8 50.1 ± 11.8 0.008 Men, n (%) 13 (20) 16 (9) 15 (17) 13 (10) Women, n (%) 53 (80) 159 (91) 0.025 76 (84) 115 (90) 0.167 Race, n (%) White 34 (52) 77 (44) 0.622 46 (51) 57 (45) 0.015 Mestizo 15 (23) 38 (22) 25 (28) 23 (18) African‑Latin American 7 (11) 27 (15) 13 (14) 18 (14) Other 10 (15) 33 (19) 7 (8) 30 (23) BMI, kg/m 26.6 ± 5.3 26.3 ± 4.8 0.669 26.3 ± 4.4 26.4 ± 5.2 0.860 CRP, mg/L 19.5 ± 25.9 21.8 ± 25.4 0.521 22.5 ± 26.8 21.1 ± 26.1 0.707 ESR, mm/h 37.3 ± 11.2 44.3 ± 17.4 0.003 39.6 ± 13.8 43.1 ± 16.5 0.104 Disease duration, years 8.2 ± 7.1 7.4 ± 6.5 0.428 7.4 ± 6.4 8.0 ± 7.0 0.534 RF positive, n (%) 55 (83) 155 (89) 0.279 73 (80) 117 (91) 0.016 HAQ total score 1.3 ± 0.7 1.7 ± 0.7 0.001 1.5 ± 0.7 1.6 ± 0.7 0.376 VAS Pain, mm 60.0 ± 23.6 66.1 ± 20.3 0.047 61.6 ± 25.7 66.0 ± 18.2 0.141 PGA 6.5 ± 1.9 7.2 ± 1.9 0.013 6.7 ± 2.2 7.1 ± 1.8 0.122 SF‑36 Mental Health Scale 41.0 ± 11.3 40.3 ± 11.0 0.665 41.5 ± 10.8 39.6 ± 11.3 0.223 Prorated number of tender joints 22.2 ± 10.9 26.0 ± 11.9 0.024 24.6 ± 11.1 25.5 ± 12.4 0.600 Prorated number of swollen joints 17.6 ± 7.9 18.4 ± 8.6 0.504 19.9 ± 8.9 17.3 ± 8.2 0.029 *Data are mean ± SD unless stated otherwise **p value from either a one-way ANOVA model to analyze continuous characteristics or a chis-square test to analyze categorical characteristics; baseline characteristics with p values < 0.05 are highlighted in bold BMI body mass index, CRP C-reactive protein, ESR erythrocyte sedimentation rate, HAQ Health Assessment Questionnaire, PGA Physician Global Assessment, RF rheumatoid factor, SD standard deviation, SF-36 36-Item Short Form Survey, VAS visual analog scale model. These observations are in line with a number been shown to predict higher responses to ETN + MTX of studies. For example, in a cohort of Chinese patients [15] and other biologics [16–18]—our analysis, surpris- treated with a TNF inhibitor, ESR ≤ 60  mm/h and total ingly, found a marginally significant association of longer HAQ sore ≤ 1.31 were identified as predictors of clinical disease duration (> 3.7  years) with clinical response at response [20]. Data from the British Society for Rheuma- Week 24 when analyzed in combination with other sig- tology Biologics registry [14], as well as a study in Swed- nificant predictors in a stepwise analyses, but it was not ish patients [21], showed that lower baseline HAQ scores significant on its own. However, other confounding fac - were correlated with higher response rates. Similarly, tors may influence the relationship between disease dura - Japanese patients with higher baseline PGA scores were tion and DAS28 remission. Overall, the role of disease less likely to achieve response to biologic agents [19]. The duration as a predictor of clinical response to treatment same study identified low levels of CRP as a predictor of of RA with biologic agents appears to be unclear, with the response, which was not the case in our analysis. In the data from the British Society for Rheumatology Biologics GO-MORE study, lower tender joint count score was registry [14] and a study in Japanese patients treated with associated with a greater likelihood of achieving DAS28- infliximab, ETN, adalimumab, or tocilizumab [19] failing ESR ≤ 3.2 and  DAS28-ESR < 2.6 at 1 and 6  months after to establish a link between disease duration and response treatment with the anti-TNF golimumab in biologic- to treatment. naïve patients with active RA despite treatment with In our analysis, parameters indicating lower disease DMARD [22]. However, in a systematic review that activity at baseline (ESR ≤ 42  mm/h, PGA score ≤ 6.0, included 4 studies of patients with RA treated with anti- tender joint count ≤ 14, and total HAQ score ≤ 1.6) were TNF therapy + MTX, tender joint count at baseline was also associated with a stronger response to ETN + MTX not associated with sustained remission [23]. treatment at Week 24 on their own and in combina- tion with other significant predictors from a stepwise de la  Vega et al. Adv Rheumatol (2021) 61:56 Page 5 of 8 p-value Age at baseline (≤49 years vs >49 years) 0.007 Disease duration (>3.7 years vs <3.7 years) 0.091 Baseline BMI (>28.5 vs ≤28.5) 0.023 CRP (≤8.3 mg/L vs >8.3 mg/L) 0.036 ESR (≤42 mm/h vs >42 mm/h) 0.002 DAS28-ESR (≤6.6 vs >6.6) < 0.001 Prorated number of tender joints (≤14 vs >14) < 0.001 Physician Global Assessment (≤6.0 vs >6.0) 0.002 Total HAQ score (≤1.6 vs >1.6) < 0.001 Subject Global Assessment score (≤6.0 vs >6.0) 0.035 VAS Subject Health Assessment (>41.0 vs ≤41.0) 0.028 VAS Pain (≤48.0 vs >48.0) 0.018 VAS Fatigue (≤50.0 vs <50.0) 0.036 SF-36 Physical Health Scale score (>30.7 vs ≤30.7) 0.007 0246 8 Odds ratio (95% CI) p-value Age at baseline (≤42 years vs >42 years) 0.003 Ethnicity (White vs other) 0.008 ESR (≤36 mm/h vs >36 mm/h) 0.030 Rheumatoid factor (negative vs positive) 0.019 Prorated number of swollen joints (>18 vs ≤18) 0.019 VAS Subject health assessment (≤44.0 vs >44.0) < 0.001 VAS Pain (≤41.0 vs >41.0) < 0.001 VAS Fatigue (≤32.0 vs >32.0) 0.003 SF-36 Mental Health Scale score (>39.6 vs ≤39.6) 0.044 02 1 46 81012 Odds ratio (95% CI) Fig. 1 Baseline Factors Associated with Response to ETN + MTX at Weeks 24 (A) and 128* (B). *Results from one-way ANOVA models and in chi-square tests. ANOVA analysis of variance, BMI body mass index, CRP C‑reactive protein, DAS28 Disease Activity Score in 28 joints, ESR erythrocyte sedimentation rate, ETN etanercept, SF-36 36‑Item Short Form Survey, HAQ Health Assessment Questionnaire, MTX methotrexate, VAS visual analog scale de la Vega et al. Adv Rheumatol (2021) 61:56 Page 6 of 8 p-value Age (≤49 years vs >49 years) 0.003 2 2 BMI (>28.5 kg/m vs ≤28.5 kg/m ) 0.002 Disease duration (>3.7 years vs ≤3.7 years) 0.028 ESR (≤42 mm/h vs >42 mm/h) 0.001 < 0.001 PGA score (≤6.0 vs >6.0) Prorated number of tender joints (≤14 vs >14) 0.047 Total HAQ score (≤1.63 vs >1.63) 0.004 Age (≤42 years vs >42 years) 0.016 SF-36 Mental Health Scale score (>39.6 vs ≤39.6) 0.016 Race (White vs other) 0.012 Number of swollen joints (>18 vs ≤18) 0.021 VAS Pain (≤41 mm vs vs >41 mm) < 0.001 01 2468 10 12 12 20 Odds ratio (95% CI) Fig. 2 Odds Ratios for Predictors of Response at Weeks 24 and 128*. *Results from a stepwise regression model of Week 24 and Week 128 DAS28‑ESR remission, with list of baseline variables in the model given in the Statistical Analysis section. BMI body mass index, CI confidence interval, ESR erythrocyte sedimentation rate, HAQ Health Assessment Questionnaire, PGA Physician Global Assessment, SF-36 36‑Item Short Form Survey, VAS visual analog scale Conversely, a higher number of swollen joints (> 18) from the United States in which African-American and on its own (from univariate analysis) and in combination Hispanic patients with RA showed higher disease activ- with other significant predictors from a stepwise model, ity and worse clinical outcomes compared with White indicating higher disease activity at baseline, was asso- patients [26]. The role of race as a predictor is likely to ciated with a stronger response at Week 128. Although be complex and include both genetic as well as socio-cul- synovitis can be a predictor for radiographic progression tural and socio-economic factors. [24], an increased number of swollen joints was associ- Interestingly, we also identified higher BMI (> 28.5  kg/ ated with a higher likelihood of achieving sustained m ) as a predictor of clinical response at Week 24 when remission in a UK observational study [25]. analyzed in combination with other significant predic - Lower pain (VAS ≤ 41  mm) and SF-36 Mental Health tors in a stepwise model but not on its own in a univari- Scale score > 39.6 at baseline were identified as predic - ate model. This is in contrast with a study showing higher tors of clinical response at Week 128 only in combination BMI (> 30  kg/m ) to be associated with lower response with other significant predictors from a stepwise model, rates to infliximab [27]. In an Italian study, patients with lower pain being only marginally significant on its with higher BMI (> 30  kg/m ) were less likely to achieve own for Week 24 response. Although we could not iden- response to infliximab, but no correlation was found for tify any studies investigating either of these potential ETN and adalimumab [28]. In another study of adali- predictors, they may be associated with lower disease mumab, BMI (> 30  kg/m ) had no impact on response activity at baseline. rates [29]; this was also apparent in studies of rituxi- In our study, White patients (on its own and in com- mab [30] and tocilizumab [31]. Overall, the role of BMI bination with other significant predictors) were more as predictor of response seems to be unclear. Although likely to achieve clinical remission at Week 128 compared higher BMI is generally associated with lower socio- with patients of other races. This is in line with a study economic status, 1 Brazilian study found a positive cor- relation between BMI and higher socio-economic status Week 128Week 24 de la  Vega et al. Adv Rheumatol (2021) 61:56 Page 7 of 8 Acknowledgements [32], which may facilitate access to health care and could Medical writing support was provided by Andrea Schauenburg, PhD, of therefore explain the favorable outcomes observed here. Engage Scientific Solutions and was funded by Pfizer Inc. In this stepwise regression analysis, RF positivity Authors’ contributions had no impact on clinical response. This is in line with MdlV, GGB, RMX, CP‑ T, AES, GS, RDP, CB, KS, BV, Conceptualization, Data cura‑ observations from studies of ETN and infliximab [14] tion, Writing – review and editing. All authors read and approved the final and of tocilizumab [13]. Based on the currently avail- manuscript. able evidence, no clear conclusion can be drawn on the Funding role of RF positivity as predictor of response, with some The Latin American RA study was funded by Wyeth, which was acquired by studies finding a positive association although others Pfizer Inc in October 2009. have identified it as a negative predictor [12]. Availability of data and materials Although Week 24 and Week 128 responders to Upon request, and subject to certain criteria, conditions, and exceptions ETN + MTX were more likely to be male, sex was not (see https:// www. pfizer. com/ scien ce/ clini cal‑ trials/ trial‑ data‑ and‑ resul ts for more information), Pfizer will provide access to individual de ‑identified par ‑ a significant predictor of clinical response in our study. ticipant data from Pfizer ‑sponsored global interventional clinical studies con‑ An earlier study in a Swedish cohort also found no ducted for medicines, vaccines, and medical devices: (1) for indications that significant predictive value of sex on clinical response have been approved in the USA and/or EU; or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer after 3 or 6  months of therapy with ETN, infliximab, will also consider requests for the protocol, data dictionary, and statistical or adalimumab [21]; although males had lower DAS28 analysis plan. Data may be requested from Pfizer trials 24 months after study scores. This is somewhat in contrast to the findings of completion. The de‑identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, other studies where males were more likely to achieve and for which an exception does not apply, via a secure portal. To gain access, clinical remission following treatment with ETN or inf- data requestors must enter into a data access agreement with Pfizer. liximab [14], and adalimumab [11]. Within the patient population with RA, differences in severity of disease Declarations between sexes and differences in other factors, such Ethics approval as biological, physical, or social, may underlie any The final protocol, any amendments, and informed consent documenta‑ observed differences by sex. tion were reviewed and approved by the Institutional Review Board(s) (IRB) Limitations of this study included the post hoc nature and/or Independent Ethics Committee(s) (IEC) at each of the investigational centers participating in the study. Investigators were required to inform their of this analysis and the absence of an adequate control IRBs or IECs of the study’s progress and occurrence of any serious and/or group. The lack of a control group limits the ability to unexpected adverse events. This study was conducted in compliance with make conclusions about the specificity of the identified the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good subset of predictive characteristics to the ETN + MTX Clinical Practice Guidelines. In addition, all local regulatory requirements were treatment regimen. The low proportion of male partici - followed, in particular, those affording greater protection to the safety of trial pants makes it difficult to ascertain the impact of sex. It participants. is not possible to generalize the results from this study, Consent to participate which was conducted in selected clinical trial partici- A signed and dated informed consent was required before any screen proce‑ pants, to other populations that were not sufficiently dures were done. The investigators explained the nature, purpose, and risks of the study to each subject. Each subject was informed that he/she could represented in the clinical trial population (e.g., men withdraw from the study at any time and for any reason. Each subject was and individuals of different ages and with different dis - given sufficient time to consider the implications of the study before deciding ease durations). whether to participate. Subjects who chose to participate signed an informed consent document. In conclusion, this post hoc logistic regression analy- sis of a trial of Latin American patients with RA yielded Consent for publication several baseline predictors of clinical response to treat- Not applicable. ment with ETN + MTX, which may be useful for future Competing interests clinical decision-making. These baseline predictors of MdlV, AbbVie, Genzyme, Lilly, Pfizer, and TRB Pharma (consulting fees); BMS, clinical response included younger age, higher BMI, Gilead, Glaxo, Pfizer, and Roche (trial investigator); AbbVie, Genzyme, Janssen Lilly, and Pfizer (speaker); GGB, no disclosures to report; RMX, AbbVie, BMS, longer disease duration, higher SF-36 Mental Health Janssen, Lilly, Novartis, Pfizer, Roche, and UCB (consulting fees, speaker); CP ‑ T, Scale score, higher swollen joint count, and overall Pfizer, Sanofi, Roche, Eli Lilly, AbbVie, UCB, and BMS (consulting fees and lower disease activity. Discrepancies between our find - speaker); AES, AES is an employee of Syneos Health and was contracted by Pfizer to provide statistical support for the development of this paper; RDP, ings and those from studies conducted in other geo- RDP was an employee of Pfizer at the time of data generation and manuscript graphic areas of the world, however, underline the need development and own stock in Pfizer; GS, CB, KS, BV, Pfizer (stock options, for further prospective studies, adequately powered to employment). detect predictors of response. Author details CEIM Investigaciones Médicas, Laprida 1307, Ciudad De Buenos Aires, 1425 Buenos Aires, Argentina. Centro de Investigación Marbella, Paitilla de la Vega et al. Adv Rheumatol (2021) 61:56 Page 8 of 8 Panamá, Panamá. Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. 16. Agarwal SK, Glass RJ, Shadick NA, et al. Predictors of discontinuation of 4 5 Universidad Autónoma de Chihuahua, Chihuahua, Mexico. 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Predictors of response to anti‑ TNF‑alpha therapy among patients with rheumatoid arthritis: results from the British Publisher’s Note Society for Rheumatology Biologics Register. Rheumatology (Oxford). Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 2006;45:1558–65. lished maps and institutional affiliations. 15. Emery P, Kvien TK, Combe B, et al. Combination etanercept and metho‑ trexate provides better disease control in very early (<=4 months) versus early rheumatoid arthritis (>4 months and <2 years): post hoc analyses from the COMET study. Ann Rheum Dis. 2012;71:989–92. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Advances in Rheumatology Springer Journals

Predictors of response to etanercept-methotrexate treatment: a post hoc logistic regression analysis of a randomized, open-label study in Latin American patients with rheumatoid arthritis

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10.1186/s42358-021-00213-4
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Abstract

Background: Determining potential predictors of clinical response would allow a more personalized rheumatoid arthritis (RA) treatment approach in heterogeneous populations such as Latin American (LA) patients. Methods: Post hoc analysis to identify baseline characteristics predictive of clinical remission in response to treat‑ ment with etanercept (ETN) plus methotrexate (MTX) in LA patients with moderate to severe MTX‑resistant RA. We report data from the group of patients who received ETN 50 mg/week plus MTX (ETN + MTX, n = 281) in a clinical trial consisting of an initial 24‑ week open‑label phase, followed by a 104‑ week extension. Remission was defined as 28‑joint Disease Activity Score with erythrocyte sedimentation rate (DAS28‑ESR) score < 2.6. Cutoff values to dichoto ‑ mize baseline variables maximizing the detection of remission were obtained from Receiver Operator Curve analyses. Baseline dichotomized and categorical variables were analyzed altogether in a stepwise logistic regression model. Odds of attaining response at Weeks 24 and 128 were estimated for each significant predictor. Results: At Week 24 and Week 128, 27% (66/241) and 42% (91/219) of patients in the ETN + MTX group achieved remission. On average, patients achieving remission were younger and had lower baseline ESR, lower Physician Global Assessment (PGA) scores, lower total Health Assessment Questionnaire (HAQ) scores, and lower visual analog scale ( VAS) Pain scores compared with patients who did not achieve remission. The best subset of baseline variables predicting Week 24 remission in the stepwise regression model were age ≤ 49 years (odds ratio [OR] 2.93), body mass index (BMI) > 28.5 kg/m (OR 3.24), disease duration > 3.7 years (OR 2.22), ESR ≤ 42 mm/h (OR 2.72), PGA ≤ 6 (OR 3.21), tender joint count ≤ 14 (OR 2.25), and total HAQ score ≤ 1.6 (OR 2.86). At Week 128, age ≤ 42 years (OR 2.21), SF‑36 Mental Health Scale score > 39.6 (OR 2.16), White race (OR 4.07), > 18 swollen joints (OR 2.11), and VAS Pain ≤ 41 (OR 6.05) at baseline were the best subset of significant predictors of remission. *Correspondence: mainadelavega.mdlv@gmail.com CEIM Investigaciones Médicas, Laprida 1307, Ciudad De Buenos Aires, 1425 Buenos Aires, Argentina Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. de la Vega et al. Adv Rheumatol (2021) 61:56 Page 2 of 8 Conclusions: In LA patients with RA, younger age, higher BMI, longer disease duration, higher SF‑36 Mental Health Scale score, higher swollen joint count, and overall lower disease activity predicted clinical response to ETN + MTX therapy. Trial registration: ClinicalTrials.gov Identifier: NCT00848354. Background plus MTX (n = 142) for 24  weeks. The second phase Rheumatoid arthritis (RA) is characterized by chronic (104  weeks) was an optional extension period allowing inflammation and joint erosion, often leading to inabil - investigators to select a treatment regimen (ETN, MTX, ity to work and poor quality of life [1]. The prevalence of hydroxychloroquine, or sulfasalazine, in any combination RA in Latin America is estimated to be around 0.4% [2], at the desired dosage) based on the participants’ previ- compared with 0.24–1.0% worldwide [3, 4]. A majority ous response to randomized treatment, their preference, of clinical trials investigating treatments for RA, includ- and local product labeling [9]. Clinical efficacy endpoints ing those of the tumor necrosis factor (TNF) inhibitor at Weeks 24 and 128 included the proportion of partici- etanercept (ETN), have been conducted in patients from pants who achieved response based on the 28-joint Dis- North America and Europe. However, the population of ease Activity Score with erythrocyte sedimentation rate Latin America is highly diverse and differs from West - (DAS28-ESR) consistent with disease remission (< 2.6). ern populations in its racial, ethnic, and socio-economic We report data from a post hoc analysis of predictors of make-up [5], factors that have been associated with the response to treatment in only the group of participants treatment outcomes of RA [6, 7]. randomized to receive ETN + MTX. In a 24-week, randomized open-label study of meth- otrexate (MTX)-resistant patients with moderate or Statistical analysis severe RA, conducted in Latin America (NCT00848354), This observed-cases analysis included participants ETN plus MTX was shown to be superior to MTX plus who were initially randomized to receive ETN + MTX another conventional disease-modifying antirheumatic (Week 24 assessment) and their subset who enrolled drug (DMARD) [8]. During the open-label, 104-week in the extension phase (Week 128 assessment). Clini- extension phase, benefits of ETN plus MTX treatment cal response at both Weeks 24 and 128 was defined as were maintained for up to 2  years [9], and a post hoc DAS28-ESR remission. Differences between Week 24 analysis demonstrated that clinical outcomes at Week 12 (and Week 128) remitters for demographic and base- could be used as predictors of patient-reported outcomes line disease characteristics were analyzed in one-way at Week 24 [10]. analysis of variance (ANOVA) models (for continuous However, as in most RA trials, treatment benefits were characteristics) and in chi-square tests (for categori- not distributed uniformly among the participants [8, 9]. cal characteristics). Each continuous baseline variable Determining potential baseline predictors of clinical was dichotomized twice using the Receiver Operator remission would allow a more personalized approach to Curve approach from logistic regression model of Week the treatment of RA in this heterogeneous patient popu- 24 remission (or Week 128 remission). Variables were lation. The aim of this post hoc analysis of the trial was dichotomized by determining the cutoff values that max - to identify potential baseline characteristics that predict imized the sensitivity (true positive rate) plus specific - which participants were more likely to respond to treat- ity (true negative rate) of detecting Week 24 (and Week ment with ETN plus MTX at Weeks 24 and 128. 128) remission. These dichotomized variables along with other categorical baseline variables were then analyzed Methods altogether in a stepwise logistic regression model, and Study design and patient selection the odds of attaining response in the ETN + MTX group The study design and primary outcomes have been at Weeks 24 and 128 (observed cases) were estimated described in detail previously [8]. Briefly, patients for each significant predictor, with the cutoff p-value to from Argentina, Chile, Colombia, Mexico, and Pan- enter of 0.15 and stay in the model set at 0.05. Baseline ama with moderate to severe active RA and inadequate characteristics used in the stepwise model as dichoto- response to MTX were included in the study. In the ini- mized/categorical variables included: age; body mass tial phase, participants were randomized 2:1 to receive index (BMI); C-reactive protein (CRP); cyclic citrulli- open-label treatment with ETN 50  mg weekly plus nated peptide antibody positive; DAS28; disease dura- MTX (ETN + MTX, n = 281) or an additional conven- tion; ESR; modified total Sharp score; morning stiffness; tional DMARD (hydroxychloroquine or sulfasalazine) prior use of MTX, non-steroidal anti-inflammatory drugs de la  Vega et al. Adv Rheumatol (2021) 61:56 Page 3 of 8 and corticosteroids; Physician Global Assessment (PGA); VAS Pain scores (all p < 0.05 at Week 24), and a lower rate race; rheumatoid factor (RF); sex; Short Form 36 (SF-36) of RF positivity (p < 0.05 at Week 128) compared with physical component summary; SF-36 mental component non-responders. There were no significant differences in summary; SF-36 vitality domain score; subject global terms of baseline CRP (Table 2). assessment; swollen joint count; tender joint count; total Health Assessment Questionnaire (HAQ) score; visual Predictors of response at weeks 24 and 128 analog scale (VAS) General Health; VAS Fatigue; and Baseline factors found to be associated with response VAS Pain. to ETN + MTX at Weeks 24 and 128 in the one-way ANOVA models and in chi-square tests are shown in Results Fig.  1. The subsets of baseline factors that predicted Baseline characteristics response to ETN + MTX therapy at Weeks 24 and 128 Most of the 281 patients assigned to ETN + MTX treat- in the stepwise regression analysis are shown in Fig.  2. ment were women (248; 88%); the average disease dura- Significantly higher odds of attaining remission at tion was 7.9  years (Table  1). A total of 269 participants Week 24 were associated with a younger age (≤ 49  years from the ETN + MTX group completed the initial phase. vs > 49  years; odds ratio [OR] 2.93 [95% CI 5.91–1.45]), 2 2 Of those, 260 participants enrolled in the ETN + MTX higher BMI (> 28.5 kg/m vs ≤ 28.5  kg/m ; OR 3.24 [95% group in the extension phase [9]. DAS28 remission data CI 1.54–6.83]), longer disease duration (> 3.7  years were available for 241 and 219 patients at Weeks 24 and vs ≤ 3.7  years; OR 2.22 [95% CI 1.09–4.52]), lower ESR 128, respectively. (≤ 42.0  mm/h vs > 42.0  mm/h; OR 2.72 [95% CI 1.28– At Week 24, 27% (66/241) of participants in the 5.80]), lower PGA score (≤ 6.0 vs > 6.0; OR 3.21 [95% CI ETN + MTX group achieved DAS28-ESR remission. 1.62–6.35]), lower prorated number of tender joints (≤ 14 This increased to 42% (91/219) of participants at Week vs > 14; OR 2.25 [95% CI 1.01–5.01]), and lower total 128 (Table  2). On average, responders were significantly HAQ score (≤ 1.6 vs > 1.6; OR 2.86 [95% CI 1.40–5.88]) younger than non-responders (p < 0.05 at Weeks 24 and (all p < 0.05). Significantly higher odds of attaining remis - 128). Responders also had, on average, a lower baseline sion at Week 128 were associated with a younger age ESR, lower PGA scores, lower total HAQ scores, lower (≤ 42  years vs > 42  years; OR 2.21 [95% CI 1.16–4.21]), higher SF-36 Mental Health Scale score (> 39.6 vs ≤ 39.6; OR 2.16 [95% CI 1.15–4.05]), White versus other race Table 1 Select Baseline Demographic and Clinical (OR 4.07 [95% CI 1.48–11.11]), higher number of swol- Characteristics of the ETN + MTX Group*. Adapted From [8] len joints (> 18 vs ≤ 18; OR 2.11 [95% CI 1.12–3.97]), and ETN + MTX a lower VAS Pain score (≤ 41  mm vs > 41  mm; OR 6.05 (n = 281) [95% CI 2.37–15.48]) (all p < 0.05). Age, years 48.4 ± 12.0 Women, n (%) 248 (88.3) Discussion and conclusions Race, n (%) To the best of our knowledge, this is the first analysis White 134 (47.7) of baseline predictors of clinical response to treatment Mestizo 60 (21.4) with ETN in Latin American patients with RA. The African‑Latin American 39 (13.9) best subset of factors that predicted clinical response Other 48 (17.1) to ETN + MTX therapy for 24  weeks were younger age, BMI, kg/m 26.4 ± 5.1 higher BMI, longer disease duration, and an overall lower CRP, mg/L 20.7 ± 25.4 disease activity (lower ESR, PGA, and total HAQ scores). ESR, mm/h 43.2 ± 16.6 At 128  weeks, the best subset of factors that predicted Disease duration, years 7.9 ± 7.0 clinical response to ETN + MTX therapy were younger RF positive, n (%) 242 (86.1) age, higher SF-36 score, White race, higher number of DAS28‑ESR 6.6 ± 0.7 swollen joints, and lower pain. In line with our findings, younger age of patients with HAQ total score 1.6 ± 0.7 RA predicted a stronger clinical response in a study of PGA 6.7 ± 1.6 the TNF inhibitor adalimumab [11, 12] and in a study of VAS Pain, mm (0–100 scale) 65.6 ± 21.3 the IL6 inhibitor tocilizumab [13]. However, age did not Data are mean ± SD unless stated otherwise predict clinical response in a British registry study of the BMI body mass index, CRP C-reactive protein, DAS28-ESR 28-joint Disease Activity Score with erythrocyte sedimentation rate, ETN etanercept, HAQ TNF inhibitor infliximab [14]. Health Assessment Questionnaire, MTX methotrexate, PGA Physician Global Although it could be argued that younger age may be a Assessment, RF rheumatoid factor, SD standard deviation, VAS visual analog surrogate marker for shorter disease duration—which has scale de la Vega et al. Adv Rheumatol (2021) 61:56 Page 4 of 8 Table 2 Select Baseline Demographic and Baseline Disease Characteristics of Responders and Non‑Responders (Observed Cases) Baseline Characteristic* Week 24 Week 128 Responders Non-responders p value** Responders Non-responders p value** (n = 66) (n = 175) (n = 91) (n = 128) Age, years 45.4 ± 11.8 49.2 ± 11.7 0.024 45.7 ± 11.8 50.1 ± 11.8 0.008 Men, n (%) 13 (20) 16 (9) 15 (17) 13 (10) Women, n (%) 53 (80) 159 (91) 0.025 76 (84) 115 (90) 0.167 Race, n (%) White 34 (52) 77 (44) 0.622 46 (51) 57 (45) 0.015 Mestizo 15 (23) 38 (22) 25 (28) 23 (18) African‑Latin American 7 (11) 27 (15) 13 (14) 18 (14) Other 10 (15) 33 (19) 7 (8) 30 (23) BMI, kg/m 26.6 ± 5.3 26.3 ± 4.8 0.669 26.3 ± 4.4 26.4 ± 5.2 0.860 CRP, mg/L 19.5 ± 25.9 21.8 ± 25.4 0.521 22.5 ± 26.8 21.1 ± 26.1 0.707 ESR, mm/h 37.3 ± 11.2 44.3 ± 17.4 0.003 39.6 ± 13.8 43.1 ± 16.5 0.104 Disease duration, years 8.2 ± 7.1 7.4 ± 6.5 0.428 7.4 ± 6.4 8.0 ± 7.0 0.534 RF positive, n (%) 55 (83) 155 (89) 0.279 73 (80) 117 (91) 0.016 HAQ total score 1.3 ± 0.7 1.7 ± 0.7 0.001 1.5 ± 0.7 1.6 ± 0.7 0.376 VAS Pain, mm 60.0 ± 23.6 66.1 ± 20.3 0.047 61.6 ± 25.7 66.0 ± 18.2 0.141 PGA 6.5 ± 1.9 7.2 ± 1.9 0.013 6.7 ± 2.2 7.1 ± 1.8 0.122 SF‑36 Mental Health Scale 41.0 ± 11.3 40.3 ± 11.0 0.665 41.5 ± 10.8 39.6 ± 11.3 0.223 Prorated number of tender joints 22.2 ± 10.9 26.0 ± 11.9 0.024 24.6 ± 11.1 25.5 ± 12.4 0.600 Prorated number of swollen joints 17.6 ± 7.9 18.4 ± 8.6 0.504 19.9 ± 8.9 17.3 ± 8.2 0.029 *Data are mean ± SD unless stated otherwise **p value from either a one-way ANOVA model to analyze continuous characteristics or a chis-square test to analyze categorical characteristics; baseline characteristics with p values < 0.05 are highlighted in bold BMI body mass index, CRP C-reactive protein, ESR erythrocyte sedimentation rate, HAQ Health Assessment Questionnaire, PGA Physician Global Assessment, RF rheumatoid factor, SD standard deviation, SF-36 36-Item Short Form Survey, VAS visual analog scale model. These observations are in line with a number been shown to predict higher responses to ETN + MTX of studies. For example, in a cohort of Chinese patients [15] and other biologics [16–18]—our analysis, surpris- treated with a TNF inhibitor, ESR ≤ 60  mm/h and total ingly, found a marginally significant association of longer HAQ sore ≤ 1.31 were identified as predictors of clinical disease duration (> 3.7  years) with clinical response at response [20]. Data from the British Society for Rheuma- Week 24 when analyzed in combination with other sig- tology Biologics registry [14], as well as a study in Swed- nificant predictors in a stepwise analyses, but it was not ish patients [21], showed that lower baseline HAQ scores significant on its own. However, other confounding fac - were correlated with higher response rates. Similarly, tors may influence the relationship between disease dura - Japanese patients with higher baseline PGA scores were tion and DAS28 remission. Overall, the role of disease less likely to achieve response to biologic agents [19]. The duration as a predictor of clinical response to treatment same study identified low levels of CRP as a predictor of of RA with biologic agents appears to be unclear, with the response, which was not the case in our analysis. In the data from the British Society for Rheumatology Biologics GO-MORE study, lower tender joint count score was registry [14] and a study in Japanese patients treated with associated with a greater likelihood of achieving DAS28- infliximab, ETN, adalimumab, or tocilizumab [19] failing ESR ≤ 3.2 and  DAS28-ESR < 2.6 at 1 and 6  months after to establish a link between disease duration and response treatment with the anti-TNF golimumab in biologic- to treatment. naïve patients with active RA despite treatment with In our analysis, parameters indicating lower disease DMARD [22]. However, in a systematic review that activity at baseline (ESR ≤ 42  mm/h, PGA score ≤ 6.0, included 4 studies of patients with RA treated with anti- tender joint count ≤ 14, and total HAQ score ≤ 1.6) were TNF therapy + MTX, tender joint count at baseline was also associated with a stronger response to ETN + MTX not associated with sustained remission [23]. treatment at Week 24 on their own and in combina- tion with other significant predictors from a stepwise de la  Vega et al. Adv Rheumatol (2021) 61:56 Page 5 of 8 p-value Age at baseline (≤49 years vs >49 years) 0.007 Disease duration (>3.7 years vs <3.7 years) 0.091 Baseline BMI (>28.5 vs ≤28.5) 0.023 CRP (≤8.3 mg/L vs >8.3 mg/L) 0.036 ESR (≤42 mm/h vs >42 mm/h) 0.002 DAS28-ESR (≤6.6 vs >6.6) < 0.001 Prorated number of tender joints (≤14 vs >14) < 0.001 Physician Global Assessment (≤6.0 vs >6.0) 0.002 Total HAQ score (≤1.6 vs >1.6) < 0.001 Subject Global Assessment score (≤6.0 vs >6.0) 0.035 VAS Subject Health Assessment (>41.0 vs ≤41.0) 0.028 VAS Pain (≤48.0 vs >48.0) 0.018 VAS Fatigue (≤50.0 vs <50.0) 0.036 SF-36 Physical Health Scale score (>30.7 vs ≤30.7) 0.007 0246 8 Odds ratio (95% CI) p-value Age at baseline (≤42 years vs >42 years) 0.003 Ethnicity (White vs other) 0.008 ESR (≤36 mm/h vs >36 mm/h) 0.030 Rheumatoid factor (negative vs positive) 0.019 Prorated number of swollen joints (>18 vs ≤18) 0.019 VAS Subject health assessment (≤44.0 vs >44.0) < 0.001 VAS Pain (≤41.0 vs >41.0) < 0.001 VAS Fatigue (≤32.0 vs >32.0) 0.003 SF-36 Mental Health Scale score (>39.6 vs ≤39.6) 0.044 02 1 46 81012 Odds ratio (95% CI) Fig. 1 Baseline Factors Associated with Response to ETN + MTX at Weeks 24 (A) and 128* (B). *Results from one-way ANOVA models and in chi-square tests. ANOVA analysis of variance, BMI body mass index, CRP C‑reactive protein, DAS28 Disease Activity Score in 28 joints, ESR erythrocyte sedimentation rate, ETN etanercept, SF-36 36‑Item Short Form Survey, HAQ Health Assessment Questionnaire, MTX methotrexate, VAS visual analog scale de la Vega et al. Adv Rheumatol (2021) 61:56 Page 6 of 8 p-value Age (≤49 years vs >49 years) 0.003 2 2 BMI (>28.5 kg/m vs ≤28.5 kg/m ) 0.002 Disease duration (>3.7 years vs ≤3.7 years) 0.028 ESR (≤42 mm/h vs >42 mm/h) 0.001 < 0.001 PGA score (≤6.0 vs >6.0) Prorated number of tender joints (≤14 vs >14) 0.047 Total HAQ score (≤1.63 vs >1.63) 0.004 Age (≤42 years vs >42 years) 0.016 SF-36 Mental Health Scale score (>39.6 vs ≤39.6) 0.016 Race (White vs other) 0.012 Number of swollen joints (>18 vs ≤18) 0.021 VAS Pain (≤41 mm vs vs >41 mm) < 0.001 01 2468 10 12 12 20 Odds ratio (95% CI) Fig. 2 Odds Ratios for Predictors of Response at Weeks 24 and 128*. *Results from a stepwise regression model of Week 24 and Week 128 DAS28‑ESR remission, with list of baseline variables in the model given in the Statistical Analysis section. BMI body mass index, CI confidence interval, ESR erythrocyte sedimentation rate, HAQ Health Assessment Questionnaire, PGA Physician Global Assessment, SF-36 36‑Item Short Form Survey, VAS visual analog scale Conversely, a higher number of swollen joints (> 18) from the United States in which African-American and on its own (from univariate analysis) and in combination Hispanic patients with RA showed higher disease activ- with other significant predictors from a stepwise model, ity and worse clinical outcomes compared with White indicating higher disease activity at baseline, was asso- patients [26]. The role of race as a predictor is likely to ciated with a stronger response at Week 128. Although be complex and include both genetic as well as socio-cul- synovitis can be a predictor for radiographic progression tural and socio-economic factors. [24], an increased number of swollen joints was associ- Interestingly, we also identified higher BMI (> 28.5  kg/ ated with a higher likelihood of achieving sustained m ) as a predictor of clinical response at Week 24 when remission in a UK observational study [25]. analyzed in combination with other significant predic - Lower pain (VAS ≤ 41  mm) and SF-36 Mental Health tors in a stepwise model but not on its own in a univari- Scale score > 39.6 at baseline were identified as predic - ate model. This is in contrast with a study showing higher tors of clinical response at Week 128 only in combination BMI (> 30  kg/m ) to be associated with lower response with other significant predictors from a stepwise model, rates to infliximab [27]. In an Italian study, patients with lower pain being only marginally significant on its with higher BMI (> 30  kg/m ) were less likely to achieve own for Week 24 response. Although we could not iden- response to infliximab, but no correlation was found for tify any studies investigating either of these potential ETN and adalimumab [28]. In another study of adali- predictors, they may be associated with lower disease mumab, BMI (> 30  kg/m ) had no impact on response activity at baseline. rates [29]; this was also apparent in studies of rituxi- In our study, White patients (on its own and in com- mab [30] and tocilizumab [31]. Overall, the role of BMI bination with other significant predictors) were more as predictor of response seems to be unclear. Although likely to achieve clinical remission at Week 128 compared higher BMI is generally associated with lower socio- with patients of other races. This is in line with a study economic status, 1 Brazilian study found a positive cor- relation between BMI and higher socio-economic status Week 128Week 24 de la  Vega et al. Adv Rheumatol (2021) 61:56 Page 7 of 8 Acknowledgements [32], which may facilitate access to health care and could Medical writing support was provided by Andrea Schauenburg, PhD, of therefore explain the favorable outcomes observed here. Engage Scientific Solutions and was funded by Pfizer Inc. In this stepwise regression analysis, RF positivity Authors’ contributions had no impact on clinical response. This is in line with MdlV, GGB, RMX, CP‑ T, AES, GS, RDP, CB, KS, BV, Conceptualization, Data cura‑ observations from studies of ETN and infliximab [14] tion, Writing – review and editing. All authors read and approved the final and of tocilizumab [13]. Based on the currently avail- manuscript. able evidence, no clear conclusion can be drawn on the Funding role of RF positivity as predictor of response, with some The Latin American RA study was funded by Wyeth, which was acquired by studies finding a positive association although others Pfizer Inc in October 2009. have identified it as a negative predictor [12]. Availability of data and materials Although Week 24 and Week 128 responders to Upon request, and subject to certain criteria, conditions, and exceptions ETN + MTX were more likely to be male, sex was not (see https:// www. pfizer. com/ scien ce/ clini cal‑ trials/ trial‑ data‑ and‑ resul ts for more information), Pfizer will provide access to individual de ‑identified par ‑ a significant predictor of clinical response in our study. ticipant data from Pfizer ‑sponsored global interventional clinical studies con‑ An earlier study in a Swedish cohort also found no ducted for medicines, vaccines, and medical devices: (1) for indications that significant predictive value of sex on clinical response have been approved in the USA and/or EU; or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer after 3 or 6  months of therapy with ETN, infliximab, will also consider requests for the protocol, data dictionary, and statistical or adalimumab [21]; although males had lower DAS28 analysis plan. Data may be requested from Pfizer trials 24 months after study scores. This is somewhat in contrast to the findings of completion. The de‑identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, other studies where males were more likely to achieve and for which an exception does not apply, via a secure portal. To gain access, clinical remission following treatment with ETN or inf- data requestors must enter into a data access agreement with Pfizer. liximab [14], and adalimumab [11]. Within the patient population with RA, differences in severity of disease Declarations between sexes and differences in other factors, such Ethics approval as biological, physical, or social, may underlie any The final protocol, any amendments, and informed consent documenta‑ observed differences by sex. tion were reviewed and approved by the Institutional Review Board(s) (IRB) Limitations of this study included the post hoc nature and/or Independent Ethics Committee(s) (IEC) at each of the investigational centers participating in the study. Investigators were required to inform their of this analysis and the absence of an adequate control IRBs or IECs of the study’s progress and occurrence of any serious and/or group. The lack of a control group limits the ability to unexpected adverse events. This study was conducted in compliance with make conclusions about the specificity of the identified the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good subset of predictive characteristics to the ETN + MTX Clinical Practice Guidelines. In addition, all local regulatory requirements were treatment regimen. The low proportion of male partici - followed, in particular, those affording greater protection to the safety of trial pants makes it difficult to ascertain the impact of sex. It participants. is not possible to generalize the results from this study, Consent to participate which was conducted in selected clinical trial partici- A signed and dated informed consent was required before any screen proce‑ pants, to other populations that were not sufficiently dures were done. The investigators explained the nature, purpose, and risks of the study to each subject. Each subject was informed that he/she could represented in the clinical trial population (e.g., men withdraw from the study at any time and for any reason. Each subject was and individuals of different ages and with different dis - given sufficient time to consider the implications of the study before deciding ease durations). whether to participate. Subjects who chose to participate signed an informed consent document. In conclusion, this post hoc logistic regression analy- sis of a trial of Latin American patients with RA yielded Consent for publication several baseline predictors of clinical response to treat- Not applicable. ment with ETN + MTX, which may be useful for future Competing interests clinical decision-making. These baseline predictors of MdlV, AbbVie, Genzyme, Lilly, Pfizer, and TRB Pharma (consulting fees); BMS, clinical response included younger age, higher BMI, Gilead, Glaxo, Pfizer, and Roche (trial investigator); AbbVie, Genzyme, Janssen Lilly, and Pfizer (speaker); GGB, no disclosures to report; RMX, AbbVie, BMS, longer disease duration, higher SF-36 Mental Health Janssen, Lilly, Novartis, Pfizer, Roche, and UCB (consulting fees, speaker); CP ‑ T, Scale score, higher swollen joint count, and overall Pfizer, Sanofi, Roche, Eli Lilly, AbbVie, UCB, and BMS (consulting fees and lower disease activity. Discrepancies between our find - speaker); AES, AES is an employee of Syneos Health and was contracted by Pfizer to provide statistical support for the development of this paper; RDP, ings and those from studies conducted in other geo- RDP was an employee of Pfizer at the time of data generation and manuscript graphic areas of the world, however, underline the need development and own stock in Pfizer; GS, CB, KS, BV, Pfizer (stock options, for further prospective studies, adequately powered to employment). detect predictors of response. Author details CEIM Investigaciones Médicas, Laprida 1307, Ciudad De Buenos Aires, 1425 Buenos Aires, Argentina. Centro de Investigación Marbella, Paitilla de la Vega et al. Adv Rheumatol (2021) 61:56 Page 8 of 8 Panamá, Panamá. Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. 16. Agarwal SK, Glass RJ, Shadick NA, et al. Predictors of discontinuation of 4 5 Universidad Autónoma de Chihuahua, Chihuahua, Mexico. 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Published: Sep 8, 2021

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