Predictors of remission with etanercept-methotrexate induction therapy and loss of remission with etanercept maintenance, reduction, or withdrawal in moderately active rheumatoid arthritis: results of the PRESERVE trial

Abstract

Background: The aim was to analyze characteristics that predict remission induction and subsequent loss of remission in patients with moderately active rheumatoid arthritis (RA) who received full-dose combination etanercept plus methotrexate induction therapy followed by reduced-dose etanercept or etanercept withdrawal.

Methods: Patients with Disease Activity Score based on 28-joint count (DAS28) >3.2 and ≤5.1 received open-label etanercept 50 mg once weekly (QW) plus methotrexate for 36 weeks. Those who achieved DAS28 low disease activity by 36 weeks were randomized to double-blind treatment with etanercept 50 mg or 25 mg QW plus methotrexate or placebo plus methotrexate for 52 weeks. All analyses were adjusted for the continuous baseline variables of their respective remission outcomes.

Results: Younger age, body mass index (BMI) <30 kg/m2, and lower Health Assessment Questionnaire (HAQ) score at baseline were significant predictors of week-36 remission (P < 0.05) based on DAS28, Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI). Baseline DAS28, SDAI, and CDAI were significantly predictive of all three remission endpoints (P < 0.05). For all three treatments, the strongest predictors of loss of DAS28 remission included failure to achieve sustained remission (DAS28 < 2.6 at weeks 12, 20, 28, and 36) with induction therapy, higher DAS28/SDAI/CDAI at randomization and at 1 month, increase in DAS28/SDAI/CDAI at 1 month, and increase in DAS28/CDAI/SDAI components and patient-reported outcomes (PROs) at 1 month. With the exception of not achieving sustained remission, very similar significant predictors were observed for loss of SDAI and CDAI remission.

Conclusion: These findings suggest that patients with moderately active RA who are younger and have lower BMI, lower HAQ, and lower disease activity at baseline are most likely to achieve remission when receiving combination etanercept and methotrexate induction therapy. In addition, patients who fail to achieve sustained remission with induction therapy and those with worse disease activity and PROs at early time points after initiating maintenance therapy with a full-dose or reduced-dose etanercept-methotrexate regimen or methotrexate monotherapy are most likely to lose remission across all treatment arms. These findings may help guide clinicians' decision-making as they treat patients to remission and beyond.

Trial registration: ClinicalTrials.gov, NCT00565409 . Registered on 28 November 2007.

Keywords: Etanercept; Low disease activity; Methotrexate; Remission; Rheumatoid arthritis; Treatment.

Conflict of interest statement

Ethics approval and consent to participate

The PRESERVE trial was conducted in accordance with the ethical principles of the Declaration of Helsinki and the guidelines for Good Clinical Practice of the International Conference on Harmonisation. All patients were required to sign an informed consent form. The institutional review board or independent ethics committee at the following participating centers reviewed and approved all consent forms and the PRESERVE study protocol: Australia – Bellberry Limited, Dulwich, SA; Flinders Clinical Research Ethics Committee, Repatriation General Hospital, Daw Park, SA; The Austin Health Human Research Ethics Committee, Heidelberg, VIC. Austria – Ethikkommission der Stadt Wien, Wien. Belgium – Comite d'ethique Hospitalo-Facultaire Universitaire de Liege, Centre Hospitalier Universitaire du Sart Tilman, Liege; CHU Liege, Comité d’Ethique de la Faculté de Médicine, Centre Hospitalier Universitaire du Sart Tilman, Liege. Chile – Comite Etico Cientifico, Servicio de Salud Metropolitano Oriente, Santiago, RM. Colombia – Comite de etica de la fundacion instituto de reumatologia Fernando Chalem, Bogota, Cundinamarca; Comité de etica independiente centro de reumatologia y ortopedia, Barranquilla, Atlantico; Comite de Etica de la Investigacion Riesgo de Fractura S.A., Bogota, Cundinamarca. Czech Republic – Eticka komise Fakultni nemocnice Olomouc a Lekarske fakulty, Univerzity Palackeho, Olomouc; Ethics Committee of Institute of Rheumatology, Praha; Eticka komise pro multicentricka klinicka hodnoceni Fakultni nemocnice v Motole, Praha; Multicentricka eticka komise Fakultni nemocnice u sv. Anny v Brne - detasovane pracoviste, Brno. France – Comité de Protection des Personnes, Sud-Ouest et Outre-Mer II Hôpital Purpan, Toulouse Cedex 9. Germany – Ethik-Kommission bei der Medizinischen Fakultaet der Universitaet Wuerzburg, Institut fuer Pharmakologie und Toxikologie, Wuerzburg. Hungary – Egeszsegugyi Tudomanyos Tanacs Klinikai Farmakologiai Etikai Bizottsaga, Budapest. Italy – Comitato Etico Scientifico dell'Azienda Ospedaliera Ospedale Niguarda Ca' Granda di Milano, Milano; Comitato Etico Azienda Ospedaliera Universitaria San Luigi Gonzaga di Orbassano, Orbassano; Comitato Etico dell'Universita' Campus Bio-Medico di Roma, Roma; Comitato Etico dell'Azienda Ospedali Vittorio Emanuele, Ferrarotto, S.Bambino, Catania. Republic of Korea – Institutional Review Board, Gangnam Severance Hospital, Seoul; Institutional Review Board/Ethics Commitee of Kangdong Sacred Heart Hospital, Seoul; Hallym University Sacred Heart Hospital Institutional Review Board, Anyang-Si, Gyeonggi-do; Institutional Review Board for Human Research, Konkuk University Hospital, Seoul; Institutional Review Board, Gachon Gil Medical Center, Incheon; Hanyang University Hospital IRB, Seoul; IRB of Eulji University Hospital, Daejeon. Mexico – Comite de Etica de la Facultad de Medidna de la UANL Hospital Universitario Dr Jose Eleuterio Gonzalez, Monterrey NL; Comite Bioetico para la Investigacion Clinica S. C., Puebla 422, Mexico, DF; Comite de Etica del Hospital San Javier, Guadalajara, Jalisco; Comité de Investigación del Hospital CEM, Merida, Yucatán. The Netherlands – Independent Review Board Nijmegen (IRBN) Nijmegen, Wijchen. Poland – Komisja Etyczna Przy Instytucie Reumatologicznym ul Spartanska 1, Warszawa. Russian Federation - Biomedical Ethics Committee at FGU "Severo-Zapadny District Medical Center of Rozdrav," St. Petersburg; Ethical council under responsibility of department of state regulation of circulation of medicines, Ministry of Public Health and Social Development of Russian Federation, Moscow; Local Ethics Committee at GU Institute of Rheumatology of RAMS, Moscow; Local Ethics Committee at GUZ "City Clinical Hospital #1 n.a., N.I.Pirogov," Rheumatology Department, Moscow; Local Ethics Committee at GUZ at Leningrad Regional Clinical Hospital, St. Petersburg; Local Ethics Committee at Moscow Regional Research Clinical Institute, n.a. M.F. Vladimirskogo, Moscow. Serbia and Montenegro – Ethics Committee of Institute of Rheumatology-Belgrade, Belgrade; Ethics Committee of Institute for Treatment and Rehabilitation "Niska Banja," Niska Banja; Ethics Committee Military Medical Academy, Belgrade. Spain – Hospital General Universitario Gregorio Marañon, Comite etico de Investigacion Clinica c/Doctor, Madrid. Sweden – Regionala etikprovningsnamnden i Uppsala, Uppsala. Taiwan – Institutional Review Board of Tri-Service General Hospital National Defense Medical Center, Neihu, Taipei; Kaohsiung Medical University Chung-Ho Memorial Hospital, Institutional Review Board, Kaohsiung. United Kingdom – Liverpool Adult Research Ethics Committee, Research Ethics Office, Liverpool; Wrightington, Wigan and Leigh LREC, Greater Manchester Strategic Health Authority, Manchester; West Midlands Research Ethics Committee, Redditch, Worcestershire.

Consent for publication

Not applicable.

Competing interests

JSS has received research grants and consulting fees from AbbVie, BMS, MSD, Pfizer, and Roche, and consulting fees from Astra-Zeneca, Boehringer Ingelheim, Celgene, Celtrion, GSK, ILTOO, Janssen, Lilly, Novartis-Sandoz, Samsung, and UCB. AS is an employee of inVentiv Health and was contracted by Pfizer to provide statistical support for the development of this paper. ASK, TVJ, and LM are employees of Pfizer and hold Pfizer stock. The authors do not report any non-financial conflicts of interest.

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Figures

Fig. 1

Continuous and categorical baseline predictors of disease activity score based on 28 joints (DAS28) (a), Simplified Disease Activity Index (SDAI) (b), and Clinical Disease Activity Index (CDAI) (c) remission using univariate logistic regression (unadjusted). If the 95% CI does not contain the value 1.0, the predictor is statistically significant at α = 0.5. Non-significant predictors, black; significant predictors, gray. For continuous predictors with odds ratios >1, higher values are associated with a greater likelihood of remission. For numeric categorical predictors with odds ratios >1, higher numeric subgroups are associated a greater likelihood of remission (e.g., patients with body mass index (BMI) 18.5–25 kg/m2 are more likely to achieve DAS28 remission than patients with BMI <18.5 kg/m2); for nominal categorical predictors, the first named subgroup is associated with a greater likelihood of remission (e.g., anti-citrullinated peptide antibody (ACPA) + patients are more likely to achieve DAS28 remission than ACPA- patients). Conversely, for continuous predictors with odds ratios <1, lower values are associated with a greater likelihood of remission. For numeric categorical predictors with odds ratios <1, lower numeric subgroups are associated with a greater likelihood of remission (e.g., patients who are ≤40 years of age are more likely to achieve DAS28 remission than patients who are >40 years of age); for nominal categorical predictors with odds ratios <1, the second named subgroup is associated with a greater likelihood of remission (e.g., patients with erythrocyte sedimentation rate (ESR) levels ≤ upper limit of normal (ULN) are more likely to achieve DAS28 remission than patients with ESR > ULN). BL, baseline; CI, confidence interval; CRP, C-reactive protein; HAQ, Health Assessment Questionnaire; JSN, joint space narrowing: mTSS, modified total Sharp score: PGA, physician global assessment; PtGA patient global assessment; RF, rheumatoid factor. Analyses were adjusted for baseline DAS28, SDAI, and CDAI (respectively). Patients included in the DAS28, SDAI, and CDAI remission models: n = 763, n = 755, and n = 762, respectively. Radiographic variables were excluded from the stepwise analyses because 55 patients did not have radiographic data

Fig. 2

Select continuous and categorical baseline predictors of Disease Activity Score based on a 28-joint count (DAS28) (a), Simplified Disease Activity Index (SDAI) (b), and Clinical Disease Activity Index (CDAI) (c) remission using stepwise models (adjusted for other variables). If the 95% confidence interval (CI) does not contain the value 1.0, the predictor is statistically significant at α = 0.5. Non-significant predictors, black; significant predictors, gray. HAQ, health assessment questionnaire

Fig. 3

Proportions of patients who were not in Disease Activity Score based on a 28-joint count (DAS28) remission in the double-blind period. ETN, etanercept; MTX, methotrexate

Fig. 4

Strongest sets of predictors of loss of Disease Activity Score based on a 28-joint count (DAS28) remission (a), DAS28 remission plus change in DAS28 ≥ 0.6 (b), Simplified Disease Activity Index (SDAI) remission (c), and Clinical Disease Activity Index (CDAI) remission (d) in the double-blind period by treatment group using stepwise models. CI, confidence interval; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HAQ, health assessment questionnaire; PGA, physician global assessment; PtGA, patient global assessment; RF, rheumatoid factor; SJC, swollen joint count; ULN, upper limit of normal; VAS, visual analog scale

Fig. 5

Predicted probability (95% CI) of the loss of Disease Activity Score based on a 28-joint count (DAS28) remission and low disease activity (LDA) in patients receiving reduced-dose combination therapy or methotrexate monotherapy in the double-blind period based on mean DAS28 at week 36 of the open-label period, using logistic regression models. Circles at the top, patients who lost response; circles at the bottom, patients who did not lose response; smooth line, model-predicted probability of loss of response as a function of week-36 DAS28; shadowed area, 95% CI

Fig. 6

Proportions of patients who lost Disease Activity Score based on a 28-joint count (DAS28) remission (a), DAS28 remission and had a change in DAS28 ≥ 0.6 (b), Simplified Disease Activity Index (SDAI) remission (c), and Clinical Disease Activity Index (CDAI) remission (d) at least once at any time point in the double-blind period by duration of remission in the open-label period. n/N, numbers of patients who lost remission in the double-blind period/numbers of patients who had remission at specified time points in the open-label period. Patients included in the loss of remission models (i.e., patients with remission at week 36). ETN, etanercept; MTX, methotrexate