Clinical, Ultrasound, and Predictability Outcomes Following Certolizumab Pegol Treatment (with Methotrexate) in Patients with Moderate-to-Severe Rheumatoid Arthritis: 52-Week Results from the CZP-SPEED Study

Abstract

Introduction: To assess the impact of certolizumab pegol (CZP) treatment on clinical, patient-reported, and musculoskeletal ultrasound outcomes and to determine the treatment response time point most predictive of long-term outcomes in Italian patients with rheumatoid arthritis (RA).

Methods: CZP-SPEED (NCT01443364) was a 52-week, open-label, prospective, interventional, multicenter study. Biologic-naïve patients with moderate-to-severe active RA, who had failed at least one DMARD treatment, received CZP (400 mg at weeks 0, 2, and 4, then 200 mg every 2 weeks) concomitantly with methotrexate. The primary objective was to identify the time point of clinical response {decrease in 28-joint Disease Activity Score [DAS28(ESR)] ≥ 1.2} most predictive of a clinical response at week 52. Additional clinical and patient-reported outcomes were measured. Power Doppler (PD) ultrasound was used to assess synovial effusion, synovial proliferation, PD signal, cartilage damage, and bone erosion according to international guidelines.

Results: A total of 132 patients were enrolled and received CZP; 91/132 (69%) completed to week 52. Predicted 52-week responses for early responders (week 2 onwards) were between 65% and 70%. Rapid improvements in joint cavity widening and PD signal were observed to week 8 and maintained to week 52. Cartilage damage and bone erosion were stable over 52 weeks. No new safety signals were identified.

Conclusion: In Italian CZP-treated patients with moderate-to-severe RA, week 12 clinical responses may be predictive of long-term response at week 52. Rapid improvements in clinical, patient-reported, and musculoskeletal ultrasound outcomes were maintained to week 52. These data may aid rheumatologists to make earlier treatment decisions.

Trial registration: ClinicalTrials.gov identifier, NCT01443364.

Funding: UCB Pharma.

Keywords: Anti-TNF; Certolizumab pegol; Patient-reported outcome; Predictability; Rheumatoid arthritis; Rheumatology; Ultrasound.

Fig. 1

CONSORT diagram showing patient disposition throughout the SPEED study. ^aPatients who provided DAS28(ESR) values (observed case). ^bPatients who provided joint cavity widening and synovial proliferation values (observed case). FAS full analysis set, PDUS Power Doppler ultrasound, SS safety set

Fig. 2

Positive predictive value (PPV): percentage of patients with DAS28(ESR) clinical response at week 52 who also had clinical response at an early time point. Data reported for the full analysis set, n = 131. Missing values were imputed using non-responder imputation (NRI). Clinical response was defined as a reduction of at least 1.2 in DAS28(ESR). DAS28 28-joint disease activity score, ESR erythrocyte sedimentation rate, NRI non-responder imputation, PPV positive predictive value

Fig. 3

Evaluation of a positive predictive values (PPV), b area under the curve (AUC), and c negative predictive values (NPV) of clinical response at time points up to week 12. Data are reported for the full analysis set (RA duration of at most 1 year, n = 29; RA duration greater than 1 year, n = 102). Missing data were imputed using non-responder imputation (NRI). Data are provided for observed cases (OC) and NRI. Clinical responses at week 1 to week 12 were defined as a reduction of at least 1.2 from baseline in DAS28(ESR). AUC and NPV data were unavailable for patients with RA duration of at most 1 year (OC) at week 12. AUC area under the curve, NPV negative predictive value, NRI non-responder imputation, OC observed case, PPV positive predictive value, RA rheumatoid arthritis

Fig. 4

DAS28(ESR) response logistic regression analysis. Data are reported for the full analysis set (n = 131). Data were imputed using non-responder imputation (NRI). ^[a]Early responders were defined as the response, for each patient, at the visit where the highest area under curve (AUC) was observed. Clinical response at week 52 is defined as a reduction of at least 1.2 from baseline in DAS28(ESR). The odds ratio, CI and p value are from a logistic regression model with early responders as fixed effects and baseline DAS28(ESR) score, gender, age, and duration of RA as factors. An odds ratio greater than 1 indicates a higher response rate in the first category [e.g., DAS28(ESR) ≥ 5.1] compared to the second category [e.g., DAS28(ESR) < 5.1]. CI confidence interval, DAS28 28-joint disease activity score, ESR erythrocyte sedimentation rate, RA rheumatoid arthritis

Fig. 5

Improvements in clinical and patient-reported outcomes up to week 52 of the CZP-SPEED study. Data are reported for the full analysis set (n = 131). Missing data were imputed using last observation carried forward for continuous variables and non-responder imputation for binary data. Patients rated their level of arthritis pain on a 100 mm VAS, where 0 indicated “no pain” and 100 indicated “most severe pain”. DAS28 28-joint disease activity score, ESR erythrocyte sedimentation rate, HAQ-DI health assessment questionnaire disability index, LOCF last observation carried forward, NRI non-responder imputation, PtAAP patient assessment of arthritis pain, VAS visual analogue scale (0–100 mm)

Fig. 6

Mean improvement in joint cavity widening (a, c) and PD signal (b, d) measured with PDUS over time in metacarpophalangeal joints (MCPs). Groups are analyzed by MCP joint, n = 66 (a, b) and duration of RA (c, d). Data are reported for the full analysis set in patients eligible for the PDUS subgroup (n = 66). Joint cavity widening scores (0–3 scale; 0 = no effusion/hypertrophy, 1 = minimal effusion/hypertrophy, 2 = moderate effusion/hypertrophy, 3 = extensive effusion/hypertrophy). Power Doppler signal was based on the 4-point scale ranging from 0 (normal/minimal blood flow) to 3 (marked blood flow). Missing values were imputed using last observation carried forward (LOCF). Patients within the PDUS subset had at most 2 years duration of RA and proof of at least two of the following: synovial proliferation, synovial vascularization, or presence of fluid in at least one MCP joint. MCP metacarpophalangeal joints, PD Power Doppler, PDUS Power Doppler ultrasound, RA rheumatoid arthritis