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.

Figures

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