Attila Pethö-Schramm

Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early) : a multicentre, randomised, double-blind, double-dummy, strategy trial

BACKGROUND For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines. METHODS We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm), or tocilizumab plus placebo-methotrexate (the tocilizumab arm), or methotrexate plus placebo-tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2·6 with a swollen joint count ≤four, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups with a two-sided Cochran-Mantel-Haenszel test. Analysis was based on an intention-to-treat method. This trial was registered at ClinicalTrials.gov, number NCT01034137. FINDINGS Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72-78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk [RR] 2·00, 95% CI 1·59-2·51 for tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48-2·32 for tocilizumab vs methotrexate, p<0·0001 for both comparisons). For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1·13, 95% CI 1·00-1·29, p=0·06 for tocilizumab plus methotrexate vs methotrexate, 1·14, 1·01-1·29, p=0·0356 for tocilizumab vs methotrexate, and p=0·59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study. INTERPRETATION For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards. FUNDING Roche Nederland BV.

FRI0215 Subcutaneous Tocilizumab as Monotherapy or in Combination with A csDMARDs in Patients with Rheumatoid Arthritis – Interim Analysis of A Large Phase IV International Umbrella Study, “Tozura”

Background Tocilizumab (TCZ), administered as intravenous (TCZ-IV) and subcutaneous (TCZ-SC) formulations, has been approved for treatment of patients (pts) with rheumatoid arthritis (RA) both as mono- and combination therapy. Objectives To evaluate the efficacy and safety of TCZ-SC 162 mg once weekly (qw) as monotherapy and in combination with conventional synthetic DMARDs (csDMARDs) over 24 weeks in adult pts with moderate to severe RA. Methods TOZURA is a multinational, open-label, single-arm umbrella study comprising 7 single-country and 4 regional multicountry protocols. It aimed to enroll

Radiographic joint damage in early rheumatoid arthritis patients: comparing tocilizumab- and methotrexate-based treat-to-target strategies

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Inadequate response to treat-to-target methotrexate therapy in patients with new-onset rheumatoid arthritis: development and validation of clinical predictors

1,850 pts who were biological DMARD inadequate responders (IR; 8/11 protocols) and/or csDMARD-IR (11/11 protocols). Pts received TCZ-SC 162 mg qw for 24 weeks, administered at the investigators discretion as monotherapy or in combination with a csDMARD. Stable oral NSAIDs and corticosteroids (CCS), ≤10 mg/day prednisone or equivalent, were allowed. Efficacy and safety were evaluated at weeks 1, 2, 4 and every 4 weeks thereafter. Results In this interim analysis, 1246 pts were included by end of 2014; 283 pts received monotherapy, 963 combination; 25% of pts were biologic DAMRD-IR (monotherapy: 36%, combination: 22%). Background characteristics: 80.5% female, mean age 54.5 years, mean RA disease duration 7.7 years and 81.4% seropositive – similar between treatment groups. Baseline oral CCS use was less frequent in the mono- group (42.8%) than in the combination group (51.2%); however, their mean dose was similar (6.673 vs 6.505 mg/day, respectively). Pts continuation of TCZ at week 24 based on Kaplan-Meier estimates (95% CI) were 0.784 (0.732, 0.828) for mono- and 0.855 (0.831, 0.875) for combination therapy. All pts had significant reductions in mean 28-joint Disease Activity (DAS28) scores by week 24 (mean decrease: monotherapy 3.41 and combination 3.44; P <0.0001 for both) with no significant difference between groups (P =0.788). Results were similar for the Clinical Disease Activity Index (CDAI), which does not include acute phase reactants (mean change by week 24: 24.03 and 23.28, P <0.0001 for both groups: between groups P =0.629). The proportion of pts who achieved DAS28 or CDAI-based remission and low disease activity and ACR20/50/70/90 responses was similar between the treatment groups (Figs 1A, 1B). Of the 231 pts (18.5%) who withdrew, 92 (7.4%) did so for safety reasons (29 [10.2%] monotherapy, 63 [6.5%] combination). Serious AEs (SAEs) occurred in 78 pts (6.3%; 11.5/100 PY) and rates of AEs and SAEs were similar between groups (Table 1). Serious infections and infestations occurred in 18 pts (1.4%; 2.2/100 PY), with similar rates between groups. Five deaths occurred, 1 in the monotherapy group (coronary artery disease) and 4 in the combination group (intestinal ischemia, myocardial infarction, pneumonia, septic shock). Conclusions TCZ-SC demonstrated convincing and comparable efficacy in mono- and combination therapy in pts with RA as previously observed with TCZ-IV. The safety profile of TCZ-SC is consistent with the known safety profile of TCZ as monotherapy and in combination with csDMARDs. Disclosure of Interest E. Choy Grant/research support from: F. Hoffmann-La Roche and Chugai Pharmaceutical, Consultant for: F. Hoffmann-La Roche and Chugai Pharmaceutical, Speakers bureau: F. Hoffmann-La Roche and Chugai Pharmaceutical, R. Caporali Consultant for: Abbvie, Bristol-Myers Squibb, F. Hoffmann-La Roche, UCB and MSD Pharmaceuticals, R. Xavier Consultant for: F. Hoffmann-La Roche, Pfizer, Janssen Pharmaceutica, Abbvie, Eli Lilly and Company, Speakers bureau: F. Hoffmann-La Roche, Pfizer, Janssen Pharmaceutica, Abbvie, Eli Lilly and Company, B. Fautrel: None declared, R. Sanmarti: None declared, C. Bernasconi Employee of: F. Hoffmann-La Roche, A. Pethö-Schramm Employee of: F. Hoffmann-La Roche

SAT0199 Subcutaneous tocilizumab monotherapy or combined with a csdmard in patients with rheumatoid arthritis: tozura, a pooled analysis of phase iv studies in 22 countries

Objective To evaluate the progression of erosions and joint space narrowing (JSN) in feet and hands in the U-Act-Early trial. Methods In this trial, 317 newly diagnosed DMARD-naïve RA patients initiated randomly tocilizumab, or step-up MTX or a combination of the two. Radiographs were scored at baseline and after 52 and 104 weeks using the Sharp-van der Heijde erosion and JSN score. Between the strategy arms, changes from baseline and the proportions of patients without radiographic progression (change from baseline ≤0) were compared. Results Mean changes from baseline in erosion and JSN scores for the whole study population were after 52 weeks 0.59 and 0.18 and after 104 weeks 0.70 and 0.50, respectively. For JSN, at both time points no differences in progression were found between strategies (P ⩾ 0.09). For erosions, the progression was significantly lower at week 104 in both tocilizumab arms when compared with the MTX arm ((p≤0.023). Less progression of erosions in the feet was found after 104 weeks in both tocilizumab arms (P ⩽ 0.046); this was not significant for the hands (P ⩾ 0.11). The proportion of patients without progression in erosions was higher in the tocilizumab arms at week 52 (tocilizumab plus MTX: 87%, P = 0.038; tocilizumab: 81%, P = 0.29) and 104 (tocilizumab plus MTX: 85%, P = 0.001; tocilizumab: 77%, P = 0.028), compared with the MTX arm (74 and 60%, respectively). Conclusion In DMARD-naïve early RA patients, initiating a tocilizumab-based treat-to-target strategy inhibits the progression of erosions, especially in the feet, more compared with initiation of a step-up MTX strategy. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT01034137.

Subcutaneous tocilizumab in rheumatoid arthritis: findings from the common-framework phase 4 study programme TOZURA conducted in 22 countries

Objective To identify and validate clinical baseline predictors associated with inadequate response (IR) to methotrexate (MTX) therapy in newly diagnosed patients with rheumatoid arthritis (RA). Methods In U-Act-Early, 108 disease-modifying antirheumatic drug (DMARD)-naive patients with RA were randomised to initiate MTX therapy and treated to target until sustained remission (disease activity score assessing 28 joints (DAS28) <2.6 with four or less swollen joints for ≥24 weeks) was achieved. If no remission, hydroxychloroquine was added to the treatment regimen (ie, ‘MTX+’) and replaced by tocilizumab if the target still was not reached thereafter. Regression analyses were performed to identify clinical predictors for IR, defined as needing addition of a biological DMARD, to ‘MTX+’. Data from the treatment in the Rotterdam Early Arthritis Cohort were used for external validation of the prediction model. Results Within 1 year, 56/108 (52%) patients in U-Act-Early showed IR to ‘MTX+’. DAS28 (adjusted OR (ORadj) 2.1, 95% CI 1.4 to 3.2), current smoking (ORadj 3.02, 95% CI 1.1 to 8.0) and alcohol consumption (ORadj 0.4, 95% CI 0.1 to 0.9) were identified as baseline predictors. The area under the receiver operator characteristic curve (AUROC) of the prediction model was 0.75 (95% CI 0.66 to 0.84); the positive (PPV) and negative predictive value (NPV) were 65% and 80%, respectively. When applying the model to the validation cohort, the AUROC slightly decreased to 0.67 (95% CI 0.55 to 0.79) and the PPV and NPV to 54% and 80%, respectively. Conclusion Higher DAS28, current smoking and no alcohol consumption are predictive factors for IR to step-up ‘MTX+’ in DMARD-naive patients with new-onset RA. Trial registration NCT01034137; Post-results, ISRCTN26791028; Post-results.

Baseline metabolic profiles of early rheumatoid arthritis patients achieving sustained drug-free remission after initiating treat-to-target tocilizumab, methotrexate, or the combination: insights from systems biology

Background Tocilizumab administered subcutaneously (TCZ-SC) has been approved for the treatment of rheumatoid arthritis (RA) both as mono- and combination therapy. Objectives To evaluate the efficacy and safety of TCZ-SC 162 mg once weekly (qw) as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) over 24 weeks in adult patients (pts) with moderate to severe RA. Methods TOZURA is a multinational, open-label, single-arm umbrella program comprising 7 single-country and 4 regional multicountry protocols (total 22 countries). Pts enrolled were inadequate responders to DMARD, and previous biologic DMARDs were allowed in 8 of 11 protocols. Pts received TCZ-SC 162 mg qw for 24 weeks administered at the investigators discretion as monotherapy or in combination with a csDMARD. Stable oral NSAIDs and corticosteroids (CS), ≤10 mg/day prednisone or equivalent, were allowed. Efficacy and safety were evaluated at weeks 1, 2, 4 and every 4 weeks for 24 weeks (plus 8 weeks for safety). Propensity score-based matching was used for between-group tests. Results Of 1804 pts treated, 353 (19.6%) received monotherapy (mono) and 1451 (80.4%) combination therapy (combo); 349 pts (19.3%) had received a prior biologic DMARD. Background characteristics: 81.6% female; mean age, 54.1 years; mean RA duration, 7.7 years; and 82.7% seropositive –similar between treatment groups. Baseline CS was less frequent in the mono vs combo group (41.1% vs 51.2%); however, the mean prednisone equivalent daily dose was similar (6.6 vs 6.5 mg/day, respectively). Pts who continued TCZ to week 24 based on Kaplan-Meier estimates (95% CI) were 79.3% (74.7%>83.2%) for mono and 85.6% (83.7%>87.3%) for combo. DAS28 scores decreased comparably from baseline to week 24 in both groups (mean change: mono −3.40 and combo −3.46), with no significant difference between groups (P =0.61). Results were similar for the Clinical Disease Activity Index (CDAI, mean change by week 24: −23.5 and −23.8, with no significant difference between groups: P=0.42). The proportion of pts who achieved DAS28 or CDAI-based remission, low disease activity or ACR20/50/70/90 responses was similar between groups (Figure 1). In all, 18.2% of pts withdrew; 6.4% did so for safety reasons (mono 9.1%, combo 5.8%). AE rates were similar between groups (Table). Serious AE (SAE) rates were 14.6/100 PY (mono: 22.8/100 PY, combo: 12.8/100 PY). Serious infection and infestation rates were 3.6/100 PY (mono: 4.0/100 PY, combo: 3.5/100 PY) – similar between groups. Six deaths occurred (0.64/100 PY), 1 in the monotherapy group (0.57/100 PY) and 5 in the combination (0.65/100 PY) group. Conclusions TCZ-SC demonstrated convincing and comparable efficacy as mono- and combination therapy in pts with RA as was previously observed with TCZ-IV. The safety profile of TCZ-SC is consistent with the known safety profile of TCZ as monotherapy and in combination with csDMARDs. Acknowledgements Funded by F. Hoffmann-La. Roche, Ltd. Disclosure of Interest E. Choy Grant/research support from: F. Hoffmann-La Roche, Chugai Pharmaceutical, Consultant for: F. Hoffmann-La Roche, Chugai Pharmaceutical, Speakers bureau: F. Hoffmann-La Roche, Chugai Pharmaceutical, R. Caporali Consultant for: AbbVie, Bristol-Myers Squibb, F. Hoffmann-La Roche, UCB and MSD Pharmaceuticals, R. Xavier Consultant for: F. Hoffmann-La Roche, Pfizer, Janssen Pharmaceuticals, AbbVie, Eli Lilly and Company, Speakers bureau: F. Hoffmann-La Roche, Pfizer, Janssen Pharmaceuticals, Abbvie, Eli Lilly and Company, B. Fautrel: None declared, R. Sanmarti: None declared, C. Bernasconi Employee of: F. Hoffmann-La Roche (contractor), A. Pethö-Schramm Employee of: F. Hoffmann-La Roche

Incidence and risk of glucocorticoid-associated adverse effects in patients with rheumatoid arthritis

Abstract Objectives The aim of this pooled analysis of the TOZURA study programme was to evaluate the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) in patients with moderate to severe RA who had an inadequate response to csDMARD or anti-TNF agent therapy or who were MTX naïve. Methods TOZURA is a multinational, open-label, single-arm, common-framework, phase 4 study programme (11 protocols, 22 countries). Patients received TCZ-SC 162 mg each week for ⩾24 weeks, administered at the investigator’s discretion, as monotherapy or in combination with a csDMARD. Efficacy, safety and immunogenicity were evaluated; propensity score–based matching was used for between-group comparisons. Results Of 1804 patients, 353 (19.6%) received monotherapy and 1451 (80.4%) received combination therapy. The 28-joint DAS using ESR (DAS28-ESR) in both groups decreased significantly from baseline to week 24 (mean change: monotherapy −3.40, combination therapy −3.46), with no significant difference between groups (P = 0.46). The proportion of patients who achieved DAS28-ESR or Clinical Disease Activity Index remission or ACR 20/50/70/90 responses was similar between groups. Overall, 13.9% of patients withdrew—6.2% for safety reasons and 1.6% for insufficient therapeutic response; 5.8% of patients experienced one or more serious adverse events [14.6/100 patient-years (PY)]; six deaths occurred (0.64/100 PY). Conclusion In a common framework of 11 studies in 22 countries, this phase 4 study programme confirmed TCZ-SC’s known efficacy and safety profile with comparable effects as monotherapy and in combination with csDMARDs. Trial registration ClinicalTrials.gov (http://www.clinicaltrials.gov) NCT01941940, NCT01941095, NCT01951170, NCT01987479, NCT01988012, NCT01995201, NCT02001987, NCT02011334, NCT02031471, NCT02046603 and NCT02046616.

Adding baseline protein biomarkers to clinical predictors does not enhance prediction of treatment response to a methotrexate strategy in early rheumatoid arthritis

BackgroundWe previously identified, in newly diagnosed rheumatoid arthritis (RA) patients, networks of co-expressed genes and proteomic biomarkers associated with achieving sustained drug-free remission (sDFR) after treatment with tocilizumab- or methotrexate-based strategies. The aim of this study was to identify, within the same patients, metabolic pathways important for achieving sDFR and to subsequently study the complex interactions between different components of the biological system and how these interactions might affect the therapeutic response in early RA.MethodsSerum samples were analyzed of 60 patients who participated in the U-Act-Early trial (ClinicalTrials.gov number NCT01034137) and initiated treatment with methotrexate, tocilizumab, or the combination and who were thereafter able to achieve sDFR (n = 37); as controls, patients were selected who never achieved a drug-free status (n = 23). Metabolomic measurements were performed using mass spectrometry on oxidative stress, amine, and oxylipin platforms covering various compounds. Partial least square discriminant analyses (PLSDA) were performed to identify, per strategy arm, relevant metabolites of which the biological pathways were studied. In addition, integrative analyses were performed correlating the previously identified transcripts and proteins with the relevant metabolites.ResultsIn the tocilizumab plus methotrexate, tocilizumab, and methotrexate strategy, respectively, 19, 13, and 12 relevant metabolites were found, which were subsequently used for pathway analyses. The most significant pathway in the tocilizumab plus methotrexate strategy was “histidine metabolism” (p < 0.001); in the tocilizumab strategy it was “arachidonic acid metabolism” (p = 0.018); and in the methotrexate strategy it was “arginine and proline metabolism” (p = 0.022). These pathways have treatment-specific drug interactions with metabolites affecting either the signaling of interleukin-6, which is inhibited by tocilizumab, or affecting protein synthesis from amino acids, which is inhibited by methotrexate.ConclusionIn early RA patients treated-to-target with a tocilizumab- or methotrexate-based strategy, several metabolites were found to be associated with achieving sDFR. In line with our previous observations, by analyzing relevant transcripts and proteins within the same patients, the metabolic profiles were found to be different between the strategy arms. Our metabolic analysis further supports the hypothesis that achieving sDFR is not only dependent on predisposing biomarkers, but also on the specific treatment that has been initiated.Trial registrationClinicalTrials.gov, NCT01034137. Registered on January 2010

SAT0218 Effect of tocilizumab in DMARD-NAÏVE early rheumatoid arthritis patients on health-related quality of life: results of the U-ACT-EARLY trial

Using the UK Clinical Practice Research Datalink, we examined the incidence of glucocorticoid (GC)‐related serious adverse events (SAEs) in rheumatoid arthritis (RA) and non‐RA patients and quantified the risk of SAEs in patients with RA.