Original article RHEUMATOLOGY

Transcription

1 RHEUMATOLOGY Rheumatology 2016;55: doi: /rheumatology/kev372 Advance Access publication 29 October 2015 CLINICAL SCIENCE Original article ROUTINE a prospective, multicentre, non-interventional, observational study to evaluate the safety and effectiveness of intravenous tocilizumab for the treatment of active rheumatoid arthritis in daily practice in Germany Christof Iking-Konert 1, Ulrich von Hinüber 2, Constanze Richter 3, Holger Schwenke 4, Irmgard Gürtler 5, Peter Kästner 6, Birgit Klapperich 7, Marvin A Peters 8 and Gerd-Rüdiger Burmester 9 Abstract Objective. To evaluate the tolerability, effectiveness and utilization of tocilizumab for the treatment of RA in a usual care setting. Methods. ROUTINE was a prospective, non-interventional, observational 52-week study performed at 174 sites throughout Germany. RA patients were selected and treated according to label. Study objectives included the targeted documentation of infections, other adverse events, and various effectiveness outcomes (e.g. DAS28, clinical disease activity). Statistical analyses were performed primarily based on the data as observed. Results. A total of 850 patients (75% women, mean age: 56 ± 13 years, mean RA duration: 10.3 ± 8.6 years) were enrolled. Most patients (79%) were pretreated with TNF-inhibitors, whereas 21% were pretreated with conventional DMARDs only. Most common DMARD pretreatments were MTX (79%), LEF (68%), adalimumab (53%) and etanercept (50%). At baseline, 60.5% of patients received tocilizumab in combination with any other RA drugs, while 39.5% were treated in monotherapy. Mean baseline DAS28 was 5.5 ± 1.3, and this decreased to 2.6 ± 1.6 at week 52. At week 52, good EULAR response was achieved in 62.3%, low disease activity state in 66.4%, and DAS28 remission in 55.1% of patients (adjusted relative frequencies). 35.3% of patients discontinued the study prematurely; common reasons were lack of effectiveness (10.5%) and intolerability (7.3%). Any infections and severe infections occurred in 37.6% and 7.2% of patients, respectively (N = 836); serious infections were seen in 5.3% (N = 850). Event rates of any, severe and serious infections were 70.3, 9.8 and 4.4 events/100 patient-years, respectively. Conclusion. Tocilizumab administered in a real-life setting showed clinically meaningful improvements and a safety profile that was consistent with data reported from pre-approval Phase III studies. Key words: antibodies, monoclonal, humanized, biological products, treatment outcome, rheumatoid arthritis, observational study, Germany, Interleukin-6. 1 Department of Nephrology and Rheumatology, Medicine III, University Clinic Hamburg-Eppendorf, Hamburg, Germany, 2 Private Practice, Hildesheim, Germany, 3 Private Practice, Stuttgart, Germany, 4 Private Practice, Dresden, Germany, 5 Private Practice, Neuss, Germany, 6 Private Practice, Erfurt, Germany, 7 Roche Diagnostics International Ltd, Rotkreuz, Switzerland, 8 Roche Pharma AG, Grenzach-Wyhlen, Germany and 9 Department of Rheumatology and Clinical Immunology, Charité University Medicine Berlin, Berlin, Germany Submitted 17 March 2015; revised version accepted 10 September 2015 Correspondence to: Gerd-Rüdiger Burmester, Department of Rheumatology and Clinical Immunology, Charité University Medicine Berlin, Free University and Humboldt University Berlin, Charitéplatz 1, Berlin, Germany. gerd.burmester@charite.de! The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Anti-IL-6 treatment of active RA Rheumatology key messages. ROUTINE study results were consistent with results of pre-approval Phase III studies on the use of tocilizumab in RA.. The favourable risk/benefit ratio of tocilizumab established during clinical development was confirmed under reallife conditions for RA.. Tocilizumab is effective and well tolerated for usual care treatment of RA. Introduction Introduced in the late 1990s, biologic DMARDs (bdmards) have revolutionized the management of immune-mediated inflammatory diseases such as RA through specific targeted modulation and inhibition of inflammatory processes. This therapeutic progress is reflected by current revisions of European treatment recommendations (e.g. treat-to-target concept), which promote treatment initiation with conventional synthetic DMARDs (csdmards) as soon as RA is diagnosed (with the goal of achieving remission). In cases of inadequate response (IR) to the first csdmard, addition of or change to a second csdmard is recommended in patients without poor prognostic factors, while bdmards may be added in patients with prognostically unfavourable factors already after 3 months [1,2]. The first biologics to treat RA were TNF-inhibitors. Subsequent developments resulted in drugs that exert their selective anti-inflammatory properties by costimulatory modulation of CD28 on T cells through the CD28 receptor, depletion of CD20-positive B cells, or inhibition of IL-1. In 2009, the novel agent tocilizumab was approved in the EU for the treatment of RA. This recombinant, humanized, monoclonal antibody acts via inhibition of the IL-6 receptor. The favourable risk/benefit profile of tocilizumab was established in five pivotal, randomized controlled trials (RCTs), in which RA patients with IR to MTX or other csdmards [3 6], or TNF-inhibitors [7] were treated for a period of mostly 24 weeks. Patients enrolled in these studies were partly transferred to a currently ongoing treatment program (GROWTH 95 and GROWTH 96) in order to evaluate the efficacy and tolerability of tocilizumab in long-term administration and to verify the favourable results obtained from an extended Phase II study over 5 years performed in Japan with 143 patients [8]. Recently, tocilizumab has become available also for subcutaneous administration, based on the results of the two Phase III studies WA22762 (SUMMACTA study) [9] and NA25220 (BREVACTA study) [10]. Following the initial licensing procedure, two non-controlled, openlabel Phase IIIb studies were conducted to assess the tolerability and efficacy of tocilizumab in a treatment setting close to daily clinical practice both in Germany (TAMARA) [11, 12] and in other European countries (ACT-SURE) [13]. In order to observe the actual utilization and effects of tocilizumab in a clinical routine setting, the noninterventional, observational study ROUTINE was initiated in Germany shortly after its approval in Here we report the main effectiveness and tolerability results of this study. The comparison of these results observed in daily clinical practice with the results reported from Phase III clinical studies was deemed of particular interest, since data from the German biologics registry Rheumatoide Arthritis: Beobachtung der Biologika-Therapie (RABBIT) showed that only 21 33% of these patients would have been eligible for major clinical trials, and clearly lower response rates as compared with RCTs were found for TNF-inhibitors in the remaining two-thirds of the patient population not eligible for major clinical trials [14]. Methods Study design and setting ROUTINE (ML 22734) was a prospective, multicentre, observational, non-interventional study conducted from January 2009 to March 2012 in 174 rheumatologic clinical practices or hospitals/centres across Germany. The study was approved by the Ethics Committee of the Charité University Medicine Berlin. Patients and treatment All adult RA patients, who were eligible for treatment with tocilizumab according to the summary of product characteristics (SPC), could be enrolled in the study after giving informed consent. Treatment consisted of intravenous (i.v.) infusions of 8 mg/kg body weight every 4 weeks and modifications as outlined in the SPC. The individual observation period per patient was up to 52 weeks; a minimum of 6 on-site visits at intervals of 2 months had to be documented (maximum: 12 visits at monthly intervals). Assessed variables and statistical analysis The study objective was to assess the utilization, effectiveness and tolerability of i.v. tocilizumab in daily clinical practice. Due to the non-interventional design, all data were retrieved from routine procedures only. Documentations comprised demographic and other baseline characteristics (including RA history and previous therapy), actual tocilizumab treatment, concomitant RA medication, DAS28 (four items, using ESR) [15, 16], routine laboratory tests (if available), and adverse events (AEs). Special emphasis was put on the occurrence of infections by active inquiry at each visit in order to minimize potential underreporting. Statistical analyses (using SAS Version 8.2) were performed descriptively (i.e. no confirmatory hypothesis testing). Continuous data were described using arithmetic mean, standard deviation, median, extremes, and 25/75%-quartiles. Categorical data were presented with 625

3 Christof Iking-Konert et al. tabulated summaries, including number of observations and absolute and relative frequencies. Analyses based on DAS28 included changes from baseline in total and per single item, EULAR response [17], and proportions of patients achieving low disease activity state (LDAS; 43.2), DAS28 remission (<2.6) or minimal clinically important improvement from baseline (MCII; improvement by at least 1.2). Additional analyses of clinical disease activity (CDAI) [18] were performed using absolute thresholds of and 42.8 points for definition of low CDAI (LCDAI) and remission, respectively. The statistical analyses were performed primarily based on data as observed. In addition, a multiple imputation approach [19, 20] was employed to impute missing data for the main effectiveness variables in order to evaluate the concordance of the results obtained by the different methods. Medical history and AEs were coded using the Medical Dictionary for Regulatory Activities (version 12.0) and displayed by preferred term and primary System Organ Class (psoc); drugs were coded based on the Anatomical Therapeutic Chemical classification of the WHO-drug dictionary (WHO-DD). Infections were primarily analysed using the entries on a specific text field in the main case report form (ad hoc analysis; N = 836 patients with at least one post-baseline observation). Severe infections were arbitrarily defined as those requiring prescription drugs and/or leading to hospitalization. Information about serious infections was derived from the regular AE log page (psoc: infections and infestations). Analyses groups Study results are generally shown for all 850 patients (safety population). For selected analyses, patients were separated by pretreatment with csdmards only (considered as patients with IR to csdmards, n= 174; 21.3%) vs. pretreatment with TNF-inhibitors (considered as patients with TNF-IR; n= 643; 78.7%; missing data or exclusive use of biologics other than TNF-inhibitors for the remaining 33 patients) and presence of any other RA therapy (as documented by investigator) in addition to tocilizumab at baseline (n = 514; 60.5%) vs. tocilizumab monotherapy at baseline (n = 335; 39.5%; missing information for one patient). Results Disposition and demographic and other baseline characteristics of patients Approximately two-thirds of the 850 study patients remained in the study until week 52, whereas 35.3% discontinued prematurely (Table 1). The three most common reasons for withdrawal were lack of effectiveness (10.5%), intolerability (7.3%) and patient s decision (5.6%). Generally, the demographic profile as well as the pattern of concomitant diseases of study patients was as expected; the mean age was 56 years and about threequarters were women (Table 2). Concomitant diseases with a prevalence of 510.0% (preferred term level) were TABLE 1 Disposition of patients Status hypertension (34.1%), OA (25.2%), osteoporosis (22.9%), spinal OA (18.9%) and diabetes mellitus (10.0%). No relevant differences in the pattern of concomitant diseases were found among subgroups related to pretreatment and combination therapy. The mean RA duration was 10.3 ± 8.6 years. Approximately 70% of patients had erosions; the prevalence of systemic manifestations (mostly rheumatoid nodules) was 21.2%. About three-quarters of patients with available data had positive tests for RF and/or anti- CCP-antibodies. Analyses by subgroups indicated that patients pretreated with TNF-inhibitors had an 3 4 years longer disease history and more erosions (difference of 15%) compared with those who were previously treated with csdmards only. No clear differences among subgroups were observed for the prevalence of systemic manifestations, RF or anti-ccp-antibodies, or baseline DAS28. Pretreatment of RA TNF-inhibitors had been used to pretreat 78.7% of the patients; the three most commonly used DMARDs prior to baseline were MTX, LEF and adalimumab (Supplementary Table S1, available at Rheumatology Online). On average, patients had received 4.0 ± 2.1 DMARDs (any DMARDs), with 2.5 ± 1.4 csdmards and 1.5 ± 1.2 bdmards. The five most common RA drugs administered at the time of baseline (WHO-DD base substance level, except folic acid) were prednisolone (66.1% of patients), MTX (44.1%), diclofenac (13.8%), prednisone (12.6%) and LEF (12.2%). Screening for tuberculosis Number of patients (%) N = 850 Completed study up to 550 (64.7) week 52 Premature discontinuation 300 (35.3) due to a : Intolerability 62 (7.3) Patient s decision 48 (5.6) Lost to follow-up 39 (4.6) Death 3 (0.4) Other reasons 122 (14.4) AE b 24 (2.8) Lack of effectiveness b 89 (10.5) Successful therapy b 3 (0.4) Non-compliance b 1 (0.1) Various b 5 (0.6) Missing information 52 (6.1) CRF: case report form. a Categories as per CRF; multiple specifications per patient were possible. b Ad hoc grouped verbatim terms for other reasons; no multiple specifications within this category. Screening for tuberculosis (TB) prior to tocilizumab treatment was reported in 669 patients (79.2% of patients with available data). Applied methods (multiple specifications 626

4 Anti-IL-6 treatment of active RA TABLE 2 Demographic and other baseline characteristics Characteristic Result (N = 850) Sex, males n (%)/females n (%) 210 (24.7)/640 (75.3) Age, mean (SD), years 55.9 (12.9) BMI, mean (SD), kg/m (5.5) Time since initial RA symptoms, 12.0 (9.3) mean (SD), years Time since initial diagnosis of RA, 10.3 (8.6) mean (SD), years RA-pretreatment, n (%) a csdmards only 174 (21.3) TNF-inhibitors 643 (78.7) Others 33 Presence of erosions a,no 230 (29.9)/540 (70.1) n (%)/yes n (%) Presence of systemic signs a,no 642 (78.8) 7/173 (21.2) n (%)/yes n (%) Type of systemic signs, n (%) b Vasculitis 10 (5.8) Iritis/scleritis 9 (5.2) Rheumatoid nodules 124 (71.7) Lung fibrosis 13 (7.5) Other 33 (19.1) RF status a, positive 296 (74.4)/102 (25.6) n (%)/negative n (%) accp-antibody status a, positive 195 (80.9)/46 (19.1) n (%)/negative n (%) Combined serology status a, n (%) RF+/CCP-AB+ 155 (73.5) RF-/CCP-AB+ 14 (6.6) RF+/CCP-AK- 8 (3.8) RF-/CCP-AK- 34 (16.1) DAS28 total, [N obs] mean (SD), [728] 5.5 (1.3) score points Tender joint count, [N obs] mean [823] 9.5 (6.7) (SD), n joints, Swollen joint count, [N obs] mean [829] 8.1 (6.0) (SD), n joints Disease activity, [N obs] mean [821] 66.8 (20.0) (SD), mm VAS ESR, [N obs] Mean (SD), mm 1 h [819] 62.7 (18.6) CDAI total, [N obs] mean (SD), [790] 30.9 (13.2) score points AB: antibody; accp: anti-cyclic citrullinated peptide; CDAI: clinical disease activity index; csdmard: conventional synthetic DMARD; max: maximum, min: minimum; n: number; N obs: number of observations: SD: standard deviation; VAS: visual analogue scale. a Adjusted relative frequencies (i.e. based on number of patients with available data). b Multiple specifications per patient were possible. Percentages are based on the number of patients with systemic manifestations (N= 173). possible) were chest X-ray (80.7%), the PPD skin test (51.3%), the QuantiFERON gold test (25.9%) and the ELISpot Assay T-Spot.TB (22.3%). The highest frequency of positive results was observed with both ex vivo tests (6.9% positive findings each), while chest X-ray was interpreted as positive in three patients (0.6%) only. Overall, test results were regarded as positive in 32 patients (5.6%), and 27 patients (4.9%) were eventually judged to have a positive screening outcome. All of these 27 patients subsequently received TB prophylaxis. Utilization of tocilizumab Treatment with tocilizumab was mainly initiated because of treatment failure of the preceding therapy (89.9% of patients), followed by intolerability of the preceding therapy (20.0% of patients; multiple specifications possible). The majority of patients (n = 514; 60.5%) received RA treatment in addition to tocilizumab at baseline; 335 patients (39.5%) were treated in monotherapy. The majority of patients with either combination or monotherapy at baseline remained on that initial assignment at the last visit of the study. The most common DMARD combination partner in addition to tocilizumab throughout the study was MTX (426 of 555 patients with a documented combination treatment at any time during the study, 76.8%), followed by LEF (20.4%), SSZ (5.8%) and HCQ (3.4%); multiple specifications were possible; all other mentions were below 2.0% at WHO-DD base substance level. The actually administered average dose of tocilizumab (total and weight-adjusted) remained stable during the course of the study: the mean total dose was 592 ± 131 mg per infusion (median: 560 mg; range: mg) at baseline (N = 848) and 584 ± 125 mg per infusion (median: 560 mg; range: mg) at week 52 (N = 532). No clinically meaningful differences were observed between the subgroups in terms of pretreatment or combination therapy. The proportion of patients with tocilizumab dose adjustment at a given visit ranged between 3.4% and 6.5% across visits. Overall, at least one dose adjustment was performed in 199 patients (23.8% of patients with available data). The prevailing reason for dose adjustments was body weight change (108/191 patients; 54.3%), while abnormal laboratory values were not so prominent [8/191 patients (4.0%) with dose adjustments due to changes in liver enzymes]. Transient treatment interruptions during the course of the study were required in 283 patients (33.9% of patients with available data). In contrast to the dose adjustments, the most common reason for these interruptions was the emergence of active severe infections [38/283 patients (13.4%)] or other infections [72/283 patients (25.4%), multiple specifications possible]. Improvements in disease activity over time The mean baseline DAS28 was 5.5 ± 1.3 (N = 728), and it decreased to 2.9 ± 1.5 at week 24 (N = 427) and 2.6 ± 1.5 at week 52 [N = 396; mean change 2.9 ± 1.7 (N = 353); data as observed]. Improvements were visible as early as week 4 and seemed to have reached the maximum by approximately week 12 (Fig. 1A). Consistently, all single components of the DAS28 (joint counts, patient-reported disease activity, ESR) showed uniform improvements that were most pronounced in the initial 12 weeks of treatment (Fig. 1B). EULAR response analyses showed increasing proportions of patients with a good EULAR response through week 52 (50.0% at week 12, 54.8% at week 24, and 62.3% at week 52; a good/moderate EULAR response at week 52 was achieved by 89.0%). Similar patterns were observed in the categorical analyses of the 627

5 Christof Iking-Konert et al. FIG. 1 Course of mean DAS28 over time A B TJC / SJC (number of joints) DAS28 total score Week (0=baseline) DAS28 total score Absolute change from Baseline Week (0=Baseline) (A) Course of mean DAS28 total score and change from baseline. Provided are arithmetic mean values with standard deviation for each available time point. Data are as observed; the numbers of observations for DAS28 decreased from n = 728 at Baseline to n = 427 at week 24 and n = 396 at week 52. (B) Course of DAS28 mean single components over time. Provided are arithmetic mean values with standard deviation for baseline and subsequent weeks 4, 12, 24, 36 and 52. For the sake of readability, only the positive standard deviation is shown. Data are as observed; the numbers of observations for DAS28 (total score) decreased from n = 728 at baseline to n = 427 at week 24 and n = 396 at week 52. DA VAS: Disease activity by patient measured on a 100-mm visual analogue scale; SJC: Swollen joint count; TJC: Tender Joint Count. TJC SJC DA VAS ESR (1h) Absolute change from baseline 628

6 Anti-IL-6 treatment of active RA FIG. 2 Proportions of patients achieving LDAS, DAS28 remission, or minimal clinically important improvement at weeks 12, 24 and Remission (DAS28 <2.6) LDAS (DAS28 3.2) MCII (Δ 1.2) 70.0 Percent pa ents proportions of patients achieving LDAS, DAS28 remission or MCII at weeks 12, 24 and 52 (Fig. 2). Consistent with the DAS28 improvement, the CDAI decreased from 30.9 ± 13.2 points at baseline to 13.2 ± 11.2 score points at week 24 (mean decrease by 18.4 ± 13.8 score points); LCDAI and CDAI remission at that time were achieved by 49.6% and 13.5% of patients, respectively. The results of the effectiveness analyses applying multiple imputation were consistently smaller than those obtained with the as-observed data analysis. However, the numerical differences were rather small at week 24 and showed a trend towards almost complete convergence at week 52 (Supplementary Table S2, available at Rheumatology Online). Effectiveness in subgroups In both the analyses with as-observed and imputed data, the subgroup results for DAS28 and CDAI suggested numerically better outcomes in DMARD-IR patients vs. TNF- IR patients: LDAS/DAS28 remission rates at week 24 were 70.8/51.7% in patients pretreated with csdmards vs. 56.1/43.6% in patients pretreated with TNF-inhibitors. Consistently, LCDAI/CDAI remission rates at week 24 were 56.6/17.7% and 46.9/11.9%, respectively (data as observed; the corresponding results based on multiple imputation were 62.4/45.1% vs. 50.1/37.2% for LDAS/ DAS28 remission and 50.2/14.4% vs. 41.1/10.1% for LCDAI/CDAI remission) Week 12 (N=459/424) Week 24 (N=427/389) Week 52 (N=396/353) Data are as observed. The first denominator (N) specification belongs to LDAS and remission, the second one to MCII. LDAS: Low disease activity state; MCII: Minimal clinically important improvement In contrast, no meaningful differences in DAS28 and CDAI treatment outcomes were observed based on either analysis mode in terms of the presence of RF/anti-CCP antibodies or combination treatment vs. monotherapy with tocilizumab. Likewise, subgroup analyses by patients with abatacept (N = 50) or rituximab (N = 46) as the most recent previous RA therapy did not show relevant differences in treatment outcomes compared with the findings observed in the total population. Occurrence of infections on treatment Overall, 314 patients (37.6%) experienced at least one acute infection (ad hoc analysis; N = 836), which affected mostly the upper airways. Severe infections occurred in 60 patients (7.2%) (Table 3). Most of the reported infections resolved completely. As per psoc infections and infestations, the incidence of serious infections was 5.3% (N = 850; Table 4). The event incidence [95% CI] per 100 patient-years (PY) was 70.3 (64.3; 76.4) for all infections (ad hoc), 9.8 (7.6; 12.1) for severe infections (ad hoc) and 4.4 (2.9; 6.0) for serious infections (as per psoc). Subgroup analyses of severe infections did not show clinically meaningful differences between the combination therapy vs. monotherapy group (9.4 vs events/100 PY), while both severe (ad hoc) and serious(as per psoc)infections occurred more frequently among patients pretreated with TNF-inhibitors compared with those pretreated with only csdmards (11.9 vs. 3.7 events/100 PY for severe infections and 5.6 vs. 1.2 events/100 PY for serious infections)

7 Christof Iking-Konert et al. TABLE 3 Incidence and pattern of most common acute infections and AEs Type of infection MedDRA-preferred term Adverse events Number of patients (%) Any acute infection a, N = (37.6) Any acute infection with an incidence of 51.0% Nasopharyngitis 71 (8.5) Bronchitis 59 (7.1) Respiratory tract infection 23 (2.8) Upper respiratory tract infection 19 (2.3) Sinusitis 18 (2.2) Urinary tract infection 18 (2.2) Oral herpes 16 (1.9) Infection 11 (1.3) Rhinitis 11 (1.3) Tonsillitis 11 (1.3) Herpes zoster 10 (1.2) Erysipelas 9 (1.1) Gastrointestinal infection 9 (1.1) Any severe b acute infection a, 60 (7.2) N = 836 Any severe acute infection with an incidence of 50.2% Bronchitis 8 (1.0) Erysipelas 8 (1.0) Pneumonia 5 (0.6) Sinusitis 5 (0.6) Device-related infection 3 (0.4) Herpes zoster 3 (0.4) Bursitis 2 (0.2) Periodontitis 2 (0.2) Salmonellosis 2 (0.2) Tonsillitis 2 (0.2) Wound infection 2 (0.2) Any AE c, N = (44.8) Any adverse event with an incidence of 51.5% Bronchitis 33 (3.9) Nasopharyngitis 30 (3.5) Pruritus 20 (2.4) Headache 18 (2.1) Hypercholesterolaemia 16 (1.9) Diarrhoea 15 (1.8) Hypertension 15 (1.8) Nausea 15 (1.8) Respiratory tract infection 15 (1.8) MedDRA: Medical Dictionary for Regulatory Activities; N: number. a Percentages based on number of patients with at least one post-baseline visit. b Severe infections were defined as those requiring prescription drugs and/or leading to hospitalization. c Percentages based on safety population. Incidence data cuts are based on the frequency of a given preferred term (number of patients with event). AEs were reported in 381 patients (44.8%; Table 3). Infections and infestations was the most commonly named psoc (23.2% of patients); other frequently reported psocs (55.0%) were skin and subcutaneous tissue disorders (8.9%), gastrointestinal disorders (7.6%), investigations (6.4%), and general disorders and administration site conditions (5.1%). Most AEs were considered drug-related by reporting investigators (however, this definition included the causal relationship unlikely). The majority of patients with AEs experienced AEs rated as mild (135 patients, 15.9%) or moderate (177 patients, 20.8%); 59 patients (6.9%) had a severe AE reported. 104 patients (12.2%) experienced any serious AEs (SAEs). SAEs with causal relationship to tocilizumab were reported in 76 patients (8.9%). In 38 patients (4.5%), these drug-related SAEs were associated with infections [including two patients with pulmonary TB: one patient with missing screening procedures (event outcome: improved) and the other patient with negative outcomes in the Quantiferon assay and in the chest X-ray (event outcome: unknown)]. Serious drug-related hypersensitivity reactions were reported in 4 patients, and serious drug-related neoplasms in one patient (squamous cell carcinoma). Most of the drug-related SAEs completely resolved by the end of the study. Three patients (0.4%) died during the study (one case each of unrelated pneumonia 4 months after last treatment, related pneumonia 7 days after last treatment, and an unrelated bleeding ulcer 5 months after last treatment). AEs leading to permanent discontinuation of tocilizumab were not directly recorded. Using the study completion page as surrogate (pre-specified category for study discontinuation intolerability and free-text entries suggesting safety issues), the rate of patients who were withdrawn from tocilizumab treatment because of AEs/SAEs was 10.1% at maximum. Discussion Effectiveness in clinical practice Tocilizumab was used in the recommended dose of (8 mg/kg every 4 weeks) in the vast majority of the patients, leading to a rapid and sustained reduction of disease activity in the majority of the patients who remained on the study drug until week 24 (LDAS rate: 59.3%) and week 52 (LDAS rate: 66.4%), respectively. Only 10.5% of patients were reported to have discontinued treatment because of lack of effectiveness (Table 1). Treatment results were generally consistent with those reported from the 24-weeks Phase IIIb open-label studies ACT-SURE and TAMARA), and were also consistent with data from the pivotal Phase III RCTs (Table 4). Of note, mean DAS28 values at baseline were slightly lower in the open-label Phase IIIb studies (both 6.0) and in the present study (5.5) than in the Phase III RCTs ( ). TNF-IR patients had a 3 4 years longer disease duration than those pretreated with csdmards only. In addition, erosions at baseline appeared to be more frequent in patients who were pretreated with TNF-inhibitors, but mean baseline DAS28 values were not significantly different between the pretreatment groups. Generally, it should 630

8 Anti-IL-6 treatment of active RA TABLE 4 Disease activity, infections, and treatment discontinuation due to AEs in ROUTINE compared with other TZC trials a Observational study Open-label Phase IIIb studies Randomized, controlled Phase III studies (pre-approval) ROUTINE b ALL N = 850 ACT-SURE [13] c ITT N = 1681 TAMARA [11,12] d ITT N = 286 AMBITION [4] Mono ITT N = 286 LITHE [5] + MTX ITT N = 389 OPTION [6] + MTX ITT N = 205 TOWARD [3] + csdmard ITT N = 803 RADIATE [7] + MTX ITT N = 170 Baseline characteristics Mean age (SD), years 55.9 (12.9) 54 (12) 54.9 (12.2) 50.7 (13.1) 53.4 (11.7) 50.8 (11.8) 53 (13) 53.9 (12.7) No. of females (%) 640 (75.3) 1356 (80.7) 216 (75.5) 236 (82.5) 82% 175 (85.4) 81% 84% Mean RA duration (SD), years 10.3 (8.6) 9.6 (8.8) Nr 6.4 (7.9) (7.3) 9.8 (8.8) 12.6 (9.3) Mean DAS28 Mean baseline value (SD) 5.5 (1.3) (No.=728) 6.0 (1.2) (No.=1681) 6.0 (1.0) (No.=274) 6.8 (1.0) 6.6 (1.0) 6.8 (0.9) 6.7 (1.0) 6.79 (0.93) Change from baseline at week 24 (SD) Change from baseline at week 52 (SD) 2.7 (1.6) (No.=389) nr 3.4 (1.4) (No.=274) 3.31 nr nr 3.17 nr 2.9 ± 1.7 (No.=353) 3.8 DAS28 remission Week 24, n/n (%) 195/427 (45.7) 826/1455 (56.8) 136/286 (47.6) 33.6% nr 47/171 (27.5) 30.2% 30.1% Week 52, n/n (%) 218/396 (55.1) 127/269 (47.2) LDAS Week 24, n/n (%) 253/427 (59.3) 1017/1455 (69.9) 163/286 (57.0) nr nr nr 45% 51.2% Week 52, n/n (%) 263/396 (66.4) 171/269 (63.6) EULAR response, good or moderate Week 24, n/n (%) 342/389 (87.9) nr 215/286 (75.2) 82.2% nr 163/205 (79.5) 79.7% 67.7% Week 52, n/n (%) 314/353 (89.0) nr Low CDAI Week 24, n/n (%) 265/534 (49.6) 876/1453 (59.7) 54.2% CDAI remission Week 24, n/n (%) 72/534 (13.5) 876/1453 (18.8) 24.1% All infections e, ad hoc Week 24, n/n (%) nr 594/1681 (35.3) nr 99/288 (34.4) nr nr nr nr Week 52, n/n (%) 314/836 (37.6) f nr All infections g, SOC Week 24, n/n (%) nr nr 130/286 (45.5) nr nr 66/206 (32.0) 300/802 (37.4) 86/175 (49.1) Week 52, n/n (%) 197/850 (23.2) nr Serious Infections e, ad hoc Week 24, n/n (%) nr 36/1681 (2.1) 9/286 (3.1) nr nr nr nr 8/175 (4.6) Week 52, n/n (%) 60/836 (7.2) h nr i Serious infections g, SOC Week 24, n/n (%) nr nr 7/286 (2.4) 4/288 (1.4) nr 6/206 (2.9) 22/802 (2.7) 8/175 (4.6) (continued) 631

9 Christof Iking-Konert et al. TABLE 4 Continued Observational study Open-label Phase IIIb studies Randomized, controlled Phase III studies (pre-approval) ROUTINE b ALL N = 850 ACT-SURE [13] c ITT N = 1681 TAMARA [11,12] d ITT N = 286 AMBITION [4] Mono ITT N = 286 LITHE [5] + MTX ITT N = 389 OPTION [6] + MTX ITT N = 205 TOWARD [3] + csdmard ITT N = 803 RADIATE [7] + MTX ITT N = 170 Week 52, n/n (%) 45/850 (5.3) j nr Treatment discontinuation due to AE nr 86/1681 (5.1) 16/286 (5.6) 11/288 (3.8) nr 12/206 (5.8) 31/802 (3.9) 10/175 (5.7) Week 24, n/n (%) 410.1% nr Week 52, n/n (%) Mean values are provided as arithmetic mean ± standard deviation. ITT: intent-to-treat (population); nr: not reported or analysed, TCZ: tocilizumab; No.: number; n: number of patients fulfilling a given criterion (numerator); N: number of patients evaluated for a given criterion (denominator); LDAS: low disease activity state; AMBITION: actemra vs. MTX double-blind investigative trial In monotherapy; LITHE: tocilizumab safety and the prevention of structural joint damage study. a Compared are the two non-controlled, open-label Phase IIIb studies ACT-SURE and TAMARA as well as the tocilizumab 8 mg/kg treatment arms in the five pivotal, randomized controlled Phase III studies AMBITION, LITHE, OPTION, TOWARD and RADIATE. b Data as observed. c Data as observed (treatment: TCZ (8 mg/kg) q4w ± DMARDs for 24 weeks); data taken from full paper. d ITT population; last observation carried forward (treatment: TCZ (8 mg/kg) q4w ± DMARDs for 24 weeks); data taken from full papers and partly from clinical study report. e Study-specific compilation of infections (i.e. across SOCs). f Ad hoc grouped, n = 836 (only patients with observations as denominator). g Infections as per standardized psoc Infections and infestations. h Ad hoc grouped, n = 836 (only patients with observations as denominator); shown are severe infections (i.e. not necessarily serious). i Information about the incidence of serious infections at week 52 in LITHE only provided adjusted to 100 patient years (4.0/100 PY). j Definition for seriousness included medically significant events and events of special interest

10 Anti-IL-6 treatment of active RA be taken into account that the frequency specifications of erosions in this study might be biased by missing data and/or lack of current (full joint) X-rays. The improvement in disease activity appeared to be slightly more favourable in DMARD-IR patients vs. TNF-IR patients, while no differences were observed between patients on combination therapy vs. tocilizumab monotherapy. Less marked improvements among TNF-pretreated patients compared with TNF-naive patients were also reported in ACT- SURE [13], where rates of patients with low disease activity or remission based on DAS28 and CDAI were consistently higher among TNF-naive patients than in patients previously or recently treated with TNF-inhibitors. Presence of RF and/or anti-ccp antibodies did not apparently affect the treatment outcomes, as with recent pretreatment with abatacept or rituximab, suggesting also that the intensively pretreated patients benefit from tocilizumab treatment. Occurrence of infections in routine clinical practice Infections are a major concern in treatment with bdmards. For TNF-inhibitors, data from a Biologics Registry in Great Britain [21] showed an increased risk of serious infections within the first 6 months (11798 patients compared with 3598 RA patients treated with csdmards), with a hazard ratio of 1.8 (95% CI: [1.3; 2.6]). Incidence rates for serious infections were 4.2/100 PY of follow-up for TNF-inhibitors (95% CI: [4.0; 4.4]) vs. 3.2/100 PY of follow-up for csdmards (95% CI: [2.8; 3.6]). For tocilizumab, the overall rate of serious infection in clinical studies (and subsequent open extensions) was comparable at 4.7/100 PY, with the most frequent events being pneumonia (1.0/100 PY), gastroenteritis, and urinary tract infections [22]. An updated analysis after 3.6 years of treatment showed a rate of serious infections of 4.6/100 PY [23]. In the present study, 37.6% of patients experienced infections during the observation period, most commonly uncomplicated infections of the upper airways. Severe infections (most commonly infections of the respiratory tract and erysipelas) were reported in 7.2% of patients. Most of the documented infections resolved by the end of the study. Importantly, subgroup group analyses considering additional RA treatment did not show clinically meaningful differences, suggesting that the risk of infections was not increased in patients who received a combination therapy compared with those who were treated with tocilizumab as monotherapy. In contrast, patients pretreated with TNF-inhibitors seemed to have been at a higher risk of severe infections than patients pretreated with csdmards. This observation was also made in ACT-SURE [13], where the rate of serious infections over 24 weeks was numerically higher in patients with previous/recent TNF-inhibitor use (6.8/6.0 events/100 PY) than in TNF-inhibitor naive patients (4.2 events/100 PY). The total infection and serious infection rates in the present study over 52 weeks were not increased compared with the results reported from the Phase III RCTs and open-label tocilizumab studies (Table 4) over 24 weeks. Consistently, the event rate of severe and serious infections over 52 weeks (9.8 [95% CI: 7.6; 12.1] and 4.4 [95% CI: 2.9; 6.0] events/100 PY, respectively) was consistent with the results for serious infections reported from ACT- SURE [13] (5.1 events/100 PY) and the RCTs tocilizumab safety and the prevention of structural joint damage (LITHE) study [5] (4.0 events/100 PY), OPTION [6] (6.05 events/100 PY), TOWARD [3] (5.9 events/100 PY) and RADIATE [7] (9.98 events/100 PY). Overall, this similarity suggested that the risk of infections with tocilizumab in daily clinical practice is not higher than previously reported in clinical studies. Limitations and implications An inherent limitation of non-interventional, observational studies is the risk of selection bias. Moreover, missing observations due to study drop-outs over time (which are usually not imputed) might distort study results. In this study, the rate of premature discontinuation was relatively high (35.3%) compared with the drop-out rates that are usually observed in RCTs, but an exploratory comparison of study outcomes based on data as observed with the results derived from a multiple imputation approach did not suggest an undue overestimation of the treatment outcomes induced by the non-imputation of missing data. Generally, results from non-controlled, observational studies are not suitable to prove an intrinsic drug effect in the strict meaning of the term confirmatory efficacy. However, observational studies nevertheless provide important, additional information about the effectiveness and tolerability of treatments administered under daily routine conditions in real life, and thus may support the confirmatory results obtained from randomized clinical trials, where patients are treated per protocol in highly specialized centres. The validity of the numerical comparisons of the study results in ROUTINE with those from the pivotal Phase III RCTs and single-arm Phase IIIb studies (Table 4) is certainly limited because of differences in study populations, treatment modalities and duration, definitions of infections and seriousness, and ways of presenting study results across the various publications. Nevertheless, the numerical comparisons consistently showed mostly similar results and thus indicated that the effects of tocilizumab administered in a usual care setting are equally favourable both in terms of effectiveness and tolerability and in line with the results of preapproval studies. Thus, the ROUTINE data showed that tocilizumab is effective when administered in a usual care setting with a tolerability profile as established in Phase III clinical trials. Acknowledgements The authors would like to thank Bernd Graulich (Winicker Norimed GmbH, Nuremberg) for medical writing support and Thomas Fischer (Winicker Norimed GmbH, Nuremberg) for performing the statistical analyses. The authors are grateful to all study sites and patients who participated in the study and thus contributed to the data base

11 Christof Iking-Konert et al. Funding: This work was funded by Roche Pharma AG, Germany and Chugai Pharma Marketing Ltd. Disclosure statement: C.I.-K. has received support for clinical trials from Roche, Abbvie, UCB; honoraria for lectures and consulting from Roche Pharma AG, Chugai Pharma Marketing Ltd, AbbVie Deutschland GmbH & Co KG, Pfizer Deutschland GmbH and UCB Pharma GmbH. B.K. is employed at Roche Diagnostics International AG, CH-6343 Rotkreuz, Schweiz and was employed at Roche Pharma AG, D-79639, Germany until February M.A.P. is employed at Roche Pharma AG, Grenzach- Wyhlen, Germany. G.-R.B. has received support for clinical trials and scientific projects from AbbVie, BMS, Roche, Chugai, Medimmune, MSD, Pfizer and UCB and honoraria for lectures and consulting from AbbVie, BMS, MSD, Pfizer, Roche and UCB. U.v.H. has received honoraria for lectures and consulting from BMS, Roche Pharma AG, Chugai Pharma Marketing Ltd, AbbVie Deutschland GmbH & Co KG, Pfizer Deutschland GmbH, UCB Pharma GmbH. All other authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology Online. References 1 Smolen JS, Landewe R, Breedveld FC et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73: Smolen JS, Landewe R, Breedveld FC et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010;69: Genovese MC, McKay JD, Nasonov EL et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 2008;58: Jones G, Sebba A, Gu J et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010;69: Kremer J, Blanco R, Brzosko M et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum 2011;63: Smolen JS, Beaulieu A, Rubbert-Roth A et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008;371: Emery P, Keystone E, Tony HP et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 2008;67: Nishimoto N, Miyasaka N, Yamamoto K et al. Long-term safety and efficacy of tocilizumab, an anti-il-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study. Ann Rheum Dis 2009;68: Burmester GR, Rubbert-Roth A, Cantagrel A et al. A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study). Ann Rheum Dis 2014;73: Kivitz A, Olech E, Borofsky M et al. Subcutaneous tocilizumab versus placebo in combination with diseasemodifying antirheumatic drugs in patients with rheumatoid arthritis. Arthritis Care Res 2014;66: Burmester GR, Feist E, Kellner H et al. Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA). Ann Rheum Dis 2011;70: Iking-Konert C, Aringer M, Wollenhaupt J et al. Performance of the new 2011 ACR/EULAR remission criteria with tocilizumab using the phase IIIb study TAMARA as an example and their comparison with traditional remission criteria. Ann Rheum Dis 2011;70: Bykerk VP, Ostor AJ, Alvaro-Gracia J et al. Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice. Ann Rheum Dis 2012;71: Zink A, Strangfeld A, Schneider M et al. Effectiveness of tumor necrosis factor inhibitors in rheumatoid arthritis in an observational cohort study: comparison of patients according to their eligibility for major randomized clinical trials. Arthritis Rheum 2006;54: Prevoo ML, van t Hof MA, Kuper HH et al. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38: van der Heijde DM, van t Hof MA, van Riel PL et al. Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis 1990;49: Fransen J, van Riel PL. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol 2005;23:S Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 2005;23:S

12 Anti-IL-6 treatment of active RA 19 Rubin DB. Multiple imputation for nonresponse in surveys. Hoboken, NJ, USA: John Wiley & Sons, Inc., Ratitch B, Lipkovich I, O Kelly M. Combining analysis results from multiply imputed categorical data. PharmaSUG 2013, 2013;1 19 (Paper SP03). 21 Galloway JB, Hyrich KL, Mercer LK et al. Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology 2011;50: Schiff MH, Kremer JM, Jahreis A et al. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther 2011;13:R Rubbert-Roth A. Assessing the safety of biologic agents in patients with rheumatoid arthritis. Rheumatology 2012;51:v