http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(3): 390–398 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.843760

ORIGINAL ARTICLE

Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: Postmarketing surveillance report of 7740 patients Takao Koike1, Masayoshi Harigai2, Naoki Ishiguro3, Shigeko Inokuma4, Syuji Takei5, Tsutomu Takeuchi6, Hisashi Yamanaka7, Shigenori Haruna8, Naoko Ushida8, Katsuyoshi Kawana8, and Yoshiya Tanaka9 1NTT Sapporo Medical Center, Sapporo Hokkaido, Japan, 2Department of Pharmacovigilance, Tokyo Medical and Dental University Graduate School,

Tokyo, Japan, 3Department of Orthopedics, Nagoya University School of Medicine, Nagoya, Japan, 4Japanese Red Cross Medical Center, Tokyo, Japan, 5Department of Maternal and Child Health Nursing, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan, 6Division

of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan, 7Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan, 8AbbVie GK, Tokyo, Japan, and 9University of Occupational and Environmental Health, Japan, Kitakyushu, Japan Abstract

Keywords

Objectives. To confirm the safety and effectiveness of adalimumab and to evaluate the influence of the concomitant use of methotrexate (MTX). Methods. Postmarketing surveillance of 7740 Japanese rheumatoid arthritis (RA) patients was performed. All patients who received adalimumab in the registration period were followed for 28 weeks after starting treatment for safety and 24 weeks for effectiveness. Effectiveness was measured by duration of morning stiffness, swollen and tender joint counts (28 joints), patient global assessment of disease activity, erythrocyte sedimentation rate and serum C-reactive protein. Results. Comparable rates of adverse drug reactions (ADRs) were reported in this study and in the interim analysis. Age, pulmonary disease history or comorbidity, co-existing diabetes mellitus, concomitant MTX at doses of ⬎ 8 mg/week and concomitant glucocorticoids at doses of ⬎ 5 mg/day were risk factors for infections. All mean values of effectiveness measurements improved. Relatively lower disease activity at baseline, biologic-naïve, concomitant MTX use and early RA stage/low functional class were background factors contributing to the effectiveness. The combination of adalimumab with MTX improved the response to adalimumab treatment. Conclusion. Adalimumab, especially with concomitant use of MTX, provided significant improvement in disease activity, without any unexpected ADRs in Japanese RA patients.

Adalimumab, Effectiveness, Postmarketing surveillance, Rheumatoid arthritis, Safety

Introduction The fact that various cytokines, including tumor necrosis factor (TNF), are overexpressed and/or activated in the synovial membrane of rheumatoid arthritis (RA) patients have suggested that they had played significant roles in the pathogenesis of RA [1,2]. Accordingly, TNF inhibitors have been developed over the last years and have demonstrated favorable efficacy for the treatment of RA [3,4]. Adalimumab (HUMIRA®; AbbVie Inc, North Chicago, IL, USA) is a genetically engineered, fully human monoclonal antibody (mAb) specific for TNF. In Japan, adalimumab was approved in April 2008 for the management of RA patients with an inadequate response to conventional therapy. As a condition of the approval of adalimumab, the Japanese regulatory authority (Pharmaceuticals and Medical Devices Agency, PMDA) requested a postmarketing surveillance for further evaluation of its safety and effectiveness in all RA patients who were treated with adalimumab (registered as NCT01076959 at ClinicalTrials. gov; hereafter referred to as “this study”) to provide a basis for its Registry study number ⫽ NCT01076959. Correspondence to: Takao Koike, NTT Sapporo Medical Center, S-1, W-15, Chuo-ku, Sapporo Hokkaido, 060-0061, Japan. Tel: ⫹ 81-11623-7300. Fax: ⫹ 81-11-623-7002. E-mail: [email protected]

History Received 1 April 2013 Accepted 12 June 2013 Published online 31 October 2013

proper use for RA patients. Similar postmarketing surveillance has been completed for infliximab (IFX; chimeric mAb to TNF), etanercept (ETA; a human soluble TNF receptor) and tocilizumab (TCZ; a humanized anti-interleukin-6 receptor antibody) [5–10], and is currently ongoing for abatacept, a recently approved selective T-cell co-stimulation modulator. Methotrexate (MTX) has been used worldwide as an “anchor” drug in RA management because of its established long-term safety and effectiveness [11]. The American College of Rheumatology (ACR) recommends the use of MTX at 7.5–20 mg/week in their RA treatment guidelines [12]. Although the maximum approved dose of MTX was 8 mg/week until January 2011, some Japanese RA patients were treated at higher doses in clinical practice. In February 2011, the use of MTX at doses up to 16 mg/week was approved in Japan following the results of cohort studies that showed MTX at ⬎ 8 mg/week improved disease activity without any specific safety concerns in Japanese RA patients [13,14]. Combination therapy with a TNF inhibitor and MTX has been reported to be more effective than monotherapy with either drug for improving RA symptoms, inhibiting the progression of joint destruction and improving functional status [15,16]. It has also been shown that there is no significant difference in the incidence of adverse drug reactions (ADRs) between patients receiving biologic monotherapy and those receiving combination therapy with MTX. The Japanese RA treatment guidelines recommend

DOI 10.3109/14397595.2013.843760

Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients

that TNF inhibitor should be used in combination with MTX to achieve better outcomes unless MTX is contraindicated for the patient [17]. In the postmarketing surveillance of IFX [5] or ETA [6] in Japan, all patients treated with IFX and 54.1% of those treated with ETA were concomitantly treated with MTX. However, the safety and effectiveness of biologic agents combined with different doses of MTX have not been thoroughly assessed. The primary objectives of this study were to determine the ADR profile, including unexpected ADRs of adalimumab, and to identify factors associated with its safety and/or effectiveness in Japanese RA patients in clinical practice. We previously reported the results of an interim analysis on the first 3000 patients in this study [18], showing that adalimumab was beneficial in clinical practice, with safety and effectiveness profiles as stated in the current Japanese labeling information. This report updates the interim analysis to include all Japanese RA patients who were prospectively enrolled and treated with adalimumab from 2008 to 2010. Because the interim analysis showed improved outcomes of adalimumab in combination with MTX [18], this full analysis also addresses the influence of concomitant MTX at doses ⬎ 8 mg/week on the safety and effectiveness of adalimumab, due to the recent approval of MTX doses up to 16 mg/week in Japan.

Methods Study sites This study included all patients initiated on therapy with adalimumab at 1722 Japanese medical institutions from June 2008 to October 2010. For participation in this study, medical institutions were required to do the following: 1) report data of all RA patients treated with adalimumab; 2) screen for and diagnose tuberculosis; and 3) diagnose and treat severe infections. Each participating investigator had to be either a rheumatologist certified by the JCR or the Japanese Orthopaedic Association, or a physician registered with the Japan Rheumatism Foundation. The study protocol was reviewed and approved by the PMDA. Patients Patients were eligible for the study if they had an inadequate response to conventional therapy as stated in the current Japanese labeling recommendations for adalimumab [19] and met the Japanese guidelines for the use of TNF inhibitors by the JCR [17]. Prior to the initiation of adalimumab therapy, patients were examined for tuberculosis using medical interviews, chest X-rays, and tuberculin tests, and computed tomography (CT) or any other methods if necessary. Patients were allowed to continue prior RA treatments, such as disease-modifying antirheumatic drugs (DMARDs), glucocorticoids (GCs) and non-steroidal antiinflammatory drugs, during the observation period. All qualified patients received adalimumab 40 mg subcutaneously every other week (EOW) for 24 weeks and were followed for safety for 24 ⫹ 4 weeks (the observation period) after the start of treatment and for effectiveness for 24 weeks. In patients who did not respond to therapy, a dose of 80 mg EOW was allowed for patients not receiving DMARDs, including MTX. If a patient discontinued the study, the date of and reason for discontinuation were recorded. Data collection The data collected at baseline included age, sex, pregnancy/breastfeeding status and gestation age, body weight, reason for adalimumab use, duration of RA, comorbidities, past illness, history of allergies, smoking status, Steinbrocker RA stage/functional class [20], prior and concomitant RA treatments, and concomitant use of other medication.

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Safety All adverse events (AEs) were collected and coded according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 14.0. Assessments were made for all AEs, serious AEs, ADRs and serious ADRs as defined in the International Conference on Harmonisation Guideline E2A (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting) [21]. Each AE was reported and recorded with date of onset, seriousness, symptoms, outcome, causal relationship to adalimumab and treatments provided. ADRs of particular interest were infections, tuberculosis, interstitial pneumonia, malignant neoplasm, congestive heart failure, pancytopenia, autoimmune disease, demyelinating disease and administrationsite reactions [18]. Effectiveness The following data were assessed at baseline and 4, 12 and 24 weeks after the initiation of adalimumab therapy, and, if possible, at the time of discontinuation of the treatment: duration of morning stiffness (min), swollen joint counts (SJC, 28 joints), tender joint counts (TJC, 28 joints), patient global assessment of disease activity (100-mm visual analog scale [VAS; mm]), erythrocyte sedimentation rate (ESR; mm/h) and serum C-reactive protein (CRP) level (mg/dL). Statistical analyses The frequencies for all ADRs and for serious ADRs, infections, respiratory infections and pneumonias were described and compared between those with concomitant MTX therapy ⱕ 8 mg/week and those with concomitant MTX therapy ⬎ 8 mg/week, using the chi-square test. To identify risk factors associated with each of the previously mentioned infections, stepwise multiple logistic regression models were used and odds ratios (ORs), and their 95% confidence intervals (CIs) were calculated. The explanatory variables used were age (numeric, per 10 years), sex (female, male), duration of RA (5–10 years or ⬎ 10 years, ⬍ 5 years), history of allergy (yes or unknown, no), previous/co-existing diabetes mellitus (yes, no), infectious respiratory disease history or comorbidity (tuberculosis or atypical mycobacteriosis and bacterial bronchitis, yes, no), pulmonary disease history or comorbidity (interstitial pneumonia, asthma and obstructive pulmonary disease, yes, no), concomitant MTX use (none, ⱕ 8 mg/week, ⬎ 8 mg/week), concomitant GC use (none, ⱕ prednisolone-equivalent dose 5 mg/day, ⬎ prednisolone-equivalent dose 5 mg/day), prior biologic therapy (yes, no), prior DMARD use (yes, no), prior GC use (yes, no), Steinbrocker RA stage (I and II, III and IV), Steinbrocker functional class (I and II, III and IV), baseline disease activity score (DAS) for 28-joint counts based on ESR (DAS28-ESR) (⬍ 2.6, ⱖ 2.6–ⱕ 3.2, ⬎ 3.2–ⱕ 5.1, ⬎ 5.1) and serum creatinine level (abnormal, normal). Age, sex and concomitant MTX use were included in all stepwise regression models, and other variables that were included in the logistic regression models were chosen using stepwise selection. Standardized mortality rates (SMR) were calculated as the ratio of observed deaths to expected deaths. Expected rates were estimated based on country-specific, age- and sex-matched population data from the Ministry of Health, Labor and Welfare, Japan (2008). For the analysis of effectiveness, missing data, other than baseline data, were imputed for each variable using the last observation carried forward method. The ACR/European League Against Rheumatism criteria (DAS28-ESR ⬎ 5.1 ⫽ high disease activity, 3.2–5.1 ⫽ moderate disease activity, 2.6–3.2 ⫽ low disease activity, ⬍ 2.6 ⫽ remission) were applied [22–25]. Patients with

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DAS28-ESR ⱕ 3.2 at Week 24 were defined as responders; for responders, ORs and 95% CIs were calculated by means of stepwise multiple logistic regression. The explanatory variables used were age (numeric, per 10 years), sex (male, female), duration of RA (⬍ 2 years, ⱖ 2 years, ⬍ 5 years, ⱖ 5 years), history of allergy (yes, no), comorbidities (yes, no), previous/co-existing diabetes mellitus (yes, no), infectious respiratory disease history or comorbidity (yes, no), pulmonary disease history or comorbidity (yes, no), concomitant MTX use (none, ⱕ 8 mg/week, ⬎ 8–ⱕ 10 mg/week, ⬎ 10 mg/week), concomitant GC use (none, ⱕ prednisolone-equivalent dose 7.5 mg/day, ⬎ prednisoloneequivalent dose 7.5 mg/day), prior biologic therapy (none [biologic-naïve], only IFX, only ETA, IFX ⫹ ETA, any other), prior DMARD use (yes, no), prior MTX use (yes, no), prior GC use (yes, no), Steinbrocker RA stage (I and II, III and IV), Steinbrocker functional class (I and II, III and IV) and baseline DAS28-ESR (⬎ 3.2 to ⱕ 5.1, ⬎ 5.1). Variables that were included in the logistic regression models were chosen using stepwise selection. To assess the influence of concomitant MTX at different doses, the percentage of responders among those with DAS28-ESR ⬎ 3.2 at baseline was calculated by MTX dose category. These percentages were tested with the Mantel extension test using modified ridit scores, after adjusting for all factors identified by the multiple logistic regression analysis described previously. In making this adjustment, age was treated not as a numeric variable but a categorical one. All statistical analyses were performed using the SAS System Version 9.2 (SAS Institute, Cary, NC, USA). All tests were twosided using a 5% level of significance (P ⬍ 0.05).

Results Demographic and baseline characteristics A total of 7972 patients were enrolled in this study and case report forms (CRFs) were retrieved for 7891 patients (99%). Of these, 151 patients were excluded either because of duplication of CRFs or because they did not meet the inclusion criteria, leaving 7740 patients to be evaluated for safety. Table 1 summarizes the demographic and baseline characteristics of the safety population. Of the 7740 patients, 7724 patients (99.8%) were diagnosed with RA; the remaining 16 patients (0.2%) were being treated with adalimumab for other conditions. The non-RA indications for adalimumab use were rheumatoid vasculitis (n ⫽ 6), ankylosing spondylitis (n ⫽ 2), adult Still’s disease (n ⫽ 2), Wegener’s granulomatosis (n ⫽ 1), Behcet’s disease (n ⫽ 1), polymyalgia rheumatica (n ⫽ 1), psoriasis (n ⫽ 1), juvenile idiopathic arthritis (n ⫽ 1) and reactive arthritis (n ⫽ 1). The demographic and baseline characteristics of the safety population in this study were similar to those of the 3000 patients included in the interim analysis [18]. In the safety population, 82.5% were women and the majority of patients were elderly. The mean duration of RA was 10.5 years, and the mean DAS28-ESR score was 5.2 at baseline. Comorbidities were recorded in 62.0% of patients, including cardiovascular (22.4%), respiratory (13.4%), hematologic (7.4%), hepatic (5.8%) and renal disorders (3.3%). Past illnesses were recorded in 35.2% of patients. The previous use of any biologic agent(s) was noted in 3260 patients (42.1%), any DMARD in 94.2% of the patients and GCs in 64.8% of the patients. Of the patients who had received biologic agents, 2711 patients (35.0%) had received one biologic agent (1534 patients received ETA [47.1%], 969 patients received IFX [29.7%] and 111 patients received TCZ [3.4%]). MTX was used concomitantly in 71.0% of the safety population, at a mean dose of 6.8 mg/week, and was used at ⬎ 8 mg/week in 12.7% of patients receiving concomitant treatment (9.1% of the safety patients). Concomitant GC use was noted in 67.2% patients, at a mean

Mod Rheumatol, 2014; 24(3): 390–398

Table 1. Patient demographics and baseline characteristics. Demographics and baseline characteristics No. of patients Sex Male/Female (%) Age (years) Mean ⫾ SD (%) ⬍ 20 20–30 30–40 40–50 50–60 60–70 70–80 ⱖ 80 Duration of RA (years) Mean ⫾ SD Baseline DAS28-ESR score Mean ⫾ SD Comorbidities Yes (%) Cardiovascular Respiratory Hematologic Hepatic Renal Others Past illnessa Yes (%) History of allergies Yes (%) Steinbrocker’s stage I/II/III/IV (%) Steinbrocker’s class I/II/III/IV (%) Prior medication (%) Biologic agents DMARDsb GC Concomitant medication MTX (%) ⬎ 8 mg/week Dose (mg/week; mean ⫾ SD) GCs (%) Dose (mg/day; mean ⫾ SD)

7740 17.5/82.5 60.1 ⫾ 13.0 0.3 2.1 6.0 10.7 23.3 32.5 21.7 3.4 10.5 ⫾ 9.6 5.2 ⫾ 1.3 62.0 22.4 13.4 7.4 5.8 3.3 48.4 35.2 16.1 11.3/26.6/29.6/32.5 13.4/60.2/24.3/2.1 42.1 94.2 64.8 71.0 12.7c 6.8 ⫾ 2.4 67.2 4.9 ⫾ 3.1

DAS28-ESR, disease activity score for 28-joint counts based on the erythrocyte sedimentation rate; DMARDs, disease modifying antirheumatic drugs; GCs, glucocorticoids; MTX, methotrexate; RA, rheumatoid arthritis; SD, standard deviation. aPast illness was defined as tuberculosis, interstitial pneumonia, follicular bronchiolitis, obstructive pulmonary disease, atypical mycobacteriosis, aplastic anemia, pancytopenia and surgery for rheumatoid arthritis. bIncluding MTX. cPercentage of all patients concomitantly treated with MTX.

dose of prednisolone-equivalent dose 4.9 mg/day, and was used at ⬎ prednisolone-equivalent dose 5 mg/day in 27.3% of patients receiving concomitant treatment (18.3% of the safety patients). During the study, adalimumab 40 mg EOW was administered to 7411 patients (95.7%); and adalimumab 80 mg EOW was administered to 24 patients (0.3%). In 130 patients (1.7%), the dose of the drug was up- or down-titrated within the range of 40–80 mg EOW. The drug was administered at a dose other than 40 or 80 mg EOW in 174 patients (2.2%), and the dosage administered was missing for one patient. Of the safety population, 5490 patients (70.9%) completed the 24-week adalimumab treatment, while the remaining 2250 patients (29.1%) discontinued treatment before Week 24. Patients discontinued because of lack of response (n ⫽ 849; 37.3%), AEs (n ⫽ 767; 34.1%), patient request (n ⫽ 274; 12.2%), lost to follow-up (n ⫽ 241; 10.7%), other reasons (n ⫽ 76; 3.4%) and unknown (n ⫽ 43; 1.9%).

DOI 10.3109/14397595.2013.843760

Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients

Table 2. ADRs reported in RA patients treated with

adalimumab.a,b

N ⫽ 7740 No. of patients ADR All ADRs by SOCc Skin and subcutaneous tissue disorders Infections and infestations General disorders and administration-site conditions Respiratory, thoracic and mediastinal disorders ADRs of particular interest Tuberculosis Interstitial pneumonia Malignant neoplasm Cardiac failure Pancytopenia Autoimmune disease Cord demyelinating disorder Administration-site reaction Infections of interest Pneumonia Influenza Herpes zoster PCP Atypical mycobacteriosis Sepsis Fungal infection

As a screening for latent tuberculosis infection at baseline, 7557 patients (97.6%) had a chest X-ray or CT scan and 6921 patients (89.4%) had tuberculin or QuantiFERON-TB-2G test (QFT) done. Prior to the initiation of adalimumab therapy, 143 patients (1.8%) were not screened for latent tuberculosis because of 1) previous screening (n ⫽ 126), 2) history of tuberculosis (n ⫽ 10), 3) chemoprophylaxis (n ⫽ 8) and 4) unknown (n ⫽ 8). A total of 1820 patients (23.5%) received chemoprophylaxis.

%

1857 (348)

24.0 (4.5)

560 (21)

7.2 (0.3)

538 (182) 459 (23)

7.0 (2.4) 5.9 (0.3)

210 (56)

2.7 (0.7)

9 (9) 52 (40) 13 (13) 2 (2) 4 (4) 11 (8) 2 (2) 317 (0)

0.1 (0.1) 0.7 (0.5) 0.2 (0.2) ⬍ 0.1 (⬍ 0.1) 0.1 (0.1) 0.1 (0.1) ⬍ 0.1 (⬍ 0.1) 4.1 (0)

103 (65) 14 (1) 56 (12) 26 (26) 6 (2) 15 (15) 8 (3)

1.3 (0.8) 0.2 (⬍ 0.1) 0.7 (0.2) 0.3 (0.3) 0.1 (⬍ 0.1) 0.2 (0.2) 0.1 (⬍ 0.1)

Safety

ADR, adverse drug reaction; PCP, Pneumocystis jirovecii pneumonia; SOC, system organ class. aData on serious ADRs are in parentheses. bADRs coded in accordance with MedDRA (Medical Dictionary for Regulatory Activities) Ver. 14.0. cOnly the most common ADR categories are listed.

Table 2 summarizes the ADR profile of the safety population. The overall frequency of ADRs was 24.0%, with serious ADRs reported in 4.5% of patients. The frequencies of ADRs and serious ADRs in this study were similar to those observed in the previously reported interim analysis of 3,000 patients [18]. The frequency of ADRs by the MedDRA system organ class (SOC) was highest for “skin and subcutaneous tissue disorders” (n ⫽ 560, 7.2%), followed by “infections and infestations” (n ⫽ 538, 7.0%) and “general disorders and administration-site conditions” (n ⫽ 459, 5.9%). There were 2.4% of serious infections. The most common site of infection was the respiratory system, followed by the skin, the gastrointestinal system and the urinary system. Active tuberculosis was reported in nine patients (0.1%). Of these nine patients, one had no tuberculin test, tuberculin test was negative for six patients and was positive for two patients, prior to the initiation of adalimumab. Eight were concomitantly treated with corticosteroids, six with MTX and one received chemoprophylaxis with isoniazid for 6 months but stopped it 1 month before development of tuberculosis. Pneumocystis jirovecii pneumonia (PCP) was reported in 26 patients (0.3%). Of those 26 patients, 20 were ⱖ 65 years of age, 4 patients were concomitantly treated with corticosteroids and 2 were treated with MTX. None of these patients had received

Table 3. Frequencies of ADRs in RA patients treated with adalimumab with and without concomitant MTX therapy.

N ADR n % Infection n % Respiratory infectionb n % Pneumoniac n %

393

Group 1 without MTX 2241

MTX Group 2 ⱕ 8 mg/week 4793

Group 3 ⬎ 8 mg/week 701

631 (123) 28.2 (5.5)

1056 (199) 22.0 (4.2)

169 (25) 24.1 (3.6)

0.217 (0.464)

149 (63) 6.6 (2.8)

314 (101) 6.6 (2.1)

75 (18) 10.7 (2.6)

⬍ 0.001 (0.434)

89 (33) 4.0 (1.5)

184 (58) 3.8 (1.2)

48 (15) 6.8 (2.1)

⬍ 0.001 (0.045)

41 (25) 1.8 (1.1)

49 (32) 1.0 (0.7)

13 (8) 1.9 (1.1)

0.051 (0.168)

P valuea Group 2 vs. Group 3

Data on serious ADRs are in parentheses. ADR, adverse drug reaction; MTX, methotrexate. aP value was calculated using the chi-square test. P values in parentheses were for serious ADRs. Group 1 was not compared with Group 2 and Group 3 because baseline characteristics of patients without MTX were substantially different from those of patients with concomitant MTX. bIncludes all ADRs coded to the following preferred terms according to MedDRA Ver. 14.0: Pneumonia; Lung infection; Pneumonia primary atypical; Pneumonia chlamydial; Pneumonia pneumococcal; Pneumonia legionella; Bronchopneumonia; Pneumonia cytomegaloviral; Pneumonia bacterial; Bronchopulmonary aspergillosis; Bronchitis; Sinusitis; Tuberculous pleurisy; Pharyngitis; Pulmonary tuberculosis; Mycobacterial infection; Influenza; Acute sinusitis; Pyothorax; Pneumonia cryptococcal; Disseminated tuberculosis; Rhinitis; Peritonsillar abscess; Acute tonsillitis; Atypical mycobacterial infection; Nasopharyngitis; Upper respiratory tract infection; Chronic sinusitis; Bronchiolitis; Pharyngotonsillitis; Pneumocystis jirovecii pneumonia; Tuberculosis; Tonsillitis. cIncludes ADRs coded as Pneumonia; Lung infection; Pneumonia primary atypical; Pneumonia chlamydial; Pneumonia pneumococcal; Pneumonia legionella; Bronchopneumonia; Pneumonia cytomegaloviral; Pneumonia bacterial.

1.76–5.14 3.01 1.95-4.50 2.96 1.89–4.40 2.88 1.85–3.09 2.39 1.65

1.17–2.34 1.24–1.94 1.55

The analysis was conducted with a stepwise logistic regression model, including 7605 patients out of the safety population (n ⫽ 7740). Age, sex and concomitant MTX use were included in all stepwise regression models. Other variables that were included in the logistic regression models were chosen using stepwise selection. CI, confidence interval; GC, glucocorticoids; MTX, methotrexate; OR, odds ratio. aData from 526 out of 538 patients who developed any type of infection were included in the model. bData from 176 out of 182 patients who developed any serious infection were included in the model. cData from 321 patients who developed any respiratory infection were included in the model. dData from 103 out of 106 patients who developed any serious respiratory infection were included in the model. eData from all 103 patients who developed any type of pneumonia were included in the model. fData from 63 out of 65 patients who developed any serious pneumonia were included in the model. gIncludes patients who had pulmonary disease history or comorbidity (including interstitial pneumonia, asthma and obstructive pulmonary disease) as well as abnormal chest X-ray findings.

– – – – – – – 1.69

1.13–2.52 1.11–1.92 1.46

–

0.41–1.43 0.85–3.14 0.77 1.63 – – – – 0.67–1.84 1.30–3.81 1.11 2.22 – – 1.31 2.26

0.89–1.94 1.48–3.46 0.94–1.43 1.21–2.00 1.16 1.56

– –

0.62–1.93 0.89–4.40 1.09 1.98 0.80–1.91 1.09–3.80 1.23 2.03 0.48–1.20 1.10–3.59 0.76 1.99 0.63–1.08 1.34–2.61

Background factor Age (per 10 years) Sex Female vs. Male Concomitant MTX Without MTX vs. ⱕ 8 mg/week ⬎ 8 mg/week vs. ⱕ 8 mg/week Concomitant GC ⱕ 5 mg/day vs. Without GC ⬎ 5 mg/day vs. Without GC Diabetes mellitus Yes vs. No Pulmonary disease history or comorbidityg Yes vs. No

0.97 1.39

0.69–1.37 0.83–2.33 0.70–1.07 1.35–2.32 0.86 1.77

0.82 1.87

1.11 0.68–1.84 1.12 0.55–1.41 0.88 0.81–1.47 1.09 0.84 0.91–1.47 1.16

0.58–1.21

Pneumoniae OR 95% CI 1.45 1.21–1.74 Serious respiratory infectiond OR 95% CI 1.54 1.28–1.86 Serious infectionb OR 95% CI 1.41 1.22–1.61

Respiratory infectionc OR 95% CI 1.11 1.02–1.22

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Infectiona OR 95% CI 1.09 1.02–1.18

Table 4. Risk factors for infections with adalimumab treatment.

0.60–2.08

T. Koike et al.

Serious pneumoniaf OR 95% CI 1.56 1.23–1.98

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chemoprophylaxis for PCP. Interstitial pneumonia was reported in 52 patients (0.7%), malignant neoplasm was reported in 13 patients (0.2%), reported malignant neoplasms were all solid and administration-site reaction was reported in 317 patients (4.1%). Thirty-one patients died during the observation period. The SMR associated with the use of adalimumab was estimated to be 0.89 (95% CI ⫽ 0.61–1.26). Additionally, nine patients died after the observation period. The primary cause was infection (n ⫽ 13, 32.5%), followed by malignant neoplasm (n ⫽ 7, 17.5%), cardiovascular disease (n ⫽ 5, 12.5%), respiratory disease (n ⫽ 5, 12.5%), sudden death (n ⫽ 4, 10.0%), hepatic/gastro-intestinal disease (n ⫽ 3, 7.5%) and others (n ⫽ 3, 7.5%). For 26 of the deaths (0.3% of 7740 patients), a causal relationship with adalimumab could not be ruled out. Recently, approved maximum dose of MTX increased to 16 mg/week from 8 mg/week in Japan. Accordingly, we focused on the influence of different doses of concomitant MTX on the ADR profile of adalimumab. The frequencies of all ADRs and serious ADRs (infections, respiratory infections and pneumonias) were analyzed among the following three groups: 1) patients without concomitant MTX therapy (n ⫽ 2241); 2) those with concomitant MTX therapy ⱕ 8 mg/week (n ⫽ 4793) and 3) those with concomitant MTX therapy ⬎ 8 mg/week (n ⫽ 701). Five patients with no MTX dose data were excluded from this analysis. The results of this analysis are shown in Table 3. The frequencies of overall ADRs were numerically similar in these three groups. However, significant difference in the overall frequencies of infections, respiratory infections and serious respiratory infections were found when comparing patients treated with MTX at ⱕ 8 mg/week and at ⬎ 8 mg/week. Group 1 (without MTX) was not compared with Group 2 (with MTX ⱕ 8 mg/week) and Group 3 (with MTX ⬎ 8 mg/week) because baseline characteristics of patients without MTX were substantially different from those of patients with concomitant MTX. A multiple logistic regression analysis was conducted to identify the patient background factors that may predict specific ADRs. This analysis was made using patients receiving MTX ⱕ 8 mg/week as the reference. In this analysis, patients without concomitant MTX treatment tended to be older, have more comorbidities or past illness and use concomitant GCs more frequently compared with MTX (data not shown). As shown in Table 4, four patient background factors were found to be risk factors for infections. Age and pulmonary disease history or comorbidity were risk factors for all infections. MTX use at ⬎ 8 mg/week was a risk factor for infection, respiratory infection, serious respiratory infection and pneumonia. GC use at ⬎ prednisolone-equivalent dose 5 mg/day was a risk factor for infection, serious infection and serious respiratory infection. In addition, co-existing diabetes mellitus was found to be a risk factor for infection and serious infection. Effectiveness Of the 7740 patients included in the safety population, 6802 patients were eligible for the evaluation of effectiveness. Nine hundred thirty-eight patients were excluded from this analysis because 1) they received off-label use of adalimumab; 2) data for the evaluation were incomplete or 3) they were treated with adalimumab for less than 2 weeks. Table 5 shows the clinical outcomes as assessed by effectiveness measurements. In all measurements, improvement from baseline occurred at 4 weeks after the initiation of adalimumab treatment and continued at Weeks 12 and 24. The mean DAS28-ESR score was 5.2 at baseline and was reduced to 4.0 at Week 4. This favorable outcome was

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Table 5. Measurements of effectiveness in RA patients treated with Measurement TJC N Mean ⫾ SD SJC N Mean ⫾ SD Patient VAS (mm) N Mean ⫾ SD ESR (mm/h) N Mean ⫾ SD CRP (mg/dL) N Mean ⫾ SD Duration of morning stiffness (min) N Mean ⫾ SD DAS28-ESR N Mean ⫾ SD

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adalimumab.a

Baseline

Week 4

Week 12

Week 24

6308 6.5 ⫾ 5.9

4898 3.6 ⫾ 4.6

5663 3.3 ⫾ 4.6

6308 3.1 ⫾ 4.5

6301 6.0 ⫾ 5.1

4893 3.4 ⫾ 4.0

5655 3.0 ⫾ 3.9

6301 2.8 ⫾ 3.9

5598 54.7 ⫾ 24.4

4349 37.3 ⫾ 23.7

5012 35.4 ⫾ 24.4

5598 34.4 ⫾ 25.3

5193 49.8 ⫾ 31.7

4003 35.9 ⫾ 29.1

4676 36.2 ⫾ 30.0

5193 35.8 ⫾ 30.3

6600 2.5 ⫾ 2.9

5145 1.3 ⫾ 2.3

5970 1.5 ⫾ 2.6

6600 1.5 ⫾ 2.7

4038 126.6 ⫾ 281.9

3218 64.3 ⫾ 195.8

3633 59.3 ⫾ 192.8

4038 55.1 ⫾ 188.5

4410 5.2 ⫾ 1.3

3340 4.0 ⫾ 1.3

3925 3.9 ⫾ 1.4

4410 3.8 ⫾ 1.4

CRP, C-reactive protein; DAS28-ESR, disease activity score for 28-joint counts based on the erythrocyte sedimentation rate; ESR, erythrocyte sedimentation rate; RA, rheumatoid arthritis; SD, standard deviation; SJC, swollen joint counts; TJC, tender joint counts; Patient VAS, visual analog scale for global disease activity assessed by patients. aLast observation carried forward method was used to carry forward the previous non-baseline values for any missed assessments.

maintained until Week 24. The percentages of patients with low disease activity (DAS28-ESR ⱖ 2.6– ⱕ 3.2) and of those achieving remission (DAS28-ESR ⬍ 2.6) increased from Week 4 (Figure 1). Of the 4410 patients eligible for assessment with DAS28-ESR, 4139 patients with DAS28-ESR ⬎ 3.2 at baseline were included in the analysis to identify factors affecting the effectiveness of adalimumab. Background factors contributing to the effectiveness of adalimumab were assessed by DAS28-ESR ⱕ 3.2 at Week 24 (Figure 2). Approximately 40% of patients achieved DAS28ESR ⱕ 3.2 at Week 24. Patients who were biologic naïve were more likely to experience improvement in disease activity than those previously treated with IFX. Among patients previously treated with any biologics, the OR of achieving DAS28-ESR ⱕ 3.2 at Week 24 of those previously treated with ETA was 0.50 (95% CI: 0.37–0.67) and were less likely to achieve lower disease activity than those previously treated with IFX. Compared with patients who did not receive concomitant MTX therapy, patients who received MTX therapy had significantly better response to treatment. Concomitant MTX therapy at doses of ⬎ 10 mg/week showed numerically higher OR of 1.74 (95% CI: 1.22–2.50), suggesting favorable outcomes from higher MTX doses. In contrast, the OR for GC use at ⬎ prednisolone-equivalent dose 7.5 mg/day was 0.66 (95% CI: 0.49–0.89), which was significantly lower than that for no GC use. In addition, relatively lower disease activity at baseline, less-advanced RA stage/better functional class, younger age, male gender and without previous/co-existing diabetes mellitus were background factors contributing to the effectiveness of adalimumab. In order to assess an association between the effectiveness of adalimumab and MTX dose, the proportion of responders, the patients whose DAS28-ESR score decreased from ⬎ 3.2 at baseline to ⱕ 3.2 at Week 24, was calculated for each MTX dose category and analyzed using the Mantel extension test with modified ridit scores. The proportion of responders significantly increased depending on MTX dose, indicating that combination therapy with MTX improved the response to adalimumab treatment (Figure 3).

Discussion The overall safety profile of adalimumab, including ADRs of particular interest of this study, was comparable to the previously reported interim analysis [18] and to clinical trials of the drug conducted in and outside Japan [26–28]. No unexpected ADRs, which would affect the overall safety of adalimumab, were observed during this study. The safety profile of adalimumab was also similar to those of other antirheumatic biologic agents (e.g. IFX, ETX and

Figure 1. Changes of categories of DAS28-ESR over time from baseline to Week 24 in patients with adalimumab treatment. The percentage of patients with DAS28-ESR ⬍ 2.6 (remission), 2.6–3.2 (low disease activity), ⬎ 3.2–5.1 (moderate disease activity), or ⬎ 5.1 (high disease activity) was calculated at baseline, Weeks 4, 12 and 24. Last-observationcarried-forward method was used to carry forward the previous nonbaseline values for any missed assessments. DAS28-ESR, disease activity score for 28-joint counts based on the erythrocyte sedimentation rate.

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Figure 2. Patient’s background factors associated with low disease activity at Week 24 of adalimumab treatment. ORs and the 95% CI were indicated as black circles and horizontal lines, respectively. The logistic regression model was constructed with data from 4055 out of 4138 patients with MTX dosages, the DAS28-ESR score ⬎ 3.2 at baseline and data on DAS28-ESR at Week 24; 83 patients (2.0%) were excluded from the analysis because they had no valid data on some adjustment factors. Variables that were included in the logistic regression models were chosen using stepwise selection. DAS28-ESR, disease activity score for 28-joint counts based on the erythrocyte sedimentation rate; ETA, etanercept; GC, glucocorticoids; IFX, infliximab; MTX, methotrexate; RA, rheumatoid arthritis.

TCZ) from postmarketing surveillance reports in Japanese RA patients [5,6,7,10]. The SMR in RA patients has been reported to be 1.27–2.64 times higher than in the general population, and patients with severe RA have been shown to be at increased risk of death [29–32]. The SMR calculated for adalimumab-treated RA patients in this study suggests that there is no notable risk of death linked to use of adalimumab at least in the short-term, although it is impossible to make direct comparisons with the SMR of a matched patient population not treated with adalimumab. Analysis of the influence of concomitant MTX treatment at different doses on the safety of adalimumab demonstrated that the overall frequency of ADRs or serious ADRs did not change in a dose-dependent manner. The multiple logistic regression analysis on patient background factors affecting infections revealed that the ORs for infections, respiratory infections, serious respiratory infections and pneumonias were higher in patients concomitantly treated with MTX therapy ⬎ 8 mg/week than in those treated with ⱕ 8 mg/week. Supportive evidence of concomitant MTX therapy ⬎ 8 mg/week as a risk factor for serious infections in RA patients

Figure 3. The percentages of patients in low disease activity (DAS28ESR ⱕ 3.2) in different doses of MTX at Week 24. The percentages of patients with low disease activity among those with DAS28-ESR ⬎ 3.2 at baseline was calculated by MTX dose category. These percentages were tested with the Mantel extension test using modified ridit scores, after adjusting for baseline DAS28-ESR, prior biologic therapy, sex, age, Steinbrocker stage, Steinbrocker class and previous/co-existing diabetes mellitus. DAS28-ESR, Disease activity score for 28-joint counts based on the erythrocyte sedimentation rate; MTX, Methotrexate.

has been reported by Komano et al. [33]. Other investigators have reported an association between combination of MTX and biologic therapy and serious infections, including PCP in Japanese [34] and non-Japanese [35] RA patients. These previous reports, as well as post-marketing surveillance studies of other biologic agents available in Japan, and other cohort studies involving RA patients [5,7,10,33–39] have also indicated that older age, pre-existence of pulmonary disease, co-existing diabetes mellitus and concomitant GC use can be risk factors for serious infections, which were also observed in this study. In addition, the JCR guidelines for MTX treatment in RA recommend that a reduction in MTX dose should be considered when using any biologic agent in patients with these risk factors for developing serious infections [12]. Careful monitoring of the patient’s general condition and disease activity should be conducted in high-risk patients receiving biologic agents, including adalimumab, especially when in combination with MTX therapy ⬎ 8 mg/week. This study also aimed to evaluate the effectiveness of adalimumab in Japanese RA patients. The mean DAS28-ESR score decreased from 5.2 at baseline to 3.8 at Week 24, with approximately 40% of patients achieving low disease activity at Week 24. The patients treated with adalimumab during this study had long-standing RA (mean duration, 10 years). The Treat to Target Recommendations clearly define optimal therapeutic targets in clinical practice and promote strategic approaches to the management of RA [40]. Its Statement 3 asserts that low disease activity may be an acceptable alternative therapeutic goal, particularly in established, long-standing RA. In this study, some patients’ background factors, predictive of the achievement of low disease activity at Week 24, were naïve to biologics, concomitant MTX use and less-advanced RA stage/better functional class, which were comparable to the interim analysis. Apart from an interim analysis of the postmarketing surveillance of ETA [6], in which the Cochran–Armitage trend test showed better response to ETA in patients concomitantly treated with higher dose of MTX, no large-scale studies in Japan have addressed the influence of concomitant MTX at different doses on the response to biologics-based RA treatment using fullscale statistics. In this study, the effectiveness of adalimumab was analyzed for three MTX dose categories using multiple logistic regression and the Mantel extension test. The analysis showed that responses were more favorable for patients with higher MTX doses. Further studies are needed to assess the impact of concomitant use of high-dose MTX on the inhibition of the progression of joint destruction and the improvement

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of patients’ quality of life, as well as on the clinical response to RA treatment in long-term. Considering the results that concomitant MTX therapy ⬎ 8 mg/week was a risk factor for infections, respiratory infections, serious respiratory infections and pneumonias, combined therapy of adalimumab and high dose of MTX should be commenced after careful assessment of benefit–risk balance of the patients. Biologic-naïve patients were more likely to respond to adalimumab than those previously treated with Biologics. Among patients previously treated with any biologic agent, those previously treated with IFX had a higher OR for achieving low disease activity than those previously treated with ETA. Conflicting findings have been reported on the response of patients previously treated with IFX or ETA; one study supported these findings [41], while others have shown a comparable response to adalimumab between patients treated with ETA and IFX [42,43]. In patients treated with adalimumab, concomitant GC use at ⬎ prednisolone-equivalent dose 5 mg/day increased the risk of infections (Table 4). Moreover, GC use at ⬎ prednisolone-equivalent dose 7.5 mg/day negatively impacted the effectiveness of adalimumab as assessed by the change in DAS28-ESR. Accordingly, we recommend reassessing the dose of GCs in patients who respond to adalimumab therapy. Our finding also indicated that co-existing diabetes mellitus was a risk factor for serious and non-serious infections and reduced the response to adalimumab treatment. Consequently, for RA patients with diabetes mellitus, adalimumab should be used with careful monitoring of infections. In conclusion, this study demonstrated an acceptable safety profile for adalimumab in a large cohort of RA patients in Japan who were treated with or without concomitant MTX. The overall safety profile of adalimumab was similar to what had been reported from postmarketing surveillance of other antirheumatic biologics, and no unexpected ADRs, which would affect the safety of adalimumab was reported. Factors associated with increased risk of ADRs or better clinical response were identified. Furthermore, this study showed that MTX improved the response to adalimumab in a dose-dependent manner. We anticipate that the results of this study will serve as a basis for improving the use of adalimumab to both ameliorate treatment response and minimize risks.

Acknowledgement We thank Noriko Takahashi of Springer Japan K.K., Springer Healthcare Business Unit, who provided medical writing support. Abbott Laboratories separated proprietary pharmaceutical business into AbbVie in January 2013.

Funding The design, study conduct and financial support for this study was provided by AbbVie under the guidance of the JCR postmarketing surveillance sub-committee. AbbVie participated in the interpretation of data, review and approval of the manuscript.

Conflict of interest Doctors T. Koike, M. Harigai, N. Ishiguro, S. Inokuma, S. Takei, T. Takeuchi, H. Yamanaka and Y. Tanaka are members of the Postmarketing Surveillance (PMS) Committee of the Japan College of Rheumatology. It is the belief of the authors that this does not constitute a conflict of interest. The doctors participated in review and analysis of the PMS data in their capacity as committee members. The financial relationships of the authors with manufacturers of biological products used in the management of RA are listed. T. Koike has received consultancies, speaking fees and honoraria from Abbott, Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Pharmaceutical, Eisai Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Santen Pharmaceutical, Takeda Pharmaceutical, Teijin Pharmaceutical and

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Pfizer. M. Harigai has received research grants, speaking fees and honoraria from Abbott Japan, Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical, Eisai Pharmaceutical, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Santen Pharmaceutical, Takeda Pharmaceutical, UCB Japan and Pfizer, and received consultant fees from Abbott Japan, Bristol Myers Squibb, Chugai Pharmaceutical and Janssen Pharmaceutical. N. Ishiguro has received speaking fees from Takeda Pharma, Mitsubishi Tanabe Pharma, Astellas Pharma, Chugai Pharma, Abbott Japan, Bristol-Myers Squibb, Eisai, Janssen Pharma and Pfizer Japan. S. Inokuma, None. S. Takei has received research grants, consulting fees and/or speaker’s fees from Eisai, Chugai, Takeda, Bristol-Myers KK, Teijin, Pfizer, Mylan, Mitsubishi Tanebe, Asahi Kasei and Astellas. T. Takeuchi has received grants from Abbott Japan Co., Ltd., Astellas Pharma, Bristol-Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Nippon Shinyaku Co., Ltd., Otsuka Pharmaceutical, Pfizer Japan Inc., Sanofi-Aventis K.K., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. and Teijin Pharma Ltd.; speaking fees from Abbott Japan Co., Ltd., Bristol-Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc. and Takeda Pharmaceutical Co., Ltd.; and consultant fees from Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co. and Asahi Kasei Medical K.K. H. Yamanaka has received speaking fees from Abbott Japan Co., Ltd, AstraZeneca K.K., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Company Ltd., Teijin Pharma Limited and UCB Japan Co. Ltd. S. Haruna is a full-time employee of AbbVie GK. N. Ushida is a full-time employee of AbbVie GK. K. Kawana is a full-time employee of AbbVie GK. Y. Tanaka, has received consulting fees, speaking fees and/or honoraria from Mitsubishi-Tanabe Pharma Corporation, Abbott Japan Co., Ltd., Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Santen Pharmaceutical Co., Ltd., Pfizer Japan Inc., Astellas Pharma Inc., Daiichi-Sankyo Co., Ltd., GlaxoSmithKline K.K., Astra-Zeneca, Otsuka Pharmaceutical Co., Ltd., Actelion Pharmaceuticals Japan Ltd., Eli Lilly Japan K.K., Nippon Kayaku Co., Ltd., UCB Japan Co., Ltd., Quintiles Transnational Japan Co. Ltd., Ono Pharmaceutical Co., Ltd. and Novartis Pharma K.K. and has received research grants from BristolMyers Squibb, MSD K.K., Chugai Pharmaceutical Co., Ltd., Mitsubishi-Tanabe Pharma Corporation, Astellas Pharma Inc., Abbott Japan Co., Ltd., Eisai Co., Ltd. and Janssen Pharmaceutical K.K.

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Notice of correction The original Early Online version of this article contained a typographical error in Table 3. The row opposite Pneumonia should have aligned with “n” This has been corrected in the current article.

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Copyright of Modern Rheumatology (Informa Healthcare) is the property of Informa Healthcare and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.