Long-term safety and effectiveness of etanercept in JIA: an 18-year experience from the BiKeR registry

Effectiveness parameters were defined as follows. The JIA-American College of Rheumatology (ACR) improvement criteria and the Juvenile Arthritis Disease Activity Score (JADAS) were calculated as previously described [11, 12]. JIA-ACR core set parameters consist of (i) physician global assessment of disease activity (PhysVAS) on a 10-cm visual analogue scale (VAS); (ii) parent/patient global assessment of overall well-being (PatVAS) on a 10-cm VAS; (iii) the Childhood Health Assessment Questionnaire (CHAQ); (iv) the number of joints with active arthritis, defined by the presence of swelling or, if no swelling is present, limitation of motion accompanied by pain, tenderness, or both; (v) the number of joints with limited range of motion; and (vi) the erythrocyte sedimentation rate (ESR). The ACR-inactive disease definition was used according to Wallace et al. [13], requiring no active uveitis or arthritis, no fever, rash, splenomegaly, serositis, generalised lymphadenopathy or elevation of ESR/C-reactive protein (CRP), best possible PhysVAS, and duration of morning stiffness ≤ 15 min. JADAS10 was chosen, which considers a maximum of ten active joints besides PatVAS, PhysVAS, and ESR or CRP, all equally weighted. Rates of JADAS-minimal disease activity (MDA) and JADAS-remission, respectively defined as JADAS10 ≤ 3.8 and JADAS10 ≤ 1, were calculated according to the definition of Consolaro et al. [14]. For each timepoint, all patients with complete data set were considered. Data from patients who discontinued etanercept treatment due to remission were analysed for disease activity also after therapy withdrawal, and rates of JADAS-MDA and JADAS-remission off-biologics were determined.

Safety was analysed based on AE reporting for all patients during the whole treatment period. AEs and serious AEs (SAEs) were defined according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 Section 1.2 [15]. Exposure-adjusted AE rates were calculated per 100 patient-years (PY) with 95% confidence interval (CI). AEs and SAEs were attributed to the etanercept treatment if the patient had been treated with etanercept at the time of the occurrence of the AE or during the last 90 days prior to the AE occurrence, regardless of a possible cotreatment with methotrexate. Malignancies, pregnancies, and deaths were additionally analysed in the ever-treated population.

For the comparison of baseline characteristics, the chi-squared, Fisher’s exact, or Mann-Whitney U test was used, depending on data distribution. Mean changes from baseline in each effectiveness parameter were compared using the unpaired t test. Differences in AE rates were analysed using risk ratios (RRs) and the Wald test. A p value < 0.05 was considered statistically significant. Analyses were conducted with IBM SPSS Statistics version 23 (IBM Corp., Armonk, NY, USA) and SAS 9.3 (SAS Institute, Cary, NC, USA).

Within the JIA patients who initiated etanercept treatment for the first time between 2001 and 2019, 2725 were eligible for the analysis. Mean etanercept dose was 0.79 ± 0.21/kg/week. The administration regimen was once weekly in 56.9% of patients and twice weekly in 43.1%. Overall, the majority of etanercept-treated patients in Germany showed to be diagnosed with (rheumatoid factor (RF)-negative) polyarthritis, extended oligoarthritis, or ERA, although the cohort subtype distribution varied considerably over the years (Fig. 1). Rates of etanercept-treated patients with RF-negative polyarthritis and with ERA increased over time (23.5 and 9.8% in 2001, 37.2 and 22.1% in 2018, respectively), while percentages of patients with systemic JIA or RF-positive polyarthritis decreased (20.4 and 19.4% in 2001, 0.9 and 8.0% in 2018, respectively). The comparison cohort of 1517 JIA biologic-naïve patients starting methotrexate significantly differed from the etanercept cohort for subtype distribution (Table 1). Age at disease onset was comparable between the cohorts, while age at baseline was significantly higher in the etanercept group (12.1 ± 4.4 versus 9.8 ± 4.8 years; p < 0.0001; Table 1). Disease duration at baseline, as calculated from symptom onset to start of cohort defining treatment, was also significantly higher in the etanercept cohort (4.1 ± 3.7 versus 2.1 ± 2.8 years; p < 0.0001). However, a significant decrease in the mean disease duration at etanercept start was observed over time (from 6.0 ± 3.9 in 2001 to 3.3 ± 3.1 years in 2018; p = 0.0001; Supplementary figure S1a). At baseline, 86.5% of etanercept patients had been pretreated with methotrexate, while only 4.2% had been preexposed to other biologics. Concomitant treatment at baseline with systemic steroids was observed more frequently in the biologic-naïve group (91.9 versus 35.7%; p = 0.0001; Table 1). All disease activity parameters at baseline, except for mean ESR levels, were significantly higher in the etanercept cohort. However, the mean JADAS10 at etanercept treatment initiation showed to decrease significantly over the years (from 20.6 ± 7.8 in 2001 to 10.7 ± 5.8 in 2018; p = 0.003; Supplementary figure S1b).

On etanercept, the mean JADAS10 decreased from 15.3 ± 7.5 at baseline to 5.6 ± 5.7 (p < 0.0001) after 3 months and to 4.1 ± 5.3 (p < 0.0001) after 12 months of treatment (Fig. 2). Patients recruited in the most recent years achieved a lower JADAS10 after 12 months on etanercept compared to those enrolled in the earlier years, although the difference did not reach significance (2.3 ± 2.0 in 2018 compared to 6.9 ± 7.2 in 2001; p = 0.0637; Supplementary figure S1b).

JADAS-defined minimal disease activity (MDA; JADAS ≤ 3.8) was reached at months 3, 12, and 24 in 844 (45.9%), 990 (58.6%), and 734 (61.8%) etanercept patients, and in 252 (63.0%), 120 (63.8%), and 49 (68.1%) patients after 5, 7, and 9 years. JADAS-remission (JADAS ≤ 1) was reached at months 3, 12, and 24 in 315 (17.2%), 591 (35.0%), and 449 (37.8%) patients, and in 175 (43.8%), 76 (40.4%), and 31 (43.1%) patients after 5, 7, and 9 years (Fig. 3). Over the course of the years, the percentage of patients who reached JADAS-MDA and JADAS-remission following 12 months of etanercept treatment increased, respectively, from 43.1 and 20.9% in 2001 to 72.8 and 45.6% in 2018 (Supplementary figure S1c).

ACR-inactive disease according to Wallace et al. [13] was reached at months 3, 12, and 24 by 166 (25.0%), 248 (42.8%), and 180 (46.3%) etanercept patients, and in 84 (46.9%), 43 (48.9%), and 15 (36.6%) patients after 5, 7, and 9 years (Fig. 3). Improvement according to JIA-ACR30/50/70/90 criteria was reached in 74/64/45/24% of patients at month 3, in 81/75/61/42% of patients at month 12, and in 82/76/64/46% of patients at month 24 (Fig. 4). JIA-ACR30/50/70/90 response rates were 84/80/68/53% after 5 years, 82/79/69/57% after 7 years, and 82/79/71/54% after 9 years on etanercept.

The effectiveness parameters JADAS-MDA, JADAS-remission, and ACR-inactive disease were also evaluated in an intention-to-treat (ITT) analysis, with patients who discontinued due to remission considered as responders, and patients discontinuing for any other reason as non-responders. In this analysis, JADAS-MDA was reached by 40.2, 41.2, and 33.8% of patients at months 3, 12, and 24, and by 21.3, 19.7, and 19.0% after 5, 7, and 9 years. JADAS-remission was reached by 15.1, 25.6, and 23.9% of patients at months 3, 12, and 24, and by 19.7, 19.1, and 18.7% after 5, 7, and 9 years. ACR-inactive disease was reached by 18.8, 27.0, and 25.0% of patients at months 3, 12, and 24, and by 19.6, 19.2, and 18.8% after 5, 7, and 9 years.

Over 18 years of observation, etanercept was discontinued by 1655 (60.7%) patients. Rates and reasons for discontinuation are listed in Table 2. The most common reason for discontinuation was remission (23.9%), followed by inefficacy (21.8%) and intolerance (7.1%). Of the 652 patients discontinuing due to remission, 521 patients had available data one year after etanercept withdrawal. In the first year, 126 (24%) patients relapsed, and 395 (76%) remained without etanercept or other biologic agents. Of these, 214 (54%) maintained at least JADAS-MDA and 121 (31%) remained in JADAS-remission off-biologics (Supplementary figure S2). Five years after etanercept discontinuation, 105 patients remained without etanercept or other biologic agents, of which 27 (26%) maintained at least JADAS-MDA and 11 (11%) JADAS-remission off-biologics.

During 5988 patient-years of etanercept exposure, a total of 2053 AEs were reported to the registry (Table 3). No significant difference in exposure-adjusted AE rates was observed between etanercept (34.3/100PY) and biologic-naïve patients (35.6/100PY; p = 0.3). The AEs qualifying as serious (SAEs) were significantly more frequent in the etanercept cohort (3.8 versus 1.4/100PY; p = 0.0001). The incidence of serious infections was significantly higher in the etanercept group (0.9 versus 0.2/100PY; p = 0.0001), while neutropenia rates were comparable in the two cohorts (0.07 versus 0.05/100PY; p = 0.8). All reported opportunistic infections, but for one case of latent tuberculosis, were herpes zoster reactivation, and were more often observed under etanercept (0.4 versus 0.1/100PY; p = 0.01). The case of latent tuberculosis consisted in a positive Quantiferon Gold test without any clinical symptom or change in chest radiograph and was documented in a patient on methotrexate and with previous etanercept treatment.

Inflammatory bowel disease (IBD) occurred with significantly greater frequency in etanercept patients (0.3 versus 0.03/100PY; p = 0.015). Nineteen patients developed IBD on etanercept (14 female, 3 HLA-B27 positive). Of these, six patients were diagnosed with RF-negative polyarthritis, six with extended polyarthritis, four with ERA (of which three male and two HLA-B27 positive), and one each with RF-positive polyarthritis, PsA, and systemic JIA. Two developed a sacroiliitis, one an iridocyclitis, and one an alpha-1-antitrypsin deficiency. Mean age at arthritis onset was 6.8 ± 4.3 years, and mean age at IBD onset was 13.7 ± 2.7 years. Patients developed IBD after 2.3 ± 1.9 years on ongoing etanercept therapy. All 19 patients had been pretreated with MTX. Rates of psoriasis (0.07 versus 0.003/100PY; p = 0.4) and aggravation/new onset of uveitis (1.9 versus 1.4/100PY; p = 0.09) did not differ significantly between the two analysed cohorts. One patient in the etanercept cohort developed demyelination and none in the biologic-naïve control cohort. The lesion, a minor alteration of the periventricular white matter, was discovered incidentally in an asymptomatic patient and has been described earlier [7]. Other reported immune-mediated events were Henoch-Schonlein purpura, leukocytoclastic cutaneous vasculitis, and lupus-like syndrome in one patient each. All three patients were on etanercept treatment.

Three pregnancies occurred in patients under etanercept treatment at the time of conception. A 17-year-old patient who was treated with etanercept and methotrexate delivered at term a healthy 3360-g male infant after a pregnancy without complications. Treatment was interrupted as her pregnancy was diagnosed at 6 weeks of gestation. The child was developing normally at two months of age. An 18-year-old patient gave birth to a healthy male infant, weight and gestational age of which have not been reported by the documenting physician. At the age of six months, the child showed normal growth and development. The third patient decided on an induced abortion at 12 weeks of gestation. Additionally, a miscarriage after 12 weeks of gestation was reported to the registry in an 18-year-old patient, two years after discontinuation of etanercept. She had been treated with etanercept 50 mg weekly over nine months. The patient received hydroxychloroquine 300 mg daily from 20 months before conception through eight weeks of pregnancy. No pregnancy was recorded in the biologic-naïve cohort.

Three malignancies were documented in patients on etanercept at the time of diagnosis (0.05/100PY). An 18-year-old male patient developed a non-familial thyroid carcinoma. One case each of Hodgkin’s and non-Hodgkin’s lymphoma was reported in two male patients. Malignancies were reported to the registry in five other patients who had been exposed to etanercept in the past: two cases of lymphoproliferative disorder and one case each of anaplastic ependymoma, yolk sac carcinoma, and cervix dysplasia. All patients recovered. In the biologic-naïve cohort with methotrexate, two cases of acute lymphatic leukaemia (ALL) were documented (0.05/100PY). One patient recovered; the second died. All malignancy cases have been previously described [16].

In all patients ever treated with etanercept, five deaths were reported, three of these during drug exposure. Two deaths occurred during adolescence and three in adulthood. One patient with systemic JIA died due to septic shock while on treatment with etanercept, after having been pretreated with cyclophosphamide and chlorambucil years before. A second patient with systemic JIA succumbed to heart failure by macrophage activation syndrome (MAS), one year after discontinuation of etanercept due to inefficacy. Both deaths occurred at the age of 16 years and have been formerly reported [17]. Of the three deaths during adulthood, one occurred in a 22-year-old due to perimyocarditis with arrhythmia, eight weeks after voluntary discontinuation of etanercept. A second patient died at the age of 22 years by suicide, seven years after etanercept discontinuation, and a third one died at the age of 23 years due to pseudomembranous enterocolitis by a septic urinary tract infection with renal failure and pancytopenia after 13 years of etanercept exposure. The events were considered as not related to etanercept treatment. In the biologic-naïve group, one death was reported. A 13-year-old female patient on methotrexate succumbed to ALL.