Abstract
Objective
This prospective study assesses the response to canakinumab monotherapy administered as three monthly subcutaneous injections in glucocorticoid‐naïve patients with newly diagnosed systemic juvenile idiopathic arthritis (sJIA) and Still disease and evaluates the durability of drug‐free inactive disease for up to nine months after canakinumab cessation.
Methods
In a multicenter, two‐phase open‐label study of newly diagnosed sJIA or Still disease, canakinumab was administered at 4 mg/kg subcutaneously every 4 weeks for 12 weeks. Thereafter, patients were followed for an additional 40 weeks. Routine care was provided to nonresponders.
Results
In total, 21 patients were recruited, and 1 was excluded due to protocol violations. Fever resolved immediately in 17/19 patients. Two nonresponders (n = 2) were managed with different strategies: one received steroids alone, and the other received steroids plus canakinumab as part of routine care. By week 12, 14 patients achieved inactive disease. Thereafter, two flares occurred at weeks 24 and 36. Macrophage activation syndrome (MAS) was diagnosed in a third patient at week 19 and responded to treatment with glucocorticoids and cyclosporine A. By week 52, 11 patients had reached drug‐free inactive disease and 3 had minimal disease activity. A total of 97 adverse events were reported; four were serious (one MAS, two disease flares, and one viral infection), but none were attributed to the study drug.
Conclusion
Canakinumab steroid‐free first‐line therapy in newly diagnosed sJIA induces long‐lasting, drug‐free inactive disease in a substantial proportion of patients. Discontinuation of canakinumab was associated with disease flares in a minority of patients.
INTRODUCTION
Systemic juvenile idiopathic arthritis (sJIA), also known as Still disease, accounts for 3% to 5% of JIA cases, making it a rare condition. 1 , 2 , 3 , 4 The prognosis of patients with sJIA or Still disease is poorer than for nonsystemic JIA, requiring complex multidisciplinary and individualized interventions. 5
SIGNIFICANCE & INNOVATIONS.
The early introduction of interleukin‐1 (IL‐1) inhibitors is part of the recent EULAR and Paediatric Rheumatology European Society recommendations. Achieving steroid‐free disease control is considered a key step toward attaining drug‐free remission.
Canakinumab shows efficacy in 90% of patients with systemic juvenile idiopathic arthritis or Still disease resulting in clinical inactive disease (systemic Juvenile Arthritis Disease Activity Score including 10 joints) on medication of 70% at three months and remission off medication in 60% of patients at one year (intention‐to‐treat analysis). This high efficacy was observed in patients treated with first‐line canakinumab without concomitant or previous treatment with glucocorticoids.
Responding patients often showed inactive disease without recurrence after only three months of treatment.
The induction of remission without the use of glucocorticoids represents a substantial clinical improvement for many patients, especially for children. Moreover, the hypothesis is gaining support that a steroid‐free treatment approach—initiated through early IL‐1 inhibition—may contribute to a sustained remission of the disease.
sJIA or Still disease is characterized by autoinflammatory and autoimmune features, 6 , 7 presenting with arthritis and systemic signs such as daily high‐spiking fevers, rash, generalized lymphadenopathy, hepatosplenomegaly, and serositis. Complications include the potentially lethal macrophage activation syndrome (MAS), interstitial lung disease, growth impairment, pericardial effusion, osteoporosis, and damage associated with treatment with glucocorticoids. 8 , 9 , 10 , 11
Pharmacological treatment targets inflammatory symptoms and pain. Nonsteroidal anti‐inflammatory drugs (NSAIDs), glucocorticoids, and disease‐modifying antirheumatic drugs (DMARDs) are among the commonly used therapeutic approaches. 12 Nevertheless, NSAID, glucocorticoids, and DMARD may be poorly tolerated, have limited efficacy, or cause adverse effects. The advent of biologics has expanded treatment options for sJIA or Still disease, particularly with the aim of achieving an inactive disease state or even remission. 13 , 14 In particular, toxicity associated with long‐term glucocorticoid treatment can be avoided with the introduction of interleukin‐1 (IL‐1) and IL‐6 inhibitors, as recommend by the recent EULAR and Paediatric Rheumatology European Society (PReS) recommendations. 15
IL‐1 and IL‐6 play a central role in the pathogenesis of JIA. IL‐6 levels correlate with the severity of joint involvement, systemic disease features, and markers of inflammation such as C‐reactive protein (CRP). 16 , 17 Blockade with IL‐1 inhibitors yields beneficial clinical responses even in patients with longstanding disease, as demonstrated in two randomized placebo‐controlled clinical trials that showed a convincing benefit of long‐acting IL‐1–blocking treatment with canakinumab. 18
In a prospective open‐label study of early treatment with daily injections of recombinant IL‐1 receptor antagonist in 20 consecutive patients with new‐onset sJIA, a high response rate could be achieved without glucocorticoids, and complete discontinuation of IL‐1 inhibitor therapy was possible in a substantial subset of patients. 19 A window of opportunity early in the disease has thus been proposed as a phase when IL‐1 inhibition can prevent further progression of disease and induce long‐lasting remission. 20 , 21
Canakinumab is a human monoclonal antibody neutralizing IL‐1β signaling and thereby preventing the expression of proinflammatory genes. 22 Beside the pivotal trial leading to approval of canakinumab, its efficacy in treating patients with sJIA or Still disease has been reported in case reports and observational studies. 23 , 24 The hypothesis for this study was that by targeting the IL‐1 pathway with canakinumab very early in the disease course, effectively blocking inflammation, high rates of response would be achieved, leading finally to a drug‐free remission in a substantial subset of patients.
PATIENTS AND METHODS
Study designs
The “Canakinumab first” trial (EudraCT no: 2018‐004284‐30) is an open‐label, multicenter, uncontrolled study designed to study the effects of a short‐term first‐line use of canakinumab in newly diagnosed patients with sJIA and Still disease. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice, and informed consent was obtained from all patients and/or parents. The protocols were approved by independent ethics committees at each site.
In the first study phase, 20 glucocorticoid‐naïve patients received canakinumab at baseline, week 4, and week 8 at a dose of 4 mg/kg (maximum 300 mg per injection). In the subsequent 40‐week study phase, patients were followed at regular intervals. Nonresponders or patients who flared or required additional treatment were withdrawn and received standard of care.
Primary objective was to demonstrate rate of response at week 12. Secondary endpoints were steroid‐free and drug‐free inactive disease at months 6 and 12, defined as no fever >38.0°C, no arthritis defined as joint swelling or pain on motion and limited range of motion, normal CRP, and no organ involvement attributed to sJIA or Still disease, and to demonstrate improvement by validated outcome criteria, such as Juvenile Arthritis Disease Activity Score (JADAS), systemic JADAS (sJADAS), and pediatric American College of Rheumatology (ACR) response. 25 , 26 , 27 Subjects were withdrawn after the occurrence of (1) clinically significant abnormal laboratory results, (2) clinically significant deterioration of the subject's medical status, (3) if the investigator believed it in the best interest of the subject, or (4) the parent or legal guardian or the patient requested withdrawal.
Patients
Children aged 2 to 17 years with newly diagnosed active systemic‐onset JIA or Still disease determined by International League of Associations for Rheumatology (ILAR) or the Yamaguchi criteria for Still disease were included. 28 , 29 ILAR definition required arthritis in one or more joints with or preceded by fever of ≥2 weeks duration that is documented to be daily for at least three days and accompanied by at least one of the following features: evanescent nonfixed erythematous rash, generalized lymph node enlargement, hepatomegaly and/or splenomegaly, and serositis. Still disease as per Yamaguchi criteria was diagnosed with at least five criteria, of which two or more had to be major (fever >39°C, lasting ≥1 week; arthralgia or arthritis, lasting two weeks or longer; typical rash; or leucocytosis >10,000/mm3 with >80% polymorphonuclear cells). Minor criteria are sore throat; recent development of significant lymphadenopathy, hepatomegaly, or splenomegaly; and abnormal liver function tests or negative tests for antinuclear antibody (IF) and rheumatoid factor (IgM). 29
Patients with sJIA or Still disease were enrolled from October 15, 2019, through December 28, 2023, at five centers. Main inclusion criteria were (1) patient is at least two years old and has not reached his or her eighteenth birthday, (2) patient is currently not treated with a DMARD and has not been treated before baseline with any biologic DMARD, (3) patient is on a stable dosage of NSAIDs, and (4) patient is currently not treated with glucocorticoids, that is patient has previously not been treated with glucocorticoids for more than seven days after diagnosis. Main exclusion criteria were (1) chronic or active infection or any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 30 days before study screening, (2) any preceding diagnosis of malignancy, (3) active gastrointestinal disease (eg, inflammatory bowel disease), (4) previous use of systemic glucocorticoids for more than seven days (>0.2 mg/kg body weight), (5) previous use of immunosuppressant (eg, methotrexate and cyclosporine), (6) previous use of biologic agents (eg, anakinra, canakinumab, and tocilizumab), and (7) MAS with its biologic features (such as hemorrhages, central nervous system dysfunction, plasma fibrinogen level <2.5 g/L, cytopenia including decreased platelet count, hypertriglyceridemia, hyperferritinemia at screening, or a history of recurrent pericarditis, myocarditis, and serositis).
Concomitant treatment with oral glucocorticoids, conventional DMARDs, or other biologics were prohibited. NSAIDs were allowed.
Assessments
Primary objective was a response defined as steroid‐free inactive disease at month 3, defined as no fever >38.0°C, no arthritis defined as joint swelling or pain on motion and limited range of motion, normal CRP, and no organ involvement attributed to sJIA or Still disease. Secondary objective was the rate of patients with steroid‐free inactive disease at months 6 and 12.
Exploratory efficacy measures included disease activity measured by JADAS including 10 joints (JADAS‐10) 26 and the course of its incorporated parameters, proportions of patients fulfilling definitions of JADAS inactive disease, JADAS minimal disease activity definitions, and pediatric ACR response criteria. 30 For calculation of the sJADAS, the Systemic Manifestations Score (SMS) was calculated, which includes the following seven clinical and/or laboratory features 31 , 32 : (1) fever (1 point if temperature exceeds 37.5–38°C, 2 points if temperature exceeds 38–39°C, 3 points if temperature exceeds 39–40°C, and 4 points if temperature exceeds 40°C); (2) evanescent erythematous rash (1 point); (3) generalized lymphadenopathy (enlargement of more than three lymph node stations; 1 point); (4) hepatomegaly and/or splenomegaly (1 point); (5) serositis (pleuritis, pericarditis, or peritonitis; 1 point); (6) anemia (hemoglobin level <9 g/dL; 1 point); and (7) platelet count >600 × 109/L or ferritin level >500 ng/mL (1 point).
Fever was defined as the maximum temperature recorded in the 24 hours before the study visit. The SMS ranges from 0 to 10 and is added to the classical JADAS10. By this, the sJADAS10 reaches up to 50 points. Cutoffs were ≤2.9 for the definition of inactive disease, 3 to ≤10 for minimal disease activity, >10 to 20.6 for moderate disease activity, and >20.6 for high disease activity. 32
All patients who received at least one dose of canakinumab were included in the safety population. Adverse events (AEs) were collected during the treatment period and the observation period and were classified using the Medical Dictionary for Regulatory Activities. 28
Statistical analysis
Only descriptive statistical analyses were planned. Results are expressed as the median with interquartile range and mean with SD when appropriate. All statistical analyses were performed using SPSS software version 26 (SPSS Inc). AEs were coded according to Medical Dictionary for Regulatory Activities System Organ Class (SOC) and Low‐Level Terms.
Ethical approval and consent to participate
The study was approved by the ethics committee of the physician board Aerztekammer Nordrhein, Duesseldorf. Written consent was obtained from patients and parents and repeated if patients became adults. Only pseudonymized data were collected.
RESULTS
Twenty patients with sJIA or Still disease were admitted from October 2019 through December 2023 at five centers. Disease duration before initiation of canakinumab was low with a median of 0.5 months (maximum 2 months). Demographic and disease characteristics at baseline are outlined in Table 1.
Table 1.
Patients’ characteristics at baseline*
| Characteristics | Total cohort, n = 20 |
|---|---|
| Male sex, n (%) | 12 (60) |
| Age, mean ± SD, median (IQR), years | 8.4 ± 4.9, 8.6 (5.8–14.1) |
| Ethnic origin, n (%) | 16 (80) |
| White | |
| Other (each 1 African, Arabian, Indian, and Turkish) | 4 (20) |
| Disease duration, mean ± SD, median (IQR), months | 1.2 ± 0.5, 1 (0–2) |
| Painful joints, mean ± SD, median (IQR) | 3.1 ± 3.4, 3 (0–6) |
| Active joints, mean ± SD, median (IQR) | 3.9 ± 4.2, 4 (0.5–7) |
| Patient Global VAS (0–10), mean ± SD, median (IQR) | 6.8 ± 1.6, 7 (6–8) |
| Physician Global VAS (0–10), mean ± SD, median (IQR) | 6.0 ± 1.3, 6 (5–7) |
| Fever, n (%) | 19 (95) |
| Rash, n (%) | 18 (90) |
| Serositis, n (%) | 4 (20) |
| Splenomegaly, n (%) | 10 (50) |
| Lymphadenopathy, n (%) | 7 (35) |
| Patients with active arthritis, n (%) | 15 (75) |
| Patients with active systemic features, n (%) a | 20 (100) |
| Number of systemic manifestations, mean ± SD, median (IQR) | 2.8 ± 1.0, 3 (2–4) |
| Systemic Manifestation Score, mean ± SD, median (IQR) | 4.3±1.6, 4 (3–5) |
| ESR, mean ± SD, mm/h | 90.5 ± 26.3 |
| CRP, mean ± SD, median (IQR), mg/l | 90.2 ± 52.2, 84.3 (55.1–127.8) |
| Ferritin, mean ± SD, median (IQR), U/mL | 1,895 ± 2,131, 769 (389–4,488) |
| JADAS10, mean ± SD, median (IQR) | 23.9 ± 5.9, 23.8 (20.2–30.8) |
| sJADAS10, mean ± SD, median (IQR) | 26.7 ± 5.6, 27.0 (24.3–34.6) |
| Pretreatment with oral steroids, n (%) b | 3 (15) |
| Pretreatment with IVIg, n (%) | 2 (10) |
CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; IQR, interquartile range; IVIg, intravenous Ig; JADAS10, Juvenile Arthritis Disease Activity Score including 10 joints; sJADAS10, systemic Juvenile Arthritis Disease Activity Score including 10 joints; VAS (0–10), 0–10 cm visual analog scale.
Presence of either fever, rash, generalized lymphadenopathy, hepatomegaly and/or splenomegaly, and serositis (pleuritis, pericarditis, or peritonitis).
Patients received glucocorticoids for a maximum of three days.
All patients showed active systemic features at baseline, 19 patients reported fever, and 75% had active arthritis. Mean levels for CRP and erythrocyte sedimentation rate (ESR) were high, and the mean JADAS10 and mean sJADAS10 indicate high disease activity at baseline (Table 1).
An additional patient experienced immediate fever resolution after the initial canakinumab dose. The patient had an urticarial rash, which according to the investigator, could have been a Still rash or an allergic rash. The patient received short‐term high‐dose systemic glucocorticoids. The patient subsequently reached inactive disease at three months and did not receive additional therapy. The patient was excluded for a protocol violation and was replaced by a newly enrolled patient to achieve the planned sample size of 20 patients. Two patients did not respond to the first study drug injection and thus had to be excluded from the study due to suspected primary nonresponse according to the study protocol. One of these nonresponders presented without confirmed arthritis, and the other nonresponder presented with eight active joints. Five patients initially presented with polyarticular disease (at least 5 active joints), with one patient presenting with 16 active joints at baseline.
In all, 18 (90%) patients completed the 12‐week study phase 1 (Supplemental Figure 1) and entered the observational study phase 2. Two patients developed a disease flare during the observational drug‐free study phase 2 at weeks 24 and 36, respectively, and discontinued with receive standard of care. A third patient developed signs and symptoms of MAS at week 19 of the observational study phase and discontinued with standard of care. The remaining 15 patients (83.3%) completed the observational study phase 2. Of the four patients presenting without confirmed arthritis, none flared during the observation phase. Of those patients presenting with polyarticular disease, four demonstrated sustained efficacy, whereas the one patient with the highest number of active joints at baseline flared during the drug‐free observation study period, with a maximum number of 34 active joints at week 24.
Efficacy analysis
The mean level of CRP decreased from 92.3 ± 54.1 mg/L at baseline to 4.0 ± 13.8 mg/L at week 12 and to 1.2 ± 1.8 mg/L at week 52. The ferritin serum levels dropped from 1,895 ± 2,131 U/L (mean ± SD) to 59 ± 95 at week 12. Only in the patient who developed MAS and discontinued from the study before week 24, ferritin levels had markedly increased from 21 U/L at week 12 to 2,451 U/L at week 19. The mean number of active joints decreased from 3.9 ± 4.2 to 0.9 ± 4.0 at week 12, and no active joints were reported in the 15 eligible patients at week 52. At baseline, all patients had active systemic features, 19 of 20 had fever, 17 of 20 had rash, 5 had serositis, and 8 had lymphadenopathy. Single patients had up to four different systemic manifestations. The SMS decreased from the baseline level of 4.3 ± 1.6 to 0.3 ± 0.7 at week 12 and 0.1 ± 0.3 at week 52 (Figure 1A–1D). The course of thrombocyte counts showed a decrease to within normal range in the majority of patients, and the hemoglobin levels increased during the study. These markers and the patient's and physician's global assessment of disease activity are outlined in Supplemental Figure 2A–2D.
Figure 1.
Courses of CRP (A), ferritin (B), number of active joints (C), and the systemic manifestation score (D). The number of patients with available data are shown below panels. Two primary nonresponders were withdrawn after baseline assessment. One patient developed macrophage activation syndrome at week 19 and was withdrawn before week 24. A disease flare occurred after week 24 in one patient and after week 36 in another, both withdrawals following these events. X indicates mean; error bars indicate SD; line indicates median; and box indicates interquartile range. CRP, C‐reactive protein.
The JADAS‐10 improved from 24.0 ± 7.3 to 2.2 ± 4.9 at week 12. At the end of the observational study phase 2, the remaining 15 patients exhibited a JADAS10 of 0.8 ± 1.3. The sJADAS10 improved markedly from 28.3 ± 7.6 to 2.4 ± 4.9 at week 12 and to 0.9 ± 1.4 at week 52 (Figure 2A and 2B). The primary outcome, the rate of steroid‐free inactive disease at month 3, was reached by 14 (77.8%) of 18 patients completing week 12, and 17 reached at least JADAS10 minimal disease activity. Of the patients not in inactive disease at three months, one had active joints, one had a rash, one was febrile (38.1°C), and one had lymphadenopathy. Secondary outcome—steroid‐free inactive disease at 6 and 12 months—was observed in 13 and 14 patients, respectively.
Figure 2.
Courses of JADAS10 (A) and the sJADAS10 (B) and achievement of JADAS10 and sJADAS10 targets. This shows the JADAS10 targets inactive disease and low disease activity as well as the sJADAS targets inactive disease and low disease activity in the as‐observed population. JADAS10, Juvenile Arthritis Disease Activity Score including 10 joints; sJADAS, systemic Juvenile Arthritis Disease Activity Score.
Three patients were withdrawn from the observational study phase. At the end of the study, 12 patients qualified for JADAS10 inactive disease and 14 for at least JADAS10 minimal disease activity. In one patient, the JADAS could not be calculated due to missing data (Figure 2C and 2D). Figure 3 outlines the course of patients using the sJADAS disease activity with sJADAS10 cutoffs for inactive disease (≤2.9), low disease activity (3 to ≤10), moderate disease activity (>10 to ≤20.6), and high disease activity (>20.6).
Figure 3.
sJADAS including 10 joints disease activity classes. The sJADAS was classified according to Tibaldi et al. 31 sJADAS10 cutoffs for inactive disease is ≤2.9, and low disease activity is indicated with a score of 3 to ≤10, moderate disease activity with a score of 10–20.6, and high disease activity 32 with a score >20.6. In one patient, the score could not be calculated due to missing laboratory values. Two primary nonresponders and also two patients who discontinued due to disease flare and one who developed macrophage activation syndrome were calculated as nonresponders. sJADAS, systemic Juvenile Arthritis Disease Activity Score.
Using the pediatric ACR response parameters, a marked response rate was observed already at week 4 with a pediatric ACR 30 (pedACR30), pedACR50, pedACR70, or pedACR90 criteria of 90%, 85%, 75%, and 55%, respectively. These rates further increased during the active treatment phase until week 12 to 85%, 85%, 85%, and 75%, respectively. Because of disease flares during the observation period, the response rate was decreased. An intention‐to‐treat analysis classified primary nonresponders and those who discontinued due to a disease flare or MAS as nonresponders. pedACR30/50/70/90 response rates at week 52 were 75%, 75%, 70%, and 70%, respectively (Figure 4). Data as observed are presented in Supplemental Figure 3.
Figure 4.
pedACR30, pedACR50, pedACR70, and pedACR90 response rates with nonresponder imputation (ITT population). Response rate was calculated in an ITT analysis, incorporating patients with primary nonresponse (n = 2) and also those who discontinued due to a disease flare (n = 2) or macrophage activation syndrome (n = 1) as nonresponders. ITT, intention‐to‐treat; PedACR, pediatric American College of Rheumatology.
Safety
Safety analyses encompassed 2.76 exposure and 18.1 follow‐up patient‐years. Ninety‐seven adverse events (AEs) were observed, including four serious AEs (SAEs). The most frequent AE belonged to infections and infestations’ SOC, followed by gastrointestinal and skin disorders (Table 2). The four SAEs were recorded in four patients with sJIA: one MAS event, one viral infection, and two sJIA flares. No clinically significant hypersensitivity reactions or anaphylaxis were observed, and no instances of gastrointestinal perforation, serious hepatic AEs, malignancy, myocardial infarction, opportunistic infections, or stroke occurred. There were no deaths. No Still disease–associated lung disease was observed at any time.
Table 2.
Number of AEs coded according to MedDRA SOC and LLTs)*
| SOC | n | LLT (if >1) |
|---|---|---|
| Blood and lymphatic system disorders | 2 | |
| Gastrointestinal disorders | 15 | Abdominal pain (5) and diarrhea (5) |
| General disorders and administration site conditions | 4 | Injection‐site discomfort (2) |
| Immune system disorders | 2 | |
| Infections and infestations | 36 | Upper respiratory tract infection (12), gastroenteritis (5), viral infection (5), rhinitis (4), and Coxsackie viral infection (2) |
| Injury, poisoning, and procedural complications | 4 | |
| Investigations | 2 | |
| Musculoskeletal and connective tissue disorders | 6 | Juvenile idiopathic arthritis flare (2) |
| Nervous system disorders | 4 | Headache (4) |
| Psychiatric disorders | 3 | |
| Reproductive system and breast disorders | 1 | |
| Respiratory, thoracic, and mediastinal disorders | 4 | Cough (4) |
| Skin and subcutaneous tissue disorders | 14 | Atopic dermatitis (7) and pruritus (2) |
LLT, Low‐Level Terms; SOC, System Organ Class.
DISCUSSION
Consistent with the EULAR consensus recommendations for JIA and the newer EULAR/PReS recommendations, the primary treatment target in sJIA or Still disease is clinical remission, defined as the absence of signs and symptoms of inflammatory disease activity, including extra‐articular manifestations. 15 Treatment targets in sJIA or Still disease include at least a 50% reduction in disease activity within four weeks and the achievement of inactive disease off glucocorticoids by six months.
In this study, early initiation of canakinumab in patients with sJIA or Still disease led to substantial improvements across individual disease activity measures, including arthritis, systemic manifestations, and laboratory markers of inflammation. Additionally, composite scores such as JADAS10, sJADAS10, and pedACR response criteria corroborated the high efficacy of this therapeutic approach.
In this study, the achievement of the therapeutic targets of inactive disease state and low disease activity, as proposed by Rosina et al, 32 was analyzed, although these criteria were published after the study commenced. Nevertheless, all data required to report sJADAS results, including body temperature, were available. Because this represents the first prospective trial to employ these criteria, we demonstrate their feasibility and ease of use in clinical studies. Baseline levels, improvement rates, and attainment rates for the treatment targets were comparable with those for other disease activity and outcome measures.
In Germany and across Europe, anakinra is approved for first‐line treatment of sJIA or Still disease, typically preceding glucocorticoid exposure; by contrast, canakinumab and IL‐6 inhibitors do not have first‐line approvals. Nevertheless, guidelines endorse all three therapeutic options. Registry data indicate real‐world use of these approaches, as reported by the Childhood Arthritis Rheumatology and Research Alliance (CARRA) registry and the German Biologika in der Kinderrheumatologie Register (BiKeR) group. 33 , 34 , 35
Initiation of canakinumab early in the disease yielded high response rates and improved both systemic manifestations and arthritis. At baseline, all patients exhibited active systemic features, and 15 (75%) had active arthritis. Only two patients showed primary nonresponse. This low rate does not allow meaningful analysis of patients’ characteristics with this outcome. However, one of the patients presented with a higher number of eight active joints, whereas in the other patient, no active arthritis was detected. Analyses of cellular and soluble biomarkers collected during the trial, together with gene activation and genetic analyses, are ongoing and may help explain why these patients did not respond.
The high response rate is very similar to that reported by the Dutch study in 2013 using anakinra for first‐line steroid‐free treatment for patients with sJIA. 19 Both cohorts were quite comparable regarding age, median number of active joints, and presenting systemic features such as rash and serositis. Although the ferritin levels were quite similar, only the median levels of CRP and ESR were higher in the Dutch cohort. Canakinumab, owing to its longer half‐life compared to anakinra, reduces the injection burden and may be especially advantageous in younger children. 18 In the present study, patients received a total of three injections only. Thus, injection‐site reactions were uncommon in contrast to daily anakinra injections as already described by Liu et al. 36
During the drug‐free observational phase, a small number of patients flared, and these events are being analyzed by ongoing laboratory studies. Overall, the majority of patients achieved inactive disease and remained flare‐free over the 40‐week observation period reported here with long‐term follow‐up planned through the German BiKeR registry.
The 2024 EULAR/PReS recommendations suggest that polycyclic and chronic forms of the disease may result from undertreatment and that early and effective treatment could enable tapering and discontinuation of all medications without disease relapse for several months. 15 A long‐term extension study proposed that an early response seemed to be a predictive factor of a good long‐term outcome, pointing to a “window of opportunity.” 35 These results are confirmed by our study performed in a limited number of patients.
The fact that infections were the most common AEs associated with canakinumab treatment is in line with the randomized clinical trials in which a higher rate of infection was observed in canakinumab‐treated patients. 18 In an open‐label trial, infections were also reported as the most common AEs. 36 , 37
Only a small number of SAEs occurred, all during the observational phase. Specifically, two JIA flares and one MAS event were observed, suggesting that a longer treatment duration than foreseen in the protocol may be necessary for some patients. In the Dutch cohort also, one patient of the cohort of 20 developed MAS and unfortunately died. Patients with sJIA or Still disease are at risk for MAS occurring at disease onset or during their disease course in up to 20% of cases. 38 Because signs of MAS were an exclusion criterion for our study and because the observation was limited to one year, the rate of MAS in our study seems low. Therefore, sJIA‐ or Still disease–associated lung disease is also less likely to occur in this cohort.
This investigator‐initiated study is limited by the rarity of sJIA or Still disease, resulting in a small sample size and limited observation time after discontinuation of the study drug. Consequently, we plan long‐term follow‐up of these patients through the BiKeR registry to extend observation periods.
Limitations include the open‐label nature of canakinumab treatment and the absence of formal statistical comparisons because all assessments were descriptive. A selection bias cannot completely be ruled out because recruiting to the study started at the end of 2020 or the beginning of 2021 (following an initiation visit) and was interrupted due to the COVID‐19 pandemic thereafter until 2022. By the end of 2022, 5 patients and, in 2023, 13 patients were recruited. In the largest center (Sankt Augustin), participation was offered to all patients diagnosed with sJIA without any recognizable bias.
In conclusion, a three‐month first‐line canakinumab regimen was effective in glucocorticoid‐naïve patients with early sJIA or Still disease. Consequently, canakinumab—in addition to anakinra—may constitute a viable first‐line option with comparable efficacy and a favorable overall benefit–risk profile. Future studies should explore the optimal timing of canakinumab initiation within the therapeutic course and assess infection surveillance strategies to address infection risk, a known adverse effect associated with this biologic agent.
AUTHOR CONTRIBUTIONS
All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Horneff confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.
ROLE OF THE STUDY SPONSOR
Novartis sponsored the trial financially, but has not had the legal role of the study sponsor. Here, GH was the sponsor/investigator with sponsor's resposibilities.
Supporting information
Disclosure Form:
Supplemental Figure 1. Consort Figure with patient disposition in the study.
Two non‐responders were withdrawn immediately. Eighteen patients continued the active treatment phase through week 12. One patient developed macrophage activation syndrome (MAS) at week 19 and was withdrawn before week 24. One patient developed a disease flare after week 24, and another after week 36, both leading to withdrawal. Fifteen patients continued into the 52‐week observational phase.
Supplemental Figure 2. Additional laboratory and clinical response parameter.
Courses of thrombocyte levels (A), haemoglobin level (B), patient global assessment of disease activity on a 10 cm VAS (C) and physician global assessment of disease activity on a 10 cm VAS (D) with 10 being the highest disease activity and 0 being no disease activity.
X: mean, error bars: standard deviation, line: median, box: interquartile range.
VAS visual analogue scale.
Supplemental Figure 3. PedACR paediatric American College of Rheumatology improvement criteria.
PedACR 30/50/70 and 90 response rate as observed. The number of patients at risk is given below the Figure.
ACKNOWLEDGMENTS
The authors thank all additional investigators for their participation in the study. ChatGPT was used for checking spelling and grammar.
EudraCT database no. 2018‐004284‐30.
The sponsor G.H. was involved in the study design, analysis and interpretation of data, critical review of the manuscript, and decision to submit the manuscript for publication. Novartis provided the study drug.
This work was supported by the Kinderrheumazentrum Sankt Augustin gGmbH and by Novartis.
Additional supplementary information cited in this article can be found online in the Supporting Information section (https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/acr2.90028).
Author disclosures are available at https://onlinelibrary.wiley.com/doi/10.1002/acr2.90028.
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Associated Data
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Supplementary Materials
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Supplemental Figure 1. Consort Figure with patient disposition in the study.
Two non‐responders were withdrawn immediately. Eighteen patients continued the active treatment phase through week 12. One patient developed macrophage activation syndrome (MAS) at week 19 and was withdrawn before week 24. One patient developed a disease flare after week 24, and another after week 36, both leading to withdrawal. Fifteen patients continued into the 52‐week observational phase.
Supplemental Figure 2. Additional laboratory and clinical response parameter.
Courses of thrombocyte levels (A), haemoglobin level (B), patient global assessment of disease activity on a 10 cm VAS (C) and physician global assessment of disease activity on a 10 cm VAS (D) with 10 being the highest disease activity and 0 being no disease activity.
X: mean, error bars: standard deviation, line: median, box: interquartile range.
VAS visual analogue scale.
Supplemental Figure 3. PedACR paediatric American College of Rheumatology improvement criteria.
PedACR 30/50/70 and 90 response rate as observed. The number of patients at risk is given below the Figure.