The Use of Canakinumab, a Novel IL-1β Long-Acting Inhibitor, in Refractory Adult-Onset Still's Disease

doi:10.1016/j.semarthrit.2012.03.004

Seminars in Arthritis and Rheumatism

Volume 42, Issue 2, October 2012, Pages 201-205

https://doi.org/10.1016/j.semarthrit.2012.03.004 Get rights and content

Objectives

We describe the successful treatment of adult-onset Still's disease (AOSD) with canakinumab, a novel anti-interleukin (IL)-1β, long-acting, monoclonal antibody, on patients refractory to anakinra and rilonacept. In many cases the expected positive therapeutic effect of short-acting IL-1 inhibitors is transient or completely absent, leading to our hypothesis that their short half-life may be associated with incomplete IL-1 blockade, given the cyclic nature of the disease.

Methods

We report 2 cases of AOSD resistant to short-acting IL-1 blockade, which were subsequently treated with canakinumab. A retrospective chart review was conducted of patients diagnosed with AOSD in our regional referral center.

Results

Response to treatment was assessed by its effect on the systemic symptoms (resolution of fever and rash), polyarthritis (using the disease activity score 28--C-reactive protein score), and the levels of serum ferritin. Canakinumab demonstrated sustained efficacy in both patients as evidenced by clinical and laboratory parameters with minimal adverse reactions.

Conclusions

This is the first documented report of successful use of canakinumab, a novel IL-1β inhibitor, in AOSD patients refractory to traditional disease-modifying antirheumatic drugs and short- to moderate-acting IL-1 blockade. Prospective comparative studies are needed to validate canakinumab's efficacy and safety.

Section snippets

Case 1

The patient is a 38-year-old Hispanic man who presented with a sore throat, daily spiking fevers for a week, bilateral elbow, knee, and ankle arthritis along with a centripetal maculopapular, nonpruritic rash that spared the face. He was admitted for further evaluation of pyrexia (40°C), hypotension (93/64), and tachycardia (116 bpm). Physical examination was remarkable for generalized erythematous rash, polyarticular synovitis, and hepatosplenomegaly. Laboratory parameters revealed elevated

Discussion

To our knowledge, this is the first published report to demonstrate the efficacy of canakinumab, the longest acting IL-1 inhibitor currently, in refractory AOSD patients who are either corticosteroid-dependent, resistant to traditional disease-modifying antirheumatic drugs (DMARDs), or partially responsive to shorter acting IL-1 inhibitors such as anakinra and rilonacept. Canakinumab is a recombinant, fully humanized monoclonal antibody, which selectively blocks IL-1β signaling and is currently

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Cited by (82)

Efficacy and safety of canakinumab in the treatment of adult-onset Still's disease: A systematic review
2021, Seminars in Arthritis and Rheumatism
Citation Excerpt :
Contrastingly, no statistical significance was reached in the differences reported for the canakinumab and placebo arms in ESR and serum CRP levels (ITT analysis), nor for serum ferritin levels (per-protocol [PP] analysis) in the RCT [57]. Concerning disease activity scores, four studies reported a reduction in one of the following indexes at the end of follow-up: DAS28 [43], DAS28(CRP) [50,58], and DAS28(ESR) [47]. Besides, Kontzias & Efthimiou [43] determined an American College of Rheumatology (ACR) response of 70% at the end of monitoring in both patients, while Feist et al. [50] found that more than half of the participants presented aACR pediatric responses and JIA ACR responses ≥ 70% (72.2% and 66.7%, respectively).
Adult-onset Still's disease (AOSD) is a rare inflammatory disease, typically characterized by spiking fever, skin rash, and arthralgia or arthritis. Its conventional treatment includes NSAIDs and corticosteroids, and DMARDs as second-line therapy. Frequently, IL-1 inhibitors are also required, mainly in patients refractory to traditional therapy. Canakinumab is a monoclonal antibody that binds IL-1β with high affinity and specificity, making it appropriate for therapeutic purposes in AOSD.
The aim of this systematic review was to identify and compile the current data on the efficacy and safety of canakinumab in the treatment of AOSD.
Following the guidelines established by the PRISMA statement, we searched Scopus, Web of Science, Pubmed, and Cochrane Library for relevant literature up to March 2021. The inclusion criteria comprised: randomized controlled trials, pooled analyses, observational studies, case series, and case reports.
Seventeen studies published from 2012 to 2021 were evaluated; 11 of these correspond to case series or case reports, four observational studies, one placebo-controlled phase II trial, and one analysis of pooled systemic juvenile idiopathic arthritis data. In general, out of a total of 99 patients, 68.7% of these presented a complete remission of the systemic and arthritic manifestations at the end of the observation period, while 16.2% of the patients showed a partial improvement of the symptoms and the remaining (15.1%) did not show clinical improvement or were excluded. Moreover, 210 adverse events were reported in 69 patients during canakinumab treatment, of which the majority correspond to respiratory tract infections, arthralgia, disease flares, abdominal pain, nausea, and diarrhea, whereas the most common severe adverse events included macrophage activation syndrome and serious infections. Also, a corticosteroid-sparing effect was observed in a large percentage of patients.
More studies with solid evidence are needed to support the efficacy of canakinumab in AOSD, although its use is encouraged by the increasing favorable results reported and the efficacy of other IL-1 inhibitors. It was also associated with an acceptable safety profile, similar to expected in IL-1 inhibitor therapy. However, future studies with well-defined endpoints are warranted to examine further the usefulness of canakinumab in AOSD.
Outcome of refractory to conventional and/or biologic treatment adult Still's disease following canakinumab treatment: Countrywide data in 50 patients
2021, Seminars in Arthritis and Rheumatism
Citation Excerpt :
Whether in some instances MAS is an adverse paradoxical effect of IL-1 inhibition, is unknown so far. Weaning from steroids was possible in at least half of treated patients (51%) vs. 21%, cumulatively, in previously published cases [9,10–13,17,18]. Moreover, 18% of our patients did not require any corticosteroid therapy during the whole follow-up.
To assess the efficacy and safety of the IL-1b inhibitor canakinumab in all adults with refractory Still's disease identified from the National Organization For Medicines for off-label drug use.
: In a retrospective longitudinal multicenter cohort of 50 patients (median age 39 years) with active Still's disease despite treatment with corticosteroids (n = 11), conventional and synthetic (n = 34) and/or biologic disease modifying anti-rheumatic drugs (n = 30), we assessed the efficacy of canakinumab 150–300 mg administered every 4 (n = 47) or 8 weeks (n = 3) as combination therapy or monotherapy (n = 7) during a median follow-up of 27 (3–84) months.
Α complete response was initially observed in 78% of patients within 3 months (median), irrespective of age at disease onset. A partial response was evident in 20%. One patient had resistant disease. Treatment de-escalation was attempted in 15 of 39 complete responders and a complete drug discontinuation in 21 patients for 8 months (median). Eleven patients (22%) relapsed during treatment, one during de-escalation process, and 11 after treatment discontinuation. Overall, 9 of 11 relapses were successfully treated with canakinumab treatment intensification or re-introduction. At last visit, 18% of patients were off treatment due to remission and 26% due to disease activity. Canakinumab had a significant corticosteroid sparing effect allowing weaning in 21 of 41 cases. Infections (20%, severe 4%) and leucopenia (6%) led to treatment cessation in one patient.
High rates of sustained remission were observed in this, largest so far, real-life cohort of adult patients with refractory Still's disease treated with canakinumab.
Role of the NLRP3 inflammasome in autoimmune diseases
2020, Biomedicine and Pharmacotherapy
NOD-like receptor family pyrin domain containing 3 (NLRP3) is an intracellular receptor that senses foreign pathogens and endogenous danger signals. It assembles with apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1 to form a multimeric protein called the NLRP3 inflammasome. Among its various functions, the NLRP3 inflammasome can induce the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 while also promoting gasdermin D (GSDMD)-mediated pyroptosis. Previous studies have established a vital role for the NLRP3 inflammasome in innate and adaptive immune system as well as its contribution to several autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), systemic sclerosis (SSc), and ankylosing spondylitis (AS). In this review, we briefly introduce the biological features of the NLRP3 inflammasome and present the mechanisms underlying its activation and regulation. We also summarize recent studies that have reported on the roles of NLRP3 inflammasome in the immune system and several autoimmune diseases, with a focus on therapeutic and clinical applications.
A comprehensive review on adult onset Still's disease
2018, Journal of Autoimmunity
Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown etiology usually affecting young adults; spiking fever, arthritis and evanescent rash are commonly observed during the disease. Other frequently observed clinical features include sore throat, hepatomegaly, splenomegaly, lymphadenopathy and serositis. Furthermore, AOSD patients may experience different life-threating complications. Macrophage activation syndrome (MAS) has been reported up to 15% of AOSD patients and it is considered to be the most severe complication of the disease being characterised by high mortality rate. During AOSD, laboratory tests reflect the systemic inflammatory process showing high levels of erythrocyte sedimentation rate and C-reactive protein. In addition, the ferritin levels are typically higher than those observed in other autoimmune, inflammatory, infectious, or neoplastic diseases. Analysing AOSD disease course, 3 different clinical patterns of AOSD have been identified: i. monocyclic pattern, characterised by a systemic single episode; ii. polycyclic pattern, characterised by multiple, ≤ 1 year lasting, flares, alternating with remissions; iii. chronic pattern, related to a persistently active disease with associated polyarthritis. At present, AOSD therapeutic strategy is aimed at targeting pro-inflammatory signs and symptoms, preventing organ damage and life-threating complications and minimising adverse effects of treatment. However, the treatment of AOSD remains largely empirical, lacking controlled clinical trials. High dosages of corticosteroids are usually the first line therapy when the systemic symptoms predominate. Despite this treatment, a large percentage of patients experiences several flares with an evolution toward the chronic disease course and up to 16% of patients die during the follow up, due to AOSD-related complications. On these bases, in the last years, biological agents have been successfully used in refractory cases. Finally, multiple recent lines of evidence have suggested new insights in AOSD pathogenesis unmasking further therapeutic targets. In fact, small molecules, used in experimental MAS models, might represent new therapeutic options.
Clinicopathologic Features of Adult-onset Still’s Disease Complicated by Severe Liver Injury
2024, Internal Medicine
Pyroptosis: the potential eye of the storm in adult-onset Still’s disease
2023, Inflammopharmacology

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MiscellaneousThe Use of Canakinumab, a Novel IL-1β Long-Acting Inhibitor, in Refractory Adult-Onset Still's Disease

Objectives

Methods

Results

Conclusions

Section snippets

Case 1

Discussion

Eur J Intern Med

Semin Arthritis Rheum

Joint Bone Spine

Autoinflammatory syndromes and infections: Pathogenetic and clinical implications

Clin Exp Rheumatol

Adult-onset Still's disease: Can recent advances in our understanding of its pathogenesis lead to targeted therapy?

Nat Clin Pract Rheumatol

Adult-onset Still's disease: Pathogenesis, clinical manifestations and therapeutic advances

Drugs

Successful treatment of adult-onset Still's disease with tocilizumab monotherapy: Two case reports and literature review

Clin Rheumatol

Rilonacept and canakinumab

Br J Clin Pharmacol

Use of canakinumab in the cryopyrin-associated periodic syndrome

N Engl J Med

Clinical features and prognosis in adult-onset Still's disease: A study of 104 cases