Adult-onset Still disease (AOSD) is a rare multisystem autoinflammatory disorder of unknown etiology that is clinically characterized by 4 cardinal signs: fever of unknown origin, arthralgia or arthritis, hyperleukocytosis, and a typical salmon-colored skin rash.1 It was first described in 1971 in 14 patients who presented with clinical symptoms and laboratory findings that were similar to those of juvenile Still disease, which had been defined nearly a century earlier. Now known as systemic-onset juvenile idiopathic arthritis (SJIA), the 2 conditions share clinical and biological similarities.2 Although it is still debated whether AOSD and SJIA belong to the same continuum of disease, evidence indicates that they are one and the same. The clinical presentation of AOSD at diagnosis strongly suggests that there are 2 distinct phenotypes: one that is highly symptomatic and evolves into a systemic (monocyclic or polycyclic) condition and one that is more indolent, with arthritis as a prominent symptom, and evolves into a chronic articular disease pattern.2,3 The systemic form demonstrates a major proinflammatory state compared with the articular phenotype, indicating distinct serologic profiles for each of the 2 subtypes.4

Incidence and Prevalence

Given the broad nonspecific clinical presentation of AOSD, its prevalence and incidence have been difficult to ascertain. AOSD is often undiagnosed or misdiagnosed because of its highly variable symptoms and rarity, making determination of its true frequency in the general population a challenge. Most of the information about this disorder is based on data from retrospective observational studies or case series.5 Studies suggest that the annual incidence of AOSD was 0.62 per 100,000 individuals in Turkey and the 5-year incidence was 0.16 per 100,000 individuals in France, independent of ethnicity. The estimated prevalence is between 0.73 and 6.77 per 100,000 individuals.6-9 Increased awareness about the disease during the past 2 decades may account for the higher incidence and prevalence rates reported in more recent studies.5

Young adults are primarily affected by AOSD. Although the mean age at diagnosis is approximately 38 years (range, 33.3-45.0 years), delayed diagnosis is common due to nonspecific symptoms and the lack of awareness of AOSD among both the medical community and general population.5 There tend to be 2 peaks of onset, with the first affecting individuals aged 16 to 25 years and the second affecting individuals aged 36 to 46 years. Approximately 45% to 80% of patients experience disease onset between the ages of 16 and 35 years.5 The male-to-female ratio appears almost equal in internal medicine case series; however, women represent up to 70% of cases in rheumatologic case studies.10



Challenges in Management

Treatment for AOSD is focused on managing symptoms to prevent complications with the goal of achieving complete remission and preventing joint damage. Although some patients achieve remission, relapse remains a lifetime risk. Few studies have focused on prognostic factors.10 AOSD is characterized by multivisceral involvement and life-threating complications, such as reactive hemophagocytic lymphohistiocytosis, can occur in 12% to 17% of patients with AOSD.2,11

No standard or internationally recognized guidelines for the management of Still disease currently exist. Treatment is primarily empirical and can be challenging for physicians. Few clinical trials are available due to the relative rarity of the disease, and management of AOSD varies widely depending on the clinical presentation.5 To help fill the void, Japan’s Ministry of Health developed clinical practice guidelines in 2017, with the main limitation being the small number of global reports available with high-quality evidence.12 A panel of experts from Italy also developed recommendations for managing patients with AOSD with interleukin (IL)-1 inhibitors and concluded that the literature supports their use in this setting.4



First-Line and Second-Line Treatments

Nonsteroidal Anti-Inflammatory Drugs and Corticosteroids

Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the first agents that most patients with AOSD receive following a diagnosis. However, treatment with NSAIDS alone is rarely effective, and approximately 20% of patients receiving NSAIDs alone experience adverse events.13,14 Some clinicians recommend that NSAIDs be reserved only for symptomatic relief in early Still disease and combined as soon as possible with systemic therapies and/or used as a supportive treatment during the diagnostic process.10,14,15 NSAIDs can also be used during a diagnostic workup for patients who have a monocyclic course of AOSD without major systemic or articular involvement and for those with isolated mild articular involvement. High-dose indomethacin (150 to 200 mg daily) is preferred in those situations.2

Although corticosteroids remain the first-line treatment for AOSD regardless of the clinical presentation, there is increasing evidence that certain biologics should be used earlier during the treatment trajectory because they allow for a rapid tapering of prednisone, preventing steroid-induced complications.2 Steroid therapy controls symptoms in approximately 65% of patients, with even higher rates observed in patients without chronic articular disease (78%).14 Patients who fail to respond to steroid therapy at the time of disease onset appear to be at risk of developing chronic arthritis.14 Patients with serious visceral involvement have responded quickly to high-dose intravenous methylprednisolone.10 However, an estimated 42% to 45% of patients become steroid-dependent.13,15

Disease-Modifying Antirheumatic Drugs and Intravenous Immunoglobulin

Although the use of NSAIDs and corticosteroids generally can achieve remission in patients presenting with the monocyclic pattern of AOSD, the polycyclic systemic pattern or chronic arthritis is more difficult to treat and may require further therapy with conventional immunosuppressants and/or biologic drugs. Methotrexate remains the first-line steroid-sparing treatment in AOSD; it can lead to complete remission in approximately 70% of patients and potentiate corticosteroid weaning.2,10,16 Other disease-modifying antirheumatic drugs (DMARDs) have been used in this setting, including cyclosporine A, leflunomide, azathioprine, hydroxychloroquine, D-penicillamine, and tacrolimus. Efficacy of these agents has been inconsistently reported in retrospective studies and case reports.2,10

Data on the use of intravenous immunoglobulin (IVIG) are more limited, with a few retrospective case series reporting that between 4% and 43% of patients with AOSD have received IVIG during the disease course.10 In one study, IVIG was prescribed significantly more often in patients with nonmonocyclic, complicated, and steroid-dependent AOSD,14 while an older randomized, open-label trial showed some efficacy when IVIG was used early in the course of the disease.2 One indication for its use is in the event of reactive hemophagocytic lymphohistiocytosis and other serious/life-threatening complications, or in case of a flare-up of AOSD occurring during pregnancy.2

Targeted Biologic Therapies

Approximately 17% to 32% of patients with AOSD have refractory disease that is resistant to both first-line corticosteroids and second-line DMARDs.17 The advent of targeted biologic treatments in rheumatic diseases has changed the management of AOSD and offers new options, especially in the setting of refractory disease. However, most of the agents that fall under this broad category of therapeutics have not been specifically approved for use in AOSD and are administered off-label.

IL-1 Inhibition

The US Food and Drug Administration (FDA) approved canakinumab injection for the treatment of AOSD in June 2020.18  Canakinumab, a fully human antibody against IL-1β, is the first approved drug for AOSD in the United States, although it previously received regulatory approval for SJIA in patients 2 years of age and older. It has also been approved for AOSD in Europe.

The phase 2 randomized, placebo-controlled CONSIDER trial (ClinicalTrials.gov Identifier: NCT02204293) investigated the efficacy and safety of canakinumab in patients with AOSD and active joint involvement. The primary endpoint was the proportion of patients with a clinically relevant reduction in disease activity at week 12, as determined by the change in disease activity score.19 In the per-protocol analysis, the canakinumab group had significantly higher American College of Rheumatology (ACR) 30% (61% vs 20%, P =.033), ACR 50% (50% vs 6.7%, P =.009), and ACR 70% (28% vs 0%, P =.049) response rates compared with the placebo group. The study was terminated early and the primary endpoint was not achieved, but treatment with canakinumab still led to improvement in several outcome measures in AOSD. The safety profile was similar to that previously reported in SJIA, and no unexpected safety issues were observed.

Anakinra, a recombinant inhibitor of the IL-1 receptor, is approved in Europe and has been found to be an effective biologic agent for the treatment of AOSD, especially for the systemic pattern and for patients experiencing life-threatening complications.20 Benefits of therapy with anakinra have been reported in many case reports, case series, small trials, and national surveys.21,22 A meta-analysis that included more than 130 patients showed an overall remission rate of 82%, a complete remission rate of 67%, and an overall frequency of steroid discontinuation of 37%.22 The only randomized study was conducted in 22 patients with refractory AOSD and it compared the efficacy of anakinra vs that of DMARDs. The investigators found that at the end of a 28-week extension period, 7 of 14 patients treated with anakinra and 2 of 3 patients treated with DMARDs achieved remission.23

A randomized, double-blind, placebo-controlled trial assessed the efficacy and safety of rilonacept, an IL-1 inhibitor, in 71 children with SJIA.24 The primary endpoint was time to response during the 12-week efficacy period as defined by time to achieve the composite endpoint of an ACR Pediatric 30 (ACR Pedi 30) response, absence of fever, and corticosteroid taper (for patients receiving corticosteroids). Time to response was shorter in the rilonacept arm (median, 4 weeks) than in the placebo arm (median, 8 weeks; P =.007). By week 12, the investigators found 77% (n=27/35) of patients receiving rilonacept continuously from trial onset and 59% (n=20/35) of patients receiving placebo for the initial 4 weeks met the primary endpoint of response.

A major reported benefit of IL-1 inhibition has been its ability to enable patients to stop or reduce the use of steroids. In a literature review, investigators reported on a study in which rapid and sustained control of systemic symptoms, good efficacy at treating joint symptoms, and very few adverse events were associated with rilonacept use.21 Those investigators reported on another study in which anakinra was associated with a 37% reduction in the frequency of steroid use. Overall, 88% of patients were able to stop or reduce steroids after using any of the evaluated IL-1 inhibitors.21 IL-1 inhibitors can interrupt disease progression even in patients who have experienced prolonged refractory disease, suggesting that it may be possible to shorten flares and avoid chronic relapses and long-term damage in this setting.

Tumor Necrosis Factor Inhibition

Tumor necrosis factor (TNF) inhibitors, including infliximab and etanercept, were the first biologic agents used for the treatment of AOSD. Results from uncontrolled trials, generally comprising small cohorts, have been inconsistent.3 A study evaluating infliximab in patients with refractory disease found that it may be helpful for some patients, although most patients who responded to therapy achieved only a partial remission.25 Some clinicians have suggested that TNF inhibitors should be considered only as third-line therapy, preferentially for patients with chronic arthritis.3,26

IL-6 Inhibition

Levels of IL-6 are significantly elevated in both serum and cutaneous lesions in patients with active AOSD. IL-6 is considered a suitable target for the treatment of refractory AOSD. Two IL-6 inhibitors, tocilizumab and sarilumab, have been investigated in this setting in varying degrees. Tocilizumab has been studied in systemic and articular AOSD, with some promising results showing symptom improvement. A 2018 meta-analysis that included 147 patients reported overall partial and complete remission rates of 85.38% and 77.91%, respectively, with a remission rate of 87.92% in patients with refractory disease.27 Another retrospective study with a cohort of 40 patients found that the use of tocilizumab prevented relapse of AOSD. In 10 patients with refractory or relapsing disease, none experienced a relapse following treatment with tocilizumab.28

Sarilumab has not been well studied in AOSD. It was reported to improve symptoms in a patient with corticosteroid-dependent AOSD.29 A post-hoc analysis of the ASCERTAIN EXTEND trial (ClinicalTrials.gov Identifier: NCT01146652), conducted in patients with rheumatoid arthritis, suggested that switching patients from tocilizumab to sarilumab may improve outcomes if patients are not responding to tocilizumab.30 Data are scant for other IL-6 inhibitors in this setting, and advantages or disadvantages that distinguish IL-6 and IL-1 inhibition in the treatment of AOSD are unclear.26

IL-18 Inhibition

Tadekinig alfa, a recombinant human IL-18 binding protein, demonstrated potential effectiveness and an acceptable safety profile in a phase 2, open-label, multicenter European study (ClinicalTrials.gov Identifier: NCT02398435).31 In this study, which was the first to evaluate an IL-18-blocking agent in AOSD, patients were assigned to receive either 80 mg or 160 mg of tadekinig alfa. A total of 155 treatment-emerging adverse events were recorded, with 47 considered related to the study drug. Most of these events were mild and resolved after the drug was stopped. There were early signs of efficacy in AOSD, and the study authors noted that further clinical investigation is warranted.

Janus Kinase Inhibitors

Janus kinase (JAK) inhibitors block the proinflammatory effect of a wide range of cytokines, and this broad range of activity can potentially benefit patients with AOSD  who are intolerant of or with disease refractory to treatment with biologics.3 Tofacitinib suppresses macrophage inactivation and function, and inhibits the effect of IL-6, IL-10, interferon-γ, interferon-α, and granulocyte macrophage-colony stimulating factor (GM-CSF). In a study assessing the efficacy of tofacitinib in 14 patients with refractory AOSD, 7 achieved complete remission and 6 achieved a partial remission.32 In addition, tofacitinib had a steroid-sparing effect, particularly in patients with the articular phenotype.



Unmet Needs

Advances have been made to understand the pathogenesis of AOSD, and new therapeutics have become available. However, important unmet needs must still be addressed.5,21

  • Canakinumab is the only FDA-approved biologic for AOSD in the United States. In Europe, both canakinumab and anakinra have regulatory approval. More targeted therapies are needed for AOSD.
  • The high efficacy of anti-IL-1 agents in AOSD suggests that their use in early treatment may allow many disease- and drug-related complications to be avoided. Biologics are usually reserved for patients with AOSD that fails to respond to therapy with conventional DMARDs. Further research is needed to assess if early biologic therapy leads to better patient outcomes and alters the natural history of AOSD.
  • A targeted treatment approach is needed that aims for comprehensive disease control (articular and systemic manifestations) and prevention of complications and chronic, irreversible disability.
  • There is a lack of well-designed randomized controlled trials reporting efficacy and safety data to inform and update guidelines on the clinical management of AOSD. No standardized international guidelines exist.
  • Significant gaps remain regarding the role of genetics and/or biomarkers in AOSD and the potential impact on approaches to treatment.
  • Data are limited regarding the epidemiology and associated mortality of AOSD, as well as the associated disease burden and direct economic burden.

References

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30. Emery P, van Hoogstraten H, Thangavelu K, Mangen E, St John G, Verschueren P. Subcutaneous sarilumab in patients with rheumatoid arthritis who previously received subcutaneous sarilumab or intravenous tocilizumab: an open-label extension of a randomized clinical trial. ACR Open Rheumatol. 2020;2(11):672-680. doi:10.1002/acr2.11188

31. Gabay C, Fautrel B, Rech J, et al. Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still’s disease. Ann Rheum Dis. 2018;77(6):840-847. doi:10.1136/annrheumdis-2017-212608

32. Hu Q, Wang M, Jia J, et al. Tofacitinib in refractory adult-onset Still’s disease: 14 cases from a single centre in China. Ann Rheum Dis. 2020;79(6):842-844. doi:10.1136/annrheumdis-2019-216699

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Reviewed February 2022