The Still syndrome in childhood and adulthood

In 1896, a form of chronic infantile rheumatism was first noted in which symptoms of massive general inflammation were present in addition to arthritis. The disease was long referred to as Still’s syndrome or Still’s disease and was classified as a form of juvenile arthritis. With the classification of Juvenile Idiopathic Arthritis (JIA), the disease was classified as Systemic JIA (SJIA). Many children have SJIA without arthritis, called juvenile still syndrome (jSD). The article provides an overview of the infantile and adult forms of Still’s syndrome.

In 1896, the English pediatrician Georg Frederic Still described for the first time a form of chronic infantile rheumatism in which, in addition to arthritis, there were also symptoms of massive general inflammation [1]. The disease was long referred to as Still’s syndrome or Still’s disease and was classified as a form of juvenile arthritis. With the classification of Juvenile Idiopathic Arthritis (JIA) by ILAR [2], the disease was classified as Systemic JIA (SJIA). Many children have SJIA without arthritis; we then refer to it as juvenile Still ‘s disease ( jSD) [3]. Despite isolated case reports, it was not until 1971 that a systematic description of adult onset Still’s disease ( AOSD) was published by the English rheumatologist E.G.L. Bywaters [4].

SJIA, jSD as infantile forms, and AOSD have other differences in addition to different times of initial manifestation, but share many similarities. This summary provides an overview of the infantile and adult forms of Still’s syndrome.

Pathogenesis

SJIA and AOSD are distinguished from the other inflammatory arthritides by the fact that, according to current pathogenetic understanding, the autoinflammatory component is more prominent than the autoimmune component. Historically, SJIA, like all other subtypes of JIA, has been classified as rheumatic diseases of childhood and adolescence in the autoimmune group. However, SJIA is now understood to be an autoinflammatory disease [5]. “Autoinflammatory” diseases ( AID) are usually the result of malfunctions of the innate immune system. Many AIDs have monogenetic causes, i.e. they are based on mutations of one of the genes encoding proteins or regulatory factors in proinflammatory signal transduction pathways of the innate immune system. Monogenic autoinflammatory diseases: here, a monogenetic dysregulation of the IL-1 signaling pathway may be causative. These include cyropyrin-associated periodic syndromes (CAPS) [6,7], familial Mediterranean fever (FMF) [7,8], and mevalonate kinase deficiency (MKD) [9]. Other pathomechanisms are found in tumor necrosis factor receptor-associated periodic syndrome (TRAPS) [10] or deficiency of IL-1 receptor antagonist (DIRA) [11].

The placement of SJIA and AOSD with AID is based primarily on three key observations:

during active disease phases, a significantly increased activation of genes is observed, which either have an amplifying effect on the IL-1 pathway or result in an activation of macrophages or granulocytes [12].

the protein S100A12 as a marker for an activation of macrophages and granulocytes is found significantly increased [13,14].

Drugs that block the IL-1 pathway, or drugs directed against IL-6 or its receptor, are therapeutically successful, whereas therapeutics, such as TNF-alpha inhibitors, that are successful in RA or other forms of JIA are usually insufficiently effective.

Clinical picture & diagnostics

In Germany, epidemiological data are only available for SJIA. According to this, the incidence of JIA is about 16.5/100 000/y. [15], of which approx. 5% are cases with SJIA, which corresponds to a number of approx. 80 new cases annually. The peak age of SJIA is between 2 and 4 years of age [5]. In Japan, SJIA has a much higher proportion of all JIA patients, accounting for approximately 50% of cases [16]. Incidence figures for adult AOSD sufferers are not available for Germany, however, according to data from France and Norway, the incidence compared to SJIA is likely to be significantly lower at 0.16-0.4/100 000/year [17]. Overall, therefore, within the rheumatoid arthritides in children and in adults, these are rather rare disease patterns. Typical features of SJIA and AOSD are the usually simultaneous occurrence of 1. arthralgias or arthritis, 2. intermittent, high (fever spikes, “spiking fever”) and 3. a mostly salmon-colored, volatile exanthema (Fig. 1B). Joint involvement preferentially affects large joints and often has a destructive course if untreated (Fig. 1A). In addition, there is often generalized lymphadenopathy, hepato- and/or splenomegaly (Fig. 1B+D). Especially in cases of high activity of Still’s syndrome, complicating organ manifestations may occur, which in some cases considerably worsen the prognosis: In life-threatening macrophage activation syndrome (MAS), a cytokine storm with consecutive activation of macrophages results in hemophagocytosis of hematopoietic stem cells in the bone marrow with persistent fever and multiple organ failure, incl. Neurological Symptoms [18]. Cardiac involvement usually manifests as pericarditis (Fig. 1C), and less commonly myocarditis, tamponade, or noninfectious endocarditis [19]. Pulmonary involvement in Still’s syndrome can be multifaceted and therefore present problems in differentiating it from infections and interstitial lung disease in particular [20]. Sytemic amyloidosis is rarely observed, usually in association with prolonged, uncontrolled disease activity [3,5,21–24].

Regarding laboratory diagnostics, there are no specific parameters for either SJIA or jSD and AOSD. In contrast to other rheumatologic diseases with arthritis, the anti-nuclear antibodies (ANA) that are frequently positive in JIA are absent, as are the rheumatoid factors (RF) typical of rheumatoid arthritis. This is congruent with the findings on pathogenesis. However, later in the course of the disease, autoantibodies (ANA and IgM-Rf) may also appear in patients with SJIA [25]. In addition to an increase in general inflammatory parameters (ESR, leukocytosis), high initial ferritin levels are observed, especially in AOSD: usually ≥ 5 times the upper normal value. Nevertheless, even at this threshold, the specificity for an AOSD is only around 50% [26], so other causes of hyperferritinemia must be considered for differential diagnosis, especially malignancies and infections [27]. In both children and adults, rapidly increasing or excessively high levels of ferritin should be considered MAS [28]. The protein S100A12, a marker of macrophage and granulocyte activation, is of interest as a laboratory value in two ways. On the one hand, the extremely high levels for this protein indicate the autoinflammatory genesis of all three disease patterns, and on the other hand, this protein seems to be a relevant biomarker for both SJIA, jSD and AOSD [13,14]. In contrast to the situation in children, however, this parameter has so far no consensual value in the diagnosis of the adult form due to insufficient validation [30,31]. Many other biomarkers have been insufficiently validated [13]. Increasingly, however, there are signs that in childhood and adulthood the determination of serum IL-18 may allow a more specific diagnosis of Still’s syndrome, e.g., also in the differentiation from sepsis [29]. However, the availability of the determination is limited in routine care.

The diagnosis of Still’s syndrome is therefore based on a characteristic constellation of symptoms in combination with elevated inflammatory parameters in children according to a consensus recommendation of a group of experts as well as in adults according to the recommendations of the guideline [3,9,30] under the condition that alternative causes are excluded. Important differential diagnoses include infections and malignancies, hereditary autoinflammatory syndromes (more common in childhood), and alternative rheumatologic diseases (Table 1).

Therapy & Prognosis

By the mid-20th century, the mortality of infantile Still’s syndrome was over 40% of cases. Only the introduction of corticosteroids into therapy [30] reduced lethality. Patients with SJIA were also the first pediatric rheumatology cases to receive therapy with methotrexate [31]. The treatment of AOSD was guided by the therapy of SJIA. Separate protocols involving cyclosporin A have been developed for the therapy of MAS [32]. Nevertheless, before the introduction of interleukin-inhibiting therapies, mortality in children and adults with Still’s syndrome exceeded 10%. Then, in the early 2000s, successful therapies were introduced in SJIA using the recombinant IL-1 receptor anatgonist anakinra [33] and the monoclonal antibody tocilizumab [34] directed against the IL-6 receptor. Systemic corticosteroids remain an essential component of therapy during the initial phase. As described above, diagnostic certainty is limited in the initial manifestation of all three diseases due to the lack of specific parameters. Nevertheless, therapy protocols that already initially use the recombinant IL-1 receptor antagonist anakinra to save steroids have become established in recent years [35]. Evidence-based consented treat-to-target therapy protocols from the Society for Childhood and Adolescent Rheumatology (GKJR) are now available for SJIA and childhood Still’s syndrome [3].

For AOSD, systemic glucocorticoids are recommended as acute therapy according to the guidelines. Methotrexate or calcineurin inhibitors (usually cyclosporine A) are suggested for glucocorticoid sparing when disease activity is low, and anakinra, canakinumab, or tocilizumab are suggested with increasing activity or failure of conventional therapies. Anakinra and canakinumab can also be used as first-line therapy in cases of high disease activity. EMA approval in Europe for AOSD currently exists only for anakinra (after glucocorticoid and NSAID failure, alternatively beforehand in moderate to high disease activity) and canakinumab (after glucocorticoid and NSAID failure), but in contrast to the situation with SJIA, not for tocilizumab.

The German Society for Rheumatology (DGRh) published a corresponding S2 guideline [23,24,36]. Generally, a staged approach is recommended in children and adults based on the current clinic, inflammatory laboratory, and comorbidities. The goal of treatment is to achieve remission while using steroid-containing drugs as sparingly as possible.

Differences of juvenile and adult Still syndrome.

By most experts, the juvenile and adult forms of Still’s syndrome are considered to be a disease continuum with different phenoytpic manifestations [30]. This is supported in particular by comparable genetic risk constellations, very similar clinical presentation except for individual domains. and a comparable therapeutic response to interleukin or corresponding receptor blockades, which in turn could indicate the same pathogenesis [37]. However, differences are also known; for example, the sex ratio in SJIA is balanced, whereas in AOSD, two-thirds of the patients are women. Other differences may be explained by a more immature immune system in children compared to adults, e.g., the strong seasonal clustering in the colder months (infectious triggers?) and the clustering of a chronic course (more aggressive disease with earlier onset and severe course?) in the juvenile form [37]. Differences in clinical presentation are also observed; for example, pharyngodynia are so characteristic of a first manifestation in adulthood (approximately 60% of cases) that they have found their way into the Yamaguchi classification criteria, but in childhood they are present in only 10% of cases [38]. In terms of joint involvement (Fig. 2) , the hip and cervical spine are a significant problem in children, accounting for 32% and 24%, respectively, whereas these joints are affected in less than 2% of adults [39]. In SJIA, there is also evidence of an autoimmune event, which seems to become increasingly relevant, at least during the course of the disease. Here, the association with the HLA system [40], the course as polyarthritis with development of autoantibodies [25], the activation of Th1 and Th17 cells and functional deficits of regulatory T cells should be mentioned [41]. Apparently, therefore, the adaptive immune system can be engaged during the course of the disease, which then also brings about changes with regard to the disease-maintaining signaling pathways [42]. The therapeutic consequences have not been adequately investigated at present.

Regarding therapy, major differences between SJIA and AOSD exist in the level of evidence and in the approval situation [23,24]: For example, while RCTs with successful primary endpoints are available for the SJIA-approved options methotrexate, NSAIDs, tocilizumab, anakinra, and canakinumab, the evidence base for adults is limited and approval for AOSD formally exists only for anakinra and canakinumab.

Summary

The infantile forms and the adult have many similarities, but also differences, in addition to the different age of first manifestation. Both SJIA and jSD, as well as AOSD, are fundamentally different in pathogenesis from the other forms of inflammatory arthritis in their respective age groups (JIA and rheumatoid arthritis) and are now understood to be autoinflammatory diseases. If SJIA/jSD is suspected, a pediatric rheumatologist should be consulted early on, and a rheumatologist should be consulted if AOSD is suspected.

Take-Home Messages

• The infantile and adult forms of Still’s syndrome are similar, but not the same.
  • Clinical hallmarks are:
    Arthralgias/arthritis (affecting mainly “large” joints) and signs of autoinflammation (fever, exanthema)
  • Children: frequent HSM, adults: strep throat
• Kinder: 
  • initial often without arthritis (40%)
  • monophasic course in 40% d.F.
  • Prevalence depending on ethnicity
• Switch to polyarticular disease without autoinflammation
• Life-threatening courses due to MAS and perimyocarditis are possible.
• Admitted pathogenetically important role of IL-1 (and IL-6) has implications for treatment planning.

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