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Adult-onset Still disease

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Adult-onset Still disease (AOSD) is an uncommon inflammatory condition of unknown origin typically characterized by four main (cardinal) symptoms: spiking fever ≥39 °C, arthralgia or arthritis, skin rash and hyperleucocytosis (≥10,000 cells/mm3) with neutrophils ≥80%. As many other manifestations are possible, diagnosis is potentially challenging. Determination of the total and glycosylated ferritin levels, although not pathognomonic, can help in diagnosis. The disease evolution of AOSD can be monocyclic, polycyclic or chronic. In chronic disease, joint involvement is often predominant and erosions are noted in one-third of patients. No prognostic factors have been identified to date. Therapeutic strategies are from observational data. Corticosteroids are usually the first-line treatment. With inadequate response to corticosteroids, methotrexate appears the best choice to control disease activity and allow for tapering of steroid use. For refractory disease, biological therapy with agents blocking interleukin-1 (anakinra) and then those blocking interleukin-6 (tocilizumab) seem the most promising.

Introduction

Adult-onset Still disease (AOSD), previously called Wissler–Fanconi syndrome, was first described by Bywaters in the early 1970s1, about a century after the description of its childhood counterpart, the systemic form of juvenile inflammatory arthritis (JIA). By definition, AOSD affects people older than 16, either de novo or those with a history of systemic JIA.*2, *3, 4 In the latter, a disease-free interval between the childhood episode and the adulthood recurrence differentiates AOSD from persistent systemic JIA.

In most patients, AOSD is characterized by four cardinal symptoms: spiking fever, an evanescent salmon-pink maculopapular rash, arthritis and a white-blood-cell count (WBC) ≥10,000/mm3, mainly neutrophilic polymorphonuclear cells (PMNs). Other features are sore throat or pharyngitis, myalgia, lymph node or spleen enlargement, pleuritis or pericarditis, multivisceral involvement, elevated levels of liver enzymes and other haematologic abnormalities.*3, 5, *6, 7, 8, 9, 10 None of these symptoms is disease specific, so diagnosis of AOSD is difficult and clinicians must first rule out neoplastic, infectious or inflammatory conditions.

Section snippets

Epidemiologic aspects

To date, epidemiologic data about AOSD have been scarce and imprecise, because of the heterogeneous clinical presentation of the disease and the complex assessment of diagnosis. Reported prevalence rates from Japanese and European data range from 1 to 10 cases per million.11, 12, 13

Although Bywaters' first description of AOSD restricted disease onset to between 16 and 35 years of age1, several subsequent case series have suggested that AOSD also affects elderly people.*3, 5, 7, 8 In most

Immunologic pathways

To date, the mechanisms underlying AOSD are not completely understood (Figure 1).14, *15 Histological study of lymph nodes has revealed reactive hyperplasia features with large cellular infiltrates of macrophages, neutrophilic PMNs and T lymphocytes, sometimes mimicking T-cell lymphomas.16, 17, 18, 19, 20 However, infiltrates are polyclonal without any monoclonal component, as compared with those in lymphoma. In addition, granulomatous lesions are absent on biopsy, and no serum autoantibodies

Clinical expression

Although AOSD has long been characterized by four cardinal symptoms, disease presentation is heterogeneous, and many manifestations have been described (Table 1).*2, *33, 37, 38, 39

Biological features

Biological features present the same heterogeneity as clinical features and, even if some abnormalities are reported as highly specific, none can certify AOSD diagnosis (Table 1).*2, *3, 5, *6, *33, 37, 38 Nonetheless, two elements can be considered suggestive: high WBC count with more than 80% PMNs and substantial increase in serum ferritinaemia with glycosylated fraction (GF) ≤20%. Moreover, three major complications must be investigated by biological work-ups: fulminant hepatitis, DICS and

Differential diagnosis

AOSD is an exclusion diagnosis. Because of presentation heterogeneity, many other diagnoses might be evoked, and afterwards ruled out, before reasonably considering AOSD (Table 2).*2, *3, *6, 32

Classification criteria

Because of lack of microbiological or histological clues to certify AOSD diagnosis, several sets of classification criteria have been proposed for research and to help in clinical diagnosis.37, 74, *75, *76, *77 The most widely cited criteria in the literature, and the most widely validated, are Yamaguchi's criteria, which have sensitivity of 96.2% and specificity of 92.1% (Table 3).75 More recently, a new set including GF has been proposed; in the original report, the sensitivity and

Natural history of AOSD

Several patterns of the natural history of AOSD have been described on the basis of the evolution of symptoms over time*3, *6, 11, *15, 78:

  • Systemic, self-limited, monocyclic evolution, with disease limited to a single flare and complete remission achieved within a couple of weeks or months; this pattern represents 19 to 44% of cases.

  • Intermittent or polycyclic pattern, characterized by the recurrence of systemic or articular flares separated by periods of remission lasting from a couple of weeks

Prognosis

The prognosis of AOSD covers life as well as function. The life prognosis is dominated by the severity of the following visceral involvements, in isolation or combination: haematological complications, such as DICS, Moschcowitz syndrome or severe haemophagocytic syndrome38, 79, 80; fulminant hepatitis with rapid liver failure*6, 37; acute respiratory distress syndrome, extensive myocarditis or multiorgan failure.*2, 81 Importantly, exacerbation of these serious symptoms has been reported within

Adult-onset Still disease therapeutic strategies

AOSD is rare, and no randomized controlled trial has been performed. Thus, the only information on therapy is from observational studies (Table 4). However, these data have allowed for determining an optimal therapeutic strategy (Figure 5).

Summary

In conclusion, AOSD is a very polymorphic disease that challenges clinicians in many ways: first, to evoke the diagnosis in an emergency context for severe patients; second, to exclude all other potential diagnoses, especially those for which AOSD treatments could be deleterious; and finally to choose the optimal strategy to achieve remission with no or minimal side effects.

Practice points

  • AOSD is a sporadic auto-inflammatory syndrome of unknown origin.

  • The four most characteristic features of

Acknowledgements

I thank Professors Pierre Bourgeois and Jacques Pouchot for many years of discussion and interaction related to AOSD, and Laura Heraty for manuscript preparation and English correction.

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