Biological treatment in adult-onset Still's disease

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder that is characterised by high spiking fever, arthritis or arthralgia, and evanescent rash. Many other systemic manifestations may occur. Pathogenesis of AOSD remains partially unknown but a major role has been recently attributed to pro-inflammatory Th1 cytokines, including tumour necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6 and IL-18. Despite limited evidence, mainly based on observational studies and the extrapolation to AOSD of the results of a few controlled studies that have been conducted in children with systemic juvenile idiopathic arthritis, biological agents represent a major therapeutic advances for patients with AOSD refractory to conventional treatment or presenting life-threatening manifestations. Both IL-1 and IL-6 blockade may be more effective than TNF-α blockers. Although debatable, therapeutic strategies are proposed.

Introduction

Adult-onset Still's disease (AOSD) is a rare multi-systemic inflammatory disorder that was described for the first time in 1971 by E.G. Bywaters who reported a case series of 14 young adult females who presented with arthritis and systemic manifestations that were identical to those of the systemic form of juvenile idiopathic arthritis (JIA) that was identified by G.F. Still in 1897 [1].

Typically, the clinical features associate a high spiking fever, arthralgia or arthritis and an evanescent salmon-pink maculo-papular skin rash that is predominantly found on the trunk and proximal limbs. Many other systemic features may occur and some of them may be life threatening. The main laboratory features include a striking leucocytosis with a high percentage of polymorphonuclear and an increase of acute-phase reactants, despite a negative infectious work-up. Except for the common presence of a high serum level of gammaglobulins, there is no evidence of autoimmunity and AOSD is not associated with the presence of immunoglobulin M (IgM) rheumatoid factor, anti-cyclic citrullinated peptide or antinuclear antibodies. Despite the diagnostic value attributed to an elevated serum ferritin level – frequently discordant with that of acute-phase reactants – associated with a decrease in its glycosylated fraction (<20%), the diagnosis of AOSD remains one of exclusion. The classification criteria proposed by Yamaguchi et al. published in 1992 are widely used [2].

Outcome of AOSD is unpredictable but approximately 70% of the patients will develop an intermittent form of the disease or a chronic course that manifests mainly with a chronic polyarthritis and eventually joint damage [3], [4].

The treatment of AOSD remains largely empiric based on the results of single case reports or small case series. The rarity of AOSD makes it difficult to carry out controlled clinical trials and none have been conducted in adults [5], [6], [7], [8]. In the years following its description, most of the patients with AOSD have been treated as children having the systemic form of the JIA with high-dose aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). However, only 15–20% of the patients with AOSD respond to this treatment and in the majority corticosteroids are necessary to control both the systemic and articular manifestations of the disease [3], [9]. In the intermittent and chronic forms of the disease most of the disease-modifying anti-rheumatic drugs (DMARDs) that have been proposed in rheumatoid arthritis were used in AOSD. Despite the absence of controlled clinical trials, methotrexate (MTX) is clearly the drug that emerged as the most useful DMARD in association with corticosteroids. It has been shown to be effective in approximately 70% of the patients and it has a corticosteroid-sparing effect [10].

More recently biological agents showed promising results in the treatment of some patients with AOSD. This chapter reviews the literature regarding the use of biological treatment in AOSD.