Adult-onset Still's disease: Advances in the treatment

Best Practice & Research Clinical Rheumatology 30 (2016) 222e238

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Adult-onset Still's disease: Advances in the treatment ~ eda a, b, Ricardo Blanco c, Santos Castan lez-Gay c, d, * Miguel A. Gonza n 62, 28006 Madrid, Spain Rheumatology Division, Hospital de La Princesa, IIS-IPrincesa, c/ Diego de Leo noma de Madrid (UAM), Madrid, Spain Universidad Auto Rheumatology Division, Hospital Universitario Marqu es de Valdecilla, Avda. de Valdecilla, s/n, 39008 Santander, Cantabria, Spain d Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, University of Cantabria, IDIVAL, Avda. de Valdecilla, s/n, 39008 Santander, Spain a

b c

a b s t r a c t Keywords: Adult-onset Still's disease DMARDs Biologic agents IL-1 receptor antagonist-anakinra TNF-a inhibitors Anti-IL-6 receptor antibody-tocilizumab Macrophage activation syndrome

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder mainly characterized by persistent high spiking fevers, evanescent rash, and joint involvement. The pathogenesis of AOSD is only partially known, but pro-inflammatory cytokines such as tumor necrosis factor (TNF)-a, interleukin (IL)-1, IL-6, IL-18, and IFN-g seem to play a major role in this disorder. AOSD is at the crossroad of auto-inflammatory syndromes and autoimmune diseases. It is diagnosed by exclusion to determine the presence of high serum ferritin levels, which is usually >1000 mg/L. AOSD is generally treated with non-steroidal anti-inflammatory drugs, corticosteroids, and disease-modifying anti-rheumatic drugs (DMARDs). Although information on biologic therapy in the management of AOSD is scarce, these drugs represent a major breakthrough in the management of patients with AOSD refractory to corticosteroids or conventional DMARDs or in patients presenting life-threatening manifestations. In this regard, TNF-a, IL-1, and IL-6 antagonists had been proved effective in patients with AOSD. © 2016 Elsevier Ltd. All rights reserved.

s de Valdecilla, Avda. de Valdecilla, s/n, 39008 * Corresponding author. Rheumatology Division, Hospital Universitario Marque Santander, Cantabria, Spain. ~ eda), [email protected] (R. Blanco), [email protected] (M.A. E-mail addresses: [email protected] (S. Castan lez-Gay). Gonza http://dx.doi.org/10.1016/j.berh.2016.08.003 1521-6942/© 2016 Elsevier Ltd. All rights reserved.

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Introduction Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease of unknown etiology characterized by persistent high spiking fevers, evanescent rash, and joint involvement. It was described in 1971 by Bywaters [1] in a series of 14 young women presenting with similar clinical features to those of systemic onset juvenile idiopathic arthritis (JIA) reported by Sir George F Still in children in 1897 [2]. AOSD is characterized by high daily spiking fever, polyarthritis, skin rash, myalgia, lymphadenopathy, sore throat, hepatosplenomegaly, serositis, myocarditis, marked leukocytosis with neutrophilia, and elevated acute phase reactants (APRs) such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). AOSD is a very uncommon disease. Its annual incidence has been estimated between 0.16 and 0.4 per 100,000 persons worldwide, independent of ethnic group [3e5]. The reported prevalence rates range from 1 to 34 cases per 1 million people [5]. Women seem to be slightly more commonly affected than men [6,7]. There is a bimodal age distribution, with one peak between 15 and 25 years and the second between 35 and 45 years of age [3]. The precise etiology of AOSD is unknown. Currently, AOSD is considered a complex autoinflammatory syndrome in which genetic factors, infectious agents, and other environmental factors trigger an auto-inflammatory systemic response leading to a dysregulation of the inflammasome complex with the overproduction of several proinflammatory cytokines such as IL-1, IL-6, IL-18, IFN-g, and TNF-a. Besides, there are some cases of AOSD associated with malignancies including solid cancer and hematological disorders [8e10]. The clinical course is marked by sporadic exacerbations of systemic inflammation and/or chronic inflammatory arthritis. Nevertheless, the evolution varies considerably from one individual to another, ranging from benign and self-limited clinical forms to severe forms with life-threatening manifestations.

Clinical picture The major clinical features of AOSD include quotidian (daily) high spiking fever with temperature often exceeding 39
C, arthralgia or true arthritis, and an evanescent salmon-colored skin rash that mainly appears on the trunk and proximal limbs and usually coincides with fever spikes. The joints more commonly affected are the knee, wrist, ankle, and hand. The involvement of the hip and shoulder at the onset of the disease implies a worse prognosis. Other common manifestations of AOSD include myalgia, pharyngitis, lymphadenopathy, organomegaly, pulmonary infiltrates, pleuritis, pericarditis, myocarditis, and abdominal pain [11,12]. AOSD presents in some patients as persistent fever of unknown etiology. The frequency of the most relevant clinical features is shown in Table 1. Laboratory findings are nonspecific and reflect the systemic inflammatory nature of the disease [8,11,12]. Marked elevation of ESR and CRP is seen in the majority of the patients. Leukocytosis with neutrophilia (>80% polymorphonuclear cells) is found in about 80% of patients. Anemia and thrombocytosis are also frequently found. Elevations in the serum liver enzyme levels, especially alanine and aspartate aminotransferases, are seen in 75% of patients. Serum ferritin level is particularly increased in AOSD, and it may be a good marker of disease activity. AOSD is also associated with a reduction in the glycosylated ferritin fraction, so that the combination of serum ferritin levels higher than 1000 mg/L with a glycosylated fraction under 20% has been found to have a high specificity for the diagnosis of AOSD [13,14]. In contrast, rheumatoid factor, anti-citrullinated protein autoantibodies, antinuclear antibodies, and other immunologic studies typical of autoimmune diseases are present in <10% of patients and only at low titers (Table 2). The clinical course of the disease can be ranked in three main patterns: monophasic or monocyclic AOSD, characterized by a unique and self-limited flare lasting several weeks to months with subsequent resolution (~30% of patients); systemic intermittent pattern characterized by recurrence of multiple flares with or without joint symptoms (~30%); and a chronic pattern, characterized by

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~ eda et al. / Best Practice & Research Clinical Rheumatology 30 (2016) 222e238 S. Castan Table 1 Prevalence of the main clinical manifestations in adult-onset Still's disease (AOSD). Clinical manifestations

Frequency range (%)a

Fever  39
C Arthralgia/arthritis Eruption (skin rash) Sore throat Myalgia Lymphadenomegaly Weight loss Hepatomegaly Splenomegaly Pleuritis Pericarditis Myocarditis Pulmonary infiltration Abdominal pain Fever of unknown origin (FUO)

90e100 70e100 70e90 50e90 50e80 40e75 30e70 20e75 20e65 10e40 10e30 5e10 10e20 5e40 Variableb

a b

Depending on the series. AOSD accounts for 3e20% of FUO.

persistent polyarthritis with progressive joint destruction (~40%) [8,11]. The chronic pattern results in the maximum long-term disability. Life-threatening complications with a high mortality rate appear in about 15e20% of patients [8,15]. Among these complications, the reactive hemophagocytic syndrome (RHS), also called macrophage activation syndrome (MAS) in the context of rheumatic diseases, is the most severe complication. The warning symptoms and main clinical features of MAS are shown in Table 3. Other uncommon manifestations as the life-threatening complications of AOSD are shown in Table 4. Classification criteria and diagnosis Several sets of classification criteria have been proposed for the diagnosis of AOSD. The most generally accepted criteria are those proposed by Yamaguchi et al., in 1992 [16] and the criteria proposed by Fautrel et al., in 2002 [17]. Yamaguchi's criteria are the most broadly used and have 79.2% sensitivity and 93.8% specificity (accuracy of 88.6%). However, in the Yamaguchi et al. criteria, AOSD diagnosis requires the exclusion of infections, cancer, and autoimmune diseases. The criteria proposed by Fautrel et al. are mainly based on serum ferritin levels and glycosylated ferritin fraction <20%. Their Table 2 Prevalence of the main laboratory findings in adult-onset Still's disease (AOSD). Laboratory findings

Frequency range (%)a

Increased ESR (>40 mm/1st h) Increased CRP Leukocytosis WBC  10,000/mm3 WBC  15,000/mm3 Neutrophils (>80%) Anemia (Hb  10 g/dL) Thrombocytosis Serum albumin (3.5 g/dL) Elevated liver function tests Hyperferritinemia Glycosylated ferritin 20% Negative ANA Negative RF

90e100 90e100 80e95 50e80 80e90 65e70 40e60 75e80 50e75 45e60 70e75 >90 >90

ESR: erythrocyte sedimentation rate; WBC: white blood cell count; CRP: C-reactive protein; ANA: antinuclear antibodies; RF: rheumatoid factor. a Depending on the series.

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Table 3 Warning symptoms and signs of macrophage activation syndrome. Clinical features High non-remitting fever Urticarial rash Lymphadenomegaly Hepato/splenomegaly CNS dysfunction Hemorrhages Laboratory findings Decreased or normal ESR Abnormal liver function tests Pancytopenia Abnormal coagulation tests Hypofibrinogenemia Hypoalbuminemia Abnormally increased triglycerides Hyperferritinemia (generally > 5000 mg/L) Histopathological features (BM aspiration/biopsy) Macrophage hemophagocytosis CNS: central nervous system; ESR: erythrocyte sedimentation rate; BM: bone marrow.

Table 4 Uncommon manifestations and life-threatening complications in adult-onset Still's disease (AOSD). Uncommon clinical manifestations Pulmonary involvement: restrictive pulmonary disease, ARDS Myocarditis/myocardial necrosis Cardiac tamponade Aseptic meningitis/encephalitis Ischemic stroke Pure red cell aplasia Intestinal pseudo-obstruction Tubulo-interstitial nephritis Inappropriate ADH secretion Neuro-sensorial deafness Inflammatory orbital pseudotumor Reversible posterior leukoencephalopathy syndrome Amyloidosis € gren's syndrome Sjo Life-threatening complications Macrophage activation syndrome/reactive hemophagocytic syndrome Fulminant hepatitis/acute hepatic failure Disseminated intravascular coagulopathy Thrombotic thrombocytopenic purpura Diffuse alveolar hemorrhage Pulmonary arterial hypertension Severe iatrogenic complications Fatal infections Septic shock ARDS: acute respiratory distress syndrome; ADH: antidiuretic hormone.

sensitivity is 80.6% with 98.5% specificity (accuracy of 92.1%). However, the clinical data required to fulfill the Fautrel et al. criteria may appear later in the course of the disease; this limits its applicability in the early stages of the disease [17]. Table 5 shows the main criteria currently used for classification of AOSD. Furthermore, it is necessary to consider other systemic diseases in the differential diagnosis of AOSD (Table 6).

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~ eda et al. / Best Practice & Research Clinical Rheumatology 30 (2016) 222e238 S. Castan Table 5 Classification criteria for adult-onset Still's disease (AOSD) proposed by Yamaguchi et al., in 1992 [16] and Fautrel et al., in 2002 [17]. Yamaguchi et al. classification criteria for AOSD Major criteria: 1. Fever 39
C lasting at least 1 week 2. Arthralgia or arthritis 2 weeks 3. Typical nonpruritic salmon-pink skin rash 4. Leukocytosis 10,000/mm3 with 80% polymorphonuclear cells Minor criteria: 1. Sore throat 2. Lymph node enlargement 3. Hepatomegaly or splenomegaly 4. Abnormal liver function tests 5. Negative ANA and RF tests Exclusion criteria: 1. Infections 2. Malignancy (mainly malignant lymphoma) 3. Other systemic disorders (mainly systemic vasculitis) (5 criteria are required and at least 2 of which should be major) Fautrel et al. classification criteria for AOSD Major criteria: 1. Spiking fever 39
C 2. Arthralgia 3. Transient erythema 4. Pharyngitis 5. Polymorphonuclear cells 80% 6. Glycosylated ferritin 20% Minor criteria: 1. Maculopapular rash 2. Leukocytosis >10,000/mm3 (4 major criteria or 3 major þ 2 minor are required) ANA: antinuclear antibodies; RF: rheumatoid factor.

Immunopathogenesis of AOSD AOSD is a heterogeneous syndrome that is at the crossroad of the auto-inflammatory syndromes and the autoimmune diseases, where innate immunity plays an essential role. In fact, in light of current knowledge, several external factors such as infectious agents (bacteria, viruses, or parasites), some malignancies (solid cancer and some hematologic disorders), and other environmental factors in patients with some genetic predisposition may activate innate immune cells through toll-like receptors (TLRs), leading to abnormal response in both innate and adaptive immunity with a cytokine overproduction [10,18].

Innate immunity cells Neutrophil and macrophage activation is the hallmark of this disease. In this regard, several macrophage activation factors such as M-CSF and IFN-g are increased in the serum of patients with AOSD and correlate well with disease activity [19,20]. Furthermore, other factors such as macrophage migration inhibitory factor (MIF) and intracellular adhesion molecule-1 (ICAM-1) may serve as useful markers of activity and severity in AOSD [21,22]. On the contrary, cytotoxicity function of natural killer (NK) cells is diminished in AOSD, which could be due to perforin deficiency in the granules of NK and cytotoxic T cells [23e25].

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Table 6 Differential diagnosis of adult-onset Still's disease (AOSD). Diseases

Diagnostic tests

Infections: Viral infections: HIV, herpesvirus, viral hepatitis, parvovirus B19 Atypical infections: Mycoplasma pneumoniae Borreliosis, Yersiniosis Infective endocarditis and sepsis Others (such as toxoplasmosis) Malignancies: Lymphomas (Hodgkin and non-Hodgkin) Angioimmunoblastic T cell Castleman's disease Myeloproliferative disorders Some solid cancers Autoimmune diseases: Systemic lupus erythematosus Rheumatoid arthritis Dermatomyositis Systemic vasculitis (PAN) Autoinflammatory diseases: Familial mediterranean fever Hyper-IgD syndrome TNF-receptor-associated periodic syndrome (TRAPS) Drug reactions/DRESS Others: Sarcoidosis Reactive arthritis Schnitzler's syndrome Sweet's syndrome Kikuchi-Fujimoto disease

Serology, PCR

Serology, PCR

Blood cultures, ultrasound Serology, PCR CT, PET/CT, BM aspiration, lymph node biopsy Specific tests/imaging techniques

Specific autoantibodies Muscle biopsy ANCA, tissue biopsy, arteriography

Familial history, genetic tests Immunoglobulin count Genetic analysis Eosinophil count, skin biopsy Specific tests and imaging techniques depending on the clinical suspicion

HIV: Human immunodeficiency virus; PCR: polymerase chain reaction; CT: computed tomography; PET: positron emission tomography; BM: bone marrow; PAN: polyarteritis nodosa; ANCA: anti-neutrophil cytoplasmic antibodies; TNF: tumor necrosis factor; DRESS: drug reaction with eosinophilia and systemic symptoms.

Innate immune system receptors TLRs play an important role in the activation of inflammasome, recruitment of neutrophils, and amplification of Th-17-driven inflammatory responses. A recent study showed that the TLR7/ MyD88 pathway was overexpressed in the dendritic cells of patients with AOSD [18]. Furthermore, the expression of TLR7 is increased in active patients, which decrease after an effective treatment. Adaptive immunity cells Several studies demonstrated a predominance of T helper cells (Th1) in AOSD, which subsequently results in the activation of macrophages and NK cells and promotion of cell-mediated immunity [26]. Furthermore, recent advances have shown higher levels of circulating Th17 cells in patients with active AOSD and a good correlation between Th17 and ferritin levels and disease activity. Finally, regulatory T cells (Treg) and transforming growth factor (TGF)-b are inversely correlated with AOSD activity [27]. Cytokines and chemokines The levels of the main pro-inflammatory cytokines are increased in sera of patients with active AOSD. These levels decrease after treatment with biologic agents targeting these cytokines,

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highlighting its crucial role in the pathogenesis of the disease. The main pro-inflammatory cytokines involved in the pathogenesis of AOSD are IL-1b, IL-6, IL-18, TNF-a, and IFN-g [8,9,28]. IL-1b is mainly secreted by macrophages. Its production is closely linked to that of inflammasome activation and has been implicated in the pathogenesis of AOSD. Its serum levels are correlated with disease activity. The pivotal role of IL-1b is confirmed by reports demonstrating the efficacy of anti-IL-1 therapy in AOSD [29]. IL-6 levels in serum also correlate with several specific clinical and laboratory disease activity markers such as skin rash, fever, CRP, ferritin, and leukocytosis. However, IL-6 and its receptor (IL-6R) are downstream of IL-1b, and the increased levels of IL-6 may be a secondary phenomenon to the overproduction of IL-1b [28,30]. Interestingly, IL-6R antagonists have shown very high efficacy in the treatment of AOSD [31,32]. IL-18 is another pro-inflammatory cytokine whose serum levels are particularly high in patients with AOSD [33]. A similar condition is not noted in other inflammatory diseases. IL-18 levels have shown a good correlation with disease activity, hepatitis, serum ferritin levels, and corticosteroid dependence. IL-18 levels were also significantly increased in patients with AOSD-related RHS [33]. Moreover, an association between AOSD and IL-18 gene polymorphisms has also been described [34]. Increased production of TNF-a has also been described in AOSD, but serum levels are lower than those detected in other chronic inflammatory rheumatic disorders and are not correlated with disease activity [19]. However, TNFa-inhibitor drugs have been proved to be effective in the AOSD treatment, particularly in patients who develop chronic arthritis. Other cytokines and chemokines involved in the pathogenesis of AOSD are IFN-g and IL-8/CXXL8 [28,35]. IFN-g promotes the macrophage activation and hepatocyte apoptosis. IL-8, also known as CXXL8, is a chemo-attractant molecule favoring the neutrophil recruitment. IFN-g and IL-8 are increased in active AOSD and correlate well with chronic articular disease [19,28,35]. Treatment: general considerations Treatment of AOSD remains empirical and is based on the results of case reports or small case series. The main goals of AOSD therapy must include controlling physical signs and symptoms of inflammation; preventing end organ damage (articular and systemic), and minimizing risk of adverse effects of therapy. First line therapies include nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, with response rates around 20% and 60%, respectively [12,36]. Among the NSAIDs, high-dose indomethacin, if tolerated, is probably the most effective. The efficacy of corticosteroids is higher in patients with systemic pattern of the disease. The initial dose of corticosteroids should range between 0.5 and 1 mg/kg/day. However, patients treated with dose between 0.8 and 1 mg/kg/day achieve faster remissions and have less relapses than those who receive lower doses [37,38]. Unfortunately, about 40e45% of patients develop corticosteroid dependence and mild or severe long-term side effects. Consequently, disease-modifying anti-rheumatic drugs (DMARDs) and immunosuppressive agents are often required, especially if therapeutic failure occurs. The most widely used DMARD is methotrexate (MTX), either oral or parenteral, at the same dose as in RA. It has been found to be effective in around 70% of patients, in both systemic and articular clinical forms with a good corticosteroid-sparing effect [12,39]. Other DMARDs or immunosuppressants successfully used in the treatment of AOSD are hydroxychloroquine, azathioprine, leflunomide, and cyclosporine A. Biologic agents in AOSD There is a growing body of evidence on the usefulness of biologic therapies in the management of corticosteroid and DMARD-refractory AOSD based on the immunopathogenesis of the disease. Indeed, in recent series, about 20e25% of patients with AOSD were treated with biologic agents [40e42]. Nevertheless, because of the low prevalence of the disease, there are no prospective, double-blind, and randomized clinical trials that confirm the efficacy of the biologic agents in the management of AOSD.

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Below, we summarize the most relevant data on the use of biologic agents in patients with AOSD. TNF-a inhibitors TNF-a inhibitors were the first biologic agents used in AOSD in single case reports or small series of patients in the early 2000s. The dose regimens were the same as those used in RA. The main TNF-a inhibitors currently used are infliximab (IFX), etanercept (ETA), and adalimumab [40]. IFX was the first TNF-a inhibitor used in AOSD. It is a murine-human chimeric monoclonal antibody that binds to soluble TNF-a, hindering the interaction with its cellular receptors. It was used at a dose of 3e5 mg/kg at weeks 0, 2, and 6 and then every 6e8 weeks, similar to its use in RA. IFX yielded a rapid efficacy of both joint and systemic symptoms as well as a marked corticosteroid-sparing effect [43e45]. With respect to this, in one of the first studies, Kraetsch et al. showed that IFX induced a rapid effect on both articular and systemic manifestations in six patients with AOSD [44]. Besides marked efficacy and a corticosteroid-sparing effect, the use of IFX was associated with a prolonged efficacy lasting up to 28 months. In another two series of AOSD unresponsive to corticosteroids and MTX that included seven patients altogether, IFX combined with MTX led to a rapid and effective improvement along with sustained effect lasting up to 18 months in some cases [43,45]. Single case reports have also emphasized the efficacy of IFX in AOSD [46,47]. Etanercept (ETA) is the second most commonly used anti-TNF-a agent in refractory AOSD. It is a recombinant soluble form of the human 75-kd TNF receptor fusion protein. The experience with ETA is also limited to a small series of patients. The first open-label prospective trial of ETA in patients with active AOSD included 12 individuals with refractory AOSD and active polyarthritis who had a mean disease duration of 10.7 years [48]. All these 12 patients were treated with ETA given in biweekly doses of 25 mg for 6 months. Before ETA, they had been treated unsuccessfully with several conventional DMARDs. The efficacy was evaluated according to the American College of Rheumatology (ACR) improvement criteria [49]. Ten patients successfully completed the study. ETA dose had to be increased in four of them from 25 mg biweekly to 25 mg thrice a week. Seven patients met ACR 20% response criteria, of whom 4 achieved ACR 50% response criteria and two reached ACR 70% response criteria. However, clinical improvement was seen in only one of the three patients with typical systemic features of AOSD (fever and rash), and arthritis did not improve in any of these three patients. Two patients discontinued ETA because of a disease flare [48]. Single cases of refractory AOSD complicated by myocarditis with heart failure and cardiac or renal amyloidosis with favorable responses to ETA have also been reported [50,51]. Since systemic JIA is the pediatric equivalent of AOSD, information on ETA in children may be of potential interest. In this regard, there are a few controlled trials of ETA in systemic JIA. Data from the withdrawal trial of ETA in JIA suggest that relapses are common following withdrawal of the biologic therapy. In this regard, 17 children with systemic JIA who experienced response to ETA were randomized to receive either ETA (nine children) or placebo (eight children). Eighty-eight percent of the children who received placebo experienced a flare, whereas a relapse of the disease was observed in only 44% of the children who continued receiving ETA [52]. These promising results in patients with AOSD undergoing TNF-a inhibitor therapy were not confirmed by Fautrel et al. in the French observational study of 20 cases with refractory AOSD treated with TNF-a blockers (IFX and ETA) [53]. In this series of patients with a mean disease duration of 8.5 years, the clinical expression of AOSD was predominantly systemic in five patients and polyarticular in 15. Response to corticosteroids and MTX had been considered inadequate in all of them. IFX was used in 15 patients, whereas ETA was used in 10, of which five received both drugs consecutively. Corticosteroids were concurrently used in 18 patients and immunosuppressive drugs in 17 patients. After a mean follow-up of 13 months, five patients had complete remission: one undergoing ETA and four undergoing IFX therapy. Partial response was observed in 16 patients (seven with ETA and nine with IFX). Treatment failed in four patients (two with each anti-TNFa). At the last visit, anti-TNF-a therapy had been discontinued in 17 patients, because of lack or loss of efficacy in 11 patients, side effect in 4 patients, and other reasons in two patients [53]. Data on adalimumab (ADA), a fully humanized monoclonal antibody targeted against TNF-a, are scarce. It was used successfully in some patients with AOSD [54]. ADA was effective in treating a patient

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who failed to respond to ETA [42]. However, in another study, ADA therapy failed to demonstrate clinical improvement in two patients with AOSD [55]. It is important to remark that RHS mimicking an AOSD flare was reported to be associated with ETA [56] and ADA use [57]. Switching from one TNF-a inhibitor to another may be useful, as demonstrated in several cases [53,58]. Aikawa et al. reported switching to another anti-TNF-a in five of six patients with AOSD who underwent IFX therapy. However, good response was not achieved in all of them [58]. Maria et al. reported a series of patients with AOSD treated with three different TNF-a blockers, through 19 different therapeutic sequences (IFX eight times, ETA eight times, and ADA three times) [9]. Overall, partial response rather than complete remissions was observed (eight versus six). Treatment was discontinued after a mean follow-up of 14 months without significant differences between IFX and ETA. Patients with predominant joint manifestations had significantly longer duration of TNF-a blocker therapy than the remaining patients with AOSD [9]. This observation suggests a distinctive pathophysiology for the chronic arthritis AOSD pattern when compared with the typical systemic AOSD pattern [48]. No data on golimumab (a humanized monoclonal antibody that inhibits TNF-a and is given subcutaneously once a month) or certolizumab pegol (pegylated anti-TNFa given subcutaneously twice a month) in the AOSD management are available. In summary, TNF-a blockers may be more useful in chronic polyarticular refractory AOSD than in the systemic forms of the disease [41,42]. Although a head-to-head comparison is not available, IFX appears to be more effective than ETA. However, the efficacy of TNF-a blockers seems to be limited in time, and switching from one to another TNF-a blocker is useful in only about 50% of patients [41,58]. Overall, TNF-a inhibitors are well tolerated and the side effect profile is similar to that reported in the management of other inflammatory diseases. IL-1b antagonists As mentioned earlier, IL-1b is one of the crucial cytokines involved in the immunopathogenesis of AOSD. Hence, it is one of the main targets in the treatment of this disease. Currently, we use three IL-1b antagonist agents: anakinra (ANK), canakinumab, and rilonacept. ANK is a recombinant nonglycosylated inhibitor of the IL-1 receptor that blocks the actions of IL-1. Approved by the FDA for the treatment of RA in 2001, it has also been used in systemic JIA, cryopyrinassociated periodic syndrome (CAPS), and other auto-inflammatory diseases [59,60]. The use of ANK in AOSD is supported by the pivotal role of IL-1b in the pathogenesis of this disease. In fact, ANK has been used for the treatment of AOSD with satisfactory results. However, information related to this issue is based on isolated case reports, small series [61e65], and a single prospective randomized open-label clinical trial [66]. The first cases of ANK-treated AOSD refractory to other therapies were reported in 2003e2005 [61e63]. In 2007, two studies including eight patients showed good efficacy of ANK in patients with AOSD presenting with systemic symptoms refractory to corticosteroids, DMARDs, and some TNF-a inhibitors. Interestingly, the symptoms disappeared in few days after the first ANK administration and the inflammatory markers returned to the normal levels in 2e4 weeks. ANK therapy also allowed a fast corticosteroid tapering. However, relapses occurred in few days after discontinuation of this therapy [64,65]. €tter et al., four patients with AOSD refractory to conventional treatment, two with In the study by Ko acute flares of the chronic form of the disease and another two with intermittent disease, were treated with ANK. Two of them had elevated IL-1b serum levels that normalized with ANK. IL-18 serum level was very high and returned to the normal level following ANK therapy in all four patients [65]. Several additional communications have emphasized the dramatic effect of ANK in AOSD, sometimes in patients with life-threatening manifestations [62,67].  et al. reported the French experience in the management of patients with AOSD [68]. It Lequerre was a retrospective study that included 15 patients with AOSD with a mean age of 38 years and mean disease duration of 7.8 years at the time of inclusion. All patients had active arthritis and had received or were receiving MTX, and 10 (67%) had also been treated with a TNF-a inhibitor. Thirteen presented systemic manifestations. Eleven of the 15 patients experienced a rapid and significant

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improvement and had been still receiving ANK at the latest follow-up (range 11e27 months). Among these 11 patients, nine showed complete response and two showed partial response (no systemic symptom and 20e49% improvement in the ACR score). The dose of corticosteroids was largely diminished. However, four of the 15 had to discontinue ANK because of lack of efficacy or side effects [68]. Several studies performed in systemic JIA suggest that ANK is more effective when this biologic agent is administered early in the course of the disease [68e70]. In this regard, 84% of patients from a series of 25 patients with AOSD treated early (mean disease duration of 7 months) with ANK achieved a rapid and sustained clinical remission after a 15-month median follow-up period [71]. Nevertheless, further data are required to fully establish if early treatment with ANK yields a higher rate of remission. n et al. have reported a multicenter retrospective open-label study Recently, Ortiz-Sanjua including the largest series of patients with AOSD treated with ANK [72]. A total of 41 patients (26 women/15 men) were assessed, whose mean age was 34.4 years and median AOSD duration was 3.5 years before ANK onset. At that time, the most common clinical features were joint manifestations (87.8%), fever (78%), and skin rash (58.5%). Anakinra showed rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and 7.3%, respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from 26.8% to 4.9%. Laboratory parameters such as ESR, CRP, leukocytosis, and serum ferritin levels also improved considerably. Interestingly, ANK was associated with rapid and sustained clinical and laboratory improvement in nonresponders to other biologic agents. The median prednisone dose was reduced from 20 mg/day at ANK onset to 5 mg/ day at 12 months. However, joint symptoms were more refractory to therapy than systemic manifestations [72]. Overall, despite the lack of randomized controlled trials in AOSD, ANK seems to have an impressive efficacy that is rapid and sustained, associated with a corticosteroid-sparing effect in most patients [64,68]. Inhibition of IL-1b with ANK seems to be more effective in patients with highly active systemic disease than in patients with AOSD with isolated chronic arthritis [68,73]. ANK is generally well tolerated except for a common self-limited erythema at the site of injection. Severe side effects are uncommon. However, acute adult respiratory distress syndrome was reported in a patient with a systemic inflammatory response [74]. Further, it should be highlighted that an MAS was reported in a few patients undergoing ANK therapy [68,70]. Although a 200 mg daily dose of ANK was used in one patient [68], ANK is usually prescribed at dose of 100 mg daily subcutaneously and is commonly associated with MTX [68,75]. Lower dose is prescribed to patients with AOSD in clinical remission, generally 50 mg/day or 100 mg every 2e3 days [72,76]. The duration of treatment with ANK has not been well established. Similarly, the usefulness of ANK on structural joint damage remains unknown. However, the short half-life of ANK (4e6 h) and the need of daily subcutaneous injections until the remission is achieved are the important disadvantages of its use. Recently, new IL-1b antagonists have been used in the management of AOSD. Canakinumab is a fully human monoclonal antibody against IL-1b with a half-life of 26 days, which enables to administer it every 8 weeks. Canakinumab has been shown to be very effective in children with systemic JIA. Moreover, it has been approved for the management of CAPS [77]. Canakinumab was successfully used in two patients with AOSD who were refractory to ANK [78]. Because of its peculiar characteristics, canakinumab is an attractive drug for cases refractory to ANK. Rilonacept, a soluble dimeric trap fusion protein, is another long-acting inhibitor of IL-1 that is administered weekly as a subcutaneous injection (160 mg/week after a first loading dose of 220 mg). It has been used successfully in four patients with AOSD [78,79]. Gevokizumab, a recombinant humanized anti-IL-1b antibody, is another interesting IL-1b antagonist, but there are no data supporting its use in AOSD. Taking all these considerations into account, we can conclude that inhibition of the IL-1b pathway may be an effective and safe alternative for the management of AOSD, with few severe adverse effects. It seems to be very effective for both systemic and articular forms of the disease, especially for the first one.

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IL-6 antagonists IL-6 is another pivotal cytokine involved in the inflammatory cascade that is also implicated in the pathogenesis of AOSD. IL-6 serum levels are commonly increased in active AOSD. Therefore, IL-6 is a suitable target for the treatment of refractory cases of this disease. Currently, the only available agent neutralizing IL-6 is tocilizumab (TCZ). TCZ is a humanized anti-IL-6 receptor antibody that recognizes both membrane-bound and solublefree forms of IL-6 receptor, blocking the actions of IL-6 specifically. Several case reports highlighted the potential efficacy of TCZ in AOSD [80e82]. In a series of three patients who were refractory to MTX and ANK, with two of them also refractory to anti-TNF-a, TCZ was highly effective [55]. A recent Japanese review reported a good response to TCZ in 11 patients with AOSD who were refractory to TNF-a blockers or ANK [83]. TCZ demonstrated efficacy in treating both systemic and arthritis symptoms and showed a corticosteroid-sparing effect. Interestingly, one patient remained in remission for more than 8 years after discontinuation of TCZ [83]. French investigators reported a series of 14 patients (nine women and five men; mean age of 38.4 years; disease duration of 13.6 years) with refractory AOSD treated with 5e8 mg/kg TCZ every 2e4 weeks. All patients had persistent arthritis, and seven of them also had systemic manifestations that were refractory to conventional DMARDs, ANK, and TNF-a blockers. Eleven patients successfully completed a 6-month study. One patient withdrew because of necrotizing angiodermatitis, one because of chest pain and chills at each TCZ infusion, and another because of a systemic flare. The mean disease activity score (DAS28) decreased from 5.6 to 2.9 at the 6-month follow-up visit. The systemic symptoms resolved in six of seven patients and corticosteroid dose was reduced by 56% [31]. In 2014, Cipriani et al. reported on 11 patients with refractory AOSD treated with 8 mg/kg TCZ monthly for 12 months [84]. The patients responded quickly and experienced a sustained clinical remission over time during the treatment. The median DAS28 decreased from 5.6 at the baseline to 1.6 at 12 months. Improvements of systemic manifestations were observed in the eight patients with such symptoms. The beneficial effect of TCZ persisted 6 months after treatment discontinuation [84]. Recent data on 15 Israeli TCZ-treated refractory patients with AOSD seem to confirm these results [85]. The study included nine men and six women, mean age 33 years with mean disease duration of 9 years. They had used a mean of 3.6 disease-modifying drugs before TCZ, including 10 patients with TNF-a inhibitors. Intravenous TCZ 8 mg/kg was administered every 4 weeks (12 patients) or every 2 weeks (three patients). All patients completed at least 6 months of treatment. The mean follow-up period was 15.7 months. After 6 months of treatment and at the end of follow-up, the number of tender and swollen joints, the ESR and CRP levels, and the prednisone dosage decreased significantly. Only two patients complained of mild arthralgia, and none reported systemic manifestations at the end of follow-up. Interestingly, a patient who had developed secondary amyloidosis with proteinuria up to 2 g/24 h in the setting of the disease showed a complete resolution of the proteinuria after 6 months of TCZ therapy [85]. Furthermore, a randomized placebo-controlled trial showed the efficacy of TCZ in the pediatric onset of the disease, in which 85% of the children with severe persistent systemic JIA met the composite primary end point versus 24% in the placebo group [86]. A retrospective open-label study with TCZ involving 34 Spanish patients with AOSD has been recently reported [32]. It included patients with AOSD who had experienced an inadequate response to corticosteroids and at least one standard synthetic immunosuppressive drug and also, in many cases, biologic agents [32]. The mean age of the patients (eight men and 26 women) was 38.7 years. The median duration of AOSD before TCZ initiation was 4.2 years. The initial doses of intravenous TCZ were 8 mg/kg every 4 weeks in 22 patients, 4 mg/kg every 4 weeks in 2 patients, and 8 mg/kg every 2 weeks in 10 patients. TCZ treatment resulted in rapid and sustained improvement in both clinical and laboratory parameters. After 1 year of TCZ therapy, the incidence of joint manifestations had decreased from 97% at the baseline to 32.4%, the incidence of both cutaneous manifestations and fever decreased from 58.8% to 5.9%, and the incidence of lymphadenopathy from 29.4% to 0%. A dramatic reduction in the laboratory markers of inflammation,

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including ESR, CRP, and ferritin levels, was also achieved. The median dosage of prednisone was also reduced from 13.8 mg/day at the initiation of TCZ to 2.5 mg/day at 12 months. After a median follow-up of 19 months, only two patients required permanent discontinuation of TCZ therapy because of severe infections [32]. Another retrospective study on 40 Japanese patients was conducted to investigate the development of relapses of the disease. In this study, 87 relapses were documented in 27 patients [87]. Ten patients with refractory or relapsing disease who received 8 mg/kg of TCZ every 2e4 weeks had experienced 11 relapses before TCZ. Interestingly, none of them had further relapses following the onset of TCZ therapy. The relapse-free rate of these 10 patients after starting TCZ was significantly higher than that of the whole group of 40 patients after the initial treatments (100% and 67% at 12 months, respectively; p ¼ 0.03). After 6 months of TCZ therapy, the median level of CRP in these 10 patients decreased from 6.3 to 0.01 mg/dl [87]. In conclusion, the beneficial effects of TCZ were well documented in patients with AOSD with the chronic arthritis pattern of the disease. Nevertheless, TCZ seems to be effective on the accompanying systemic symptoms. As described for ANK, TCZ yielded a marked corticosteroidsparing effect, preventing relapses, and showing a good safety profile. However, two patients undergoing TCZ therapy were reported to develop an MAS, one of them related to cytomegalovirus infection [81,88].

Intravenous immunoglobulins Intravenous immunoglobulins (IVIG) have been given to patients with AOSD at the usual dose of 2 g/ kg administered in 2e5 days every month. They were found to be effective in 8 of 14 patients in two open-label studies, early in the disease course [89e92]. Efficacy of IVIG has also been reported in single case reports [93,94]. They should be used in patients with acute life-threatening manifestations [41]. However, no controlled study has been conducted on IVIG in AOSD and a controlled study in systemic JIA failed to demonstrate their efficacy [95]. In this regard, therapeutic failure to IVIG in AOSD has also been reported [31,96].

Other biological agents Rituximab (RTX) is a chimeric monoclonal anti-CD20 antibody that induces depletion of peripheral B cells for periods of 6e12 months or longer and that has been widely used in patients with RA. Few case reports showed a response to RTX in patients with AOSD refractory to conventional DMARDs and other biologic agents [97,98]. However, the lack of response to RTX in some patients with AOSD refractory to other therapies has also been described [31,68,69]. Abatacept is a CTLA4 Ig fusion protein that blocks the interaction between CD80/86 and CD28, decreasing the T-lymphocyte activation. It has been successfully used in two patients with AOSD refractory to other biologics [99,100]. However, it failed to achieve good response in another two patients [31,79]. Diagnostic and therapeutic approach to AOSD AOSD is a rare multi-systemic auto-inflammatory disease. The disease is diagnosed by exclusion, generally based on the presence of the characteristic clinical triad and typical laboratory findings, in the absence of other disorders that may cause similar symptomatology. The most characteristic features are daily spiking fever, arthralgia or true arthritis, an evanescent salmon-colored maculopapular skin eruption that is most often present during the febrile hours, sore throat, leukocytosis with neutrophilia, and a marked elevation of serum ferritin levels. The differential diagnosis of AOSD is extensive and requires exclusion of the following conditions: infectious diseases, especially acute viral infections; malignancies; systemic autoimmune rheumatic diseases; vasculitis; auto-inflammatory disorders; and adverse reactions to drugs and neutrophilic dermatoses.

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Several sets of classification criteria have been proposed. They are probably more useful for research than for diagnosis. Currently, the criteria more commonly used in the daily clinical practice are those proposed by Yamaguchi et al. [16] and Fautrel et al. [17]. The course of the disease is variable, ranging from self-limiting clinical forms to other more severe forms with serious life-threatening complications. One of the most ominous complications among them is the MAS, also called RHS, whose symptoms and signs of alarm are shown in Table 3. As AOSD is an uncommon condition, it is not possible to perform controlled clinical trials comparing the efficacies of various agents or the usefulness of different therapeutic strategies. Therefore, it is difficult to offer strong therapeutic recommendations as they are essentially based on observational studies, small case series, or single case reports. Moreover, many of the considerations on the management of AOSD are based on data from the systemic form of JIA. Furthermore, the AOSD is a heterogeneous disease with several different subtypes ranging from self-limited and benign clinical forms to destructive polyarthritis or systemic forms with life-threatening complications. With regard to the management of AOSD, the first line therapy consists of an NSAID, especially in the absence of systemic manifestations. However, NSAIDs are only beneficial in approximately 15e20% of patients. Corticosteroids are the cornerstone of the AOSD therapy, and they are required in approximately 80% of the patients (usually at an initial dose of 0.8e1 mg/kg/day). Corticosteroids should be kept at least 4e6 weeks before considering a gradual tapering. DMARDs, generally MTX, should be administered to patients who develop corticosteroid resistance or to those who require high corticosteroid doses. Biologic therapy should be considered when MTX fails to control the disease or sometimes as a first step in severe or life-threatening systemic manifestations. IL-1 and IL-6 antagonists have been proved to be the most effective biologic agents. They should be used along with corticosteroids and DMARDs, particularly MTX. IL-1b blockers are more effective for the systemic manifestations, whereas the use of an IL-6 antagonist has proved to be useful for both joint and systemic manifestations. Anti-TNF-a IFX may be an attractive therapeutic option in refractory AOSD with a predominant articular pattern. In general, the safety profile of these biologic agents is favorable. An approach to the management of AOSD is shown in Fig. 1. Aggressive treatment with high-dose corticosteroids and biologic agents should be started early in the severe forms or in AOSD-affecting patients with life-threatening complications. A dual X-ray bone absorptiometry should be considered in patients with AOSD who had received prolonged corticosteroid therapy, in particular those with risk factors for osteoporosis and fracture. In

Fig. 1. Work-up of management of AOSD. Abbreviations: AOSD: adult-onset Still's disease; NSAIDs: nonsteroidal anti-inflammatory drugs; DMARDs: disease-modifying anti-rheumatic drugs; MTX: methotrexate; IL: interleukin; ANK: anakinra; TNF: tumor necrosis factor; IFX: infliximab; ETA: etanercept; ADA: adalimumab; RTX: rituximab; IV: intravenous; DXA: dual X-ray bone absorptiometry.

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these patients, pharmacological therapy should also be considered to decrease the risk of fracture (Fig. 1). Summary Currently, AOSD remains to be a debatable entity at the crossroad of autoimmune diseases and autoinflammatory disorders. It is usually diagnosed by exclusion. Several sets of classification criteria are available, with those by Yamaguchi et al. (1992) and Fautrel et al. (2002) being the most widely used ones. Recent advances in the understanding of the immunopathogenesis of AOSD have enabled us to use new biologic agents such as TNF-a, IL-1, and IL-6 antagonists. They have proved to be effective in the management of refractory patients with AOSD. Nevertheless, IL-1 and IL-6 inhibitors seem to be more effective than TNF-a blockers. Although it is remains debatable, we support the use of these biologic agents in patients with AOSD who are refractory to conventional DMARDs. Further investigation, including the search of novel biomarkers, is needed to fully elucidate the nature of this syndrome and better define the different phenotypes of the disease.

Practice points  AOSD is a complex and heterogeneous disorder at the crossroad of autoinflammatory and autoimmune diseases.  The pathogenesis of AOSD remains unknown, but some of the key proinflammatory cytokines (TNF-a, IL-1, IL-6, and IL-18) and an innate immunity disorder are involved.  The first line therapy for AOSD is based on corticosteroids. In the presence of corticosteroid resistance or dependence, conventional DMARDs should be used, especially methotrexate.  In corticosteroid or DMARD-refractory patients or in life-threatening AOSD, biologic agents should be considered.  IL-1b and IL-6 antagonists seem to be more effective than anti-TNF-a agents. TNFa blockers and anti-IL-6 agents seem be more useful for the polyarticular manifestations. Anti-IL-1b and anti-IL-6 agents are proved to be effective for AOSD with predominant systemic manifestations.

Research agenda  Advances in the understanding of the AOSD immunopathogenesis will help us to develop new therapeutic strategies.  Development of biomarkers allows us to differentiate and monitor the two main phenotypes of AOSD: the predominant articular and the systemic patterns.  Despite AOSD being an uncommon disease, controlled clinical trials with new drugs should be conducted.  Development of inhibitors of other pro-inflammatory cytokines, including IL-18 and IFN-g, may open new avenues in the management of this disease.

Conflict of interest statement Dr RB received grants/research supports from Abbott, MSD, and Roche, and had consultation fees/ participation in company-sponsored speaker's bureau from Abbott, Pfizer, Roche, Bristol-Myers, Janssen, and MSD.

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