Abstract
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)-α, interleukin (IL)-1, IL-6, IL-18, and IFN-γ 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 μg/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-α, IL-1, and IL-6 antagonists had been proved effective in patients with AOSD.
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 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 . 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 . The reported prevalence rates range from 1 to 34 cases per 1 million people . Women seem to be slightly more commonly affected than men . There is a bimodal age distribution, with one peak between 15 and 25 years and the second between 35 and 45 years of age .
The precise etiology of AOSD is unknown. Currently, AOSD is considered a complex auto-inflammatory 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-γ, and TNF-α. Besides, there are some cases of AOSD associated with malignancies including solid cancer and hematological disorders .
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 . AOSD presents in some patients as persistent fever of unknown etiology. The frequency of the most relevant clinical features is shown in Table 1 .
| Clinical manifestations | Frequency range (%) a |
|---|---|
| Fever ≥ 39 °C | 90–100 |
| Arthralgia/arthritis | 70–100 |
| Eruption (skin rash) | 70–90 |
| Sore throat | 50–90 |
| Myalgia | 50–80 |
| Lymphadenomegaly | 40–75 |
| Weight loss | 30–70 |
| Hepatomegaly | 20–75 |
| Splenomegaly | 20–65 |
| Pleuritis | 10–40 |
| Pericarditis | 10–30 |
| Myocarditis | 5–10 |
| Pulmonary infiltration | 10–20 |
| Abdominal pain | 5–40 |
| Fever of unknown origin (FUO) | Variable b |
Laboratory findings are nonspecific and reflect the systemic inflammatory nature of the disease . 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 μg/L with a glycosylated fraction under 20% has been found to have a high specificity for the diagnosis of AOSD . 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 ).
| Laboratory findings | Frequency range (%) a |
|---|---|
| Increased ESR (>40 mm/1st h) | 90–100 |
| Increased CRP | 90–100 |
| Leukocytosis | |
| WBC ≥ 10,000/mm 3 | 80–95 |
| WBC ≥ 15,000/mm 3 | 50–80 |
| Neutrophils (>80%) | 80–90 |
| Anemia (Hb ≤ 10 g/dL) | 65–70 |
| Thrombocytosis | 40–60 |
| Serum albumin (≤3.5 g/dL) | 75–80 |
| Elevated liver function tests | 50–75 |
| Hyperferritinemia | 45–60 |
| Glycosylated ferritin ≤20% | 70–75 |
| Negative ANA | >90 |
| Negative RF | >90 |
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 persistent polyarthritis with progressive joint destruction (∼40%) . The chronic pattern results in the maximum long-term disability. Life-threatening complications with a high mortality rate appear in about 15–20% of patients . 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 .
| 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 μg/L) |
| Histopathological features (BM aspiration/biopsy) |
| Macrophage hemophagocytosis |
| 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 |
| Sjögren’s syndrome |
| 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 |
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 . AOSD presents in some patients as persistent fever of unknown etiology. The frequency of the most relevant clinical features is shown in Table 1 .
| Clinical manifestations | Frequency range (%) a |
|---|---|
| Fever ≥ 39 °C | 90–100 |
| Arthralgia/arthritis | 70–100 |
| Eruption (skin rash) | 70–90 |
| Sore throat | 50–90 |
| Myalgia | 50–80 |
| Lymphadenomegaly | 40–75 |
| Weight loss | 30–70 |
| Hepatomegaly | 20–75 |
| Splenomegaly | 20–65 |
| Pleuritis | 10–40 |
| Pericarditis | 10–30 |
| Myocarditis | 5–10 |
| Pulmonary infiltration | 10–20 |
| Abdominal pain | 5–40 |
| Fever of unknown origin (FUO) | Variable b |
Laboratory findings are nonspecific and reflect the systemic inflammatory nature of the disease . 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 μg/L with a glycosylated fraction under 20% has been found to have a high specificity for the diagnosis of AOSD . 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 ).
| Laboratory findings | Frequency range (%) a |
|---|---|
| Increased ESR (>40 mm/1st h) | 90–100 |
| Increased CRP | 90–100 |
| Leukocytosis | |
| WBC ≥ 10,000/mm 3 | 80–95 |
| WBC ≥ 15,000/mm 3 | 50–80 |
| Neutrophils (>80%) | 80–90 |
| Anemia (Hb ≤ 10 g/dL) | 65–70 |
| Thrombocytosis | 40–60 |
| Serum albumin (≤3.5 g/dL) | 75–80 |
| Elevated liver function tests | 50–75 |
| Hyperferritinemia | 45–60 |
| Glycosylated ferritin ≤20% | 70–75 |
| Negative ANA | >90 |
| Negative RF | >90 |
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 persistent polyarthritis with progressive joint destruction (∼40%) . The chronic pattern results in the maximum long-term disability. Life-threatening complications with a high mortality rate appear in about 15–20% of patients . 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 .
| 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 μg/L) |
| Histopathological features (BM aspiration/biopsy) |
| Macrophage hemophagocytosis |
| 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 |
| Sjögren’s syndrome |
| 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 |
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 and the criteria proposed by Fautrel et al., in 2002 . 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 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 . 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 ).
| 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/mm 3 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/mm 3 (≥4 major criteria or 3 major + 2 minor are required) |
| Diseases | Diagnostic tests |
|---|---|
| Infections: | Serology, PCR |
| Viral infections: HIV, herpesvirus, viral hepatitis, parvovirus B19 | |
| Atypical infections: | Serology, PCR |
| Mycoplasma pneumoniae | |
| Borreliosis, Yersiniosis | |
| Infective endocarditis and sepsis | Blood cultures, ultrasound |
| Others (such as toxoplasmosis) | Serology, PCR |
| Malignancies: Lymphomas (Hodgkin and non-Hodgkin) Angioimmunoblastic T cell Castleman’s disease Myeloproliferative disorders Some solid cancers | CT, PET/CT, BM aspiration, lymph node biopsy Specific tests/imaging techniques |
| Autoimmune diseases: Systemic lupus erythematosus Rheumatoid arthritis Dermatomyositis Systemic vasculitis (PAN) | Specific autoantibodies Muscle biopsy ANCA, tissue biopsy, arteriography |
| Autoinflammatory diseases: Familial mediterranean fever Hyper-IgD syndrome TNF-receptor-associated periodic syndrome (TRAPS) | Familial history, genetic tests Immunoglobulin count Genetic analysis |
| Drug reactions/DRESS | Eosinophil count, skin biopsy |
| Others: Sarcoidosis Reactive arthritis Schnitzler’s syndrome Sweet’s syndrome Kikuchi-Fujimoto disease | Specific tests and imaging techniques depending on the clinical suspicion |
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 .
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-γ are increased in the serum of patients with AOSD and correlate well with disease activity . 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 . 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 .
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 . 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 . 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)-β are inversely correlated with AOSD activity .
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, highlighting its crucial role in the pathogenesis of the disease. The main pro-inflammatory cytokines involved in the pathogenesis of AOSD are IL-1β, IL-6, IL-18, TNF-α, and IFN-γ .
IL-1β 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-1β is confirmed by reports demonstrating the efficacy of anti-IL-1 therapy in AOSD .
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-1β, and the increased levels of IL-6 may be a secondary phenomenon to the overproduction of IL-1β . Interestingly, IL-6R antagonists have shown very high efficacy in the treatment of AOSD .
IL-18 is another pro-inflammatory cytokine whose serum levels are particularly high in patients with AOSD . 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 . Moreover, an association between AOSD and IL-18 gene polymorphisms has also been described .
Increased production of TNF-α 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 . However, TNFα-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-γ and IL-8/CXXL8 . IFN-γ promotes the macrophage activation and hepatocyte apoptosis. IL-8, also known as CXXL8, is a chemo-attractant molecule favoring the neutrophil recruitment. IFN-γ and IL-8 are increased in active AOSD and correlate well with chronic articular disease .
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