DEFINITION
Adult onset Still's disease (AOSD) or Wissler-Fanconi syndrome is a rare systemic inflammatory disorder of unknown etiology, characterised by quotidian high spiking fevers and evanescent (transient) salmon-colored rash,Adult onset Still's disease (AOSD)or Wissler-Fanconi syndrome is a rare systemic inflammatory disorder of unknown etiology, characterised by quotidian high spiking fevers and evanescent (transient) salmon-colored rash, arthritis, and multiorgan involvement. arthritis, and multiorgan involvement.
HISTORY
It owes its name to George Still who published in 1897 his monograph, On a form of chronic joint disease in children, describing 22 children with signs and symptoms of the disease entity currently known as systemic onset juvenile idiopathic arthritis. In 1971, Eric Bywaters described 14 adults with similar presentation with paediatric Still's disease, convincingly establishing the new disease entity. However, the first description of an adult patient with signs and symptoms of AOSD, erroneously labelled rheumatoid arthritis, was published in the Lancet in 1896, one year before George Still's monograph.
EPIDEMIOLOGY
Adult-onset Still's Disease is rare and has been described all over the world. Prevalence is estimated at 1.5 cases per 100,000-1,000,000 population. There is a bimodal age distribution with one peak incidence between ages 15–25 and a second peak between ages of 36–46 years.
SYMPTOMS
A Japanese study attempted to design classification criteria for adult Still's disease.
The proposed criteria consisted of a major criteria:
- A fever (equal to or greater than 39°C) that comes on quickly once per day, usually in the afternoon or evening. For most people, these fevers resolve without treatment.
- Joint pain, warmth, and swelling affecting a few joints at first -- often knees and wrists -- then several joints. ( Especially carpal and tarsal ankylosis ). Morning joint stiffness often lasts for several hours.
- A salmon pink-colored skin rash that usually comes and goes with the fever and is usually not itchy. Flat spots or both flat spots and small, raised bumps may appear on your torso, upper arms or legs, or face.
- Increased number of white cells (leukocytes, especially neutrophils)
and a minor criteria:
- A sore throat that can be severe, constant, and burning
- Lymphadenopathy and/or splenomegaly
- Liver dysfunction
- the absence of rheumatoid factor and antinuclear antibody
Requiring 5 or more criteria including 2 or more major criteria yielded 96.2% sensitivity and 92.1% specificity.
Sometimes thoracic pains suggestive of effusion (presence of liquids) or infiammation (pleuritis) in the pleura or around the heart (pericarditis).
Frequently, the clinical presentation, is “incomplete”, that is, only 1 o 2 signs are presents.
However, an exclusion process will be needed for an accurate classification, since this disease is relatively rare.
DIAGNOSIS
The orientation of the sign and synthoms are important to make a diagnostic hypothesis, that may be confirmated from the laboratory exams, like neutrophilic leukocytosis and especially the value of ferritin .
Ferritin,in fact, has got a diagnostic and prognostic character, especially the glycosylated
ferritin (GF), that is lowered respect the normal level, because the liver couldn’t
glycosilate in a good way.
There are no specific laboratory tests for AOSD, but there are studies in which it is examinated the potential role of adenosine deaminase in the diagnosis.
In any case,the laboratory tests reflect the systemic inflammatory nature of the disease process present in almost all patients with AOSD. The lab findings are important clues to the diagnosis of this frequently puzzling condition. The most common laboratory abnormalities include:
-greatly elevated sedimentation rate
-leukocytosis (in most cases between 15,000-30,000, mainly neutrophiles)
-thrombocytosis >400,000
-elevated ferritin levels.
The absence of certain abnormal laboratory tests is frequently helpful in the diagnosis of AOSD. These include:
-negative or very low titers ANA and rheumatoid factor
-synovial and serosal fluids demonstrate sterile inflammatory exudates.
PATHOGENESIS
In the absence of any familial aggregation, the integration of Still’s disease into the group of monogenic AIDs needs to considered the hypothesis of pro-inflammatory cellular pathways and in particular the fact that this pathology probably is mediated from cytokine (role of the IL-1 family).
Also it was really tempting to examine the possible implication of mitochondrial metabolism, since concordant works recently stressed the role played by mitochondria in the innate immune process.
Interleukin-1β (IL-1β) and IL-18 contribute to host defense against infection, that one of the factor that probably triggers the syndrome, to the by augmenting antimicrobial properties of phagocytes and initiating Th1 and Th17 adaptive immune responses. Protein complexes called inflammasomes activate intracellular caspase-1 autocatalytically, which cleaves the inactive precursors of IL-1β and IL-18 into bioactive cytokines. It seems that the role of IL-18 isn’t important to the cytokine production, but is fundamental for the amplification of the signal. The major role is playing by a group of molecules called DAMPs (as ATP, uric acid. Etc.) , that are important to signalize that the pathogen is really dangerous for the survival of the cell.
The mitochondrian, standing for the whole ensemble of mitochondria in an individual, not only produces the energy necessary to the cell, but also contributes, in certain conditions, to the activation of the innate immune system and to the systemic inflammatory responses.
All these molecules can induce or amplify the tissutal lesions observed in different inflammatory diseases. Of note, the reactive oxygen species produced by dysfunctional mitochondria, together with the inhibition of mitophagy, can activate NLRP3 inflammasome . Moreover, it has been speculated that an NLRP3-binding protein could be released from dysfunctional mitochondria .
The very high levels of PMNS that is usually registered during bouts of Still’s disease could be related to the fact that PMNs are the main target of MTDs.
Interestingly, infections due to Bartonella henselae, an agent belonging to the group of proteobacteria, can induce systemic manifestations resembling those observed in Still’s disease
PATIENT RISK FACTORS
There are not risk factors knowed for this pathology, but there are negative prognostic factors, that are important to the therapy and to make a correct follow up.
EVOLUTION AND PROGNOSIS
There are three types of manifestation, that are important for the therapy and prognosis: monocyclic systemic ( 26% of the patients with only 1 episode of systemic manifestations, followed by complete remission within 1 year after disease onset); polycyclic systemic (30% of the patient >1 episode of systemic manifestations, followed by partial or complete remission after onset of the initial or the subsequent attack); and chronic /persistent articular ( 44% persistent arthritis involving at least 1 joint area, lasting >6 months).
There are three negative prognostic factors : male sex,
the type chronic /persistent articular manifestation and the high level of ferritin.
THERAPY
Still’s disease can cause serious damage to the joints,
particularly the wrists knees and hips. It can also impair the function of the heart and lungs. Treatment of Still’s disease is directed toward the
individual areas of inflammation. Many symptoms are often controlled with anti-inflammatory drugs, such as aspirin or other non-steroid drugs (NSAIDs).
Cortisone medications (steroids), such as prednisone, are used to treat more severe features of the illness. For patients with persistent illness,
medications that affect the inflammatory aspects of the immune system are used.
Medications now being used are analogous to the classic “second-line” therapies used for patients with Rheumatoid Arthritis. These include Gold, Hydroxychloroquine
(PLAQUENIL), Penicillamine, Azathioprine (IMURAN), Methotrexate(RHEUMATREX), and Cyclophosphamide. There is a new class of drugs called biologics that are
very promising in treating Still’s.
Different approaches are now proposed and the most interesting is the use of Anakinra,an IL-1 inhibitor
Diagnosis and management of adult onset Still's disease.,2006
Adult - onset Still's disease : A review.,2009
Still’s disease and the mitochondrion: The other face of an old friend,2012
Potential role of adenosine deaminase in the diagnosis of adult-onset Still's disease.,
2013
Inflammasome activation and IL-1β and IL-18 processing during infection,2011
Mitochondria: Sovereign of inflammation?, 2011
A role for mitochondria in NLRP3 inflammasome activation., 2012
Beneficial effect of interleukin 1 inhibition with anakinra
in adult-onset Still's disease. An open, randomized, multicenterstudy., 2012
Emanuela Gambetta
Marta Nazha
