Adult Onset Still's Disease

Juan Javier Lichauco, M.D., Jayashree Sinha, M.D., and Peter Barland, M.D.

Drs. Lichauco and Sinha are Fellows in Rheumatology, Department of
Medicine, Montefiore Medical Center and the Albert Einstein College of
Medicine, New York.

Drs. Lichauco and Sinha report no commercial conflicts of interest.


Adult Onset Still's disease (AOSD) is a multisystemic inflammatory disorder
of unknown etiology characterized by spiking fever, skin rash,
arthralgia/arthritis and myalgia. The syndrome gets its name from the fact
that it resembles the systemic form of juvenile rheumatoid arthritis first
described by Dr. Still, a renowned British pediatrician. It is rare, found
worldwide and predominantly affects young adults 16-35 years old. A familial
tendency has not been reported. Although inconsistent results have been
reported with HLA typing, an increased frequency of HLA B-35 has been found
in both children and adults with the disease.


Clinical Manifestations
Common clinical manifestations of AOSD include:


Fever
Patients most often present with high spiking fever (>39oC), occurring
usually in the evening with return of temperature to normal the next
morning. Occasionally, an unusual pattern of two fever spikes per day is
seen and in 20% of patients the temperature does not return to normal level.

Rash
The typical Still's rash is macular or maculopapular, salmon pink in color
and often fleeting and likely to be observed with a fever spike. The rash is
most commonly found in the trunk and proximal extremities but may involve
the face. In one-third of patients, the rash is mildly pruritic and develops
at sites of pressure or trauma (Koebner's phenomenon).

Arthralgia/Arthritis and Myalgia
Intense arthralgias are a universal finding. When arthritis occurs, the
affected joints resemble those of other polyarticular inflammatory joint
diseases. However, a notable feature of Still's disease is the usual
involvement of the distal interphalangeal (DIP) joints of the hand, which,
with the exception of psoriatic arthritis, is a joint commonly spared in
inflammatory joint diseases of young adults (e.g., rheumatoid arthritis, SLE
and acute rheumatic fever).

Myalgias can be severe and, like arthralgias, can increase in intensity
with the fever spike.

Sore Throat
The sore throat of AOSD has been described as a severe, constant burning
pain localized to the pharyngeal area. A review of 341 cases revealed 69% of
patients experienced sore throat early in the disease course.2

Cardio-pulmonary Manifestations
Pleuritic pain is common with pleural and pericardial effusions. Aseptic
pneumonitis, often transient and affecting upper and lower lung fields, has
been reported. Other rare manifestations, including acute respiratory
distress syndrome (ARDS), chronic restrictive lung disease, pericardial
tamponade, myocarditis and valvular vegetations mimicking infective
endocarditis have been observed.

Lymphoreticular Involvement
Lymph nodes are mobile and mildly tender with the cervical region commonly
affected. Splenomegaly and hepatomegaly are common. Although abdominal pain
is generally mild, it can in some severe cases simulate a surgical abdomen.



It is important to note that the full constellation of features may not be
present at disease onset and it may take weeks before a "classic case" with
typical features develops.



Laboratory Investigations
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:



1. greatly elevated sedimentation rate

2. leukocytosis (in most cases between 15,000-30,000, mainly neutrophiles)

3. thrombocytosis >400,000

4. elevated ferritin levels.



Elevated ferritin is a nonspecific but helpful feature of the disease.
Extremely high serum ferritin levels (>10,000 ug/dl) can be observed and it
has been postulated that response to therapy seems to be related to serum
ferritin levels. The elevated ferritin may reflect increased synthesis of
ferritin by hepatocytes as acute phase reactants. It has also been shown
that hyperferritenemia is linked to acute hemophagocytosis by hyperactivated
macrophages, while recent observations suggest that interleukin 6 may induce
synthesis of ferritin by increasing the association of mRNA with
polyribosomes in human hepatoma cells.

Several isoforms of ferritin have been described, one of which is
glycosylated ferritin. In AOSD there is a decrease in the proportion of
gycosylated ferritn. It has been shown that the combination of a
glycosylated ferritin fraction of <20% and ferritin levels above the upper
limit of normal improved the sensitivity and specificity (to 70.5 % and
83.2% respectively) as compared with using elevated ferritin levels alone.

Less common (in <50% of patients) laboratory findings include:

1. serum albumin <3.5 gm/dl

2. anemia of chronic disease with negative tests for hemolysis

3. elevated hepatic transaminase levels.



The absence of certain abnormal laboratory tests is frequently helpful in
the diagnosis of AOSD. These include:

1. negative or very low titers ANA and rheumatoid factor

2. synovial and serosal fluids demonstrate sterile inflammatory exudates.


Criteria for Adult Still's Disease
Several authors have proposed criteria for the diagnosis of AOSD. Yamaguchi
et al.7 suggested the following preliminary criteria:



Major Criteria
1. Fever of 39oC or higher, lasting one week or longer

2. Arthralgias lasting two weeks or longer

3. Typical rash

4. Leukocytosis (10,000/mm3 or greater) including > 80% granulocytes.

Minor Criteria
1. Sore throat

2. Lymphadenopathy and/or splenomegaly

3. Liver dysfunction

4. Negative rheumatoid factor and negative ANA.



Classification of AOSD disease requires five or more criteria including two
or more major criteria, as well as the exclusion of other major disease
entities in the differential diagnosis. Unfortunately, these criteria were
proposed before the observation of greatly elevated ferritin levels in the
majority of patients with AOSD.



Radiograhpic Changes
The radiographic changes at presentation may be normal, or demonstrate soft
tissue swelling or periarticular osteopenia. In patients with chronic
articular disease, carpometacarpal and/or intercarpal ankylosis is a typical
finding, with changes most marked in the pericapitate area. Similar changes
in the intertarsal and tarsometatarsal area can occur, although less
frequently than wrist involvement. Other uncommon features include ankylosis
of the cervical spine's interapophyseal joints (that connect the vertebrae)
and distal interphalangeal joints (DIP) resulting in Heberden's nodes.
Although erosive disease is not a prominent feature, rapid destruction of
the hip or knee joint has been reported.



Differential Diagnosis
Because of the multisystemic nature of the disease and the lack of a
specific diagnostic or confirmatory test, the diagnosis of Still's disease
is one of exclusion. The major disease entities, which should be considered,
are:

Infections
a.. viral infections such as hepatitis, rubella, parvovirus, coxsackie,
EBV, CMV and HI
b.. infective endocarditi
c.. tuberculosis
d.. Lyme disease, Ehrlichiosis
Granulomatous Disorders
a.. sarcoidosis
b.. idiopathic granulomatous hepatitis
c.. Crohn's disease
Malignancy
a.. leukemia
b.. lymphoma
Connective Tissue Disease
a.. SLE
b.. Mixed connective tissue disease
c.. Vasculitis associated with polyarteritis nodosa (PAN), Wegener's
granulomatosus or Takayasu's arteritis
d.. Hypersensitivity vasculitis with serum sickness-like reaction.


Etiology
Uncertainty remains as to the etiology of the disease. Several proposed
mechanisms include:



Infectious
The abrupt onset of fever, sore throat, rash, lymphadenopathy and
leukocytosis suggests an infectious trigger.

No common infective agent has been implicated, although rubella virus has
been isolated in several cases. Isolated case reports have noted an
association with EB virus, CMV, mumps, parainfluenza virus, Yersinia
enterocolitica and Mycoplasma pneumonia.

Immune Complex
This hypothesis is based on the observation that some patients have
detectable circulating immune complexes leading to the development of a
non-necrotizing immune complex vasculitis.

Genetic
No consistent results have been obtained for an association between AOSD
and HLA loci.

Hormonal Influences
This has been considered but, unlike SLE or RA, both sexes are equally
affected in adult Still's disease.

Pregnancy may play a role in disease onset and risk of relapse.



Disease Course
The disease pattern of patients with adult Still's disease may be divided
into:


Cyclic Systemic Pattern
This pattern represents individuals in whom systemic disease is the
dominant aspect of the illness. Articular involvement tends to be mild and
its course parallels the more prominent systemic features. This can be
further subdivided into:

Monocyclic Systemic
Characterized by a single bout of systemic disease of variable duration
followed by laboratory and clinical remission

Polycyclic Systemic
Two or more episodes of systemic disease separated by clinical remission
lasting a minimum of two months

Chronic Articular Pattern
This pattern recognizes patients in whom articular disease activity is
chronic and dominates the clinical picture. Patients in this category may or
may not have co-existing polycyclic systemic disease.



Prognostic Features
In several studies of prognosis,8,9 a poorer outcome has been observed in
patients with :



1. polyarticular onset

2. proximal joint arthritis (shoulder or hip involvement)

3. prior episode in childhood

4. requirement for systemic steroids for more than two years.



In contrast, long-term follow up of patients with monocyclic or polycyclic
systemic disease, no arthritis at presentation or an oligoarticular onset
and course showed better functional status.



Management
For the acute disease, 20-25% of patients respond to NSAIDs at
anti-inflammatory doses and an initial therapeutic trial with these agents
is reasonable. Those who respond frequently fall into the good prognosis
group with mild disease activity. The major concerns of NSAID use are
hepatotoxicity and intravascular coagulopathy. NSAIDs should be continued
for 1-3 months after the disease has remitted.

Systemic corticosteroids provide prompt control of the acute disease and are
indicated in cases of pericardial tamponade, myocarditis, intravascular
coagulopathy and other life-threatening manifestations of the disease. Doses
of 0.5 mg/kg to 1.0 mg/kg/day of prednisone may be required initially and
during corticosteroid tapering. During this period, close monitoring of the
patient is necessary as disease flares are common.

For patients with chronic disease (persistent disease activity 12 months
after diagnosis), weekly oral methotrexate has been used to limit steroid
use. Other second line drugs, such as IM gold, D-penicillamine,
hydroxychloroquine and azathioprine, have been used as well.
Cyclophosphamide, because of its toxicity, should be reserved for the most
exceptional cases. Lastly, the role of anti-TNF therapy in the treatment of
adult Still's disease refractory to conventional therapy appears promising10
but further studies to evaluate the long-term safety and efficacy are
needed.


References
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1998.

2. Nguyen K, Weisman M. Severe sore throat as a presenting symptom of adult
onset Still's disease: a case series and review of the literature. J
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3. Zenagui D, De Coninck JP. Atypical presentation of adult Still's disease
mimicking acute bacterial endocarditis. Eur Heart J 1995; 16: 1448-50.

4. Schwarz-Eywill M, Heilig B, Bauer H, Breitbart A. Evaluation of serum
ferritin as a marker for adult Still's disease activity. Ann Rheum Dis 1992;
51: 683-5.

5. Kumakura S, Ishikura H, Munemasa S, Adachi T, et al. Adult onset Still's
disease associated hemophagocytosis. J Rheumatol 1997; 24: 1645-7.

6. Fautrel B, Le Moel G, Saint-Marcoux B, Taupin P, et al. Diagnostic value
of ferritinand glycosylated ferritin in adult onset Still's disease. J
Rheumatol 2001; 28: 322-8.

7. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for
classification of adult Still's disease. J Rheumatol 1992; 19: 424-30.
return

8. Ohta A, Yamaguchi M, Kaneoka H, et al. Adult Still's disease: review of
228 cases from the literature. J Rheumatol 1987; 14: 1139-46. return

9. Cush JJ, Medsger TA, Christy WC, et al. Adult-onset Still's disease.
Clinical course and outcome. Arthritis Rheum 1987; 30: 186-94. return

10. Cavagna L, Caporali R, Epis O, et al. Infliximab in the treatment of
adult Still's disease refractory to conventional therapy. Clin Exp Rheumatol
2001; 19: 329-32. return