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AOSD Bulletin
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BULLETIN ON
THE RHEUMATIC DISEASES Arthritis
Foundation FOR
EVIDENCE-BASED MANAGEMENT OF RHEUMATIC DISEASESA PUBLICATION OF THE ARTHRITIS FOUNDATION VOL.49 NO.6 SUMMARY
POINTS · AOSD presents
with a triad of quotidian fever, evanescent rash, and polyarthritis. · The etiology of
AOSD is unknown, but circadian release cytokines accounts for many features. · Morbidity is
largely linked to chronic arthritis, which may be destructive in 20% to 25% of
patients with AOSD.
Adult-Onset Still's Disease John J. Cush, MD Chief, Rheumatology and Clinical Immunology,Presbyterian Hospital of Dallas, Clinical Professor of Internal Medicine, The University of Texas SouthWestern Medical Center at Dallas, Dallas, TX Adult-onset
Still's disease (AOSD) is a systemic inflammatory disorder of unknown cause. The
clinical course is dominated by systemic activity with exacerbations and/or
chronic arthritis. There is no diagnostic test or pathognomonic histopathology,
so the diagnosis of AOSD is often a diagnosis of exclusion. Etiology No
etiologic trigger has been proven for AOSD; however, an infectious agent has
been inferred based on symptom complex (ie, sore throat, fever). Many of the
clinical manifestations are reminiscent of those seen during self-limited viral
infections. Investigators have also demonstrated the persistence of
viral antigens, especially rubella, in patients with juvenile arthritis
and AQSD. The circadian release of proinflammatory cytokines (especially
interleukin 6) appears to account for many features of AOSD. Demographics AOSD has
been described in nearly all countries and races. Few (n = 13) large-series
studies (>10 patients) have been undertaken. From these series we estimate
that AOSD is a relatively rare condition and that major academic medical centers
may see 1-3 new cases of AOSD per year. In several large series of people with
fever of unknown origin (FUO), AOSD was consistently the most common rheumatic
cause of FUO, ranging from 5% to 9% of all FUOs. AOSD is
typically a disease of young adults, affecting men and women equally. Disease
onset is before age 35 years in nearly 76% of patients.
From a review of the medical literature it can also he estimated that
fewer than 10% of patients will have disease onset after 50 years of age. AOSD
in the elderly may be difficult to diagnose, primarily because of comorbid
conditions, a wider age-related differential diagnosis, atypical cutaneous
features, and fevers that tend to be lower. Disease Onset The onset of AOSD
is often heralded by a sore throat and other constitutional symptoms. A
prodromal sore throat occurring days to weeks before the onset of fever or rash
is seen in more than 70% of patients. It is typically nonexudative, lasts for
several days, and is unresponsive to antibiotics. Whether this represents a
triggering mucosal infection or is a manifestation of lymphoid activity and
inflammation is unknown. Constitutional features soon follow and may include
severe myalgias or arthralgias, fatigue, anorexia, nausea, and rapid weight
loss. Weight loss is seen in 50%-60% of patients, may be dramatic and rapid, and
tends to parallel inflammatory activity as measured by dropping hemogloin and
serum albumin values. Quotidian Fever A quotidian fever
is a once daily febrile spike >3~C (102.20F) with intervening afebrile intervals.
Nearly two-thirds of patients will have peak temperatures greater than 400C
(104) More than 94% of patients will demonstrate a quotidian or double quotidian
(twice daily spikes) fever pattern. A minority of patients may exhibit a
remittent pattern with febrile spikes and an elevated baseline temperature. Thus
one of the more distinctive features of AOSD is the occurrence of fever at
nearly the same time every day, usually late at night or, less commonly, late
morning or afternoon. This circadian feature may be diagnostically important.
Fevers are heralded by the onset of shaking chills, followed by 24 hours of
high fever (often >4~C), and then defervescence with drenching sweats. It is
also common for fever to be accompanied by the appearance or exacerbation of
rash, myalgias, arthralgias, headache, nausea, or serositis. Quotidian fever is
most prominent during disease onset and flares of systemic activity. Evanescent
flash The
characteristic rash of AOSD has been called the Still's rash, or juvenile
rheumatoid arthritis (J RA) rash, in the literature. Rash is seen in more than
92% of patients. It is evanescent, frequently appears during febrile attacks,
lasts for hours, and tends to change from day to day. It is typically a faint
salmon-colored (infrequently erythematous), morbilliform exanthem found on the
extremities (extensor surfaces), trunk, and neck. Koebner phenomenon, dermatographism,
pruritis, and/or urticaria are commonly seen. Involvement of the face, palms, or
soles is exceedingly rare. Cutaneous manifestations of AOSD are most prominent
early in the disease and tend to decline with time. In nearly all instances,
skin biopsies and immunofluorescent studies are nondiagnostic. Pathology of
lesional skin reveals a nonspecific chronic inflarnrnatory picture with a
perivascutar mononuclear (and seldom polymorphnuclear) infiltrate, vascular
dilation, and dermal edema. Articular
Manifestations Arthritis
is found in nearly 93% of people with AOSD, and is usually the last feature of
the triad to appear. The early clinical picture is likely to be dominated by
complaints of arthralgia, myalgia, morning stiffness, and less commonly,
synovitis. Although the arthritis may begin as oligoarticular and migratory, it
will develop into an additive polyarthritis that will affect both small and
large joints if the AOSD is persistent. Chronic monarthritis has not been
observed in AOSD and should prompt other diagnostic considerations. The most
commonly involved joints at the outset include the knee, wrist, ankle, elbow,
shoulder, proximal interphalangeal joints (PIP), and cervical spine. If the
arthritis becomes chronic (lasting longer than 6 months) the wrists are
prominently affected, with less common involvement of the tarsal, cervical, and
PIP joints. Neck pain is seen in nearly half of patients. AOSD is
associated with carpal or carpopmetacarpal ankylosis (wrist fusion). Nearly
50% of people with systemic JA or AOSD will develop carpal ankylosis that will
become painless once fused. A lesser tendency for ankylosis has also been noted
in the tarsal joints and cervical spine. The risk
of chronic, destructive, and disabling polyarthritis is quite high in both
systemic JA and AOSD, occurring in 20%-25% of cases. Disability and significant
joint damage may result from early, progressive inflammatory arthritis and,
later, secondary degenerative changes. Erosive disease has the greatest impact
on weight-bearing joints (hips and knees), shoulders, and hands. Synovial
biopsies have not revealed a distinctive pathology but instead demonstrate
chronic synovitis with proliferation of the synovial lining layer and
perivascular infiltration of mononuclear cells (eg, lymphs, plasma cells). Other
Systemic Features Lymphadenopathy (65%), splenomegaly,
(42%) and hepatomegaly (40%) are very common early in the disease and reflect
tissue infiltration with inflammatory cells and heightened immunologic activity
within the reticuloendothelial system (RES). More than 70% of patients will
exhibit some degree of liver dysfunction as demonstrated by elevation of hepatic
enzymes (eg, AST, ALT, alkaline phosphatase). Liver biopsies have demonstrated
periportal mononuclear infiltrates (lymphocytes, plasma cells) and Kupffer cell
hyperplasia. Hypoalbuminemia is often impressive and is seen in 76% of people
with AOSD. Lymphadenopathy is usually generalized and manifests as
mild-to-moderate, painless nodal enlargement. Isolated or focal lymph node
enlargement is rare and should question the diagnosis and may require lymph node
biopsy. Lymph node biopsies in AOSD patients are nondiagnostic and tend to show
reactive hyperplasia or lymphadentis. At least six cases of Kikuchi’s
syndrome, or necrotizing lymphadenitis, have been described in AOSD. Kikuchi's
syndrome is a benign disorder that is usually associated with viral infection,
and may manifest as fever, tender lymphadenopathy, hepatomegaly, leukopenia,
and elevated ESR Pleuritis
(40%) and pericarditis (30%) occur in AOSD and may be one of the presenting
complaints. Thoracentesis or pericardiocentesis often yields exudative
effusions. Although uncommon, a worrisome manifestation of AOSD is acute pericardial
tamponade. In such cases emergent drainage and high-dose corticosteroids are
indicated. Pneumonitis is found in more than 20% and may present as bilateral
alveolar and interstitial infi1trates on radiographs. Abdominal pain has also
been described in 30% of people with AOSD and may be ascribed to several etiologies,
including serous peritonitis, mesenteric adenitis, hepatic or splenic
distention, and ileus or small bowel obstruction. Renal
involvement is not usually seen in AOSD, although minor degrees of proteinuria
may be noted during febrile episodes. Other uncommon or rare findings in AOSD
include sensorineural hearing loss, aseptic meningitis, meningoencephalitis,
orbital pseudotumor, disseminated intravascular coagulation, hemopliagocytic
syndrome, and keratoconjunctivitis sicca. Laboratory
and Radiographic Findings Despite the systemic inflammatory
features present in AOSD, patients are uniformly seronegative for RF and ANA.
Laboratory findings in AOSD reflect the degree of inflammatory and cytokine
activity present. The majority of people with AOSD will have a neutrophilic
leukocytosis, with white blood cell counts usually ranging from 12,500 to 40,000
cells(mm3. Leukopenia or extreme leukocytosis are rare in AOSD and
should raise the possibility of another diagnosis (eg, leukemia; lymphoma;
Kikuchi's or hemophagocytic syndrome). Nearly all patients will have marked
elevations of the acute phase reactants, including erythrocyte sedimentation
rate (ESR), C-reactive protein (CRP), serum amyloid A (SAA), serum complement
levels, haptoglobin, and serum ferritin. It may be helpful to note
that 90% of AOSD patients have an ESR >50 mm/hr and 50% have and an
ESR >90 mm/h. Other signs of systemic inflammation during the early active
systemic stage include drop in hemoglobin and hematocrit, anemia of chronic
disease, and thrombocytosis. Much has
been made of tile potential diagnostic utility of extreme elevations of serum
ferritin. Fenitin is also an acute phase reactant, and extreme elevations, or
hyperferritineinia (>4,000 ng/ml). are seen in fewer than 50% of patients.
Extreme levels may range from 4,000 to 30,000 ng/ml, although levels as high
as 250,000 ng/rnl have been reported. Hyperferritinemia may also be seen in
other conditions, including iron overload conditions (hemochromatosis,
polytransfisions), neoplasia (eg, leukemia, lymphomas), hepatitis, pancreatitis,
sepsis, other systemic inflammatory diseases (eg, rheumatoid arthritis, systemic
lupus erythematosus), and hemophagocytic syndrome. Other
major laboratory abnormalities seen in people with AOSD include elevation of
hepatic enzymes (70%), hypoalbuminemia (76%), and hypergammaglobulinemia
(50%). Elevations of the hepatic enzymes may show either a cholestatic or
hepatocellular pattern. Hyperbilirubinemia is very uncommon, but if present, it
may indicate severe hepatic involvement and the need for high-dose
glucocorticoids. Up to one-third of patients may have an elevated anti-streptolysin-O
titer at disease onset, although throat cultures are invariably negative. Such
a finding reflects nonspecific heightened immunologic activity during active
disease. Radiographs
will reveal the distinctive pattern of intercarpal pericapitate ankylosis will
develop in nearly half of these patients and usually manifests in the first few
years of disease. There is also a tendency for intertarsal (19%) and cervical
zygapophyseal (12%) ankylosis to occur in AOSD patients. Erosive arhritis and
juxta-articular osteopenia may be found in the minority who demonstrate a
chronic arthropathy. Diagnosis The
differential diagnosis of AOSD is large and has considerable overlap with other
disorders capable of causing a FUO. Nonetheless, several conditions are often
confused with AOSD and bear specific mention. Viral syndromes are the most
common cause of misdiagnosis. In such patients the viral condition seldom
persists beyond 3 months and may be confirmed by obtaining acute and
convalescent viral serologies. Viral pathogens that may behave as AOSD include
rubella, Epstein-Barr virus, mumps, cytomegalovirus, Coxackie, and adenovirus.
Acute leukemia and lymphoma may also mimic AOSD. Such patients are unlikely to
have all three features of the diagnostic triad, often have isolated lymph
node enlargement, atypical rashes, and/or hematologic abnormalities not commonly
seen in AOSD. In some instances, it may be necessary to perform lymph node or
bone marrow biopsies to distinguish these diagnoses. Other
conditions commonly confused with AOSD include Reiter's syndrome,
dermatomyositis, hemophagocytic syndrome, Kikuchi's syndrome, or a systemic
febrile onset of rheumatoid artitritis. The diagnosis requires a
comprehensive, noninvasive evaluation; close observation (usually during
hospitalization); documentation of fever pattern, exanthem, and other systemic
features; and laboratory evidence of systemic inflammation. Table 1 lists my
diagnostic criteria. Patients can be diagnosed with AOSD if they possess all
five major criteria (at two points each) or any combination of major and minor
criteria (one point each)that yields a score of l0 points or more. Proposed Criteria for AOSD Diagnosis Major
(two points) Quotidian
fever> 39'C Still's
(evanescent) rash WBC>
12.0 + ESR > 40 mm/h Negative
RF and ANA Carpal
ankylosis Minor (one point) Onset
age <35 years Arthritis Prodromal sore throat RES involvement or abnormal LFTs Serositis Cervical or tarsal ankylosis Probable AOSD: 10 points with 12 weeks observation Definite AOSD: 10 points with six months observation The diagnosis of AOSD is probable
after 3 months of clinical Ictivity and definite after 6 months of ol)servation. Patients
who present with several features suggestive of AOSD, but eithher do not have
the classic triad or do not meet diagnostic criteria may be more common than
those with AOSD itself. Some clinicians have referred to such patients as having
a forme fruste of AOSD or incomplete AOSD. Experience with people with
incomplete AOSD suggests they will have more limited disease and a
favorable outcome, especially with regard to their joints. Clinical
Course and Prognosis Fewer than
20% of patients will have a self-limiting monocyclic pattern of systemic
disease (eg, fever, rash, serositis, organomegaly, etc). In this group, systemic
activity will last for at least 4-12 months. A majority
of patients demonstrate a pattern of recurrent systemic disease (polycyclic
systemic) with or without chronic articular disease. Multiple systemic flares,
may be interspersed by disease-free intervals that may last for years. All
patients should be told of the potential for disease recurrence. There is a
small risk of life-threatening complications (ie, pericardial tamponade, liver
or respiratory failure). However, the vast majority of patients with a
predominance of systemic disease will have favorable outcomes. The infrequent
causes of death reported in AOSD are related to either iatrogenic causes from
medications (eg, infections, gastrointestinal bleeding) or to other comorbid
conditions or acidents. A
substantial minority of cases (25%) will evolve into chronic inflammatory
articular disease that can be destructive and debilitating. It has been shown
that patients with a polyarticular onset and course, hip involvement, and
HLA-DR4 positivity will have the poorest outcomes. In contrast, patients with an
HLA-Bw35 haplotype are more likely to exhibit systemic disease and a favorable
outcome. Therapy
of AOSD For many
patients, NSAIDs will be the initial choice of therapy to control both systemic
and articular features. Although any NSAID therapy at anti-inflammatory doses
can be used, sustained release indomethacin (75-150 mglday) appears to be
effective in 40%~60% of patients early in the disease. Aspirin is seldom
effective and may be associated with salicylate-induced -hepatotoxicity.
Glucocorticoids are often employed, but should be reserved for those patients
with markedly elevated hepatic enzymes, pericardial tamponade, severe serositis,
or pneumonitis and in those resistant to NSADs. High-dose prednisone (40-60
mg/day) may be necessary to control systemic manifestations. Weekly oral
methotrexate (7.5-20 mglweek) has successfully been used to control systemic
and articular manifestations and should be used early in those with severe
-to-protracted disease to limit steroid exposure. Patients who are not
adequately controlled by NSADs, prednisone, and methotrexate appear to respond
well to the addition of a TNF inhibitor (etanercept or infliximab). Unresponsive
patients may also be treated with leflunomide, hydroxychloroquine, azathioprine,
or cyclosporine, but there is no literature to support their use in AOSD.
Chronic, progressive polyarthritis can be managed in the same manner as that
employed for rheumatoid arthritis. Bibliography 1.
Bywaters EG. Still's disease in ~ite adt~lt. Ann Rheum Dis 1971;
30:121-33. 2.
Cush JJ, Medsger TA Jr, Christy WC, Herbert DC,
Cooperstein LA. Adult-Ons('f Still's disease. Clinical
course and outcomC. A i-thritis Rheunt 1987;
30:186-94. 3.
DeBenedilti F, Massa M, Pignatti P, Albani S. Novick D,
Martini A. Seruin soltdble interleukin 6(11-6) receptor a,nl 1L,titsoluble 1~6
necelpor conwiex in systemic juvenile rht's,,'tat~nd arthritis. J Clin
luvestigafion 1994; 93:2114-9 4.
. 5.
Elh'oft MJ, Woo P, CharLes P, 1~ng-For A, Woody JN, Maini RN.
Suppnessiofl offeter and tise acute-phase response in a patient withjuyenile
chmisic arthritis treated with monoclonal antibody to tutsut'our
necmsisfactor-olpha (cA2). Br J Rheunatol 1997; 36:589-93. 6.
5.
Fujii 7: Akizuki M, Kameda H. Matst'mara M. Hirakata
M, Yoshida 7: Shinozawa 7; Mirnori 7:
Methotrexate tneat'netst in potients with adult onset
Still's disease - r,tmspective study of 13 Japwtese
cases. Ann Rheum Dk 1997: 56:144-& 6.
PolLchot J. Sampalis JS, Beaadet F. et aL Adult Still's disease:
nan'yestations. dis'tae course, a,td outcome in 62 patients. Medicine. 1991;
70:118-36. PUBLISHING STAFF: Publisher, William M. Otto; Managing
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