Case report

J Indian Rheumatol Assoc 2002 : 10 : 19 - 21

ADULT-ONSET STILLS DISEASE

Vinod Chandran, Amita Aggarwal, Ramnath Misra
Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow.
The adult counterpart of Stills disease, Adult- onset Stills
disease (AoSD) was first described by Eric GL Bywaters in
1971, with description of 14 patients.1 Subsequently more than
2,3
300 patients have been reported including a few small series from India.2,3,4,5,6 We describe herein a patient with Adultonset Stills Disease, who had been having fever for more
than a year.
A 46-year old male power-loom worker presented
with fever of 14 months duration. The fever was high grade
and intermittent in character, with a single daily spike of more
than 39Celsius. It was associated with dermographism and
severe sore throat. He had been extensively investigated for
possible infectious disease. He had received antibiotics and
antimalarial drugs without any response.
Two months after onset of fever, he developed pain
and stiffness of the neck. He was thought to have tuberculosis
of the cervical spine and received anti-tubercular drugs for 8
months without any relief. One month after onset of neck pain
and stiffness, he developed arthralgia involving both knee
joints and 6 months later, symmetric arthritis involving the
knees, wrists, elbows, ankles, small joints of the hands and
the tempero-mandibular joints. The intensity of the fever decreased with the onset of arthritis. He gradually
developed restriction of movement of wrists and the neck. He
also developed symptomatic anemia with onset of arthritis.
There was no history of abdominal pain, diarrhoea,
non-healing ulcers, neuropathy, chest pain, breathlessness,
haemoptysis, nocturia, oliguria, hypertension or symptoms
related to eyes and ears.
Physical examination revealed pallor, hepatosplenomegaly, and marked restriction of movement of the
wrists and cervical spine. Investigations revealed
haemoglobin of 6.5 gm/dL, polymorphonuclear leucocytosis
(TLC 16000/mm3 with 90% polymorphs), thrombocytosis
(platelet count 5.72 lacs/ mm3), a markedly raised ESR (110
mm in the first hour by Westergren method), negative
antinuclear antibodies and rheumatoid factor. X-ray of the
hands showed severe juxta-articular osteoporosis (Fig-1) without any erosion. Cervical spine X-ray showed apophyseal joint
fusion.
Address for correspondence
Prof R Misra
Department of Immunology, Sanjay Gandhi Postgraduate
Institute of Medical Sciences, Lucknow. 226 014.
E-mail : rnmisra@sgpgi.ac.in

Figure 1 : Hand radiograph showing severe juxtaarticular osteoporosis

In view of the presence of characteristic fever, sore
throat, polyarthritis, markedly raised ESR, leucocytosis, and
the absence of antinuclear antibodies and rheumatoid factor,
a diagnosis of Adult-onset Stills disease was made. He was
treated successfully with Prednisone (0.5 mg/kg) and Naproxen
sodium.
Discussion:
Adult-onset Stills disease accounts for 6% cases of prolonged
fever of undetermined origin (>6 months duration), along with
diseases like granulomatous hepatitis (9%),
neoplasia (7%), infection (6%) and collagen vascular disease
(4%).7 The diagnosis of AoSD is made after exclusion of
infections and malignancies.
In view of lack of diagnostic physical signs and tests, criteria
for the diagnosis of AoSD have been laid down.8 (Table )
Table: Diagnostic criteria for Stills disease
Diagnosis of Stills disease requires the presence of all
criteria in A and any two from B
A
Fever >or =39 degree Celsius
Arthralgia or arthritis
RF<1:80
ANA <1:100
B
TLC> or =15000/mm3
Stills rash
Pleuritis or pericarditis
Hepatomegaly or splenomegaly or generalized
lymphadenopathy.
Fever is present in more than 95% of cases.2
Classically, it is >39C, with one daily evening spike.

Vinod Chandran et al

However, the fever can have more than one spike and may be
continuous. Characteristically, the patient looks well when he
is afebrile. Around 90% of patients also have sore throat due
to non-exudative pharyngitis. Most patients also develop
weight loss of more than 10%.
The typical Stills rash is an evanescent, salmon
pink macular or maculopapular rash, seen along with the spike
of fever on the trunk and proximal extremities. Even though
>90% patients in series reported from the West 2,3 have this
characteristic rash, this has been less reported in studies from
India4,5 probably due to the difficulty in identifying the rash in
people with dark skin. The rash can be induced by minor
trauma (Koebner phenomenon). Dermographism has also been
described.
Arthritis occurs in about 95%, 2,3 and flare up of
joint symptoms occurs during the febrile spike. As the
duration of the disease increases the arthritis becomes more
prominent and the fever decreases in intensity. The most
common joints involved are the knees, followed by the wrists,
ankles, elbows, metacarpophalangeal, metatarsophalangeal,
and distal interphalangeal joints, hips, neck and
temperomandibular joint and interphalangeal joints of the feet.
Polyarthritis is most common. However, a few patients have
oligoarthritis and rarely a single joint is involved. 5% of
patients do not have arthritis. 2 About 18% have distal
interphalangeal joint involvement.2 Radiographs of the affected
joints in early disease show juxta-articular osteoporosis and
soft tissue swelling. Later in established arthritis, erosions and
joint space narrowing might be detected. A selective
non-erosive narrowing of the carpometacarpal and
intercarpal joint spaces, later leading to a intercarpal bony
fusion is more specific for AoSD as compared to more
radiocarpal involvement in rheumatoid arthritis.9 Ankylosis of
the apophyseal joints of the cervical spine occurs uncommonly.
Destructive arthritis of the hips occurs in 5-33% of patients.2,3
Lymphadenopathy, splenomegaly and hepatomegaly are detected in 63, 52 and 42% of patients, respectively2,3.
Cervical lymph nodes are most commonly affected. About a
third of patients have pleural effusion, and 27% of patients
have pneumonitis affecting the upper or lower lobes. Rarely,
patients develop acute respiratory distress syndrome and
interstitial lung disease. Pericarditis is seen in about a third of
patients rarely leading on to tamponade. Myocarditis has also
been reported. Close to 50% patients have abdominal pain
and can occasionally simulate an acute surgical abdomen2,3.
Rare manifestations like secondary Sjogrens
syndrome, aseptic meningitis, cranial nerve palsies,
peripheral neuropathy, retinal lesions, iritis, panophthalmitis,
interstitial nephritis, glomerulonephritis and thrombotic
thrombocytopenic purpura have also been described.

Close to 75% of patients have elevated liver

enzymes. Although this might be due to drug toxicity
(NSAIDs), in most patients the abnormality seems to be
primary2. Liver biopsies have demonstrated mononuclear
sinusoidal and portal tract infiltrates and mild kupffer cell
hyperplasia. Occasionally focal hepatitis with feathery
degeneration and necrosis of hepatocytes may be seen10.
The laboratory investigations reflect an exaggerated systemic
inflammatory response. There is polymorphonuclear
leucocytosis (92%), raised ESR (99%), hypoalbuminemia
(81%), anemia of chronic disease 65%) and thrombocytosis
(62%)3. Of the various acute phase responses, elevation of
serum ferritin seems to be characteristic of AoSD. Marked
hyper-ferritinemia is pathognomonic of AoSD. Levels of
serum ferritin correlate with disease activity and have been
used to monitor the same11. However, the percentage of
glycosylated serum ferritin remains low throughout the course
of AoSD, both during the active phase and during remission12.
The serum levels of various pro-inflammatory cytokines
(IL-1, IL-6, TNF, IFN) are elevated. Recently, the levels of
IL-18, a pro-inflammatory cytokine, have been shown to be
markedly elevated in AoSD. The levels correlate with disease
activity and serum ferritin levels. IL-18 elevations in active
AoSD, is much greater than that found in other systemic rheumatic diseases including rheumatoid arthritis and in febrile
patients with bacterial infection and malignancy. The raised
IL-18 levels result in elevated liver enzymes in 75% of cases13.
Tests for anti nuclear antibodies and rheumatoid factor are
negative in 92% and 93% respectively. If positive, they are
present only in low titres2,3.
The disease may have a monocyclic (25-30%),
polycyclic (25-30%) or chronic course (30-50%)3. In those
with monocyclic course, the disease remits within a year, never
to appear again. Those with polycyclic course have
intermittent disease and characteristically the intensity tends
to be less severe and the duration shorter in the subsequent
episodes in comparison to the first. Chronic disease is the most
disabling, leading to chronic disabling arthritis. The presence
of polyarthritis earlier in the disease course, involvement of
hip or shoulder joints, prior episode in childhood and
requirement of more than 2 years of treatment with steroids
are poor prognostic factors3,8. The absence of Stills rash
predicts a better outcome. When compared to rheumatoid
arthritis of similar duration, AoSD has a better functional
outcome with most patients being in functional class 1 or 2.3
Deaths in AoSD are due to infection, amyloidosis, hepatic
failure, acute respiratory distress syndrome and diffuse
intravascular coagulation (DIC).
20

Adult onset Still's disease

For treatment of acute disease an initial course with

NSAIDs is recommended. Liver functions need to be
monitored as NSAIDs can cause significant hepatotoxicity
compounding the liver dysfunction associated with Stills
disease. More than two-thirds of patients treated initially with
NSAIDs would subsequently require steroids in dosages
ranging from 0.5mg/kg to more than 1mg/kg for control of
disease activity. Absolute indications for steroids include the
presence of myocarditis, pericardial tamponade, DIC and
increasing liver enzymes on treatment with NSAIDs. Once
the disease is controlled and inflammatory parameters improve
the dose of steroids needs to be reduced to the minimum. Flare
of disease while tapering steroids and relapse of disease, once
steroids are stopped does occur. However, relapses tend to
be milder and briefer and respond to similar or even lower
doses of steroids than used initially.
Chronic disease: The most important manifestation of chronic
disease is chronic polyarthritis, which is not controlled by low
dose steroids. This necessitates the use of agents like
methotrexate, salazopyrine, hydroxychloroquine and
D-penicillamine. Therapy with gold has been associated with
serious complications like multi organ failure and therefore
should be avoided. If disease remains uncontrolled, drugs like
azathioprine or cyclophosphamide would have to be used. High
dose chemotherapy with autologous stem cell rescue has also
been tried in refractory AoSD14. However, the disease tends
to relapse after a few years. Chimeric anti-TNF monoclonal
antibody has also been tried in refractory AoSD or those
requiring high dose maintenance steroids15. However, the
disease relapses when treatment is stopped.
AoSD, an important cause of FUO, remains a
diagnosis of exclusion in the absence of one or more classical
features, notwithstanding the reported specificity of
hyperferritinemia, very high IL-18 levels and alterations in
the radiology of the hand joints. NSAIDs and steroids remain
the cornerstone of treatment with DMARDs being used for
chronic polyarthritis.
References:
1. Bywaters EGL. Stills disease in the adult. Ann Rheum Dis
1971; 30: 121-132.
2. Onta A, Yamaguchi M, Kaneoka H, Nagayashi T, Hiida
M. Adult Stills disease: Review of 228 cases from the
literature. J Rheumatol 1987; 14: 1139-46.

3.
4.
5.

6.

7.

8.
9.

10.
11.
12.

13.

14.

15.

Pouchot J, Sampalis JS, Beardet F, et al. Adult Stills disease:

Manifestations, disease course and outcome in 62 patients. Medicine (Baltimore) 1991; 70: 118-136.
Singh YN, Adya CM, Kumar A, Malaviya AN. Adult-onset
Stills in India. Br J Rheumatol 1992; 31: 417-9.
Bambery P, Thomas RJ, Malhotra HS, Kaur U, Bhusnurmath
SR, Deodhar SD.Adult onset Stills disease: clinical
experience with 18 patients over 15 years in northern India.
Ann Rheum Dis 1992; 51: 529-32.
Uppal SS, Pande Kumar A, Kailash S, Sekharan NG, Adya CM,
Malaviya AN. Adult onset Stills disease in northern
India: comparison with juvenile onset Stills disease. Br J
Rheumatol 1995; 34: 429-34.
Gelfand JA. Fever of unknown origin. Harrisons Principles of
Internal Medicine. 15th Edition. Editors Braunwald E, Fauci AS,
Kasper DL, Hauser SL, Longo DL, Jameson JL.
McGraw-Hill, 2001; 804-809.
Cush JT, Medsger Jr TA, Christy WC, Herbert DC, Cooperstein
LA. Adult-onset Stills disease: clinical course and outcome.
Arthritis Rheum 1987; 30: 186-94.
Bjorkengren AG, Pathria MN, Sartoris DJ, Terkeltaub R, Esdaile
JM, Weisman M, et al. Carpal alterations in adult-onset Still
disease, juvenile chronic arthritis and adult-onset
rheumatoid arthritis: a comparative study. Radiology 1987; 165:
545-8.
Esdaile JM, Tannenbaum H, Lougn J, Hawkins D. Hepatic
abnormality in adult onset Stills disease. J Rheumatol 1979; 6:
673-9.
Akritidis N, Giannakakis Y, Sakkas L. Very high serum ferritin
levels in adult-onset Stills disease. Br J Rheumatol 1997; 36:
608-9.
Fautrel B, Le Moel G, Saint-Marcoux B, Taupin P, Vignes S,
Rozenberg S, et al. Diagnostic value of ferritin and glycosylated
ferritin in adult onset Stills disease. J Rheumatol 2001;
28: 322-9.
Kawashima M, Yamamura M, Taniai M, Yamauchi H, Tanimoto
T, Kurimoto et al. Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset
Stills disease. Arthritis Rheum 2001; 44: 550-60.
Lanza F, Dominici M, Govoni M, Moretti S, Campioni D, Corte
RL, et al. Prolonged remission state of refractory adult onset
Stills disease following CD34-selected autologous peripheral
blood stem transplantation. Bone Marrow Transplant 2000; 25:
1307-10.
Cavagna L, Caporali R, Epis O, Bobbio-Pallavicini F,
Montecucco C. Infliximab in the treatment of adult onset Stills
disease refractory to conventional therapy. Clin Exp Rheumatol
2001; 19: 329-32.

21