Adult Onset Still’s Disease

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

  1. viral infections such as hepatitis, rubella, parvovirus, coxsackie, EBV, CMV and HI
  2. infective endocarditi
  3. tuberculosis
  4. Lyme disease, Ehrlichiosis

Granulomatous Disorders

  1. sarcoidosis
  2. idiopathic granulomatous hepatitis
  3. Crohn’s disease

Malignancy

  1. leukemia
  2. lymphoma

Connective Tissue Disease

  1. SLE
  2. Mixed connective tissue disease
  3. Vasculitis associated with polyarteritis nodosa (PAN), Wegener’s granulomatosus or Takayasu’s arteritis
  4. 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

  1. Klippel J, Dieppe P. Rheumatology. 2nd ed. London: Mosby International; 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 Rheumatol 1997; 24: 592-7.
  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.
  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.
  9. Cush JJ, Medsger TA, Christy WC, et al. Adult-onset Still’s disease. Clinical course and outcome. Arthritis Rheum 1987; 30: 186-94.
  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.