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The conjunction of sore throat and hyperferritinaemia is a diagnostic clue easily missed.
A previously well woman aged 23 had experienced sore throat, rash and polyarthralgia for 3 weeks. Initially, the sore throat had been severe enough to prevent her taking solids. Positive findings on examination were a temperature of 39°C; a widespread, non-pruritic, macular erythematous rash; pharyngeal injection; right wrist swelling; and a sinus tachycardia. The results of preliminary investigations were as follows: haemoglobin 11.4 g/dL (reference range 11.5-16.5), white cell count 40.3 × 109/L (4.0-11.0), neutrophils 38.7 × 109/L (2.0-7.5), platelets 470 × 109/L (150-400). The erythrocyte sedimentation rate (ESR) was 92 mm/h (0-20). Albumin was 21 g/L (35-46), alkaline phosphatase 252 IU/L (31-116), gamma-glutamyl transpeptidase 208 IU/L (0-72), C-reactive protein 411 mg/L (0-7). Urea, electrolytes, creatinine, glucose, calcium, creatine kinase, other liver function tests, thyroid function tests, urinalysis and microscopy were normal.
The profound acute-phase response initially suggested an infective substrate. However, serial blood cultures, antistreptolysin O titres, an atypical-pneumonia screen, throat swab and VDRL were negative, as were titres to Epstein—Barr virus, cytomegalovirus, rubella, parvovirus and hepatitis A and B. Abdominal ultrasound revealed slight hepatosplenomegaly, without lymphadenopathy. Autoantibodies were negative. Serum ferritin was greatly raised at 15628 μg/L (15-400).
The patient remained unwell over the next few days, with intermittent fevers (Figure 1) often accompanied by transient worsening of the rash. The haemoglobin and serum albumin decreased further. Pleuritic chest pain developed, accompanied by pericardial and bilateral pleural rubs. An electrocardiogram showed new widespread concave-up ST elevation, and transthoracic echocardiography revealed a small pericardial effusion. Adult-onset Still's disease was diagnosed (Box 1) and the pleuropericarditis resolved within 24 hours from the start of prednisolone therapy. Methotrexate was later added, and over the next few weeks the joint pains lessened, her wellbeing improved and acute-phase reactants became normal.
Adult-onset Still's disease is a systemic inflammatory disease of uncertain aetiology with a prevalence of around 1 in 100 000 adults, presenting with a striking constellation of clinical and laboratory features, none of them pathognomonic1. Most patients develop fever, rash and arthralgia, but this classic triad is often absent during the first month of illness and diagnostic delays are common1. The fever usually exceeds 39°C, with temperature tending to be high in the evening and normal in the morning. The rash is generally non-pruritic, macular or maculopapular and salmon-pink, and is most prominent on the trunk and proximal portions of the limbs. It becomes more apparent during periods of fever and is readily precipitated by thermal or mechanical stimulation. The arthritis is polyarticular in two-thirds of cases, oligoarticular in one-third, and has a predilection for large joints, particularly the wrists. The knees and ankles are also frequently affected1,2,3. Other common features are sore throat, lymphadenopathy, hepatosplenomegaly, pleuropericarditis, raised ESR, hypoalbuminaemia, abnormal liver function tests and anaemia1. The classification criteria proposed by Yamaguchi are the most sensitive and specific2 (Box 1).
Two forms of adult-onset Still's disease are recognized, though they may be difficult to differentiate early on. Two-thirds exhibit a predominantly systemic form, in which articular symptoms may occur but are overshadowed by systemic features. The other third have a chronic articular form, in which joint involvement predominates over systemic features. This group have a worse prognosis and are characterized by chronic progressive polyarthritis with joint ankylosis and destruction1,3. The clinical course in adult-onset Still's disease is therefore highly variable, just under a quarter of patients presenting with an episode of predominantly systemic illness followed by prolonged remission at one end of the spectrum, another third with a chronic persistent disorder who develop progressive joint damage at the other, and a group characterized by intermittent exacerbations in between1,3. Overall, half the patients still require medication 10 years after diagnosis but pain and disability are less than in other rheumatic diseases and functional outcomes tend not to be compromised4.
Box 1 Classification criteria for adult-onset Still's disease (Ref. 2) (Presence of five or more criteria, including at least two major, has diagnostic sensitivity of 96.2% and specificity of 92.1%)
Treatments for adult-onset Still's disease have not been evaluated in controlled studies and remain empirical. Non-steroidal anti-inflammatory drugs are occasionally effective as monotherapy but most patients require steroids, which may be needed in high doses for 6 months, followed by long-term low-dose maintenance in severe disease. Disease modifying drugs and immunosuppressives are used, and there is some evidence that methotrexate is effective5.
This case illustrates two features which are important early diagnostic clues—sore throat and extreme elevation of serum ferritin. In a review of 341 cases, sore throat was reported in 69%6. This symptom is therefore a cardinal feature of adult-onset Still's disease and is particularly prevalent in the first month of illness, often predating other symptoms. Typically, it persists for a few days and may be associated with odynophagia, resolving shortly after the full range of systemic symptoms are manifest. Examination reveals mild pharyngeal injection only, and throat cultures are negative. An awareness of this association is important since it is uncommon in other rheumatic diseases and considerably diminishes the differential diagnosis in a patient with fever, rash and arthralgia1,6.
Serum ferritin is usually high in active adult-onset Still's disease. The concentration is five or more times the upper limit of normal in almost three-quarters of patients and values above 10 000 μg/L have been recorded7 (as here). As an acute-phase reactant, ferritin is also raised in infectious and inflammatory conditions, hepatocellular disease, haemochromatosis and secondary iron overload, and malignancy. However, the increment in adult-onset Still's disease is disproportionate to the inflammatory state alone and, with the exception of acute hepatic necrosis, concentrations exceeding 5000 μg/L are seldom encountered in other disorders7,8.
Hyperferritinaemia in an appropriate clinical context, such as an undefined rheumatological disorder or pyrexia of unknown origin, is therefore suggestive of adult-onset Still's disease7,8. Furthermore, serum ferritin becomes normal with treatment and can be used to monitor disease activity.