Complex presentation of adult-onset Still’s disease

Abstract

A 61-year-old woman was admitted with feeling generally unwell with influenza-like symptoms, for almost a month. This was followed by dyspnoea, productive cough and fever of >40°C. She was started on oral antibiotics in community, but due to rising inflammatory markers, she was referred for admission to our hospital. Chest X-ray showed left basal pneumonia and SE was started on intravenous antibiotics according to microbiologist’s advice. During admission she developed deranged liver functions with right upper quadrant tenderness, pleural and pericardial effusions. This was followed by multiple joint aches, mouth ulcers and a rash on her chest. Finally, after several days and clinical dilemma, she was diagnosed with adult-onset Still’s disease by the rheumatologist and was started on prednisolone, to which she showed marked improvement, and was later maintained on methotrexate and hydrotherapy. She was in remission during her follow-up in the rheumatology clinic.

Background

This patient had prolonged illness and fever of unknown origin (FUO) for which she had multiple courses of intravenous antibiotics without any significant improvement. It was a diagnostic challenge, with thorough investigations, a diagnosis of adult-onset Still’s disease (AOSD) triggered by pneumonia was finally made and all her symptoms improved dramatically with steroids and she has been in remission since.

Case presentation

A 61-year-old woman who was known to have bronchial asthma and paroxysmal atrial fibrillation, presented with influenza-like illness for almost a month. Afterwards she developed a productive cough with green sputum, dyspnoea and spiking high temperature. She was using her salbutamol inhaler very frequently and was started by her general practitioner on oral antibiotics for presumed community acquired pneumonia. However, she continued to have spikes of temperature and her inflammatory markers were rising. On the fourth day, she was referred for hospital admission. Previous to this illness, she was on a holiday in Turkey 2 months before. She was well during her holiday, but all other family members were not well with cold-like symptoms. Afterwards, she developed a sore throat and fatigue. She had a medical history of cholecystectomy and paroxysmal atrial fibrillation for which she was anticoagulated with rivaroxaban. Chest examination revealed coarse crackles bilaterally and the chest X-ray showed left basal pneumonia and was started on intravenous clarithromycin and ceftriaxone (figure 1). However, her inflammatory markers were not improving, and she had spikes of temperature and the antibiotics were changed as per microbiologists’ advice to levofloxacin and vancomycin after 3 days of intravenous antibiotics. During her hospital stay she developed right upper quadrant pain and tenderness with deranged liver functions. Ultrasound of the abdomen showed an enlarged liver with increased echogenicity in addition to splenomegaly and there was no evidence of bile duct dilatation or stones. A week after her admission she developed multiple joints and arm aches, in addition to chest tightness. The next day she was noted to have pericardial rub on examination with bilateral basal lung crackles. Subsequently she had an echocardiography, which showed moderate pericardial effusion of 1.5 cm with no echocardiographic features of cardiac tamponade and there was no evidence of vegetations or any valve disease. Infective endocarditis was excluded by cardiologists as she had negative blood culture and no vegetations or murmurs. There was a suspicion that this was a drug reaction and as she continued to be feverish, the intravenous antibiotics were stopped.

Figure 1.

Left basal consolidation patch.

A CT chest abdomen and pelvis showed left basal consolidation, pleural and pericardial effusions (figures 2 and 3). She continued to spike high temperature reaching 39°C and with deranged liver functions, and the microbiologist readvised to add tigecycline and gentamicin. Afterwards, she developed oral and mucosal ulcers and with maculopaplular rash on her chest after about 3 weeks of her presentation, and she was referred to the rheumatologist. She was found to have a raised ferritin of 14 880 ng/mL and she was diagnosed with AOSD triggered by pneumonia, which was complicated by oral ulcers, arthralgia, pleuro-pericardial effusion and fast atrial fibrillation. With initiation of steroids she improved dramatically and remained afebrile, inflammatory markers improved and she was discharged home. She was started on methotrexate and hydrotherapy and was in remission during her follow-up with the rheumatology team after several months.

Figure 2.

Left basal consolidation demonstrated by CT.

Figure 3.

CT chest showing pericardial effusion and left basal pleural effusion and left lower lobe consolidation.

Investigations

On admission, the blood results showed raised C reactive protein (CRP) of 308 mg/L, white cell count 21x10⁹/L with neutrophils predominance 17.8%.

Deranged liver functions with a bilirubin of 17 mg/dL, alkaline phosphatase 174 U/L, alkaline transaminase 93 U/L, bili 17, normal lactate level.

Procalcitonin was 0.37 µg /L (normal range 0.02–0.05 µg/L).

The ferritin level was raised to 14 880 µg/L. Rheumatoid factor was negative with positive ANA and C-ANCA with negative P-ANCA and anti-dsDNA. Immunoglobulins, creatine kinase and complement levels were normal. Myeloperoxidase and proteinase were negative.

Urine legionella and pneumococcal antigens were negative, in addition to respiratory virus PCR was negative. HIV was negative, mycoplasma serology was negative and HSV 1 serology was positive.

Initial and consequent blood cultures were negative taken during five separate occasions of temperature spikes. Tora and adenovirus serology was negative, as well as cryptosporidium and giardia lamblia.

ECG was initially sinus tachycardia then she had rapid atrial fibrillation.

Echocardiography showed no vegetations.

CXR showed left basal pneumonia (figure 1).

A CT chest abdomen and pelvis revealed left basal consolidation, pleural effusion and pericardial effusion (figures 2 and 3).

Differential diagnosis

Community acquired pneumonia.

Autoimmune hepatitis.

Cholangitis.

Atypical pneumonia.

Infective endocarditis.

Treatment

Initially a wide range of intravenous antibiotics including ceftriaxone, clarithromycin followed by vancomycin, levofloxacilin and finally tigecycline and gentamicin. After diagnosis was established she was started on high dose prednisolone, while an in-patient and methotrexate and hydrotherapy as outpatient.

Outcome and follow-up

She showed significant improvement on prednisolone before discharge and is currently in remission on methotrexate and hydrotherapy and under follow-up by the rheumatologist.

Discussion

First described in 1971, AOSD is a rare multisystemic disorder considered as a complex autoinflammatory syndrome. Macrophage and neutrophil activation is the hallmark of AOSD¹

The prevalence per year is estimated to be 1.6 per 1 million of the population.² This autoinflammatory disease is of unknown aetiology and pathogenesis. It presents in 5%–10% of patients as FUO accompanied by systemic manifestations.³

AOSD is characterised by a triad of persistent fever, arthralgia and a salmon coloured rash or a maculopapular rash.² This triad is associated with lymphadenopathy, hepatosplenomegaly and systemic manifestations.^{2 4} Complications can include transient pulmonary hypertension, macrophage activation syndrome, diffuse alveolar haemorrhage, thrombotic thrombocytopenic purpura and amyloidosis.⁴

The diagnosis is clinical by exclusion, as there are no clear-cut diagnostic radiological or laboratory signs.⁵

The Yamaguchi criteria are the most widely cited criteria and are shown to be the most sensitive with a 93% sensitivity rate. Diagnosis requires at least five features, with at least two of these being major diagnostic criteria (table 1).⁶

Table 1.

Yamaguchi criteria for adult-onset Still’s disease

Major criteria	Minor criteria
Fever of at least 39°C for at least 1 week	Sore throat
Arthralgia or arthritis for at least 2 weeks	Lymphadenopathy
Non-pruritic salmon-coloured rash (usually over trunk or extremities while febrile)	Hepatomegaly or splenomegaly
Leucocytosis (10 000/µL or greater), with granulocyte predominance	Abnormal liver function tests
	Negative tests for antinuclear antibody and rheumatoid factor

Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still’s disease’. J. Rheumatol. 1992;19(3): 424–30. PMID 1578458.

Ferritin levels often exceed the upper limit of normal. A recent retrospective observational study reported that serum ferritin was raised in 82% of patients. However, it is not included in the diagnostic criteria by Yamaguchi et al. ⁶ However, a glycosylated ferritin ≤20% was included among the new classification criteria proposed by Fautrel et al for diagnosing ASOD.^{7 8}

Common laboratory abnormalities include neutrophils predominant leucocytosis, abnormal liver function tests, and elevated acute-phase reactants like ESR and CRP.⁴ Treatment consists of corticosteroid therapy and disease-modifying agents, as non-steroidal anti-inflammatory drugs have limited efficacy.⁴

Studies encompassing large number of patients, suggest that anti-IL1-receptor or anti-IL6-receptor agents are more effective in patients with AOSD refractory to glucocorticoids and conventional disease modifying antirheumatic drugs (DMARDS) namely methotrexate. TNF-a blockers may be more useful in chronic polyarticular refractory AOSD than in the systemic forms of the disease. However, the efficacy of TNF-a blockers seems to be limited in time and switching from one to another TNF-a blocker is useful in only about 50% of patients.^{9 10}

Relapses are frequent and relapsing patients often require biologics; tocilizumab if the main pattern is persistent arthritis or anakinra/canakimumab if the if the main feature is fever along with systemic manifestations.^{11 12}

Learning points.

• Adult-onset Still’s disease (AOSD) is an underlying aetiology in 5%–10% of patients presenting with fever of unknown origin.

• Adult-onset Still’s disease has a triad of persistent fever, arthralgia and a salmon-coloured or a maculopapular rash.

• A ferritin is usually raised with ASOD.