How are multisystem diseases diagnosed ?

Diagnosis of multisystem inflammatory disease relies on careful clinical assessment, supported by targeted investigations. The primary role of investigations is to exclude infection and malignancy, and to identify disease-specific markers where present.

Diagnosis may take time, which can be distressing for children and families, so clear communication and ongoing review are important.

Clinical assessment

Important clinical clues include the pattern of fever, relevant family history, and findings on examination. A temperature chart may help identify specific conditions. Examination should look for features such as rash (particularly when febrile), lymphadenopathy, mouth ulcers, heart murmurs, nailfold changes, joint involvement and fundal abnormalities.

First-line investigations

Initial investigations aim to exclude infection and identify organ involvement. These typically include blood cultures (if febrile), urine microscopy and culture, inflammatory markers, full blood count, and urinalysis. Depending on the clinical context, further tests may include autoantibody screening, chest radiography, cerebrospinal fluid analysis, and imaging such as ultrasound, MRI or CT. In selected cases, angiography or bone marrow biopsy may be required.

Autoantibodies in multisystem disease

Autoantibodies can support diagnosis, but interpretation is essential. Some are highly disease-specific, whereas others (such as ANA) are nonspecific and may be present in healthy children or following viral infection.

• ANA – seen in JSLE, undifferentiated connective tissue disease, Sjögren’s syndrome, JDM and scleroderma (nonspecific)
• Anti–double-stranded DNA (dsDNA) – strongly associated with JSLE and lupus nephritis
• Anti-Sm, anti-RNP, anti-Ro and anti-La – associated with connective tissue disease and overlap syndromes
• Antiphospholipid antibodies – associated with antiphospholipid syndrome, JSLE and vasculitis
• ANCA (PR3, MPO) – associated with vasculitides such as GPA and MPA
• Anti-topoisomerase I (Scl-70) and anti-centromere antibodies – associated with systemic sclerosis
• Anti-U1RNP – associated with mixed connective tissue disease
• Anti-Jo antibodies – associated with juvenile dermatomyositis and interstitial lung disease

Persistent or recurrent fever

Persistent or recurrent fever should always prompt careful assessment. Fever lasting more than 5 days without a clear cause requires investigation. A quotidian (evening) fever pattern lasting more than 7 days strongly suggests systemic JIA. Periodic fever syndromes should also be considered, and genetic testing is available for selected conditions.

Key points for healthcare professionals

• Always exclude infection and malignancy first before diagnosing multisystem or autoimmune disease
• Autoantibody results must be interpreted in clinical context — ANA alone is not diagnostic
• Be alert to red flag features, including prolonged fever, weight loss and organ involvement
• Provide clear explanation and reassurance to families, as diagnosis may take time, but a structured approach reduces misdiagnosis