Approach
Many patients with FS remain asymptomatic, and the neutropenia may remain undetected unless blood tests are performed to monitor toxicity of anti-rheumatic drugs. Others may present with infections as a result of severe neutropenia, commonly pulmonary or skin infections.
FS is a clinical diagnosis and there is no specific diagnostic test. It is suspected in a patient with long-standing rheumatoid arthritis (RA), associated with neutropenia and frequently (>90% patients) with splenomegaly. Spleen size does not always correlate with the clinical course of the disease or the degree of neutropenia, and so is not considered an absolute diagnostic requirement.[2][4] Most importantly, other causes of neutropenia should be excluded first.
History
Typically, patients have a long history (>10 years) of seropositive, erosive, aggressive RA preceding the development of FS. They may have a strong family history of RA. Patients with suspected FS may report symptoms suggestive of intercurrent infection, especially of the skin or respiratory tract.[2] These can be a major cause of morbidity and mortality.
A thorough history should be taken, investigating alternative causes of neutropenia such as drug-induced neutropenia, chronic infections, myeloproliferative and lymphoproliferative disorders, and systemic lupus erythematosus (SLE).
Patients should be asked about recent changes to their anti-rheumatic treatment, because most disease-modifying anti-rheumatic drugs (DMARDs) can cause neutropenia. Patients taking DMARDs should be asked when the drug was initiated and whether their dose was changed recently.
Examination
Patients are likely to have typical articular features of RA with joint deformities, although synovitis may be mild or absent at presentation. There may be evidence of extra-articular features of RA, such as rheumatoid nodules, vasculitis, and leg ulcers. Splenomegaly and hepatomegaly may be present on examination.
As the neutropenia of FS predisposes to infections, especially of the skin and respiratory tract, it is important to look for symptoms and signs of these during history taking and examination. Patients taking anti-TNF-alpha therapy should be assessed for development of anti-TNF-induced lupus and its clinical features, such as fever, myalgia, and rash.[12]
Laboratory tests
The following tests are indicated in all patients with possible FS:
Full blood count
The principal feature of FS is persistent, idiopathic neutropenia, defined as neutrophil count <2 x 10⁹/L (<2000/microlitre).[2] Persistence is usually defined as a duration >6 months.
Neutrophil count <1 x 10⁹/L (<1000/microlitre) is classed as severe and is the biggest risk factor for recurrent infection.[13]
Full blood count (FBC) may also show anaemia due to chronic disease or hypersplenism. Thrombocytopenia may also be present because of hypersplenism. Anaemia and thrombocytopenia are not required for a diagnosis of FS.
Peripheral blood smear
This is necessary to exclude other haematological causes of neutropenia, including large granular lymphocyte (LGL) syndrome.
Homogeneous expansion of LGLs is a low-grade malignant disease, associated with neutropenia and splenomegaly. Approximately 25% of patients with LGL syndrome have RA, which precedes or develops concurrently with the haematological process and may fulfil criteria for FS. 30% of FS patients have evidence of LGL expansion.[3][11]
LGL syndrome with RA and FS form an overlap condition with similar immunogenetic background.[14]
Acute-phase reactants
Serological studies
Rheumatoid factor is found in 95% to 100% of patients with FS, usually in high titres.[7]
Patients with FS are typically positive for anti-cyclic citrullinated peptide antibodies and have higher levels than RA patients without extra-articular manifestations.[15]
Antinuclear antibodies are found in 47% to 100% of patients with FS.[7]
Liver function tests
Mild elevations of alkaline phosphatase and aminotransaminases have been described in 25% of patients with FS and are thought to be related to nodular regenerative hyperplasia of the liver.[3]
Virological testing
To exclude other causes of neutropenia, virological tests for cytomegalovirus, HIV, and parvovirus B19 may be considered.
Imaging
Ultrasonography or computed tomography scanning may be performed to investigate the presence of splenomegaly, although a large spleen is not a requirement for a diagnosis of FS. These imaging modalities may also be useful to exclude other possible diagnoses such as lymphoproliferative disorders, by investigating the presence of lymphadenopathy.
A chest x-ray may be considered to investigate the presence of infection, if this is suspected after clinical examination.
Bone marrow aspiration and trephine biopsy
This is required to confirm FS and to exclude other causes of neutropenia.[3]
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