Introduction

Felty syndrome, also known as Chauffard-Still-Felty disease, affects 1-3% of adults with seropositive rheumatoid arthritis (RA), usually after over 10 years.^{1, 2} In extremely rare cases, Felty syndrome affects paediatric patients with juvenile idiopathic arthritis (JIA). In children, it is characterised by severe arthritis, thrombocytopenia (low platelet count), splenomegaly (enlarged spleen) and hepatomegaly (enlarged liver). Unlike adults, neutropenia (low white blood cells called neutrophils) is rarely present. However, the prevalence in paediatric patients is extremely rare, with only six cases reported globally.² Treatment requires a multidisciplinary approach involving immunotherapy, although no standardised treatment is available and the prognosis is poor.

Key terms

Felty syndrome affects the immune system. Some of the medical terms have been defined below:

• Leukocytes: leukocytes are white blood cells, which form part of the immune system. They are divided into granulocytes (neutrophils, basophils and eosinophils) and agranulocytes (lymphocytes and monocytes)³
• Neutrophils: a type of granulocyte (white blood cell) responsible for the initial immune response. Neutrophils ingest and destroy antigens such as bacteria. Neutropenia is a condition characterised by low neutrophils⁴
• Lymphocyte: a type of agranulocyte (white blood cell) that makes antibodies. There are two types: B cells and T cells
• Antibodies: antibodies, also known as immunoglobulins, are proteins made by B cells (one type of lymphocyte). They are found in blood plasma and recognise, bind to, and destroy antigens⁵ 
• Plasma: part of the blood mainly composed of water, containing certain proteins, antibodies, electrolytes, coagulants and complement – which enables antibodies to kill bacteria.^{6, 7} The rest of the blood contains leukocytes (white blood cells), platelets and erythrocytes (red blood cells)⁸ 
• Antigen: foreign substances in the body such as bacteria or viruses 
• Self-antigen: parts of the cell that indicate that a cell belongs to that individual
• Autoimmune condition: the immune system mistakenly attacks self-antigens in healthy tissue, leading to inflammation⁹ 
• Rheumatoid arthritis (RA): a chronic autoimmune condition causing inflammation in the joints, leading to pain and stiffness
• Seropositive: A type of RA characterised by the presence of either rheumatoid factor (RF) or anti-cyclic citrullinated peptides (anti-CCPs) antibodies in blood tests, and more clinically severe symptoms, such as joint deformities. Neither are present in seronegative RA¹⁰
• Extra-articular: disease features such as nodules (lumps or masses under the skin) occurring in tissue and/or organs outside of the joints; such as the eyes, skin and organs^{11, 12}

Signs and symptoms of Felty syndrome

Signs

In paediatric patients, FS is characterised by the following:

Juvenile idiopathic arthritis (JIA)

Juvenile idiopathic arthritis (JIA) is an autoimmune, rheumatological condition affecting children under the age of 16. It has a slightly higher prevalence in children assigned female at birth. Idiopathic means the cause is unknown, but it may be caused by several genetic and environmental factors. JIA is characterised by joint inflammation, recurrent fever, fatigue, unexplained limp and/or eye inflammation. Symptoms often fluctuate over time.

There are six subtypes of JIA; oligoarticular, polyarticular, psoriatic, enthesitis-related, systemic onset and undifferentiated. These differ in terms of the number of joints affected, symptoms and genetic predisposition.¹² 

Felty syndrome has been documented in cases with: 

• Polyarticular JIA: It affects five or more joints, including large and smaller joints, such as fingers, leading to painful swelling. It can be rheumatoid factor (RF) positive or negative.
• Systemic-onset JIA: Is the least common, causing joint pain, inflammation and splenomegaly (enlarged spleen)^{2, 12}

Thrombocytopenia 

Low platelet count in blood. Platelets are produced in the bone marrow and form blood clots (coagulation) in response to injury. A low platelet count may cause excessive bleeding.

Splenomegaly 

An enlarged spleen. The spleen is an organ responsible for platelet storage, lymphocyte storage and maturation, and the removal of abnormal erythrocytes (red blood cells), antigens and leukocytes (white blood cells).¹³

Neutropenia

Low blood neutrophil count, increases the risk of infection. This is a characteristic feature of FS in adults but is rare in paediatric patients.²

Symptoms

FS may be asymptomatic, but symptoms may include:

• Fatigue
• Weight loss and loss of appetite 
•  Fever
• Recurrent inflection
• Skin ulceration
• Eye irritation
• Joint deformities relating to JIA¹⁴

Adult and paediatric differences

FS is typically associated with rheumatoid arthritis in adults and juvenile idiopathic arthritis (JIA) in children. JIA is similar to rheumatoid arthritis, although symptoms vary by subtype. However, in adults, FS typically develops after 16 years of the onset of arthritis. Patients are typically 50-70 years old, and there is a threefold prevalence in individuals assigned female at birth. The age of onset is earlier in paediatric patients, ranging from 4 to 15, and all cases identified as female.^{1, 2}

There are also differences in the laboratory results. Children typically present with thrombocytopenia, and low platelet count, whereas adults do not. Alternatively, adults typically present with neutropenia (low neutrophil count), whereas this is rare in children. Adults with FS typically have low levels of complement, part of the plasma that helps antibodies to kill antigens such as bacteria, whereas this has not been reported in paediatric patients.² 

Paediatric case studies 

To date, there have only been six documented cases of Felty syndrome in paediatric patients.^{2,15,16,17,18}

• Five cases had polyarticular JIA, one case had systemic JIA
• All were assigned female at birth
• All had thrombocytopenia (low platelet count)
• All had abnormal levels of autoantibodies 
• All had normal bone marrow findings
• All presented with splenomegaly (enlarged spleen)
• Half the cases had hepatomegaly (enlarged liver)
• None of the cases had persistent neutropenia (in contrast to adults)²

Causes of felty syndrome

The exact cause of FS is unknown. However, the probable cause is an autoimmune condition.² Autoimmune conditions are characterised by autoantibodies, antibodies that react with self-antigens; your cells. In autoimmune conditions, self-antigens are mistakenly attacked, leading to inflammation.^9,19,20 

Almost all patients with FS (adult and paediatric) have abnormal levels of antibodies such as rheumatoid factor (RF), antinuclear antibodies and granulocyte-colony stimulating factor (G-CSF). 94% of adults with FS tested positive for RF, but only 2 of the 6 reported paediatric cases tested positive.² 3 of the 6 paediatric cases tested positive for antinuclear (ANA)  antibodies, and 73% of adults with FS have high levels of G-CSF.²¹ 

FS also has a genetic component. In adults, FS is more likely in RA with a strong family history. Over 90% of adult cases test positive for the HLA-DR4 allele.¹ However, due to the low prevalence in children, research is limited.

Diagnosis

Diagnosis of FS in paediatric cases is incredibly rare, but may be based on the following:

Laboratory tests

Blood tests may be conducted to assess the following:

• Full blood count (FBC)- includes white blood cells, red blood cells and platelets. 
• Peripheral blood smear- can help to detect changes to these cells.
• Serum erythrocyte sedimentation rate -indicates inflammation by measuring how long it takes red blood cells to fall in the test tube.
• Serum c- reactive protein (CRP)- high levels can indicate active inflammation
• Liver function test (LFT).
• HLA-typing can be used to identify genetic biomarkers¹⁷ 

Antibodies that are often present in FS:

• Rheumatoid factor (RF) 
• Anti-CCP antibodies 
• ANA antibodies²

Imaging studies

An abdominal ultrasound or CT scan may help to identify splenomegaly or hepatomegaly. 

• An ultrasound is performed by a sonographer and usually takes around 20 minutes. A handheld transducer is rubbed over a gel to produce images of internal organs
• A CT scan is conducted by a radiographer and also takes around 20 minutes. It involves lying in a machine and produces more detailed images of internal organs

Biopsy 

A liver or bone marrow biopsy may be performed to analyse a sample of tissue.¹ This is usually performed under local anaesthetic and takes around 30 minutes, although bone marrow findings were normal in paediatric patients.²

Differential diagnosis

In paediatric patients, diagnosis will involve excluding other causes of thrombocytopenia, splenomegaly or leukopenia (low leukocytes).¹⁷

Treatment 

Treatment aims to reduce inflammation and improve immune functioning.¹

This may involve:

• Disease-modifying anti-rheumatic drugs (DMARDs): such as methotrexate are first-line treatments to reduce inflammation (Patel). However, DMARDs showed inconsistent results in paediatric patients with FS²  
• Monoclonal antibody therapies: act like antibodies in arthritis diseases; decreasing inflammation. One such medication, rituximab, was somewhat effective in a paediatric case of FS²
• Glucocorticoids: can be used to increase neutrophil count and reduce inflammation. Prednisolone may be effective in children¹⁵  
• Granulocyte Colony-Stimulating Factor (G-CSF): a type of growth factor that may be used if neutropenia is present ²¹
• Antibiotics: may be prescribed to treat active infections¹ 
• A splenectomy: surgical spleen removal, may be considered as a last resort²¹ 

Prognosis 

Treatment options are of limited effectiveness in paediatric patients, and prognosis is poor, with a high risk of severe infection.

Conclusion

In conclusion, Felty syndrome is extremely rare in paediatric patients, with only six cases documented worldwide. In children, it is characterised by juvenile idiopathic arthritis, thrombocytopenia, splenomegaly and hepatomegaly. Symptoms may include fever, joint deformities, fatigue and recurrent infection. The exact cause is unknown but includes genetics and autoantibodies. Diagnosis is based on blood tests, imaging and biopsy. Treatment is tailored to symptoms and involves immunotherapy such as disease-modifying anti-rheumatic drugs and monoclonal antibody therapies, and in some cases a splenectomy. However, there is limited research and awareness of FS in paediatric patients.