Felty Syndrome – Causes, Symptoms, Diagnosis, Treatment

Felty Syndrome (FS) is an uncommon extra-articular manifestation of seropositive rheumatoid arthritis (RA) characterized by RA, neutropenia, and splenomegaly. Felty syndrome was first described in 1924 at Johns Hopkins hospital by the American physician, Augustus Felty. He described five unusual cases with common features of chronic arthritis of about four years duration, splenomegaly, and striking leukopenia. The term was first used by Hanrahan and Miller in 1932 when they described the beneficial effect of splenectomy in a patient with features similar to the five cases reported by Felty. While Felty syndrome characteristically demonstrates chronic arthritis, splenomegaly, and neutropenia; completion of the triad is not necessary for the diagnosis. Neutropenia, however, is a hallmark feature of the disease and cannot be absent.[rx]

Felty’s syndrome, also called Felty syndrome, (FS)^[rx] is rare autoimmune disease characterized by the triad of rheumatoid arthritis, enlargement of the spleen and too few neutrophils in the blood. The condition is more common in those aged 50–70 years, specifically more prevalent in females than males, and more so in Caucasians than those of African descent. It is a deforming disease that causes many complications for the individual.^[rx][rx]

Pathophysiology

The exact pathophysiology of Felty syndrome is not clear, and it may be multifactorial. It is thought to involve both humoral and cellular immune mechanisms, which contribute to survival and proliferation defects of neutrophils resulting in neutropenia.[rx] Neutropenia can be explained by inadequate production due to infiltration of bone marrow by cytotoxic lymphocytes and increased sequestration due to splenomegaly supported by the improvement of neutropenia after splenectomy. A case-control study done for the presence of antibodies against granulocyte-colony stimulating factor (G-CSF), showed that 73% of patients with neutropenia due to FS had IgG Anti-G-CSF, which was associated with an exaggerated serum level of G-CSF and a low neutrophil count. This finding suggests that a high level of G-CSF and hyposensitivity of myeloid cells to G-CSF might be responsible for the development of neutropenia in patients with Felty syndrome.[rx] Another study concluded that autoantibodies present in FS bind to deaminated histones and neutrophil extracellular chromatin traps (NETs) leading to neutrophil sequestration, supporting the role of peripheral destruction of neutrophils in the pathophysiology of Felty syndrome.[rx] Some have suggested that chronic large granular lymphocyte (LGL) leukemia and FS may have a common pathologic link because of similar clinical presentation and common genetic etiology of HLA-DR4.[rx] Neutropenia in LGL leukemia has been attributed to increased secretion of circulating Fas ligand which induces neutrophil apoptosis. Patients with LGL leukemia also often have other autoimmune diseases like RA as well as elevated levels of Fas ligand, suggesting a similar pathogenic mechanism.[rx][rx]

Causes of Felty Syndrome

There is strong evidence suggesting the presence of HLA-DRB1 allele shared epitope as a risk factor for anti-cyclic citrullinated peptide (CCP) antibody development. Rheumatoid factor (RF) and anti-CCP positivity are associated with an increased risk of development of extraarticular RA (ExRA).[rx]

HLA-DRB1 includes DRB1*01 and DRB1*04. HLADRB1*04 homozygosity has correlations with the development of more severe and erosive RA. A large multicenter study evaluating the impact of HLA-DRB1 genes in patients with ExRA confirmed a strong association of HLA-DRB1*0401 and FS. In the same study, there was a lack of association between ExRA and HLA-DQB1 alleles and DRB1-DQB1 haplotypes favoring the specific role of HLA-DRB1 genes.[rx]

Some experts believe it may be an autoimmune disorder, and that it may sometimes be inherited in an autosomal dominant manner.^[rx] Other proposed risk factors have included:^[rx]

• RF (rheumatoid factor) positivity – being positive for a test used to help diagnose rheumatoid arthritis
• Long-term rheumatoid arthritis
• Aggressive and erosive synovitis (inflammation of the tissue that lines the joints)
• HLA-DR4 positivity (having a specific gene for the immune system that is associated with RA) and DR4 homozygosity (having 2 identical copies of this gene)
• Extra-articular RA manifestations (symptoms that are not joint-related)

Diagnosis of Felty Syndrome

History and Physical

Described as a manifestation of severe RA; Felty syndrome usually occurs in patients with severe, long-standing, erosive, and seropositive arthritis. However, the diagnosis of Felty syndrome can precede arthritis symptoms in a few cases.[rx] Although articular involvement at the onset of FS can be quiet or active, most patients have radiographic evidence of erosive disease. Synovial effusions may be present in about 75% of patients.

Patients usually present with an infection because Felty syndrome is otherwise asymptomatic. The most common type of infection is dermatological and respiratory. Many patients have other extra-articular manifestations. These have been reported as rheumatoid nodules (74%), hepatomegaly (68%), lymphadenopathy (42%), Sjogren syndrome (48%), pulmonary fibrosis (50%), pleuritis (22%), peripheral neuropathy (14%), leg ulcers (16%). Systemic symptoms, including fever and weight loss, may also be present.[rx] Although splenomegaly is present in most cases, the involvement of spleen is not necessary for diagnosis. Spleen is usually palpable on clinical examination. Some patients can also have idiopathic non-cirrhotic portal hypertension which can lead to variceal bleeding.

Evaluation

Complete Blood Count

Complete blood count with differential shows an absolute neutrophil count of less than 2000/microliter, which is a hallmark feature and required for the diagnosis of Felty syndrome, accounting for an increased risk of bacterial infections. Diagnosis of Felty syndrome can sometimes be made earlier if the patient’s blood counts are under surveillance for another reason, such as medications’ toxicity monitoring. There is no correlation between splenic enlargement and degree of neutropenia.[rx] Anemia and thrombocytopenia may be present in patients with splenic enlargement. Anemia of chronic inflammation is present in almost all patients.

Serology

Laboratory findings of RA, like positive rheumatoid factor (RF) and anti-CCP, are almost always present in FS. Antinuclear antibodies, anti-histone antibodies, and HLA-DR4 can also be present.

Imaging

Plain radiographs of small peripheral joints may show severe joint destruction. Imaging of spleen with ultrasound or radionuclide scan can be done to detect splenomegaly.

• MRI (magnetic resonance imaging) – Powerful magnets and radio waves are used to make detailed images.
• CT scan (computerized tomography) – Several X-rays taken from different angles are put together to show a more complete picture.

Bone Marrow Biopsy

Bone marrow biopsy shows myeloid hyperplasia in most cases with increased granulopoiesis and relative excess of immature forms described as “maturation arrest.”[rx] Bone marrow biopsy helps rule out LGL leukemia, and a hypoplastic marrow should raise suspicion for other pathology. Immunophenotyping of marrow can also help to diagnose LGL leukemia.

Histology

Splenic histology in autopsies and post-splenectomy cases has shown non-specific findings such as congestion of venous sinusoids, reticular cell hyperplasia, and germinal cell hyperplasia.

Splenomegaly

If rheumatoid arthritis is present and other symptoms occur that are not commonly found within RA itself, such as a palpable spleen, further testing should be done. A palpable spleen is not always a clinical significance, therefore CT scan, MRI, or ultrasound can be administered in order to help diagnose the condition. According to Poulin et al, dimensional guidelines for diagnosing splenomegaly are as follows:^[rx]

• Moderate if the largest dimension is 11–20 cm
• Severe if the largest dimension is greater than 20 cm

Treatment of Felty Syndrome

Treatment for Felty syndrome focuses on controlling the underlying RA and treating the neutropenia to prevent infections.

• Drugs that slow down the disease – low-dose methotrexate (Rheumatrex, Otrexup, Trexall) is often used to stop your FS from getting worse. It can cause some side effects, such as nausea and mouth ulcers. You’ll also need regular tests to make sure MTX isn’t hurting your liver. Other drugs your doctor might advise you to take include glucocorticoids or disease-modifying antirheumatic drugs (DMARDs) that are used to treat RA, such as abatacept (Orencia) and leflunomide ( Arava ).
• Drugs that affect your immune system – Rituximab (Rituxan) is also a preferred treatment for FS and can shut off the part of your immune system that isn’t working as it should. They’re given by IV but may take up to a few weeks to work.
• Drugs that stimulate your white blood cells – Granulocyte colony-stimulating factor (G-CSF) can help increase the number of white blood cells and help fight infection.
• Home care – Your doctor will tell you how much physical activity and rest you need. A heating pad may help with mild aches and pains. A nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen can also help.

The goal is to achieve a granulocyte count of more than 2000/microliter. Neutropenia without evidence of infection is not an indication for treatment; however, the presence of neutropenia in patients with RA can help in adjusting disease-modifying antirheumatic drugs (DMARD) therapy. Improvement of the neutrophil count with the treatment of RA indicates a component of FS. Patients with neutropenia should undergo a thorough examination to look for signs of infection. The presence of systemic symptoms should prompt treatment. Care of neutropenic patients involves good dental and oral hygiene as well as scheduled age-appropriate immunizations. The clinician should initiate appropriate treatment of infections with broad-spectrum antibiotics, and neutropenic precautions are necessary. An infectious disease specialist consult can be helpful.

There are no randomized control studies available for the treatment of Felty syndrome, and most of the data directing treatment are from observational studies. Low dose oral methotrexate is considered first-line treatment. It has demonstrated benefit in the improvement of neutrophil count and helpful in preventing recurrence of infection. Studies have shown that a dose of less than 7.5mg/week results in prompt improvement of neutrophil count within 4 to 6 weeks. Because the effect of methotrexate is dose-dependent with noticeable change seen after 4 to 8 weeks, an adequate trial with a maximum tolerated dose should be considered before deeming it unresponsive.[rx][rx][rx]

Other DMARDs have been reported to be beneficial in some reports. A case report described a patient with RA who developed Felty syndrome while on MTX therapy and then severe cutaneous allergy to etanercept, but subsequently, significant improvement in neutropenia with leflunomide.[rx] Parenteral gold therapy was previously used in Felty syndrome but is outdated now due to the extensive adverse side effect profile.[rx] Cyclosporine has shown response in a few reports but is not generally an option because of the availability of other medications with a better side effect profile.[rx][rx] Amongst the biologic agents, Rituximab, a monoclonal antibody against CD20 antigen, has been shown to provide sustained improvement in neutropenia without major side effects.[rx][rx] It can be considered in patients who fail to respond to an adequate trial of non-biologic DMARD therapy. Limited reports on anti-tumor necrosis factor agents like infliximab, adalimumab, and etanercept have not shown any benefit in neutrophil response.[rx]

Initially, glucocorticoids can be used in patients with Felty syndrome to provide a rapid improvement in neutrophil count. Because of the immunosuppressive effect, however, long term use is generally not advised, and use should be avoided in patients with active infection.[rx] Granulocyte colony-stimulating factor (G-CSF) is usually used in patients with absolute neutrophil count (ANC) of less than 1000/microliter with severe and recurrent infections who fail to respond to DMARDs and rituximab adequately. In a systemic review, all patients with FS receiving G-CSF had a significant increase in ANC within one week of treatment. In most of the patients, discontinuation of G-CSF resulted in the decline of ANC; however, it stabilized above a pre-treatment level over time. There was also improvement in infectious complications. During an active infection, short term treatment with goal ANC of over 1000/microliter can be beneficial. There will be an additional stimulatory effect on neutrophil function as well. Although long term G-CSF therapy has a risk of exacerbation of the underlying autoimmune condition, its use is a consideration in patients with severe recurrent infections with consistent ANC below 1000/microliter despite immunosuppressive therapy.[rx]

Surgery

• If your FS is severe and other treatments don’t work, your doctor may recommend that your spleen be taken out. This could return your red and white blood cells to normal levels and may lower your risk of infection for an indefinite amount of time.
• Splenectomy in a patient with Felty syndrome was first tried by Hanrahan and Miller in a 50-year-old woman who had marked improvement in neutropenia and arthritis over five months follow up. After this, splenectomy was the main treatment option for Felty syndrome.[rx][rx] With the development of DMARDs and other biologic agents, the surgical approach has limited indications.
• It is reserved for patients who have significant recurrent infections with neutropenia and those who have failed to respond to all medical therapies, including DMARDs, biologic agents, and G-CSF. Other rare indications of splenectomy are severe anemia requiring multiple transfusions and severe hemorrhage due to thrombocytopenia which is not responsive to conventional treatment.[rx]

• https://www.ncbi.nlm.nih.gov/books/NBK541102/
• https://www.ncbi.nlm.nih.gov/books/NBK373678/
• https://www.ncbi.nlm.nih.gov/books/NBK459118/
• https://www.ncbi.nlm.nih.gov/books/NBK546693/
• https://www.ncbi.nlm.nih.gov/books/NBK559282/
• https://www.ncbi.nlm.nih.gov/books/NBK532893/
• https://www.ncbi.nlm.nih.gov/books/NBK541102/
• https://www.ncbi.nlm.nih.gov/books/NBK507702/
• https://www.ncbi.nlm.nih.gov/books/NBK557396/
• https://www.ncbi.nlm.nih.gov/books/NBK1533/
• https://en.wikipedia.org/wiki/Neutropenia
• https://en.wikipedia.org/wiki/Febrile_neutropenia
• https://www.ncbi.nlm.nih.gov/books/NBK546693/
• https://rarediseases.info.nih.gov/diseases/8234/feltys-syndrome
• https://www.sciencedirect.com/topics/medicine-and-dentistry/feltys-syndrome