Felty Syndrome

Etiology

There is strong evidence suggesting the presence of the HLA-DRB1 allele shared epitope as a risk factor for anticyclic citrullinated peptide (CCP) antibody development. Anti-CCP antibodies are highly specific for RA, with a specificity of about 96%.[3] Rheumatoid factor (RF) and anti-CCP positivity are associated with an increased risk of the development of extra-articular RA (ExRA).[4] HLA-DRB1 includes DRB1*01 and DRB1*04. HLADRB1*04 homozygosity correlates 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 between HLA-DRB1*0401 and Felty syndrome. 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.[5] 

Epidemiology

The prevalence of Felty syndrome in patients with RA is reported to be approximately 1% to 3%.[6] With the evolution of RA pharmacotherapy, including increased use of methotrexate (MTX) and biologics, the risk of Felty syndrome seems to be declining, and true prevalence is very low.[7] Felty syndrome usually develops about 16.1 years after RA presentation, with increased risk in patients with a positive family history of RA. There is also a stronger association of RA with HLA DR4 in patients with Felty syndrome[2] The disease follows the same pattern as RA and affects females 3 times more than males, is diagnosed in middle age, and affects the White population more compared to non-White populations.[8][9]

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, contributing to neutrophil survival and proliferation defects resulting in neutropenia.[10] 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 Felty syndrome 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.[11]

Another study concluded that autoantibodies present in Felty syndrome bind to deaminated histones and neutrophil extracellular chromatin traps (NETs), leading to neutrophil sequestration and supporting the role of peripheral destruction of neutrophils in the pathophysiology of Felty syndrome.[12]

Some have suggested that chronic large granular lymphocyte (LGL) leukemia and Felty syndrome may have a common pathologic link because of similar clinical presentation and common genetic etiology of HLA-DR4.[13] About a third of Felty syndrome patients have a clonal LGL  (CD3+/CD8+) population.[14]  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.[15][16] About 20% of T-cell LGL leukemia (T-LGLL) patients will have RA.[17][18] The clinical overlap of T-LGLL and Felty syndrome has led to the belief that they are 2 entities on a spectrum of a common disease.[19]  

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.[20][21] Although articular involvement at the onset of Felty syndromecan be quiet or active, most patients have radiographic evidence of erosive disease. Synovial effusions may be present in about 75% of patients.[22]

Patients usually present with an infection because Felty syndrome is otherwise asymptomatic.[23] The most common types of infections are dermatological and respiratory.[14] 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%), and leg ulcers (16%).[24] Systemic symptoms, including fever and weight loss, may also be present.[25] Although splenomegaly is present in most cases, the involvement of the spleen is not necessary for diagnosis. The 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 (CBC) with differential shows an absolute neutrophil count of <2000/µL, a hallmark feature 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 medication toxicity monitoring. There is no correlation between splenic enlargement and the degree of neutropenia.[26] Anemia and thrombocytopenia may be present in patients with splenic enlargement. Anemia of chronic inflammation is present in almost all patients. Felty syndrome has a greater association with autoimmune hemolytic anemia (+ Coombs) than RA.[14]

Serology

Laboratory findings of RA, like positive rheumatoid factor (RF) and anti-CCP, are almost always present in Felty syndrome. Antinuclear antibodies, anti-histone antibodies, and HLA-DR4 can also be present. Anti-histone antibodies are present in 83% of Felty syndrome patients; the existence of anti-histone antibodies in a patient with RA is felt to be diagnostic of Felty syndrome.[14]

Imaging

Plain radiographs of small peripheral joints may show severe joint destruction.[27] Imaging of the spleen with ultrasound or radionuclide scan can be done to detect splenomegaly (see Image. CT Splenomegaly).

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.”[25] Bone marrow biopsy helps rule out LGL leukemia; a hypoplastic marrow should raise suspicion for other pathology. Immunophenotyping of the marrow can also help diagnose LGL leukemia, denoting either T-cell (CD3+/CD8+/CD57+) or natural killer cell (CD3-/CD56+) subsets.[14]

Histology

Splenic histology in autopsies and postsplenectomy cases has shown nonspecific findings such as congestion of venous sinusoids, reticular cell hyperplasia, and germinal cell hyperplasia. 

Treatment / Management

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

The goal is to achieve a granulocyte count of >2000/µL. 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 Felty syndrome. 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.

No randomized control studies are available to guide the treatment of Felty syndrome, and most of the data directing treatment are from observational studies. Low-dose oral MTX with folic acid (thwarts the anti-folate toxicity of MTX manifested in the liver, marrow, and gastrointestinal tract) is considered a first-line treatment.[1] This treatment has demonstrated benefits in improving the neutrophil count and helps prevent the recurrence of infection. Studies have shown that a dose of <7.5 mg/week results in prompt improvement of the neutrophil count within 4 to 6 weeks. Because the effect of MTX 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 patients unresponsive.[28][29][30](B2)

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.[31] Parenteral gold therapy was previously used in Felty syndrome but is outdated now due to the extensive adverse side effect profile.[32] Cyclosporine has shown a response in a few reports but is not generally an option because of the availability of other medications with a better side effect profile.[33][34] Amongst the biologic agents, rituximab, a monoclonal antibody against CD20 antigen, has been shown to provide sustained improvement in neutropenia without major adverse effects.[35][36] It can be considered in patients who fail to respond to an adequate trial of nonbiologic DMARD therapy. Limited reports on anti-tumor necrosis factor agents like infliximab, adalimumab, and etanercept have not shown any benefit in neutrophil response.[36](B3)

Initially, glucocorticoids can be used in patients with Felty syndrome to improve neutrophil count rapidly. Because of the immunosuppressive effect, however, long-term use is generally not advised, and use should be avoided in patients with an active infection.[37] G-CSF is usually used in patients with absolute neutrophil count (ANC) of <1000/µL with severe and recurrent infections who fail to respond to DMARDs and rituximab adequately. In a systemic review, all patients with Felty syndrome receiving G-CSF significantly increased ANC within 1 week of treatment. In most patients, discontinuing G-CSF resulted in the decline of ANC; however, it stabilized above a pretreatment level over time. There was also an improvement in infectious complications. During an active infection, short-term treatment with the goal of an ANC >1000/µL 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 worsening the underlying autoimmune condition, its use is a consideration in patients with severe recurrent infections with consistent ANC <1000/µL despite immunosuppressive therapy.[38](B3)

Hanrahan and Miller first performed splenectomy on a patient with Felty syndrome, a 50-year-old woman, who had marked improvement in neutropenia and arthritis over 5 months of follow-up. Subsequently, splenectomy was the main treatment option for patients with Felty syndrome.[39][26] With the development of DMARDs and other biological agents, the surgical approach now has limited indications. It is reserved for patients with significant recurrent infections with neutropenia and those who 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 unresponsive to conventional treatment.[40] Neutropenia recurs postoperatively in a quarter of cases. G-CSF has no role in this disorder beyond the transitory improvement in neutropenia when necessary. Patients with RA or Felty syndrome can have anti-GCSF antibodies that can further compound treatment challenges.[3](B3)

Differential Diagnosis

The most important differential to consider in patients with RA and neutropenia is LGL leukemia. Also termed "pseudo-Felty syndrome," it can present as neutropenia with or without splenomegaly. Most patients with LGL leukemia have an associated autoimmune condition, particularly RA; therefore, it can be challenging to distinguish Felty syndrome from LGL leukemia. Immunophenotyping showing cytotoxic T lymphocytes with CD 2, 3, 8, 16, and 57 surface marker positivity, together with bone marrow biopsy and peripheral smear showing increased LGL cells, can help in differentiating the 2 diseases. Many consider these conditions part of the same disease continuum rather than separate entities. The involvement of a hematologist to rule out hematological malignancy as the cause of neutropenia is important.[41][42] 

Other causes of neutropenia and splenomegaly should be evaluated and ruled out. Medications are an important cause to consider. MTX can cause bone marrow suppression and neutropenia in patients with RA. Similarly, TNF inhibitors can cause neutropenia. Worsening of neutropenia after temporary cessation of these agents provides a clue to the diagnosis of Felty syndrome.[43] Viral infections like Epstein-Barr virus and HIV can present with neutropenia and splenomegaly. If suspected, serological tests can help rule out these conditions. Other autoimmune conditions, such as lupus, which can have similar features as an extra-articular RA, can usually be distinguished through clinical features and serological tests.  

Prognosis

The severity and extra-articular manifestations of RA have been decreasing gradually since MTX and biological treatments became available for the treatment of RA.[7] The incorporation of G-CSF in the treatment of chronic neutropenia has resulted in a decrease in the need for splenectomy.[44] One study conducted before the advent of MTX reported a 5-year mortality of 36% in patients with Felty syndrome, infections being the most common cause of death.[45] Recent data regarding the prognosis of Felty syndrome is lacking. However, the availability of advanced treatment options has significantly improved the prognosis for Felty syndrome.  

Complications

The most important complication of Felty syndrome is severe or recurrent infections, particularly of the respiratory tract and skin, because of neutropenia. Other complications like anemia due to splenic sequestration and hemorrhage due to severe thrombocytopenia can also occur. Variceal bleeding due to portal hypertension is possible. Treatment modalities like splenectomy for refractory neutropenia can increase the risk of infections after surgery and have been fatal in a few cases. G-CSF carries a small risk of exacerbation of underlying autoimmune disorders.