Clinical manifestations and diagnosis of Felty syndrome

INTRODUCTION — Patients with Felty syndrome (FS) comprise an infrequently occurring but severe subset of seropositive rheumatoid arthritis (RA) complicated by neutropenia and splenomegaly [1].

The clinical manifestations and diagnosis of this disorder are discussed here. Drug therapy and surgery for FS, as well as a review of large granular lymphocyte leukemia in RA, are presented separately. (See "Drug therapy in Felty syndrome" and "Role of splenectomy for Felty syndrome" and "Large granular lymphocyte leukemia in rheumatoid arthritis".)

PATHOGENESIS — The cause of Felty syndrome (FS), which occurs within a subset of patients with rheumatoid arthritis (RA), is unknown. Its presence primarily in patients with longstanding active disease who test positive for rheumatoid factor (RF) or anti-citrullinated peptide antibodies (ACPA), and for human leukocyte antigen (HLA)-DR4, suggests important roles for chronic inflammation in a genetically predisposed individual.

Neutropenia in patients with FS results from an imbalance between granulocyte production and granulocyte removal from the circulating pool. One or more of the following can contribute to the development of neutropenia [2-10]:

●Autoantibodies to deiminated histones (predominantly histone H3) and other components of neutrophil extracellular chromatin traps (NETs) that bind to activated neutrophils, which are then sequestered in the spleen (see 'Splenomegaly' below) and depleted.

●Autoantibodies that bind and neutralize granulocyte colony-stimulating factor (G-CSF).

●Cytotoxic lymphocytes, which infiltrate the bone marrow and inhibit myelopoiesis. Bone marrow abnormalities most commonly include a maturation arrest of the granulocyte cell line. Overall bone marrow cellularity either is normal or reveals myeloid hyperplasia.

●Increased white blood cell margination.

EPIDEMIOLOGY — The lifetime risk of developing Felty syndrome (FS) for a patient initially diagnosed with rheumatoid arthritis (RA) had been estimated to be approximately 1 percent [11,12]. A subsequent study, utilizing a large Veterans Administration database, showed a steady decline in prevalence during the two decades ending in 2006 [13]. However, no more recent data have been published about the prevalence of FS.

The basis for this decrease in prevalence is not entirely understood. One proposed explanation is that the reclassification of some cases of FS as large granular lymphocytic (LGL) leukemia may have contributed to the decreased number of patients diagnosed with FS since 1985, when the diagnosis of LGL leukemia was established, although this would not account for the entire decline (see "Large granular lymphocyte leukemia in rheumatoid arthritis"). Other factors have not been identified, but the widespread use of methotrexate and the introduction of targeted biologic therapies for RA during that time period might also play a role.

The demographic features of patients with FS and of RA controls are similar [14]. Women comprise 60 to 80 percent of patients, and the onset of arthritis usually occurs in the patients' late 30s or early 40s [12,14]. FS patients are more likely to have a family history of RA, and the major histocompatibility complex (MHC) class II DR4 allele is present in about 95 percent of cases, a frequency that is significantly higher than in RA controls [12,14,15]. FS is rare in patients of African ancestry, who have a low frequency of human leukocyte antigen (HLA)-DR4 [11].

CLINICAL MANIFESTATIONS

Major features — Felty described a syndrome characterized by the triad of rheumatoid arthritis (RA), neutropenia, and splenomegaly, with the following features [1]:

●Rheumatoid arthritis – The arthritis is typically severe, erosive, and seropositive for rheumatoid factor (RF) and/or anti-citrullinated peptide antibodies (ACPA). (See 'Rheumatoid arthritis' below.)

●Neutropenia – Neutropenia is present in all patients, with absolute neutrophil counts below 2000/microL. (See 'Neutropenia' below.)

●Splenomegaly – Splenomegaly is present in most patients, although infrequently splenomegaly is undetectable in RA despite marked neutropenia; spleen size does not correlate with the degree of neutropenia or clinical course. (See 'Splenomegaly' below.)

Rheumatoid arthritis — RA in patients with Felty syndrome (FS) is typically severe, with erosions and deformities, and is more frequently associated with extraarticular manifestations than is RA without FS:

●Articular features – The arthritis almost always appears first and typically has been present for at least 10 years before neutropenia is recognized [11]. Infrequently, however, neutropenia and splenomegaly appear before or simultaneously with the onset of arthritis [16]. (See "Clinical manifestations of rheumatoid arthritis".)

Although FS is typically associated with severe erosive joint disease and deformity, one study found that the erosive process was equally advanced both in patients with FS and in matched controls with RA of similar disease duration [12]. Approximately one-third of patients with FS have longstanding disease without active synovitis, although even these individuals almost always have a markedly elevated erythrocyte sedimentation rate (ESR) [11,17], the mean value for which was 85 mm/hour in one large series [18].

●Extraarticular features – Patients with FS tend to have more frequent and severe extraarticular manifestations than other patients with RA [11,14,17-19]. These features and their estimated frequencies in several case series include: vasculitis, which can result in mononeuritis multiplex (14 to 24 percent) and necrotizing skin lesions (16 to 41 percent); pleuropericarditis (0 to 22 percent); rheumatoid nodules in subcutaneous and visceral locations (53 to 82 percent); lymphadenopathy (0 to 42 percent); and episcleritis (3 to 11 percent). (See "Clinical manifestations and diagnosis of rheumatoid vasculitis" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)

Some of these extraarticular manifestations may be associated with serious morbidity and mortality [12,14]. As in other patients with seropositive RA, the extraarticular features are seldom prominent at the onset of arthritis and generally do not play a role in establishing the diagnosis of FS.

Neutropenia — Neutropenia (absolute neutrophil count below 2000/microL) is present, by definition, in all patients with FS. It does not cause symptoms unless it leads to infection (see 'Bacterial infection' below). As a result, it may not be detected for a prolonged period unless blood counts are being monitored for some other reason, such as the detection of possible toxicity to antirheumatic drugs. However, the initial diagnosis of FS may not be evident in patients who present with infection because in infection, the white blood cell count may be normal or even slightly elevated. However, the neutropenia typically reappears within a short time after successful treatment of the infection.

Splenomegaly — Splenomegaly is present in most patients with FS and can be detected in more than 90 percent of patients with FS by carefully palpating the abdomen [20]. Ultrasonography or radionuclide scanning can be used to confirm splenic enlargement. The mean splenic weight in FS is about four times the normal weight, and massive splenomegaly can occur [20].

The spleen size does not correlate with either the degree of neutropenia or the clinical course and severity of arthritis [17,18]. Patients with seropositive RA and chronic idiopathic neutropenia, but without splenomegaly, otherwise resemble patients with the full triad [2,14,21].

Splenomegaly can also occur in patients with RA who never develop neutropenia; however, these individuals should not be considered to have FS [11].

Associated clinical features

Bacterial infection — The neutropenia in FS predisposes to recurrent bacterial infections [11,14] (see 'Neutropenia' above). Respiratory tract and skin infections due to usual pathogenic bacteria are most common. Risk factors for infection include neutrophil counts below 1000/microL, skin ulcers, glucocorticoid therapy, increases in overall disease severity and in functional impairment, low serum levels of soluble Fc-gamma receptor III (Fc-gamma RIII or CD16, shed from the surface of neutrophils), and elevated levels of granulocyte colony-stimulating factor (G-CSF) [3,22,23]. However, serum Fc-gamma RIII and G-CSF concentrations are seldom measured in clinical practice.

Fever in the absence of underlying infection is as unusual in FS as it is in adult-onset RA, with the exception that it may occur in patients with rheumatoid vasculitis or with fulminant polyarticular synovitis [24].

Extraarticular rheumatoid arthritis — Leg ulcers, which are a feature of rheumatoid vasculitis, as well as other extraarticular manifestations of RA, may be present in patients with FS. (See 'Rheumatoid arthritis' above.)

Portal hypertension — Portal hypertension in FS is the result of idiopathic noncirrhotic portal hypertension (an entity that includes nodular regenerative hyperplasia) and can result in variceal bleeding [11,25,26]. How this occurs is not well understood, but immune-mediated injury to the endothelial cells of the portal venules may play a role.

Malignancy — Patients with FS have a greater risk for developing non-Hodgkin lymphoma than both the general population and other patients with RA [27]. Similar to other patients with RA, FS patients have an increased risk of lung cancer and other malignancies [27].

Laboratory findings — In addition to neutropenia, which is present by definition in patients with FS, these patients also exhibit laboratory findings typical of seropositive RA, with positive serologic testing for RF and/or ACPA, usually in high titer [18,28] (see "Clinical manifestations of rheumatoid arthritis", section on 'Laboratory findings'). Findings in patients with active disease often include anemia and elevated acute phase reactants. Thrombocytopenia may be present. The bone marrow usually shows myeloid hyperplasia with a relative excess of immature forms [11]. The following findings may be present:

●Hematologic

•Neutropenia – Neutropenia, with absolute neutrophil counts below 2000/microL, is typically present and one of the findings that characterize the condition. The neutropenia is typically persistent and unexplained by concurrent illnesses or drug therapy. The degree of neutropenia may vary through the clinical course of FS. The neutrophil count may increase temporarily into the normal range or even become mildly elevated during an episode of infection. However, sustained resolution of neutropenia rarely occurs in FS unless a patient receives effective treatment [29].

•Anemia and thrombocytopenia – Anemia of chronic inflammation is often present. Splenomegaly, with sequestration of platelets and red blood cells, results in thrombocytopenia (platelet count below 150,000/microL) and anemia [30].

•Bone marrow – The bone marrow usually shows myeloid hyperplasia with a relative excess of immature forms [11]. This pathologic finding has often been described as "maturation arrest," but premature release of granulocytes into the circulation can produce the same picture. Less common findings are a hypocellular marrow, suggesting failure of the normal development of the myeloid cell lineage, and an increase in marrow lymphocytes, which should arouse suspicion of the large granular lymphocyte (LGL) syndrome. (See 'Differential diagnosis' below and "Large granular lymphocyte leukemia in rheumatoid arthritis".)

●Immunologic – Autoantibodies and other immune abnormalities are typically more prominent in FS than in RA. The following have been noted:

•Antinuclear antibodies (ANA); antihistone antibodies; and antineutrophil cytoplasmic antibodies (ANCA), mostly reactive to lactoferrin; are each found in 65 to 83 percent of patients with FS [11,31,32].

•Circulating autoantibodies in FS preferentially bind peptidylarginine deiminase type 4 (PAD-4)-deiminated histones 3 and 2A over non-deiminated histones and bind to activated neutrophils and neutrophil extracellular chromatin traps [10].

•Anti-double-stranded DNA (anti-dsDNA) antibody titers are occasionally elevated [14].

•Anti-glucose-6-phosphate isomerase antibody titers are elevated in 92 percent of patients with FS [33].

•Circulating immune complexes are found more commonly in patients with FS than in other RA patients [11].

•Immunoglobulin levels are higher and complement component levels are lower in patients with FS than in other RA patients. However, most values still fall within the normal range [11,17,18].

DIAGNOSIS — Felty syndrome (FS) is a clinical diagnosis that is suspected in a patient with rheumatoid arthritis (RA), splenomegaly, and neutropenia. There is no specific single diagnostic test. Absolute neutrophil counts below 2000/microL are required for the diagnosis. The neutropenia should be persistent and should not be explainable by concurrent illnesses or drug therapy. Other causes of neutropenia, particularly those associated with polyarthritis, should be considered and excluded before concluding that FS is present. Systemic lupus erythematosus (SLE) and its variants, for example, may usually be excluded based upon unique features of the history and physical examination and the results of selected laboratory studies. (See 'Differential diagnosis' below.)

We suggest the following diagnostic testing in patients suspected of having FS:

●Complete blood count and differential white blood cell count, from which the absolute neutrophil count can be calculated.

●Consultation with a hematologist for the following:

•Review of the peripheral smear morphology and immunophenotypic analysis to exclude large granular lymphocyte (LGL) leukemia. (See 'Differential diagnosis' below and "Large granular lymphocyte leukemia in rheumatoid arthritis".)

•Bone marrow aspiration and biopsy – Immunophenotypic analysis of the bone marrow and analysis for clonality may be required in patients in whom analysis of the peripheral blood is insufficient to exclude leukemia. Additionally, on bone marrow examination, findings of myeloid hyperplasia with left-shifted maturation further support the diagnosis of FS, while myeloid hypoplasia necessitates consideration of other causes [2]. (See "Large granular lymphocyte leukemia in rheumatoid arthritis", section on 'Diagnosis' and 'Differential diagnosis' below.)

●Serologic studies, including measurement of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies – Patients with FS typically have both RF and anti-CCP antibodies, each of which is usually present in high titer [18,28].

Infrequently, patients without splenomegaly present with a similar clinical course who otherwise resemble patients with the full triad [2,14,21]. Although splenomegaly was a component of the triad originally described by Felty [1] and is present in most cases, the author and most experts agree that splenomegaly is not an absolute diagnostic requirement, although it is present in most cases. In the absence of splenomegaly, a diagnosis of FS may be appropriate if other causes of granulocytopenia are ruled out.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of Felty syndrome (FS) includes conditions other than rheumatoid arthritis (RA), such as systemic lupus erythematosus (SLE), which may also be associated with both polyarthritis and neutropenia. In addition, other conditions superimposed on RA may cause splenomegaly and/or neutropenia, such as myeloproliferative or lymphoproliferative disorders, and must also be excluded with reasonable certainty.

●Systemic lupus erythematosus – Both polyarthritis and neutropenia can occur in patients with SLE and patients with FS. Further, because antinuclear antibodies (ANA) and anti-double-stranded (ds)DNA antibodies may be present in both conditions, and platelets and complement component levels may be decreased in both SLE and FS, laboratory testing may not be sufficient alone to differentiate SLE from FS (see 'Laboratory findings' above). Thus, both clinical and serologic criteria are usually used to distinguish between RA and SLE [21,34]; both are somewhat less useful when FS complicates RA because the spectrum of extraarticular disease and immunologic abnormalities among patients with FS is often similar to that of patients with SLE.

However, despite their potential similarities, laboratory findings are sometimes helpful. Laboratory features more consistent with SLE than FS include the presence of lymphopenia (absolute lymphocyte count less than 1500/microL) and hemolytic anemia with a positive direct Coombs test. The neutropenia in SLE typically occurs with concomitant lymphopenia.

FS and SLE can generally be distinguished based upon the clinical findings. Examples of helpful clinical features include the presence of nephritis, central nervous system disease, and/or typical photosensitive rash, which point toward a diagnosis of SLE; while erosive arthritis and/or typical rheumatoid nodules are generally indicative of RA. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Diagnosis and differential diagnosis of rheumatoid arthritis".)

●Large granular lymphocytic (LGL) leukemia – LGL leukemia may be associated with neutropenia with or without splenomegaly in the 10 to 20 percent of patients with LGL leukemia who have RA. The diagnosis is suggested by an increased proportion of LGL cells on the peripheral smear or in a bone marrow aspirate or biopsy. FS may be difficult to differentiate from LGL leukemia, particularly when arthritis and splenomegaly are present in the latter. (See "Large granular lymphocyte leukemia in rheumatoid arthritis".)

Molecular differentiation of LGL leukemia from FS is based upon the demonstration in LGL leukemia of a characteristic, expanded (and usually clonal) lymphocyte population. Immunophenotyping in the T cell form of LGL leukemia (T-LGL) reveals an expanded population of CD3⁺CD8⁺CD57⁺ cytotoxic T lymphocytes, while the rarer natural killer (NK) form of LGL (NK-LGL) is characterized by an increased number of CD3^-CD8⁺CD16⁺CD56⁺ NK cells; these expanded immune cell populations are rarely observed in patients with FS. The diagnosis of LGL leukemia in patients with RA is described separately. (See "Large granular lymphocyte leukemia in rheumatoid arthritis", section on 'Diagnosis'.)

Somatic mutations in the hotspot exon 21 in the Src homology 2 domain of STAT3, which result in constitutive STAT3 activation, have been identified in lymphocytes of 30 to 75 percent of patients with LGL leukemia and in approximately 40 percent of patients with FS. Several plasma cytokines, including interleukin 15 receptor subunit alpha, C-X-C motif chemokine 10, and programmed death-ligand 1, are elevated in both patients with FS and those with LGL leukemia compared with healthy individuals. These findings suggest that FS and LGL leukemia may represent a continuum of disease rather than distinct disease entities [35,36].

●Other causes of neutropenia and splenomegaly – Other conditions that may cause splenomegaly and/or neutropenia can mimic FS when they occur in patients with RA. These include:

•Drug reactions or toxicities – Antibiotics and many other drugs can cause neutropenia; those drugs likeliest to be used in patients with RA or other forms of inflammatory arthritis include methotrexate (with which neutropenia is unusual, except in the setting of a viral infection or with concomitant use of trimethoprim-sulfamethoxazole or another folate antagonist drug), tumor necrosis factor (TNF) inhibitors [37], rituximab (with which neutropenia is usually transient), and nonsteroidal antiinflammatory drugs (NSAIDs). (See "Drug-induced neutropenia and agranulocytosis".)

•Amyloidosis – Splenomegaly, caused by amyloid deposition in the spleen, is seen in 4 to 15 percent of patients with primary (AL) or secondary (AA) amyloidosis [38]. Patients with RA may develop AA amyloidosis as a result of chronic inflammation, with associated splenomegaly mimicking FS. However, these patients typically do not exhibit neutropenia, and Congo red staining of an abdominal fat pad aspirate may confirm the diagnosis of amyloidosis. (See "Overview of amyloidosis".)

•Hematologic malignancies – Splenomegaly frequently occurs in patients with hematological malignancies, predominantly in those with acute leukemia, but also in patients with lymphomas or with chronic leukemia. Neutropenia may also be present in these patients, especially after chemotherapy. Bone marrow aspiration and biopsy or lymph node biopsy will differentiate a hematologic malignancy from FS in a patient with RA. (See "Splenomegaly and other splenic disorders in adults", section on 'Splenomegaly'.)

•HIV infection – Splenomegaly may be present in patients with HIV infection. However, serologic evidence of HIV infection distinguishes these patients from those with FS. (See "Splenomegaly and other splenic disorders in adults", section on 'Splenomegaly'.)

•Sarcoidosis – Splenomegaly is present in up to a third of patients with sarcoidosis. Although RA may occur concomitantly with sarcoidosis, the presence of lymphadenopathy with identification of noncaseating granulomata in a lymph node biopsy distinguishes those patients with sarcoidosis from those with FS. (See "Overview of extrapulmonary manifestations of sarcoidosis".)

•Tuberculosis – Splenomegaly may be seen in patients with tuberculosis (TB). However, evidence of infection with Mycobacterium tuberculosis, by skin testing, interferon-gamma release assays, or culture, distinguishes these patients from those with FS. (See "Splenomegaly and other splenic disorders in adults", section on 'Splenomegaly'.)

•Epstein-Barr viral infection – Splenomegaly is present in 50 to 60 percent of patients with infectious mononucleosis caused by Epstein-Barr viral (EBV) infection. However, serologic evidence of EBV infection distinguishes these patients from those with FS. (See "Infectious mononucleosis", section on 'Splenomegaly and splenic rupture'.)

•Malaria – Patients with malaria develop splenic enlargement as a result of parasitemia, as well as because of clearance of immune complexes caused by chronic antigenic stimulation by cells of the reticuloendothelial system. These patients typically are anemic and may exhibit pancytopenia, but the presence of fever or of plasmodia on examination of the peripheral blood smear distinguish patients with malaria from those with FS. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children", section on 'Severe malaria' and "Laboratory tools for diagnosis of malaria" and "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)

•Cirrhosis – Patients with hepatic cirrhosis have abnormal liver function studies and may develop portal hypertension, which can result in variceal bleeding. Portal hypertension may also occur in FS (see 'Portal hypertension' above). In patients with FS, portal hypertension is not due to cirrhosis, but rather is the result of idiopathic noncirrhotic portal hypertension. Liver biopsy can distinguish between idiopathic noncirrhotic portal hypertension and hepatic cirrhosis. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)

SUMMARY AND RECOMMENDATIONS

●Definition – As originally described, Felty syndrome (FS) refers to patients with rheumatoid arthritis (RA), otherwise unexplained neutropenia, and splenomegaly. (See 'Clinical manifestations' above.)

•Concurrent rheumatoid arthritis – RA associated with FS is typically severe, longstanding, erosive, and seropositive (rheumatoid factor [RF]- and anticyclic citrullinated peptide [anti-CCP] antibody-positive). Other extraarticular manifestations of RA are often present. (See 'Rheumatoid arthritis' above.)

•Neutropenia – Neutropenia (absolute neutrophil count <2000/microL) may be asymptomatic or may be noted in association with recurrent bacterial infections. Various mechanisms may contribute to the neutropenia of FS. (See 'Pathogenesis' above.)

•Splenomegaly – Splenomegaly, as determined by physical examination, is present in more than 90 percent of patients with FS. However, a diagnosis of FS may be appropriate in a patient with RA and neutropenia in whom no other cause is apparent. (See 'Splenomegaly' above.)

●Bacterial infection – Bacterial infections of the respiratory tract and skin, due to typical pathogens of these sites, are increased in frequency. Neutrophil counts <1000/microL and the presence of other clinical and laboratory features are associated with an increased risk of infection. (See 'Bacterial infection' above.)

●Diagnosis – There is no diagnostic laboratory test for FS. A complete blood count and differential white blood cell count and review of the peripheral smear to exclude large granular lymphocyte (LGL) leukemia should be performed. Elevated markers of the acute phase response (eg, erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) and the presence of RF and anti-CCP antibodies in serum are usually noted. (See 'Laboratory findings' above and 'Diagnosis' above.)

•Bone marrow biopsy – Bone marrow examination is usually necessary to exclude other causes of neutropenia. Adequate or increased myeloid elements with a relative increase in immature granulocyte precursors are the most common finding. Hypocellularity or an excess of lymphocytes is less frequently noted. Immunophenotyping can distinguish FS from LGL leukemia. (See 'Diagnosis' above and 'Differential diagnosis' above.)

•Autoantibodies – Autoantibodies other than RF (eg, antinuclear antibodies [ANA], antihistone antibodies, antineutrophil cytoplasmic antibodies [ANCA], anti-double-stranded DNA [anti-dsDNA] antibodies, anti-glucose-6-phosphate isomerase antibodies) are commonly present in sera from those with FS. (See 'Laboratory findings' above.)

●Differential diagnosis – Systemic lupus erythematosus (SLE), the LGL syndrome, drug reactions, and hepatic cirrhosis are among the other causes of neutropenia and splenomegaly that should be considered in the differential diagnosis of FS. (See 'Differential diagnosis' above and 'Laboratory findings' above.)