Felty Syndrome

Although the pathophysiology of FS is not fully understood, evidence points to splenic sequestration and subsequent granulocyte destruction.

Early studies demonstrated that granulocyte counts were lower in the splenic vein than in the splenic artery. Researchers have shown immune complexes coating granulocytes, diminished granulocyte growth factor levels, and numerous circulating autoantibodies, including those against granulocyte surface antigens. T-cell large granular lymphocyte leukemia and FS share overlapping pathophysiologic features.[3, 4]

In a 2002 study from Germany, 15 patients with neutropenia due to FS were matched to a control group of 16 patients with normocytic RA, and 16 patients with neutropenia and systemic lupus erythematosus (SLE) were matched to a control group of 16 patients with SLE.[5] Antibodies against granulocyte colony-stimulating factor (G-CSF) were measured.

In this study, 11 patients with FS demonstrated anti–G-CSF immunoglobulin G (IgG); none of the patients in the RA control group demonstrated anti–G-CSF IgG.[5] In addition, 6 of the patients with both neutropenia and SLE and 6 of the patients in the SLE control group had anti–G-CSF antibodies. These antibodies appeared to have a neutralizing effect on G-CSF.

Risk factors for FS include the following:

• RF positivity in high titers

• Long-standing disease

• Aggressive and erosive synovitis – Patient with FS may present with mild RA, but FS is clearly associated with severe disease and extra-articular manifestations

• Human leukocyte antigen (HLA)-DR4 positivity and DR4 homozygosity – HLA-DR4 homozygosity is also associated with more severe and erosive RA

• Extra-articular RA manifestations

United States and international statistics

FS affects approximately 1-3% of all patients diagnosed with RA, and RA occurs in about 1% of the general population. FS a and the Black population. The true prevalence of FS is difficult to ascertain because many affected patients are asymptomatic. Prevalence may be decreasing with the advent of more potent antirheumatic agents. Few data suggest that the international frequency of FS differs significantly from the US frequency.

Age-, sex-, and race-related demographics

FS is most common during the fifth through seventh decades of life and is usually associated with more than 10 years of preceding RA activity; itppears to be rare in children. Men are affected with FS earlier in the course of RA than women are. FS is about 3 times more common in females, though underreporting and asymptomatic cases hinder determination of the true sex ratio. FS is most common in Whites and is uncommon in Blacks. The HLA-DR4 genotype, a marker for more aggressive RA and more frequent extra-articular manifestations in Whites, is strongly associated with FS.

Although many individuals with FS are asymptomatic, others become symptomatic and may develop life-threatening infections. Pulmonary and skin infections are common. Mortality and morbidity are heavily influenced by the level of debilitation due to the underlying RA, along with the extent of immunosuppressive therapy used in treating both RA and FS. One study from southwest England observed 32 patients with Felty syndrome; 5 patients died of overwhelming bronchopneumonia during a mean follow-up period of 5.2 years.[6]

Curiously, over the past 20 years in the United States, the frequency of hospitalization for rheumatoid vasculitis and ultimate splenectomy in patients with FS has dropped, possibly because earlier and more aggressive treatment of RA tends to control the disease before the manifestations of FS appear.

Granulocytopenia is defined as an absolute neutrophil count (ANC) lower than 2000/µL, and the infection risk increases as the ANC drops. Infection incidence increases significantly when the polymorphonuclear leukocyte (PMN) count is lower than 1000/µL.

In a retrospective study of male patients with FS treated at the Department of Veterans Affairs, lymphoproliferative malignancies were more prevalent; in particular, the patients had an increased prevalence of non-Hodgkin lymphoma.[7]

Educate patients with FS about the warning signs of infection and ensure that they have ready access to medical care.

Some practitioners supply FS patients with a broad-spectrum oral antibiotic that is to be taken at the first signs of a bacterial infection. Instruct patients that the decision to initiate antibiotic therapy is a decision that must be made on an individual basis, and advise them to contact their physician immediately if such a situation develops.

Many years of aggressive destructive rheumatoid arthritis (RA) precede the onset of Felty syndrome (FS). On occasion, RA and FS develop simultaneously.[8] The extra-articular manifestations of RA (eg, rheumatoid nodules, pleuropericarditis, vasculitis, peripheral neuropathy, episcleritis, other forms of eye involvement, Sjögren syndrome, adenopathy, skin ulcers) are more common in those patients who develop FS.

Patients with FS often report symptoms of mild inflammatory joint disease caused by synovitis; it is often the case that their burden of synovitis is less than that experienced previously. The history usually reveals a long preceding period of active and aggressive joint disease, which can be confirmed by means of physical examination and plain radiography. Some patients present with quiescent or so-called “burned-out” joint disease. A lack of synovitis or active joint disease should not dissuade the clinician from considering the diagnosis of FS in an RA patient.

Patients with FS commonly present with bacterial infections of the skin and respiratory tract. An aggressive level of immunosuppression directed at the underlying RA may contribute to this susceptibility to infection.

Patients may present with left upper quadrant pain, initiated by splenic infarcts or capsular distension of the spleen.

Physical findings in FS include the following:

• Splenomegaly, possibly nonpalpable

• Hepatomegaly, usually mild

• Lymphadenopathy

• Weight loss

• Rheumatoid nodules

• Sjögren syndrome

• Articular findings of long-standing RA – Joint deformities typical of RA, as well as synovitis (joint swelling and tenderness), which may be mild at presentation

• Small-vessel inflammation (vasculitis) – Lower-extremity ulcers, palpable purpura and brownish pigmentary changes of the lower extremities, and periungual infarcts

• Signs of systemic vasculitis – Mononeuritis multiplex and extremity ischemia

• Other findings – Pleuritis, peripheral neuropathy, episcleritis, and signs of portal hypertension

Complications of FS include the following:

• Splenic rupture

• Life-threatening infection

• Toxicity due to immunosuppressive regimens

• Portal hypertension and gastrointestinal bleeding due to nodular regenerative hyperplasia of the liver

Laboratory tests

Obtain a white blood cell (WBC) count and differential, which are crucial when determining the degree of granulocytopenia. Studies show that the greatest risk for infection is a granulocyte count lower than 1000/µL. It must be kept in mind, however, that the level of neutropenia varies over time without medical intervention. Granulocyte dysfunction and an absolute decrease in the number of granulocytes may predispose to infection.

Anemia and thrombocytopenia may result from hypersplenism. Anemia of chronic disease may result from the underlying inflammatory disease.

Mild elevations of alkaline phosphatase and transaminase levels may occur.

Some 98% of patients with Felty syndrome (FS) have high titers of rheumatoid factor (RF). This is because extra-articular manifestations of rheumatoid arthritis (RA) are strongly associated with RF.

Antinuclear antibodies (ANAs), found in 67% of cases; antihistone antibodies; and even antineutrophil cytoplasmic antibodies (perinuclear pattern; p-ANCA), found in 77% of cases, commonly occur in patients with Felty syndrome. The significance of autoantibodies in Felty syndrome is unknown, and their contribution, if any, to the disease itself is uncertain.

Erythrocyte sedimentation rate (ESR) and serum immunoglobulin levels are invariably elevated in patients with FS. Cryoglobulins may be present.

Diagnostic imaging

Radionuclide studies, ultrasonography, or computed tomography (CT) may define the presence and extent of splenomegaly. The same modalities can also be used to assess patient response to therapy.

Bone marrow aspiration and biopsy are especially important to rule out large granular lymphocytosis (LGL). The bone marrow of patients with FS shows adequate megakaryocytes and myeloid hyperplasia with arrested development at the level of immature cell forms.

An unusual type of liver involvement known as nodular regenerative hyperplasia is associated with FS. This condition is characterized by mild portal fibrosis or lymphocyte and plasma cell infiltration but is not typical of cirrhosis. It may be complicated by portal venule occlusion and regenerative nodule formation.

The best way of treating Felty syndrome (FS) is to control the underlying rheumatoid arthritis (RA). Immunosuppressive therapy for RA often improves granulocytopenia and splenomegaly; this finding reflects the immune-mediated nature of FS. Most of the traditional medications used to treat RA have been used in the treatment of FS. No well-conducted, randomized, controlled trials support the use of any single agent. Most reports on treatment regimens involve small numbers of patients.

Surgical treatment (ie, splenectomy) may be warranted in certain cases.

Hospital admission is mandatory for patients with serious life-threatening infections; cultures and parenteral antibiotics are indicated in such situations. It is important to acknowledge the possibility of infection with encapsulated organisms because splenomegaly may be a marker for a dysfunctional reticuloendothelial system incapable of clearing these organisms. Staphylococcus aureus, streptococcal species, and gram-negative rods are potential infecting organisms.

Consult the following specialists as needed:

• Rheumatologist
• Hematologist
• Infectious diseases specialist

Methotrexate is the agent preferred by rheumatologists for treating RA. Currently, almost all patients with RA are treated with methotrexate. If urgent correction of neutropenia is unnecessary, most practicing rheumatologists use methotrexate first when treating FS, usually in combination with folic acid to minimize adverse effects. Methotrexate is typically administered orally in low doses for FS.[1] The beneficial effects of methotrexate may not be evident until 4-8 weeks after the initiation of therapy.

Because of the potential for leukopenia, cyclophosphamide is of limited utility in this setting, although it may have a role in some cases. A small number of patients with refractory FS have been reported to respond to high-dose cyclophosphamide[10] ; however, physicians have had far more experience using cyclophosphamide for rheumatoid vasculitis and other serious RA extra-articular manifestations than for FS. For this reason, this agent is not a preferred initial choice for treatment of FS.

Recombinant granulopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), effectively and quickly raise the granulocyte count, which is important in patients with life-threatening infections. Initial treatment of patients with FS and life-threatening infections should include administration of a growth factor. Long-term use of G-CSF appears to be well tolerated, though hypersensitivity vasculitis and flareups of the underlying RA have been reported.

The tumor necrosis factor alpha (TNF-α) inhibitors etanercept, adalimumab, and infliximab are disease-modifying antirheumatic drugs (DMARDs) that have proved very effective in the treatment and control of RA. Clinical experience with them in FS is comparatively limited, but consensus has built that they do not offer much benefit in FS.[11]

Initial reports on using rituximab to treat FS were negative,[12] but subsequent reports were more encouraging.[13, 14, 15] Current data suggest that rituximab should be considered in refractory FS.[16]  Rituximab is becoming a preferred biologic treatment choice, with a better response pattern than anti-TNF agents.[17]  

Case reports describe successful treatment of FS with other DMARDs approved for use in RA. One report describes relief of clinical symptoms and resolution of splenomegaly with the interleukin-6 receptor antagonist tocilizumab.[18] In another patient with FS, whose neutropenia had not responded to G-CSF, the absolute neutrophil count normalized after initiation of abatacept, a chimeric protein that inhibits T-lymphocyte activation.[19]

At high doses, corticosteroids can increase the granulocyte count, partly through demargination. This effect does not persist when the dose is tapered to a typical low dose (< 10 mg/day) used for RA articular disease. Empiric administration of high-dose IV methylprednisolone is often prescribed for FS, but the effect is time-limited. Long-term use of high-dose corticosteroids further increases the risk of infection. Corticosteroids should probably be viewed as a second-line treatment modality.

Case reports from the 2000s noted a lack of response to leflunomide[20] and a response to salazosulfapyridine.[21]  Penicillamine is used infrequently in RA because of its adverse effect profile, and it is never a first-choice therapy for patients with FS. Intravenous immunoglobulin (IVIg) has not been demonstrably successful on a reproducible basis.

At one time, most FS patients were treated with gold salts, on the basis of these agents’ long history of use in RA before the advent of methotrexate; however, FS responds only slowly to gold salts. Older studies report a response rate of 60-80%. Intramuscular aurothioglucose was once the most commonly used agent for FS but is now of only historic note.

Splenectomy is recommended only in patients with severe intractable disease who exhibit no improvement with medical therapy and who are experiencing recurrent or serious infection. Less commonly, extrinsic hemolysis or recurrent cutaneous ulcers may indicate a need for splenectomy. Granulocytopenia recurs in approximately 25% of patients who have undergone splenectomy.

Patients with FS should be scheduled for regular follow-up with a rheumatologist to monitor therapy and to assess progress.

No firm guidelines address immunization practice in FS patients, but ensuring vaccination against encapsulated organisms seems prudent.

Recommended patient activity levels should be dictated by infection risk and spleen size. In general, patients should avoid any activity that could result in blunt trauma to the left upper quadrant.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Agents used to treat Felty syndrome (FS) include immunosuppressive agents and hematopoietic growth factors.

Class Summary

Immunosuppressive agents inhibit key factors in the immune system responsible for immune reactions.

Methotrexate (Rheumatrex, Trexall)

Methotrexate is an antineoplastic agent that is immunosuppressive at lower doses. It is very effective in treating rheumatoid arthritis (RA). Antirheumatic effects may take several weeks to become apparent. Its mechanism of action in treatment of inflammatory disorders is unknown; it may affect immune function. Methotrexate ameliorates symptoms of inflammation (eg, pain, swelling, and stiffness). Succinct guidelines for use and monitoring are available from the American College of Rheumatology.

Cyclophosphamide

Cyclophosphamide is an antineoplastic alkylating agent and immunosuppressive agent. It reduces the numbers of B and T cells and increases the risk of infection.

Class Summary

CSFs stimulate production, maturation, and activation of neutrophils and increase migration and cytotoxicity of neutrophils.

Filgrastim (Neupogen)

A solid record of success is emerging with the use of CSFs in patients with FS and infections that are not responding to antibiotics alone. Most experience has been with the use of granulocyte CSF (G-CSF).

Sargramostim (Leukine)

Granulocyte-macrophage CSF (GM-CSF) stimulates division and maturation of earlier myeloid and macrophage precursor cells. It reportedly increases granulocytes in 48-91% of patients.

Class Summary

Monoclonal antibodies are genetically engineered chimeric murine-human immunoglobulins directed against proteins involved in cell cycle initiation.

Rituximab (Rituxan)

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody (immunoglobulin G1 [IgG1] kappa) against CD20 antigen on the surface of normal and malignant B cells. It is not to be administered as an intravenous bolus. Current data suggest that rituximab should be considered a second-line therapy in patients with refractory FS.