Role of splenectomy for Felty syndrome

INTRODUCTION — Felty syndrome (FS) is an uncommon but severe subset of seropositive rheumatoid arthritis complicated by granulocytopenia and splenomegaly. The granulocytopenia in FS may improve when rheumatoid arthritis is treated with disease-modifying antirheumatic drugs (DMARDs), presumably because these drugs reverse underlying abnormalities in the immune and reticuloendothelial systems. Other therapies for FS increase circulating neutrophils by mechanisms which are not disease-specific.

Surgical intervention with splenectomy can result in improvement in the neutropenia and a reduction in infections in patients with FS and was first performed for this purpose in 1931 [1,2]. The need for splenectomy has decreased with the availability of medications that are often effective and because of the reduced incidence of the disorder; however, it remains a useful treatment option in patients who have granulocytopenia and recurrent infections and have not responded to all available medical therapies.

This topic will discuss the role of splenectomy in the treatment of FS. The clinical manifestations and diagnosis of FS and drug therapy for this disorder are reviewed separately. (See "Clinical manifestations and diagnosis of Felty syndrome" and "Drug therapy in Felty syndrome".)

GOALS OF THERAPY — The treatment goal in Felty syndrome (FS) is reversal of the granulocytopenia to prevent recurrent and severe infections and febrile episodes, and to facilitate the resolution of ongoing bacterial infections. This may be accomplished by interventions that raise the granulocyte count, including the use of conventional synthetic, biologic, and targeted synthetic disease-modifying antirheumatic drugs (DMARDs), growth factors, and other medications, and by splenectomy, although infections may also result from granulocyte dysfunction and other disease-related factors [3-9]. (See "Drug therapy in Felty syndrome".)

INDICATIONS FOR SPLENECTOMY — Splenectomy is generally indicated in the patient with Felty syndrome (FS) with nonhealing leg ulcers or with recurrent or severe infections (eg, pneumonia or septicemia) despite medical therapies [3,10]; such patients usually have severe granulocytopenia (<1000 cells/microL). Prophylactic splenectomy is not justified in patients who do not become infected, even in the presence of marked granulocytopenia. The decision to perform splenectomy may also be influenced by the frequency and severity of infections, the degree and nature of comorbid conditions, and the patient's overall medical status.

Splenectomy may also be of benefit in rare patients in whom thrombocytopenia due to FS is refractory to medical therapies. (See 'Thrombocytopenia and anemia' below and "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults", section on 'Splenectomy'.)

Medical interventions that should be used prior to referral for possible splenectomy include treatment with the conventional synthetic, biologic, and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) used for patients with FS and therapy using granulocyte colony-stimulating factor (G-CSF) [1,11]. A hematologist should also be consulted to exclude any other potential causes of neutropenia. (See "Drug therapy in Felty syndrome" and "Drug therapy in Felty syndrome", section on 'Neutropenia and infection inadequately responsive to nonbiologic and biologic DMARDs' and "Management of the adult with non-chemotherapy-induced neutropenia".)

Every effort should be made to reduce the susceptibility to infection before resorting to surgery:

●General strategies to prevent infection in neutropenic patients should be employed, including good dental hygiene and care; good hand hygiene; and age-, disease-, and medication-appropriate immunizations. (See "Management of the adult with non-chemotherapy-induced neutropenia", section on 'Overview of infection prevention'.)

●Strategies to reduce susceptibility to infection that are particular to rheumatoid arthritis include reducing glucocorticoid dose and modifying other immunosuppressive therapies without causing sustained worsening of the arthritis; local treatment of skin ulcerations; and physical therapy to avoid prolonged immobility.

●Consultation with a specialist in infectious disease may also be helpful to identify or exclude other potential risk factors or sources of infection.

For many years, splenectomy was the principal therapy for FS. However, the indications for splenectomy are now limited, since this procedure has largely been replaced by treatment with effective medications such as methotrexate, biologic agents, and targeted synthetic DMARDs. The hospitalization rate for splenectomy was 71 percent lower between 1998 and 2001 than between 1983 and 1987 [12].

Survival is reduced in severe rheumatoid arthritis, including patients with FS. However, the main cause of death among patients with rheumatoid arthritis is cardiovascular disease rather than infection. Neither infection nor splenectomy changed long-term survival in a cohort of FS patients followed prospectively, beginning in 1966 [13]. This observation and the availability of the medical therapies, as well as the unpredictable effect of splenectomy on FS, has limited the indications for this procedure. (See "Drug therapy in Felty syndrome".)

PERIOPERATIVE INFECTION RISK REDUCTION — In addition to standard measures for reducing the risk of infection in patients with Felty syndrome (FS) patients should also undergo immunizations and should be assessed to determine if preoperative treatment with granulocyte colony-stimulating factor (G-CSF) would be beneficial. (See 'Role of immunization' below and 'Preoperative granulocyte-colony stimulating factor therapy' below.)

Role of immunization — Splenectomized patients are at high risk of serious infections, especially with encapsulated bacteria; thus, immunization against such bacteria should be performed before or soon after surgery. The approach to immunization and specific recommendations for patients undergoing splenectomy are described in detail separately.

Preoperative granulocyte-colony stimulating factor therapy — Treatment with a granulopoietic growth factor such as G-CSF may lead to short-term improvement in granulocytopenia and facilitate control of perioperative infection, as shown for joint replacement surgery in patients with FS [14]. Caution in this setting should be exercised, given the lack of data regarding preoperative use of G-CSF in patients undergoing splenectomy for FS. Drug dosing and timing should be chosen in close collaboration with a hematologist with expertise in the therapeutic use of these growth factors, with attention to minimizing the theoretical risk of excessive neutrophilia (a leukemoid reaction) from the combination of interventions. (See "Drug therapy in Felty syndrome", section on 'Neutropenia and infection inadequately responsive to nonbiologic and biologic DMARDs'.)

EFFICACY FOR NEUTROPENIA AND INFECTION — Support for the use of splenectomy to treat Felty syndrome (FS) comes largely from case reports and case series, most of which were published prior to the availability of methotrexate, hematopoietic growth factors, biologic therapies, or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) [15,16]. There have not been any randomized trials.

Following splenectomy, the absolute granulocyte count increases within minutes to hours, often to the normal range, in more than 80 percent of patients with FS [3,15]. The granulocytopenia recurs in at least one-quarter of cases, but the granulocyte count usually remains above the pre-splenectomy level.

The degree of granulocytopenia appears to be an important determinant of risk, as the frequency of infection is increased when the absolute granulocyte count is below 1000 cells/microL [11]. However, the value of splenectomy in preventing serious infection and improving survival is unclear [15]. Since there have been no randomized trials and splenectomy is rarely performed to treat FS, this issue probably will never be resolved satisfactorily. Most reports conclude that patients without recurrent infections prior to splenectomy are likely to remain free of infection afterward [3,15]. Furthermore, ongoing infections may resolve dramatically as the granulocyte count rises in the postoperative period [3].

The frequency of subsequent infections was reduced following splenectomy in data aggregated from 10 reports (nine published between 1961 and 1982 and one in 1990) involving 118 patients who had undergone splenectomy for FS [1]. Of these, 88 had prior infections, and 30 did not but underwent splenectomy because of neutropenia. Cell counts improved similarly in the two groups, with about 80 percent of patients in each group maintaining normal neutrophil counts beyond six months. Patients with a history of infections before splenectomy were more likely to have subsequent infections than those without (fatal infections in 15 versus 3 percent, nonfatal infections in 31 versus 20 percent).

The rapid increase in granulocytes in the peripheral blood within minutes or hours following splenectomy in most cases supports involvement of the spleen in the pathogenesis of granulocytopenia in FS [16,17]; however, the role of the spleen in the pathogenesis of FS is only incompletely understood, and the precise mechanism by which splenectomy is effective in some patients is not known. Both granulocyte sequestration within the spleen and production of antibodies or other factors that inhibit granulopoiesis may contribute [15]. The old observation that splenic arterial blood contains a far greater number of granulocytes than splenic venous blood is compatible with an important role for sequestration [18]. Subsequent studies suggested that both granulocyte survival defects, mediated by humoral mechanisms, and proliferation defects, through cell-mediated mechanisms, may play a significant role in the pathogenesis of granulocytopenia [16].

The observation that some patients who experienced recurrent infections prior to surgery continued to do so after splenectomy, even with an adequate hematologic response, indicates that factors in addition to granulocytopenia play an important role in the pathogenesis of infection in FS [1,13,15]. These include several granulocyte functions, including chemotaxis, phagocytosis, and intracellular killing, which are impaired in FS [5,11,19]. Severe disability, skin ulcers, glucocorticoid therapy, and hypocomplementemia are other risk factors for infection in FS. (See "Clinical manifestations and diagnosis of Felty syndrome".)

OTHER BENEFITS OF SPLENECTOMY

Thrombocytopenia and anemia — Splenectomy has beneficial effects in Felty syndrome (FS) other than resolution of granulocytopenia. Concurrent thrombocytopenia usually improves after splenectomy, but thrombocytopenia in FS is seldom severe enough to result in spontaneous bleeding. There may also be some improvement in anemia; the degree of improvement is determined by the degree to which red cell survival has been shortened by splenomegaly [3].

Nonhematologic changes — Three nonhematologic problems also may improve after splenectomy:

●Synovitis may improve, but this improvement does not occur in most patients and is often temporary [20].

●Chronic, refractory leg ulcers may heal after splenectomy [3,17].

●Esophageal varices associated with idiopathic noncirrhotic portal hypertension (including hepatic nodular regenerative hyperplasia), which occurs infrequently in patients with splenomegaly associated with FS, have been observed to resolve after splenectomy, but other treatment approaches are preferred for this condition [21]. (See "Noncirrhotic portal hypertension", section on 'Idiopathic noncirrhotic portal hypertension/Porto-sinusoidal vascular disease'.)

COMPLICATIONS — Surgical morbidity and mortality following splenectomy may be higher in this group of immunosuppressed, disabled patients than in otherwise healthy individuals, but the issue has not been specifically studied. The perioperative risk is probably higher if splenectomy is performed when there is a serious systemic infection or extraarticular manifestation of rheumatoid arthritis, such as vasculitis. Splenectomy performed for any indication results in a long-term increase in susceptibility to bacterial infection; this risk can be reduced by immunization. (See 'Role of immunization' above.)

Laparoscopic splenectomy may reduce the risk of intraoperative and postoperative complications, as when this technique has been employed to treat idiopathic thrombocytopenic purpura (ITP); however, an insufficient number of patients with FS who underwent splenectomy have been reported to allow adequate assessment of this approach [22]. Choice of the appropriate procedure to treat a given patient should be made together with a surgeon who has experience with the relevant techniques and the various treatment options, with the goal of minimizing the risks of surgical morbidity and mortality.

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SUMMARY AND RECOMMENDATIONS

●Splenectomy is generally indicated in the patient with Felty syndrome (FS) with granulocytopenia and nonhealing leg ulcers or with recurrent or severe infections (pneumonia or septicemia) despite nonpharmacologic efforts to reduce risk of infection and use of medical therapies, including the conventional synthetic, biologic, and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) used for patients with FS and granulocyte colony-stimulating factor (G-CSF). Patients with recurrent or severe infections usually have severe granulocytopenia (<1000 cells/microL). (See 'Indications for splenectomy' above.)

●Prophylactic splenectomy is not justified in patients who do not become infected, even in the presence of marked granulocytopenia. The decision to perform splenectomy may also be influenced by the frequency and severity of infections, the degree and nature of comorbid conditions, and the patient's overall medical status. (See 'Indications for splenectomy' above.)

●Splenectomized patients are at high risk of serious infections, especially with encapsulated bacteria; thus, immunization against such bacteria should be performed prior to or soon after surgery. Preoperative G-CSF may also be of benefit in reducing perioperative risk of infection, but should be employed with particular caution in this setting. (See 'Perioperative infection risk reduction' above.)

●Splenectomy is followed by a short-term increase in the absolute granulocyte count, often to the normal range, within minutes to hours, in more than 80 percent of patients with FS. The granulocytopenia recurs in at least one-quarter of cases, but the granulocyte count usually remains above the pre-splenectomy level. Splenectomy reduces but does not eliminate the risk of subsequent or recurrent infection. Thrombocytopenia and anemia may also improve, and some patients experience improvement in chronic leg ulcers and in synovitis. (See 'Efficacy for neutropenia and infection' above and 'Other benefits of splenectomy' above.)

●Surgical morbidity and mortality following splenectomy may be increased in this group of immunosuppressed, disabled patients. The risk is probably higher if splenectomy is performed in the presence of serious systemic infection or extraarticular manifestations of rheumatoid arthritis, such as vasculitis. (See 'Complications' above.)