Drug therapy in Felty syndrome

INTRODUCTION — Felty syndrome (FS) is an uncommon but severe subset of seropositive rheumatoid arthritis (RA) that is complicated by neutropenia and splenomegaly. Patients with FS are at substantially increased risk for recurrent and severe bacterial infections. Medications that raise the neutrophil count may provide therapeutic benefit [1], but the risk of infection is also affected by neutrophil dysfunction and other disease-related factors [2-4].

Treatments for the neutropenia of FS include selected nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs), which are presumed to reverse underlying abnormalities in the immune and reticuloendothelial systems. Other medical therapies for FS, including granulocytopoietic growth factors, increase circulating neutrophils by mechanisms that are not disease-specific. Splenectomy is reserved primarily to treat patients with severe neutropenia and recurrent infections who are refractory to medical therapy.

Drug therapy for FS is described here. The clinical manifestations and diagnosis of FS and the indications for splenectomy in the treatment of FS are discussed separately. (See "Clinical manifestations and diagnosis of Felty syndrome" and "Role of splenectomy for Felty syndrome".)

GOALS OF THERAPY — The management of Felty syndrome (FS) is focused upon the partial or complete reversal of neutropenia to facilitate the resolution of ongoing bacterial infections and to prevent recurrent infections. Rheumatoid arthritis (RA) disease activity may also improve with many of these therapies independently of any change in the white blood cell count. A response to therapy is characterized by an increased neutrophil count accompanied by a clinical response that can include reductions in the frequency of infections and other clinical features. (See "Clinical manifestations and diagnosis of Felty syndrome".)

A complete response to therapy was defined in one study as [2]:

●An increase in the neutrophil count to at least 2000 cells/microL plus two of the following:

•Infection rate decreased by at least 50 percent

•Incidence of cutaneous ulcers decreased by at least 50 percent

•Incidence of febrile episodes decreased by at least 75 percent

APPROACH TO THERAPY — Treatment of Felty syndrome (FS) is indicated in patients with recurring or severe infections, although the presence of FS can also impact the choice of disease-modifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA) but without infections. The principal treatment interventions include nonpharmacologic measures to reduce the risk of infection and medications to control RA disease activity and alleviate the neutropenia. (See 'General interventions' below and 'Drug choices' below.)

General interventions — Patients with active infections should be treated for those infections prior to initiating antirheumatic drug therapy. Efforts to reduce the susceptibility to infection should include:

●General strategies for the prevention of infection in neutropenic patients, 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'.)

●Vaccination, according to the American College of Rheumatology (ACR) guidelines for vaccinations in patients with RA [5]. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)

●Additional strategies to reduce susceptibility to infection in RA, which include local treatment of skin ulcerations and physical therapy to avoid prolonged immobility.

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

Drug choices — The initial choice of therapy depends primarily upon whether the patient is experiencing recurrent or severe infections (defined as two or more severe infections in one year, three or more respiratory infections [eg, sinusitis, otitis, bronchitis] in one year, or the need for antibiotics for two months/year), joint disease activity, and the potential response to treatment with selected DMARDs.

●Nonbiologic and biologic DMARDs and glucocorticoids – Certain drugs may be preferred because of demonstrated benefit or a reduced likelihood of harm compared with other agents, while others should be avoided in patients with FS:

•Methotrexate (MTX) and rituximab (RTX) are the DMARDs that are preferred in patients with FS, as their benefit has been described in case reports and case series. The efficacy of abatacept, leflunomide, and glucocorticoids for the treatment of FS is uncertain and may be considered second-line therapy after MTX and RTX. Use of glucocorticoids is generally minimized to reduce risk of infection. (See 'Initial therapy' below and 'Inadequate response to methotrexate' below and 'Inadequate response to methotrexate and rituximab' below and 'Role of glucocorticoids' below.)

•Tumor necrosis factor (TNF) inhibitors are avoided as they have been found to be ineffective treatment for FS, although evidence is also limited to case reports and case series. Tocilizumab and tofacitinib have not been studied for the treatment of FS and are generally avoided because they may cause neutropenia. (See 'Inadequate response to methotrexate' below and 'Role of other biologic agents' below.)

Our approach to the treatment of FS is based upon case reports, small series, and our clinical experience. Most patients with FS have RA of long duration and have already received DMARD therapy. This prior experience and possible adverse effects will influence the choice of a pharmacologic agent to treat the RA while reversing progressive neutropenia.

●Granulocyte colony-stimulating factor (G-CSF) – Patients with an absolute neutrophil count <1000 cells/microL who continue to develop infections despite adjustments in their DMARD therapy may require treatment with G-CSF. (See 'Neutropenia and infection inadequately responsive to nonbiologic and biologic DMARDs' below.)

PATIENTS WITH RECURRENT OR SEVERE INFECTIONS — The primary approach to managing Felty syndrome (FS) is to employ selected nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate (MTX) or rituximab (RTX), to control the arthritis and the other clinical manifestation of FS, including both the neutropenia and recurrent infections. However, if a patient has an active severe infection, such as sepsis, MTX and biologic DMARDs should be held until the infection has resolved. (See 'Initial therapy' below and 'Inadequate response to methotrexate' below and 'Inadequate response to methotrexate and rituximab' below and 'Well-controlled arthritis' below.)

In patients with life-threatening infections and neutropenia and in those who have not responded to DMARD therapy with a reduction in the frequency and severity of infections, we use granulocyte colony-stimulating factor (G-CSF) to rapidly improve the neutrophil count and facilitate management of the infections. (See 'Neutropenia and infection inadequately responsive to nonbiologic and biologic DMARDs' below.)

Active arthritis

Initial therapy — MTX has been reported to be effective for the treatment of FS in several case series [6-10]. Low-dose weekly oral MTX therapy results in improvement of both articular disease and neutropenia in most patients, often within one to two months. Short-term experience suggests that the frequency of infection may also decrease. However, these encouraging results are based upon small numbers of patients in each report. In one study, seven patients with FS received MTX at a mean dose of 13 mg per week [11]. The mean neutrophil count rose insignificantly after one month but doubled after a year. However, since that case series in 1998, no reports of larger series of FS patients treated with MTX and followed for longer than one year have been published. (See "Use of methotrexate in the treatment of rheumatoid arthritis".)

The precautions, administration, and dosing of MTX are the same as for patients without FS. The dose should be increased to maximum tolerated levels up to 25 mg once weekly in patients not responding to lower doses. (See "Initial treatment of rheumatoid arthritis in adults" and "Use of methotrexate in the treatment of rheumatoid arthritis" and "Major side effects of low-dose methotrexate".)

We do not limit the dose of MTX based upon the presence of neutropenia. However, in patients with neutropenia, we monitor complete blood counts and absolute neutrophil counts frequently (eg, monthly) in addition to routine drug safety monitoring. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Monitoring and reevaluation'.)

Other conventional synthetic DMARDs for which neutropenia is a known adverse effect, such as sulfasalazine (SSZ), should be discontinued.

Patients with inadequate control of disease activity (moderate or severe disease activity) and no improvement of neutropenia after two months of MTX therapy at maximum tolerated doses of up to 25 mg weekly (administered by subcutaneous injection) are considered inadequately responsive to MTX therapy.

We use leflunomide as an alternative to MTX in patients unable to take MTX or who had responded inadequately to MTX in the past. The precautions, administration, and dosing of leflunomide are the same as in patients without FS. There is very limited evidence regarding its efficacy specifically for FS. In a case report, successful treatment with leflunomide was described in a patient who developed FS while receiving MTX [12]. After six months of leflunomide treatment, leg ulcers healed without any adverse effects (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Leflunomide' and "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis".)

Inadequate response to methotrexate — In patients who are inadequately responsive to MTX, we suggest adding RTX, rather than another nonbiologic DMARD or a tumor necrosis factor (TNF) inhibitor. The precautions, administration, and dosing are the same as in patients without FS. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Rituximab'.)

At least eight cases of FS have been reported in which synovitis and neutropenia both improved following intravenous treatment with RTX [13-20]. However, other cases of FS have been described in which only articular disease, but not neutropenia, improved following a course of intravenous RTX treatment [13,21].

We prefer RTX and other selected agents over a TNF inhibitor because of the lack of efficacy of TNF inhibitors for FS that has been described in case reports. In six published case reports in which adalimumab, etanercept, or infliximab was used to treat FS, each was ineffective in correcting the neutropenia of FS [13]. Although synovitis improved and acute phase reactant levels decreased in the two FS patients treated with subcutaneous etanercept 25 mg twice weekly, neither patient exhibited an increase in the absolute neutrophil counts [22,23].

Patients are considered to have responded inadequately to RTX if they have not improved during the three months following the initial course of therapy.

Inadequate response to methotrexate and rituximab

Role of glucocorticoids — We treat FS with glucocorticoids in patients who inadequately respond to MTX and/or RTX, or who are intolerant of these medications. Glucocorticoids and other immunosuppressive agents should generally be avoided in the presence of active infection (see 'General interventions' above). Glucocorticoids may also be useful for short-term bridging therapy until a patient realizes any benefit from a recently initiated DMARD, such as MTX or RTX. Typical dosing of prednisone is 30 to 40 mg daily, which is then gradually tapered as the neutropenia improves. The rate by which the prednisone dose is tapered to 10 mg daily, or less, depends upon the timing and degree of clinical response and the patient's comorbidities. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Glucocorticoids' and "Use of glucocorticoids in the treatment of rheumatoid arthritis".)

We avoid long-term glucocorticoids at doses greater than prednisone 15 mg daily, and we aim to reduce the dose to less than 10 mg daily, if possible. The white blood cell count may begin to rise within several weeks of initiating glucocorticoid therapy in responders.

Glucocorticoids can raise the neutrophil count in FS, both by an immunosuppressive action and by altering neutrophil kinetics: they stimulate the release of mature neutrophils from the bone marrow, mobilize neutrophils from the marginal pool into the circulation, and impair egress of neutrophils into tissues [24-26]. Prednisone doses of 30 mg daily or higher, often can normalize the neutrophil count [27]. However, this effect usually is not sustained when the dose is reduced to that usually used as maintenance treatment (less than 10 mg daily) of RA, unless other treatments are added.

Concern about overwhelming infection is the main obstacle to using high-dose glucocorticoids in FS. Low doses of glucocorticoids, which still may increase the risk of infection, do not consistently improve the neutrophil count [28].

Role of other biologic agents — For patients intolerant of MTX or in those with an inadequate response to MTX and RTX and who require prednisone at doses greater than 10 to 15 mg daily for control of the arthritis and neutropenia, we use abatacept rather than a TNF inhibitor, an interleukin (IL) 6 inhibitor, or a Janus kinase (JAK) inhibitor to treat FS. Abatacept is used in the same regimen as for patients with RA without FS; the administration, dosing, and adverse effects are described separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Abatacept'.)

We prefer abatacept over TNF inhibitors because of the lack of efficacy of TNF inhibitors for FS described in case reports (see 'Inadequate response to methotrexate' above); however, the effects of abatacept in patients with FS have not been described. We prefer abatacept over IL-6 inhibitors and JAK inhibitors, which also have not been studied in this setting because use of these agents is known to be associated with a reduction in the neutrophil count.

Well-controlled arthritis — In patients with FS whose arthritis is well-controlled on DMARD therapy, but who continue to experience recurrent or severe infections, we take the following steps:

●We re-evaluate the patient to identify and minimize or exclude other factors that may be contributing to infection risk. (See 'General interventions' above.)

●We minimize the doses and use of medications that may be increasing the risk of infection, including glucocorticoids and DMARDs. As in patients without FS, we temporarily discontinue DMARDs that may be impairing host defense in the setting of a new or ongoing infection. Once the infection has been effectively treated, we resume treatment with the DMARD. However, in patients with recurrent infections associated with the use of a specific agent, we discontinue that medication and instead use another appropriate DMARD. (See 'Drug choices' above.)

●In patients who are being treated with prednisone, hydroxychloroquine (HCQ), and/or SSZ, we stop SSZ because it may cause neutropenia, and we add MTX unless it has been poorly tolerated in the past, or previously has been ineffective at optimal doses/route of administration. If a patient is being treated with an IL-6 inhibitor or a JAK inhibitor, we switch them to MTX, if possible, since both of these classes of DMARD are known to cause neutropenia. If MTX is not effective at 25 mg weekly administered by subcutaneous injection, we add RTX.

●In patients with recurring or severe infections with persistent neutropenia despite DMARD therapy, we treat the neutropenia with G-CSF. (See 'Neutropenia and infection inadequately responsive to nonbiologic and biologic DMARDs' below.)

Neutropenia and infection inadequately responsive to nonbiologic and biologic DMARDs — In patients with FS and recurrent or severe infections inadequately responsive to DMARD therapy who have an absolute neutrophil count <1000 cells/microL, we suggest using G-CSF (filgrastim); the decision to use G-CSF should be made in collaboration with a hematologist experienced in the use of such therapy. G-CSF may also be of benefit in patients with marked neutropenia and life-threatening infections in whom the neutropenia needs to be reversed quickly, including those in whom DMARD therapy was recently initiated or modified but has not yet had sufficient time to be effective.

We use G-CSF dosing regimens also used in other forms of non-chemotherapy-induced neutropenia. The administration, dosing, and adverse effects of G-CSF, which may include bone pain, nausea, vomiting, and splenomegaly, are described in detail separately. (See "Management of the adult with non-chemotherapy-induced neutropenia", section on 'Myeloid growth factors to reduce infectious risk'.)

G-CSF was shown to be effective in patients with FS in several small case series, with follow-up for up to three and a half years [29,30]. As an example, the benefits and adverse reactions associated with prolonged G-CSF therapy were reported in one study of eight patients with FS who were treated with G-CSF because of recurrent infections or infection prophylaxis before joint surgery [29]. Significant side effects occurred in five of the eight patients, including nausea, malaise, and exacerbation of joint pain and vasculitic skin lesions. However, only two of these five required discontinuation of G-CSF, whereas the other three individuals continued G-CSF treatment at reduced doses. The underlying arthritis was not exacerbated. Several reports of individual cases and other small case series with short-term follow-up also support its use [31-36].

Both granulocyte macrophage colony-stimulating factor (GM-CSF) and G-CSF effectively reverse neutropenia and reduce infectious complications in many patients. However, some patients do not respond at all to colony-stimulating factor treatment, and secondary treatment failures also have been reported. The incidence of these events is unknown. In addition, cost is often a limiting factor, particularly with extended use. Significant adverse effects with these agents include arthralgias, rarely with exacerbation of synovitis, and the development of leukocytoclastic vasculitis [30].

Although some patients have been treated with G-CSF for an extended duration, the colony-stimulating factors are employed primarily for short-term use during periods of neutropenia with active infection. Additional therapies such as DMARDs should be continued and optimized for the clinical setting, and splenectomy may be an option when neutropenia is incompletely reversed by colony-stimulating factors and serious infections persist. (See "Role of splenectomy for Felty syndrome".)

FELTY SYNDROME WITHOUT RECURRENT INFECTION — In patients with Felty syndrome (FS) who do not have recurrent or severe infections, despite fulfilling diagnostic criteria for FS (see "Clinical manifestations and diagnosis of Felty syndrome"), we take the same approach to choosing drug therapy for active arthritis as in other patients with FS, including use of methotrexate (MTX) and rituximab (RTX) and generally avoiding the use of tumor necrosis factor (TNF) inhibitors, tocilizumab, or tofacitinib (see 'Drug choices' above and 'Patients with recurrent or severe infections' above). We also employ the same preventive general measures as in patients with recurrent infections. (See 'General interventions' above.)

In patients without infections and whose arthritis is well-controlled on DMARD therapy, we take standard precautions to minimize the risks of infection with therapy but do not intervene based upon the degree of neutropenia alone. (See 'Approach to therapy' above.)

OTHER AGENTS

Antirheumatic drugs — Other agents that were used historically and were somewhat effective for Felty syndrome (FS) are now employed extremely infrequently to treat FS, since methotrexate (MTX) and biologic agents for rheumatoid arthritis (RA) have become available and are commonly used. (See 'Active arthritis' above.)

These other rarely used antirheumatic drugs include:

●Sulfasalazine – Use of sulfasalazine (SSZ) was described in one case report [37]. However, because SSZ is known to cause neutropenia, we would not initiate SSZ monotherapy in a patient with FS and active arthritis, and we would discontinue this drug, even if it was being used as part of an effective drug combination (eg, with hydroxychloroquine [HCQ] and MTX). The use and adverse effects of SSZ in RA are described separately. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Sulfasalazine'.)

●Hydroxychloroquine – We would use HCQ as the primary therapy for FS only in patients who could not use or did not respond to MTX and biologic disease-modifying antirheumatic drugs (DMARDs) used for FS. However, there are no data in such patients to indicate that HCQ would be effective. In patients with RA being treated with HCQ and who develop FS, we would add MTX. Two patients with FS, who were unable to continue MTX therapy because of toxicity, experienced resolution of neutropenia when treated with HCQ 400 mg daily. However, each patient required concomitant therapy with glucocorticoids to control articular disease activity [38]. It is likely that the improvement in neutropenia in these two cases was due, at least in part, to demargination of neutrophils resulting from glucocorticoid therapy. The use and adverse effects of HCQ in RA are described separately. (See "Antimalarial drugs in the treatment of rheumatic disease" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Hydroxychloroquine'.)

●Other medications – We generally would not use D-penicillamine, cyclophosphamide, cyclosporine, or azathioprine for the treatment of FS. There are extremely limited data regarding these medications and other drugs have a much better risk/benefit profile for the treatment of RA [39-43]. Azathioprine was effective for FS in only one of seven patients in one study, despite its known efficacy for RA [42].

Non-antirheumatic agents — Several other drugs that do not affect the activity of RA, including lithium salts [42,44,45] and testosterone [46], have been tried to raise the white cell count nonspecifically in patients with neutropenia. However, since effective DMARDs and hematopoietic growth factor therapies have become available to treat patients with FS, these agents are no longer used. Intravenous gamma globulin was ineffective in improving neutropenia in on small series of patients with FS [47]. Plasma exchange has not been evaluated.

PROGNOSIS — It is likely that the prognosis of Felty syndrome (FS) has improved with the use of methotrexate (MTX) and biologic agents, together with the commercial availability of granulocyte colony-stimulating factor (G-CSF); however, because the frequency of FS has decreased substantially, compared with that prior to the 1980s, there are insufficient data to document this clinical impression. (See "Clinical manifestations and diagnosis of Felty syndrome".)

For many years, splenectomy was the principal therapy for FS. However, this surgical modality has now been largely replaced by medical therapy. The hospitalization rate for splenectomy was 71 percent lower between 1998 and 2001 than between 1983 and 1987 [48]. The indications for splenectomy are now more limited, suggesting that the prognosis of FS has also improved. (See "Role of splenectomy for Felty syndrome".)

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

●Management of Felty syndrome (FS) is focused upon the partial or complete reversal of neutropenia to facilitate the resolution of ongoing bacterial infections and to prevent recurrent infections. Rheumatoid arthritis (RA) disease activity may also improve with many of these therapies independently of any change in the white blood cell count. A response to therapy is characterized by an increased neutrophil count accompanied by a clinical response that can include reductions in the frequency of infections and other clinical features. (See 'Goals of therapy' above.)

●Treatment of FS is indicated in patients with recurring or severe infections, although the presence of FS can also impact the choice of disease-modifying antirheumatic drugs (DMARDs) in patients with active RA but without infections. The principal treatment interventions include nonpharmacologic measures to reduce the risk of infection and medications to control RA disease activity and alleviate the neutropenia. (See 'Approach to therapy' above.)

●For patients with active RA and FS who have recurrent or severe infections, we suggest initial therapy with methotrexate (MTX) rather than another DMARD (Grade 2C). We use the same dosing as in patients without FS, and the dose should be increased to maximum tolerated levels up to 25 mg once weekly in patients not responding to lower doses. (See 'Initial therapy' above.)

●For patients inadequately responsive to MTX, we suggest adding rituximab (RTX) rather than another nonbiologic, biologic, or targeted synthetic DMARD (Grade 2C). Tumor necrosis factor (TNF) inhibitors are avoided as they have been found ineffective treatment for FS. The precautions, administration, and dosing for RTX are the same as in patients without FS. (See 'Inadequate response to methotrexate' above.)

●We treat FS with glucocorticoids when patients respond inadequately to MTX and RTX or are intolerant of these DMARDs. Glucocorticoids and other immunosuppressive agents should generally be avoided in the presence of active infection. Glucocorticoids may also be useful for short-term bridging therapy between the initiation of a potentially effective DMARD such as MTX or RTX until the realization of any therapeutic benefit. Typical dosing of prednisone is 30 to 40 mg daily, which is then gradually tapered as the neutropenia improves. (See 'Role of glucocorticoids' above.)

●For patients intolerant of MTX or in those with an inadequate response to MTX and to RTX and who require prednisone at doses greater than 10 to 15 mg daily for control of arthritis and neutropenia, we prefer to use abatacept, despite the lack of data regarding this agent for FS, rather than a TNF inhibitor, interleukin (IL) 6 inhibitor, or Janus kinase (JAK) inhibitor. Abatacept is used in the same regimen as for patients without FS. IL-6 inhibitors and JAK inhibitors are avoided because each may cause neutropenia. (See 'Role of other biologic agents' above.)

●For patients with FS whose arthritis is well-controlled on DMARD therapy, but who continue to experience recurrent or severe infections, we re-evaluate the patient to identify and minimize or exclude other factors that may be contributing to infectious risk, minimize the doses and use of medications that may be increasing the risk of infection, and temporarily discontinue DMARDs that may be impairing host defense, as in patients without FS. We resume treatment with the drug once the infection is resolved unless use of the medication is itself associated with recurrent infections. (See 'Well-controlled arthritis' above and 'General interventions' above.)

●For patients with FS and recurrent or severe infections inadequately responsive to DMARD therapy who have an absolute neutrophil count <1000 cells/microL, we suggest granulocyte colony-stimulating factor (G-CSF, filgrastim) (Grade 2C); the decision to use G-CSF should be made in collaboration with a hematologist experienced in the use of such therapy. G-CSF may also benefit patients with marked neutropenia and life-threatening infections in whom the neutropenia needs to be reversed quickly, including those in whom DMARD therapy was recently initiated or modified but has not yet had sufficient time to be effective. (See 'Neutropenia and infection inadequately responsive to nonbiologic and biologic DMARDs' above.)

●For patients with FS who do not have recurrent or severe infections, we take a modified approach in choosing DMARD therapy for active arthritis. We prefer the use of MTX and RTX and generally avoid the use of TNF, IL-6, and JAK inhibitors. We also employ the same preventive general measures as in patients with recurrent infections. In patients without infections and whose arthritis is well-controlled on DMARD therapy, we take standard precautions to minimize the risks of infection with therapy but do not intervene based upon the degree of neutropenia alone. (See 'Felty syndrome without recurrent infection' above and 'General interventions' above.)

●It is likely that the prognosis of FS has improved with the use of MTX and biologic agents, together with the commercial availability of G-CSF. (See 'Prognosis' above.)