Tocilizumab treatment in Felty's syndrome.

Felty's syndrome (FS) is a deforming disease, characterized by the triad of rheumatoid arthritis (RA), neutropenia, and splenomegaly. Currently, FS patients are treated mainly with immunosuppressants, such as methotrexate and glucocorticoids, which however are not suitable to some patients and may cause severe side effects. Here we report a clinical FS case that was treated with Tocilizumab (TCZ) successfully. The patient had symmetrical swelling and pain of multiple joints, deformity of elbow joints with obvious morning stiffness. Joint color Doppler ultrasound showed synovial hyperplasia and bone erosion of wrist and proximal interphalangeal joints and CT scan suggested splenomegaly. Further examination showed neutropenia and anemia, a high titer of anti-cyclic citrullinated peptide antibody, rheumatoid factor and anti-nuclear antibodies, positive p-ANCA, and elevated IgA and IgG. After treating with TCZ, the patient has been relieved of clinical symptoms. His spleen has recovered to normal size. The absolute neutrophil count (ANC) tended to be stable, and joint erosion did not deteriorate. We have reviewed the literatures on FS treatment with biological agents and found only a few reports using TNF-α antagonist and rituximab treating FS, but none with TCZ. So, it is the first time to report a successful FS case treated with TCZ. This case suggests that the TCZ may be a new choice for FS treatment, under the condition of closely monitoring the ANC.

Management of autoimmune neutropenia in Felty's syndrome and systemic lupus erythematosus.

Autoimmune neutropenia, caused by neutrophil-specific autoantibodies is a common phenomenon in autoimmune disorders such as Felty's syndrome and systemic lupus erythematosus. Felty's syndrome is associated with neutropenia and splenomegaly in seropositive rheumatoid arthritis which can be severe and with recurrent bacterial infections. Neutropenia is also common in systemic lupus erythematosus and it is included in the current systemic lupus classification criteria. The pathobiology of the autoimmune neutropenia in Felty's syndrome and systemic lupus erythematosus is complex, and it could be a major cause of morbidity and mortality due to increased risk of sepsis. Treatment should be individualized on the basis of patient's clinical situation, and prevention or treatment of the infection. Recombinant human granulocyte colony-stimulating factor is a safe and effective therapeutic modality in management of autoimmune neutropenia associated with Felty's syndrome and systemic lupus erythematosus, which stimulates neutrophil production. There is a slight increased risk of exacerbation of the underlying autoimmune disorder, and recombinant human granulocyte colony-stimulating factor dose and frequency should be adjusted at the lowest effective dose.

Rituximab is useful in the treatment of Felty's syndrome.

Felty's syndrome is regarded as a severe variant of rheumatoid arthritis (RA) that develops in less than 1% of patients with RA. It consists of a triad of RA, splenomegaly, and leukopenia, which tends to develop after a long course of RA. Treatment of neutropenia is mainly comprised of disease-modifying antirheumatic drugs including methotrexate, hydroxychloroquine, auronofin, penicillamine, glucocorticoids, and granulocyte monocyte colony stimulating factor. Recently, there has been a growing interest in the biologic agent rituximab in the treatment of Felty's syndrome. To our knowledge, only one previous case of rituximab being beneficial in the treatment of Felty's syndrome has been reported. We report the case of a 60-year-old man with Felty's syndrome in whom treatment with rituximab led to a sustained neutrophil response and marked symptomatic improvement in the form of decrease in the size of rheumatoid nodules and better pain control.

Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome.

T-cell large granular lymphocyte leukemia (TLGL) is an atypical chronic lymphoproliferative disorder derived from cytotoxic T-cells (CTL). Unlike most forms of leukemia, the pattern of bone marrow infiltration in TLGL may be subtle and the cytopenias are often lineage specific, with neutropenia dominating. Both granulocytic survival and proliferation defects are observed and are mediated by humoral and cell-mediated mechanisms respectively. Splenic production of immune complexes induces a neutrophil survival defect, where as Fas expression by leukemic CTL results in a marrow based proliferation defect. These humoral and cell-mediated pathways induce granulocytic apoptosis through independent intracellular mechanisms which are not mutually exclusive and may be observed concurrently in individual patients with either TLGL or FS. A variety of therapeutic interventions have been utilized in the management of TLGL and Felty syndrome, including methotrexate, cyclosporine A, cyclophosphamide, glucocorticoids, myeloid colony stimulating factors and splenectomy. Their efficacy and mechanisms of action are reviewed.

Treatment of the neutropenia of Felty syndrome.

This review sets out to synthesize and critically evaluate the current reported data regarding therapeutic options for the neutropenia associated with Felty syndrome (Felty neutropenia). A MEDLINE search and bibliographies from recent reviews were used to identify trials and case reports that provided sufficient data to evaluate the effect of various interventions on both the neutropenia and the clinical course of patients with Felty syndrome. Data were obtained on baseline hematologic profiles, bone-marrow biopsies, and patient characteristics; length of follow-up; hematologic and clinical responses to the various interventions; and side-effect profiles. Treatment with hemopoietic growth factors or methotrexate can produce sustained hematologic and clinical responses with an acceptable side-effect profile. Splenectomy produces a long-term hematologic response in 80% of patients. Patients who do not respond hematologically have a higher incidence of non-fatal infections, but a significant minority (46%) do not experience any infections; the incidence of fatal infections is 12%, regardless of whether a hematologic response occurs. Of the patients who had infections prior to surgery, 55% did not experience further infections after splenectomy. Initial treatment of Felty neutropenia should consist of hemopoietic growth factors because of their rapid onset of action and relatively low incidence of side-effects. Splenectomy is a reasonable option if growth factors are ineffective and rapid amelioration of neutropenia is needed. Methotrexate offers a potentially promising alternative for the treatment of both the rheumatologic and the hematologic manifestations of Felty syndrome.

Pseudo-felty's syndrome. Report of a case with no symptoms for at least 15 years.

The prognosis of large granular lymphocyte proliferation with rheumatoid arthritis (pseudo-Felty's syndrome) remains uncertain. We report a case with a 15-year follow-up. To date, the patient has not developed lymphadenopathy, splenomegaly, abnormalities in erythrocyte or platelet counts, neutropenia or severe or unexplained infections. This favorable course is not ascribable to an unusual lymphocyte phenotype (CD3+, CD8+, CD57+). A beneficial effect of methotrexate therapy is possible.

Felty's syndrome treated with rhG-CSF associated with flare of arthritis and skin rash.

A patient with Felty's syndrome and rheumatoid arthritis was treated with recombinant granulocyte stimulating factor rhG-CSF (Neupogen) in view of severe neutropenia. He had a prompt rise in his neutrophil count and associated with this a severe flare of his arthritis and a skin rash. rhG-CSF was stopped, his neutrophil count fell rapidly and his symptoms resolved. rhG-CSF and the resulting rise in neutrophil count may be associated with flare of autoimmune disease in susceptible individuals.

Flare of arthritis with successful treatment of Felty's syndrome with granulocyte colony stimulating factor (GCSF).

A 58-year-old white male with Felty's syndrome was successfully treated with granulocyte colony stimulating factor (GCSF). GCSF can correct the granulocytopenia of Felty's syndrome and may be a beneficial therapeutic adjunct in patients who have serious infections associated with neutropenia. The patient developed a flare of arthritis concomitant with increased circulating neutrophils following GCSF therapy.

[Felty's syndrome: retrospective study of 12 cases]. / Syndrome de Felty: étude rétrospective de 12 cas.

A retrospective study of twelve cases of Felty's syndrome was performed. The main points of this syndrome (clinical presentation, physiopathology, complications, treatment) are described.

Felty's and pseudo-Felty's syndromes.

Felty's syndrome, consisting of rheumatoid arthritis, leukopenia, and splenomegaly, has been recognized as a distinct clinical entity for more than 60 years. Clinical and laboratory manifestations of the condition are reviewed. The major sources of morbidity and mortality remain recurrent local and systemic infections. Immunogenetic analysis shows a strong association with HLA-DR4, in addition to DQ beta 3b and C4B null allele. Potential mechanisms of neutropenia are contrasted, including impaired granulopoiesis and neutrophil-immune complex interactions. Lithium carbonate and splenectomy may have a role in the treatment of fulminant disease. Maintenance therapy should be directed at control of the underlying inflammatory arthropathy. A syndrome of proliferation of large granular lymphocytes and neutropenia, associated with rheumatoid arthritis in 23% to 39% of cases, has been described recently. Cases of "pseudo-Felty's" syndrome are often confused with traditional Felty's syndrome, which has twice the prevalence. The clinical and laboratory distinctions between these two conditions are elaborated.

[Mechanism of Felty's syndrome and long-term course]. / Mécanisme du syndrome de Felty et évolution à long terme.

The authors report 18 cases of Felty's syndrome followed, in an average, for 5 years (1 to 12 years). There were 3 deaths, 9 patients are in complete remission, 6 others still show signs of the disease: splenomegaly (4 cases), leucopenia (1 case) and only one complete Felty's syndrome. Steroid therapy has proved to be effective regardless of the mechanism of the neutropenia specified in 9 cases by an isotopic study. Prognosis and infectious risk are difficult to determine but the overall course was rather favorable.

Parenteral gold therapy in the Felty syndrome. Experience with 20 patients.

Most of the patients with the Felty syndrome suffer from such complications as fevers, infections, cutaneous ulcers, and vasculitis. Unfortunately, there are no therapeutic interventions that are predictably beneficial. We report our experience with 20 patients who received parenteral gold therapy for 2 to 114 months (mean, 23.6 months). All had complications of the Felty syndrome. On parenteral gold therapy, 60% had a complete response, 20% had a partial response, and 20% were unresponsive by preselected criteria. No serious complications were encountered. We think that parenteral gold therapy should be considered early, before other agents, in the treatment of this condition.

Felty's syndrome: when is splenectomy indicated?

The spectrum of disease was assessed in 43 patients with Felty's syndrome. Twenty-three underwent splenectomy. Although complete remission of neutropenia occurred in only two nonoperated patients, most of the patients had no serious infections during the subsequent period of observation. Operative morbidity was minimal in the splenectomized patients. On the basis of natural history of this condition, splenectomy should probably be restricted to neutropenic patients with serious or recurrent infections, patients with severe anemia requiring transfusions, those with the rare circumstance of profound thrombocytopenia, and those with non-healing leg ulcers.