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Rituximab in the refractory Felty's syndrome

Thiago Sotero Fragoso Andréa Tavares Dantas Maria Roberta Melo Gomes Pereira Cláudia Diniz Lopes Marques Fernando de Souza Cavalcanti Ângela Pinto Duarte About the authors

Abstracts

Os autores relatam o caso de uma paciente de 29 anos com diagnóstico de artrite reumatoide soropositiva que com seis meses de evolução desenvolveu granulocitopenia severa e esplenomegalia, embora mantivesse em remissão o quadro articular. Não apresentou resposta à corticoterapia oral e em forma de pulsos, além do metotrexato e leflunomida, tendo apresentado reação adversa ao uso do infliximabe e falta de resposta ao adalimumabe. Diante das infecções de repetição, apesar dos vários esquemas de antibióticos e uso crônico do G-CSF, dos altos títulos de fator reumatoide, dos níveis elevados da VHS e da PCR, utilizou-se o rituximabe no esquema clássico de tratamento da artrite reumatoide. Houve resposta clínica completa com aumento crescente do número de neutrófilos e normalização dos mesmos além da queda dos títulos de fator reumatoide, da VHS e da PCR. Atualmente, a paciente encontra-se em remissão clínica e laboratorial, em uso de prednisona 5 mg/dia e metotrexato 10 mg/semana.

artrite reumatoide; síndrome de Felty; tratamento; rituximabe


The authors report a case of a 29 year old woman who has seropositive rheumatoid arthritis for six months, and developed severe granulocytopenia and important splenomegaly, however she didn´t show any joint inflammation. She did not respond either to pulse or oral steroids, or to oral methotrexate and leflunomide. She also developed an adverse reaction to the use of infliximab and did not respond well to adalimumab. Although she has had repeated infections, despite the various forms of antibiotics and long-term use of G-CSF, with high titers of rheumatoid factor, and high levels of ESR and CRP, the classic Rituximab method for treating rheumatoid arthritis was used. There was a good clinical response with an increase in the number of neutrophils following normalization of them, together with the reduction of rheumatoid factor titers, ESR and CRP. At the moment, the patient is in remission, according to both clinical and laboratory criteria and taking 5mg of prednisone per day and 10mg of methotrexate per week.

rheumatoid arthritis; Felty's syndrome; treatment; rituximab


CASE REPORT

  • Rituximab in the refractory Felty's syndrome

    Thiago Sotero FragosoI; Andréa Tavares DantasI; Maria Roberta Melo Gomes PereiraII; Cláudia Diniz Lopes MarquesIII; Fernando de Souza CavalcantiIV; Ângela Pinto DuarteV
  • IResident of the Rheumatology Department at HC-UFPE

    IIEx-resident of the Rheumatology Department at HC-UFPE

    IIIRheumatologist, MPH and professor of the Escola Pernambucana de Medicina - FBV/IMIP

    IVAssociate Professor of Rheumatology at UFPE

    VProfessor and head of the Rheumatology Department at HC-UFPE

    Correspondence to

    ABSTRACT

    The authors report a case of a 29 year old woman who has seropositive rheumatoid arthritis for six months, and developed severe granulocytopenia and important splenomegaly, however she didn´t show any joint inflammation. She did not respond either to pulse or oral steroids, or to oral methotrexate and leflunomide. She also developed an adverse reaction to the use of infliximab and did not respond well to adalimumab. Although she has had repeated infections, despite the various forms of antibiotics and long-term use of G-CSF, with high titers of rheumatoid factor, and high levels of ESR and CRP, the classic Rituximab method for treating rheumatoid arthritis was used. There was a good clinical response with an increase in the number of neutrophils following normalization of them, together with the reduction of rheumatoid factor titers, ESR and CRP. At the moment, the patient is in remission, according to both clinical and laboratory criteria and taking 5mg of prednisone per day and 10mg of methotrexate per week.

    Keywords: rheumatoid arthritis, Felty's syndrome, treatment, rituximab.

    INTRODUCTION

    Felty's syndrome (FS) is a rare and severe form of seropositive rheumatoid arthritis, generally associated with neutropenia and, in some cases, splenomegaly.1 For many years, splenectomy was the main therapy, however this modality has been replaced by immunosuppressive and biological agents, and its current indication is restricted to cases refractory to clinical treatment.2 The use of rituximab, a monoclonal anti-CD20 antibody, for treating Felty's syndrome has been described in the literature in six patients up to the present moment, and in two of them there was no response.3-7 The authors report the case of a patient with refractory FS characterized by important neutropenia and recurring infections, who has been treated successfully with rituximab.

    CASE REPORT

    Female patient, 29 years old with a two years history of rheumatoid arthritis (RA) carrier diagnosed according to the American College of Rheumatology (ACR)8 criteria. She first presented with symmetric polyarthritis of the wrists, shoulders, metacarpophalangeal, proximal interphalangeal and temporomandibular joints, accompanied by morning stiffness longer than one hour and rheumatoid factor of 791U (normal < 20 U).

    After six months of treatment with corticosteroids (10 mg/day) and methotrexate (20 mg/week), she presented a satisfactory clinical response (DAS28 < 2.6) and there were no destructive articular alterations.

    At the occasion the patient presented agranulocytosis of rapid and severe evolution, with neutrophils levels getting to 96/mm3, splenomegaly (14 cm below the costal arch) and without recurrence of the arthritis. At that moment, the rheumatoid factor titer was of 3,590U, ESR of 98 mm/1h and CRP of 135 mg/dl. Serologies for HCV, HIV, HBV, dengue fever, toxoplasmosis, CMV, Parvovirus B19 and Mantoux test were negative.

    The myelogram revealed hypercellularity of all lineages, and the bone marrow biopsy didn't reveal any myelodysplasia pattern, lymphoproliferation or large granular lymphocyte syndrome. It was then defined the Felty's syndrome diagnosis. Treatment was begun with a granulocyte colony stimulating factor (G-CSF), methotrexate was kept and the dosage of oral prednisone raised to 40 mg/day, taken for three months, without clinical response. Leflunomid was chosen in replacement to methotrexate, in a dosage of 20 mg/day, and intravenous metilprednisolone, also without clinical response after three months. Due to the persistence of the neutropenia, infliximab was started as per the standart protocol and suspended after the second infusion due to a severe cutaneous allergic reaction. Then, adalimumab was prescribed for three months, also without clinical response.

    Since the beginning of the neutropenia, the patient presented recurrent infections episodes, especially in the upper respiratory tract, always accompanied by fever and intense compromising of the general state, needing hospitalization. With the failure of the instituted treatment and the persistence of infectious recurrences, despite the various antibiotic schemes, the use of G-CSF (filgrastine) and prophylaxis with azitromicin, rituximab was started as per the standart RA protocol. Adverse events were not observed prior or post infusion.

    After three months of rituximab, the patient presented complete clinical response, with decrease of the febrile episodes in more than 75% and the infection rate in more than 50% (Table 1). In addition it was noticed an increase in the neutophil count with posterior normalization (Figure 1) and a decrease in the rheumatoid factor titer, ESR and CRP (Table 2).


    Currently, nine months after rituximab infusions, she is on 5 mg of prednisone daily and 10 mg of methotrexate weekly and her disease activity is well under control.

    DISCUSSION

    FS is characterized by chronic arthritis, splenomegaly and leukopenia, occurring in less than 1% of RA patients. The predominant age bracket is from the fifth to the seventh decades, RA usually has been present for 10 years or more before granulocytopenia is recognized. Two thirds are female, 95% HLA-DR4 and it is rare in black people. It's generally associated to a severe disease, positive rheumatoid factor in high titers, besides extra-articular exuberant manifestations including vasculitis, which can result in mononeuritis multiplex and necrotizing skin lesions, heapatomegaly, pleuropericarditis, rheumatoid nodules in subcutaneous, lymphadenopathy, thrombocytopenia, fever and episcleritis.10-14

    The articular disease is usually severe in terms of both erosions and deformities. Approximately one third of the patients have inactive synovitis, although almost always showing elevated levels of ESR. Rarely granulocytopenia and splenomegaly appear before or simultaneously with the arthritis.10,13,14

    The cause of granulocytopenia in FS is multifactorial, and it is a result of the unbalance between granulocyte production and their removal from the circulatory pool, besides the splenic sequestration, generally not causing symptoms unless bacterial infections occur. Those are usually recurrent and the respiratory tract infection and the skin are the most common, occurring more often when the of granulocyte count is below 1000/mm3, a determinant prognostic factor.14,15

    Methotrexate is an effective drug in most FS patients, with improvement generally occurring in the first two months of treatment. Nevertheless, there are no randomized controlled clinical trials, and these results are based on reports with few cases. The average dosage used in these reports was 13 mg/week, orally.16,17

    There are reports with limited experience of the use of other drugs, such as sulfassalazine, azathioprine, cyclosporine, cyclophosphamide and leflunomide.18-21

    Corticosteroids can elevate the granulocyte count in FS by two mechanisms: immunosuppressive action and granulocyte kinetics alteration.22-24 Prednisone, at least 30 mg/day, generally normalizes the number of granulocytes, although its effect is not sustained when the dosage is reduced to less than 10 mg/day, unless other drugs are added.25 Intravenous metilprednisolone has been used for granulocytopenia, and infections are the main obstacle for its use.26

    The use of etanercept and infliximab in the treatment of FS didn't show benefit in three cases reported in the literature.4,27,28 Endovenous gamaglobulin does not seem to be effective for treatment of neutropenia occurring in the FS also.29

    Growth stimulating factors are frequently used in the FS, and are effective in reversing granulocytopenia and reducing infectious complications in most patients. However, flaws have been reported and cost is another limiting factor, particularly with prolonged use. Besides that, adverse effects like synovitis and leukocytoclastic vasculitis can occur.30

    For many years, splenectomy was the main therapy, however this modality has been replaced by immunosuppressive and biological agents, and its current indication is restricted to cases refractory to clinical treatment.2

    Rituximab, a chimeric monoclonal antibody directed against the CD-20 antigen on B-lymphocytes, has been used in the treatment of FS. The mechanism of neutropenia is multifactorial and in that subtype of patients in which there is autoantibodies formation, rituximab can be beneficial. Nevertheless, various factors can concur to the lack of its effectiveness in FS.31,32

    Rituximab's inability of to bind to plasma cells, which are CD-20 negatives;

    Other B cell-dependant mechanisms (immunoglobulins, antigen presentation, T cell cooperation); and

    Subpopulations of T lymphocytes that have anti-granulocytic activity can exist independently of the B cells.

    These mechanisms can justify the controversial results found in the existing reports in the literature of the use of rituximab in refractory FS (Table 3).

    Although FS occurs more frequently in active and severe RA, a percentage of patients do not present inflammatory articular activity,14 as occurred with our patient, maintaining DAS28 always lower than 2.6, since the beginning of the neutropenia, even though she presented elevated levels of inflammatory markers (CRP and ESR) and of RF.

    Interestingly, our patient age was (29 years old) very inferior to the one in which the appearance of FS is more frequent14 (between 50 and 70 years old). The average age of patients earlier reported was of 51.2 years (35 to 67 years).3-7

    As well as in the literature reports,3-7 our patient used various drugs, such as prednisone, metilprednisolone, methotrexate, leflunomide, G-CSF and anti-TNF, without response to neutropenia.

    Rituximab is an already well-established therapy for patients with seropositive RA which showed to be promising in some reported cases of FS. The choice of using it was based on the fact that the patient presented elevated titers of rheumatoid factor, myelogram demonstrating hypercellurarity and refractoriness to the drugs previously used. Despite the multifactorial pathogeny of FS, rituximab can be an effective and safe therapeutical option, and it can be used before splenectomy, decreasing the morbidity and mortality of these patients.

    REFERENCES

    • 1
      Capsoni F, Sarzi-Puttini P, Zanella A. Primary and secondary autoimmune neutropenia. Arthritis Res Ther 2005;7(5):208-14.
    • 2
      Pinals RS. Indications for splenectomy in Felty's syndrome. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2007.
    • 3
      Sordet C, Gottenberg JE, Hellmich B, Kieffer P, Mariette X, Sibilia J. Lack of efficacy of rituximab in Felty's syndrome. Ann Rheum Dis 2005;64(2):332-3.
    • 4
      Weinreb N, Rabinowitz A, Dellaripa PF. Beneficial response to rituximab in refractory Felty syndrome. J Clin Rheumatol 2006;12(1):48.
    • 5
      Lekharaju V, Chattopadhyay C. Efficacy of rituximab in Felty's syndrome. Ann Rheum Dis 2008;67(9):1352.
    • 6
      Chandra PA, Margulis Y, Schiff C. Rituximab is useful in the treatment of Felty's syndrome. Am J Ther 2008;15(4):321-2.
    • 7
      Salama A, Schneider U, Dorner T. Beneficial response to rituximab in a patient with haemolisis and refractory Felty Syndrome. Ann Rheum Dis 2008;67(6):894-5.
    • 8
      Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al The American Rheumatism Association 1987 revised criteria for classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-24.
    • 9
      Pinals RS. Drug therapy in Felty's syndrome. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2007.
    • 10
      Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH: Rheumatology, 4th ed, Philadelphia, Editora Elsevier, 2007.
    • 11
      Klippel JH, Stone JH, Crofford LJ, White PH: Primer on the Rheumatic Diseases, 13th ed, New York, Editora Springer, 2008.
    • 12
      Inboden J, Hellmann D, Stone J: Current Rheumatology Diagnosis & Treatment, 2nd ed, Editora McGraw-Hill, 2007.
    • 13
      Pinals RS. Clinical manifestations and diagnosis of Felty's syndrome. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2007.
    • 14
      Campion G, Maddison PJ, Goulding N, James I, Ahern MJ, Watt I et al The Felty's syndrome: a case-matched study of clinical manifestations and outcome, serologic features, and immunogenetic associations. Medicine 1990;69:69-80.
    • 15
      Burks EJ, Loughran TP Jr. Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome. Blood Rev 2006;20(5):245-66.
    • 16
      Wassenberg S, Rau R, Herborn G. Methotrexate treatment of Felty's syndrome. Arthritis Rheum 1992;35:S150.
    • 17
      Tan N, Grisanti MW, Grisanti JM. Oral methotrexate in the treatment of Felty's syndrome. J Rheumatol 1993; 20:599-601.
    • 18
      Wiesner KB, Shapiro RF, Bryan BL, Fuller C, Utsinger PD. Immunosuppressive therapy in Felty's syndrome. N Engl J Med 1977;296(20):1172.
    • 19
       Canvin JM, Dalal BI, Baragar F, Johnston JB. Cyclosporin for the treatment of granulocytopenia in Felty's syndrome. Am J Hematol 1991;36(3):219-20.
    • 20
      Talip F, Walker N, Khan W, Zimmermann B. Treatment of Felty's syndrome with leflunomide. J Rheumatol 2001; 28(4):868-870.
    • 21
      Brodsky RA, Petri M, Smith BD, Seifter EJ, Spivak JL, Styler M et al Immunoablative high-dose cyclophosphamide without stem-cell rescue for refractory, severe autoimmune disease. Ann Int Med 1998;129(12):1031-5.
    • 22
      Bisho, CR, Athens JW, Boggs DR, Warner HR, Cartwright GE, Wintrobe MM. Leukokinetic studies. 13. A non-steady-state kinetic evaluation of the mechanism of cortisone-induced granulocytosis. J Clin Invest 1968;47(2):249-60.
    • 23
      Shoenfeld Y, Gurewich Y, Gallant LA, Pinkhas J. Prednisone-induced leukocytosis. Influence of dosage, method and duration of administration on the degree of leukocytosis. Am J Med 1981;71(5):773-8.
    • 24
      Smith MD, Ahern MJ, Brooks PM, RobertsThomson PJ. The clinical and immunological effects of pulse methylprednisolone therapy in rheumatoid arthritis. III Effects on immune and inflammatory indices in synovial fluid. J Rheumatol 1988;15(2):238-41.
    • 25
      Kaprove RE. Felty's syndrome: Case report and rationale for disease suppressant immunosuppressive therapy. J Rheumatol 1981;8(5):791-6.
    • 26
      Job-Deslandre C, Menkes CJ. Treatment of Felty's syndrome accompanied by agranulocytosis using high-dose corticoids. 3 cases. Presse Med 1987;16(12):569-70.
    • 27
      Ravindran J, Shenker N, Bhalla AK, Lachmann H, Hawkins P. Case report: Response in proteinuria due to AA amyloidosis but not Felty's syndrome in a patient with rheumatoid arthritis treated with TNF-alpha blockade. Rheumatology 2004;43(5):669-72.
    • 28
      Ghavami A, Genevay S, Fulpius T, Gabay C. Etanercept in treatment of Felty's syndrome. Ann Rheum Dis 2005;64(7):1090-1.
    • 29
      Breedveld FC, Brand A, van Aken WG. High dose intravenous gamma globulin for Felty's syndrome. J Rheumatol 1985;12(4):700-2.
    • 30
      Hellmich, B, Schnabel, A, Gross, WL. Treatment of severe neutropenia due to Felty's syndrome or systemic lupus erythematosus with granulocyte colony-stimulating factor. Semin Arthritis Rheum 1999;29(2):82-99.
    • 31
      Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum 2003;48(6):1484-92.
    • 32
      Coakley G, Iqbal M, Brooks D, Panayi GS, Lanchbury JS. CD8+ CD57+ T cells from healthy elderly subjects suppress neutrophil development in vitro: implications for the neutropenia of Felty's and large granular lymphocyte syndrome. Arthritis Rheum 2000;43(4):834-43.

    Rituximab in the refractory Felty's syndrome Thiago Sotero FragosoI; Andréa Tavares DantasI; Maria Roberta Melo Gomes PereiraII; Cláudia Diniz Lopes MarquesIII; Fernando de Souza CavalcantiIV; Ângela Pinto DuarteV

    Publication Dates

    • Publication in this collection
      07 Apr 2009
    • Date of issue
      Apr 2009

    History

    • Received
      02 Oct 2008
    • Accepted
      02 Jan 2009
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