The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019

Targeted Therapy with Rituximab in Felty’s Syndrome: A Case Report



Line Heylen 1, Daan Dierickx 2, Peter Vandenberghe 3, René Westhovens*, 1
1 Rheumatology, University Hospital Leuven, Leuven, Belgium
2 Haematology, University Hospital Leuven, Leuven, Belgium
3 Human Genetics, University Hospital Leuven, Leuven, Belgium

Abstract

Felty’s syndrome is a rare, severe extra-articular manifestation of rheumatoid arthritis (RA). There is no standard therapy, and several disease-modifying antirheumatic drugs have been used with varying success. Only very few reports exist in literature on the use of biologicals in this indication and this with a variable efficacy. We report the case of a 53-year-old woman with severe refractory/partly undertreated RA who presented with Felty’s syndrome and pancytopenia, in whom treatment with rituximab led to an marked increase of red blood cells, neutrophils and thrombocytes. In addition, the RA disease activity status improved dramatically and treatment with steroids could be reduced. The current sparse literature on this topic is reviewed.

Keywords: Felty’s syndrome, Rituximab, rheumatoid arthritis..


Article Information


Identifiers and Pagination:

Year: 2012
Volume: 6
First Page: 312
Last Page: 314
Publisher Id: TORJ-6-312
DOI: 10.2174/1874312901206010312

Article History:

Received Date: 25/9/2012
Revision Received Date: 20/10/2012
Acceptance Date: 25/10/2012
Electronic publication date: 16/11/2012
Collection year: 2012

Article Metrics:

CrossRef Citations:
0

Total Statistics:

Full-Text HTML Views: 1232
Abstract HTML Views: 869
PDF Downloads: 242
Total Views/Downloads: 2343

Unique Statistics:

Full-Text HTML Views: 535
Abstract HTML Views: 459
PDF Downloads: 166
Total Views/Downloads: 1160
Geographical View

© Heylen et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Rheumatology, UZ KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Tel: +32-16-342541; Fax: +32-16-342543; E-mail: rene.westhovens@uzleuven.be




INTRODUCTION

Felty’s syndrome is a rare but severe extra-articular manifestation of rheumatoid arthritis (RA), in most cases developing after a longer refractory disease course. The syndrome is defined as a triad of RA, neutropenia and splenomegaly [1 Balint GP, Balint PV. Felty's syndrome Best Pract Res Clin Rheumatol 2004; 18: 631-45.]. Due to recurrent infections, patients with Felty’s syndrome have an increased mortality, with a 5-year mortality rate of up to 36% [2 Campion G, Maddison PJ, Goulding N, et al. The Felty syndrome a case-matched study of clinical manifestations and outcome serologic features and immunogenetic associations Medicine (Baltimore) 1990; 69: 69-80., 3 Thorne C, Urowitz MB. Long-term outcome in Felty's syndrome Ann Rheum Dis 1982; 41: 486-9.]. To treat Felty’s syndrome, various disease-modifying antirheumatic drugs have been used with mixed success and few data are available on the use of biologicals that might even increase the infection risk. Because of the rarity of the disease, definite efficacy and safety results from biological therapies are not expected to become available in the future. Few case reports in the literature deal with the use of rituximab which might be seen as a preferred treatment in RA patients with major systemic features. We report on a severe refractory and partly undertreated RA patient with Felty’s syndrome and discuss her successful treatment with rituximab. Oral consent was obtained from the patient to report her evolution anonymously.

CASE REPORT

A 53-year old Caucasian woman with a 22-year history of refractory rheumatoid factor and CCP positive RA was referred to our University Hospital in October 2010 because of a 2-year history of pancytopenia and hepatosplenomegaly, diagnosed as Felty’s syndrome and a very severe disease activity status of her RA. In addition, she was known with arterial hypertension and an allergy to penicillin. She smoked >30 pack years but stopped smoking a few years ago. Epilepsy was diagnosed in 1992 after a generalized tonic-clonic seizure, for which she was treated with phenytoin and primidone. Previous therapies for RA consisted of sulphasalazine and intermittent glucocorticoids. Methotrexate in recent years was never considered because of pancytopenia. A bone marrow biopsy was performed in the referring hospital in 2009, showing only mild dysmegakaryocytosis and a modest decrease of the white blood cell maturation. Treatment with sulphasalazine was temporarily interrupted because of this pancytopenia. Because of persisting pancytopenia, hepatosplenomgaly and enlarged axillary and mediastinal lymph nodes on computer tomography of the chest, a lymph node biopsy was done beginning of 2010 which showed follicular hyperplasia and no evidence of lymphoma. Meanwhile she was on oral glucocorticoid therapy but a severe polyarthritis persisted and purpura on the lower limbs appeared clinically compatible with rheumatoid vasculitis. Treatment with topical steroids and hydroxychloroquine was added, the dose of glucocorticoids was increased and the patient was referred to our third care referral centre.

She presented in our hospital with an active destructive polyarthritis and large RA nodules, with a disease activity score (DAS28) of 4.7 while on methylprednisolone 16 mg, hydroxychloroquine 200mg, sulphasalazine 2000mg and piroxicam 20mg daily. In addition, she was treated with phenytoin and primidon for epilepsy, acebutalol and furosemide for hypertension, pantoprazol for oesophagitis as well with escitalopram 10mg and lormetazepam. Her spleen was enlarged (17x11 cm), as well as her liver (19 cm craniocaudal diameter). She had purpura on the lower limbs and a diffuse lymphadenopathy, with follicular hyperplasia on biopsy. Study of her files revealed a white cell count remaining persistently less than 1.0x109/l and a hemoglobin level below 10.9 g/dl. Thrombocytes decreased continuously during the last year, and were less than 20x109/l at presentation in our hospital. A new bone marrow biopsy showed some hypocellularity without dysplasia, no blast cells and a normal central lymphocytosis without atypia. Immunophenotyping showed no monoclonal B- or T-cell process. Hydroxychloroquine and sulphasalazine were stopped. Methylprednisolone was maintained at 16mg daily and a treatment with rituximab was started twice 1000mg over 2 weeks in November 2010, and again twice 1000mg (588 mg/m2) in July 2011. DAS score dropped from 4.7 to 3.0, 17 months after treatment start. CRP decreased from 41 mg/L to 7 mg/L, and the erythrocyte sedimentation rate (ESR) decreased from 73 mm/h to 32 mm/h. An overview of the evolution of DAS and the pancytopenia in the first year of follow up is presented in Fig. (1). The number of red blood cells, neutrophils and thrombocytes increased significantly: hemoglobin from 10.9 g/dl to 15.1 g/dl, white blood cells from 0.81 x 109/L to 3.92 x 109/L and thrombocytes from 18 x 109/L to 120 x 109/L. Interestingly the hypergammaglobulinemia dropped from 23.9 g/l at treatment start to 19.2 g/l and 15.8 g/l, 6 and 18 months after treatment initiation. Patient was satisfied as also pain, general well being and quality of life dramatically improved. From month 4 on gradually tapering of glucocorticoids was initiated and 1 year after start of rituximab she was on 6mg daily. There were no infections within the first treatment year and planned foot surgery because of severe deformities could be performed without any problem.

Fig. (1)

The evolution of hemoglobin (Hb) (A), white cell count (WCC) (B), thrombocytes (C) and the DAS28 score (D) up to 19 months after therapy start. Arrows indicate time of Rituximab infusions.



DISCUSSION

We report an important beneficial effect of rituximab in a patient with Felty’s syndrome, without immediate side effects. Both the arthritis and the hematological features of the syndrome were much better controlled by 4 months after therapy start and steroid tapering was successful. The purpura on the lower limbs did not reoccur and there were no infectious complications.

Rituximab is chimeric monoclonal antibody against CD20, which is expressed on the surface of B-lymphocytes, causing B-cell depletion. It was originally developed for the treatment of B-cell lymphoma [4 Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al. IDEC-C2B8 results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma J Clin Oncol 1997; 15: 3266-74., 5 McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program J Clin Oncol 1998; 16: 2825-33.]. As T-cell activation is classically described as the key component of the pathogenesis of rheumatoid arthritis (RA), the efficacy of rituximab in RA came initially as a surprise. In 1999 Protheroe et al. wrote a case in which a patient with erosive arthritis was treated with rituximab for a B-cell lymphoma [6 Protheroe A, Edwards JC, Simmons A, Maclennan K, Selby P. Remission of inflammatory arthropathy in association with anti- CD20 therapy for non-Hodgkin's lymphoma Rheumatology (Oxford) 1999; 38: 1150-2.]. Following this treatment, the patient unexpectedly became free of musculoskeletal symptoms and joint inflammation. The role for B-cells in RA was later confirmed in randomised controlled studies, in which response rates of 51% and 85% were noticed with rituximab [7 Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-celltargeted therapy with rituximab in patients with rheumatoid arthritis N Engl J Med 2004; 350: 2572-81., 8 Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter randomized double-blind placebo-controlled phase III trial evaluating primary efficacy and safety at twenty-four weeks Arthritis Rheum 2006; 54: 2793-806.].

While the immunopathogenesis of RA becomes further unraveled, Felty’s syndrome remains still a mystery. Traditionally, splenomegaly was seen as a feature of systemic inflammation, causing neutropenia by sequestration and justifying splenectomy as treatment. When Gupta et al. described reduced colony-stimulating activity in the serum of patients with Felty’s syndrome [9 Gupta R, Robinson WA, Albrecht D. Granulopoietic activity in Felty's syndrome Ann Rheum Dis 1975; 34: 156-61.], a role for impaired regulation of granulopoiesis became recognized in addition to peripheral destruction or sequestration (hypersplenism) as cause of neutropenia. As Felty’s syndrome is an autoimmune disease, the loss of immunologic tolerance to self-antigens can cause neutropenia through both peripheral immunological destruction and impaired granulopoiesis. This is traditionally described as a cell-mediated destruction. However, humoral immunity might be important as well in causing neutropenia. Humoral suppression of normal granulopoiesis has been reported [10 Duckham DJ, Rhyne RL Jr, Smith FE, Williams RC Jr. Retardation of colony growth of in vitro bone marrow culture using sera from patients with Felty's syndrome disseminated lupus erythematosus (SLE) rheumatoid arthritis and other disease states Arthritis Rheum 1975; 18: 323-3.], as well as serum antibodies against mature neutrophils [11 Wiik A, Munthe E. Complement-fixing granulocyte-specific antinuclear factors in neutropenic cases of rheumatoid arthritis Immunology 1974; 26: 1127-34.]. The antibody production against circulating neutrophils and against granulopoiesis can be suppressed by B-cell depletion, providing a rationale for the use of rituximab. However, the role of B-cells in autoimmune cytopenias can not only be limited to the production of antibodies, as the efficacy of rituximab in certain conditions associated with antibodies, is not correlated with a reduction of these antibodies [12 Cooper N, Arnold DM. The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases Br J Haematol 2010; 149: 3-13.]. They could also play a role through the production of cytokines and by acting as antigen-presenting cells supporting the activation of autoreactive cells [13 Dierickx D, Delannoy A, Saja K, Verhoef G, Provan D. Anti-CD20 monoclonal antibodies and their use in adult autoimmune hematological disorders Am J Hematol 2011; 86: 278-91.].

The use of rituximab in patients with Felty’s syndrome is rarely mentioned in the literature. Weinreb et al. [14 Weinreb N, Rabinowitz A, Dellaripa PF. Beneficial response to rituximab in refractory Felty Syndrome J Clin Rheumatol 2006; 12: 48.], Salama et al. [15 Salama A, Schneider U, Dorner T. Beneficial response to rituximab in a patient with haemolysis and refractory Felty syndrome Ann Rheum Dis 2008; 67: 894-5.] and Lekharaju et al. [16 Lekharaju V, Chattopadhyay C. Efficacy of rituximab in Felty's syndrome Ann Rheum Dis 2008; 67: 1352.] described a beneficial response. In contrast, Sordet et al. described two cases of Felty’s syndrome where rituximab lacked efficacy [17 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: 332-.]. These varying results underscore the multifactorial pathogenesis of Felty’s syndrome and could suggest the existence of subsets of patients where rituximab could be beneficial [16 Lekharaju V, Chattopadhyay C. Efficacy of rituximab in Felty's syndrome Ann Rheum Dis 2008; 67: 1352.]. The exact role of rituximab in Felty’s syndrome needs further investigation. In this particular case it should also been noted that methotrexate was never used in the past because of fear for the hematological status. In our opinion and according to literature, this therapy option might also be effective in Felty syndrome and whenever her disease would relapse in the future the addition of methotrexate will be considered [18 Allen LS, Groff G. Treatment of Felty's syndrome with low-dose oral methotrexate Arthritis Rheum 1986; 7: 902-5.].

CONCLUSION

This observation contributes in the absence of randomized controlled data to the understanding of the role of specific biological therapies as rituximab in rare immune mediated disorders and appeals to further collaborative studies to increase robustness of data in these challenging situations.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflicts of interest.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

[1] Balint GP, Balint PV. Felty's syndrome Best Pract Res Clin Rheumatol 2004; 18: 631-45.
[2] Campion G, Maddison PJ, Goulding N, et al. The Felty syndrome a case-matched study of clinical manifestations and outcome serologic features and immunogenetic associations Medicine (Baltimore) 1990; 69: 69-80.
[3] Thorne C, Urowitz MB. Long-term outcome in Felty's syndrome Ann Rheum Dis 1982; 41: 486-9.
[4] Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al. IDEC-C2B8 results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma J Clin Oncol 1997; 15: 3266-74.
[5] McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program J Clin Oncol 1998; 16: 2825-33.
[6] Protheroe A, Edwards JC, Simmons A, Maclennan K, Selby P. Remission of inflammatory arthropathy in association with anti- CD20 therapy for non-Hodgkin's lymphoma Rheumatology (Oxford) 1999; 38: 1150-2.
[7] Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-celltargeted therapy with rituximab in patients with rheumatoid arthritis N Engl J Med 2004; 350: 2572-81.
[8] Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter randomized double-blind placebo-controlled phase III trial evaluating primary efficacy and safety at twenty-four weeks Arthritis Rheum 2006; 54: 2793-806.
[9] Gupta R, Robinson WA, Albrecht D. Granulopoietic activity in Felty's syndrome Ann Rheum Dis 1975; 34: 156-61.
[10] Duckham DJ, Rhyne RL Jr, Smith FE, Williams RC Jr. Retardation of colony growth of in vitro bone marrow culture using sera from patients with Felty's syndrome disseminated lupus erythematosus (SLE) rheumatoid arthritis and other disease states Arthritis Rheum 1975; 18: 323-3.
[11] Wiik A, Munthe E. Complement-fixing granulocyte-specific antinuclear factors in neutropenic cases of rheumatoid arthritis Immunology 1974; 26: 1127-34.
[12] Cooper N, Arnold DM. The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases Br J Haematol 2010; 149: 3-13.
[13] Dierickx D, Delannoy A, Saja K, Verhoef G, Provan D. Anti-CD20 monoclonal antibodies and their use in adult autoimmune hematological disorders Am J Hematol 2011; 86: 278-91.
[14] Weinreb N, Rabinowitz A, Dellaripa PF. Beneficial response to rituximab in refractory Felty Syndrome J Clin Rheumatol 2006; 12: 48.
[15] Salama A, Schneider U, Dorner T. Beneficial response to rituximab in a patient with haemolysis and refractory Felty syndrome Ann Rheum Dis 2008; 67: 894-5.
[16] Lekharaju V, Chattopadhyay C. Efficacy of rituximab in Felty's syndrome Ann Rheum Dis 2008; 67: 1352.
[17] 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: 332-.
[18] Allen LS, Groff G. Treatment of Felty's syndrome with low-dose oral methotrexate Arthritis Rheum 1986; 7: 902-5.

Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


SCImago Journal Ranking

SCImago Journal & Country Rank

Browse Contents



Webmaster Contact: info@benthamopen.net
Copyright © 2019 Bentham Open