Felty's Syndrome is a complication of rheumatoid arthritis (RA). It is the triad of rheumatoid arthritis, neutropenia and splenomegaly. It was first described by Dr Augustus Felty in 1924.¹

Epidemiology

• Occurs in <1% of those with RA.²
• Incidence is likely to be decreasing with the development and use of more effective treatment for RA.
• Most common in people who have had RA for more than 10 years³ and who have more severe disease with extra-articular manifestations.

Aetiology

The precise cause is unknown.

• Hypotheses include sequestration of white blood cells in the spleen, an immune-mediated destruction of white blood cells and abnormal white blood cell development in the bone marrow.³
• Felty's Syndrome is associated with the HLA-DR4 genotype. This genotype is a marker for more aggressive RA with greater extra-articular manifestations.⁴

Neutropenia in Felty's syndrome:⁵

• May have multifactorial causes, including destruction of neutrophils by autoantibodies and immune complexes and inhibition of bone marrow granulopoiesis by proinflammatory cytokines.
• The neutropenia is often severe (<0.2 x 10⁹/L).
• There may also be functional deterioration in the available neutrophils.

Presentation

Overview²

• May be asymptomatic.⁴
• May present with severe or recurrent infection due to neutropenia (see Complications below).
• There is usually a background of longstanding rheumatoid arthritis (RA).
• The clinical picture of RA in this scenario is typically one of severe joint destruction contrasting with moderate or absent joint inflammation; and severe extra-articular disease, e.g. including rheumatoid nodules, lymphadenopathy, hepatopathy, vasculitis, leg ulcers and skin pigmentation.

Symptoms

• Fatigue
• Anorexia
• Weight loss
• Eye symptoms (including dry eyes and irritation due to Sjögren's syndrome and red and painful eyes due to episcleritis).
• Recurrent infections due to neutropenia (lung and skin infections are most common).
• Left upper quadrant pain (due to splenomegaly or splenic infarcts).
• Symptoms related to RA, including joint swelling, pain, stiffness and deformity.

Signs

• Splenomegaly
• Hepatomegaly
• Lymphadenopathy
• Typical RA joint deformities ± active synovitis causing joint swelling and tenderness.
• Pallor
• Rheumatoid nodules
• Features of vasculitis - leg ulcers, brown pigmentation on the legs, periungual infarcts, ischaemia of the extremities
• Peripheral neuropathy
• Eye involvement including episcleritis

Investigations and diagnosis⁶

The diagnosis is a clinical one, based on the features of unexplained neutropenia and splenomegaly in a patient with rheumatoid arthritis (RA).⁶ Relevant investigations are:

• Blood tests:
  • Full blood count - for neutropenia ± anaemia of chronic disease
  • Autoantibodies:
    • 95% of patients with Felty's syndrome are positive for rheumatoid factor²
    • Anti-cyclic citrullinated peptide (anti-CCP) antibody (has high specificity for RA).⁶
  • Inflammatory markers (ESR and CRP).⁶
  • Liver function tests - may be raised if there is liver involvement (see Complications below).
• Radiology:
  Ultrasound or CT scan to evaluate splenomegaly.
• Bone marrow biopsy:
  • May be required to differentiate Felty's syndrome from other diseases such as large granular lymphocyte syndrome or low-grade non-Hodgkin's lymphoma.⁷

Differential diagnosis

• Other causes of neutropenia or splenomegaly
• Large granular lymphocyte syndrome⁵
• Non-Hodgkin's lymphoma⁷

Management

Because Felty's syndrome is rare, information about management relies on small studies and case reports.

Treatment to improve neutropenia⁵

• Immune modulating drugs:
  • Some of these may be the same drugs used to treat the underlying rheumatoid arthritis (RA).
  • Methotrexate is usually first choice, as there is most experience with this drug.^2,8
  • Other drugs which have been used are hydroxychloroquine,^6,9 ciclosporin, leflunomide ± methotrexate,⁵ gold,^5,10 sulfasalazine,⁶ salazosulfapyridine¹¹ and cyclophosphamide.⁶
• Biological agents:
  • Rituximab ± methotrexate has been used in a few cases, with variable results reported.^12,13 (Current guidance requires use of methotrexate with rituxinab.)¹⁴
  • Note that etanercept (used to treat RA) has been reported to reduce the neutrophil count in one patient with Felty's syndrome; the authors advised caution when using etanercept with Felty's syndrome.¹⁵
• Splenectomy:
  • Generally reserved for those not responding to medical treatment.⁶
  • Splenectomy improves neutropenia in most patients (80%), but has less effect on rates of infection,² and there is a higher rate of postoperative infection.⁵
• Prevention of infection:
  • Immunisation against influenza and pneumococcus.
  • Patient awareness to seek immediate treatment for symptoms of infection.
  • Splenectomy patients require additional measures for prevention of infection (see separate article Splenectomy, Hyposplenism and Asplenia).

Mangement of splenomegaly⁴

• Advise patients about activities, depending on their infection risk and spleen size.
• For example, advise patients to avoid any activity that could result in blunt trauma to the left upper quadrant (re the risk of splenic rupture).

Management of infectious complications⁵

The most common infections in this scenario affect the skin, mouth, and upper and lower respiratory tract. Principles of management are:

• Identify and treat any acute sepsis (e.g. take swabs/cultures, give appropriate antibacterial or antifungal treatment, etc.).
• Continue usual therapy (as above).
• Add a growth factor, specifically G-CSF, to achieve prompt recovery of the circulating neutrophil count and better control of infection.
• However, the larger supply of circulating activated leukocytes raises the risk of arthritic flare-ups and/or leukocytoclastic vasculitis in these patients. These complications may be reduced by using low doses of G-CSF with medium or low doses of corticosteroids.
• The optimal duration of G-CSF treatment is uncertain. Once the infection has been resolved, good control of the underlying disease with the usual drugs may be sufficient to keep neutropenia within safe limits. If severe neutropenia persists (<0.2 x 10⁹/L) then G-CSF could be continued at the lowest effective dose (to maintain circulating neutrophils >1 x 10⁹/L).

Complications

• Life-threatening infections, including severe forms of candidiasis.^16,17,18
• Splenic rupture.
• Liver complications which may occur, leading to portal hypertension and bleeding from oesophageal varices.^19,20
• Hyperviscosity syndrome.²¹
• There may be expansion of large granular lymphocytes (LGL) in the bone marrow, which could lead to LGL leukaemia.⁵
• Eye complications - episcleritis, nodular scleritis, corneal ulcer, Sjögren's syndrome, iridocyclitis and retinal vasculitis have been discussed as relating to Felty's syndrome.²²

Prognosis

• Serious infection can lead to death.
• Spontaneous remission can occur.²
• One study found an increased risk of cancers (particularly non-Hodgkin's lymphoma) in patients with Felty's syndrome.²³

Prevention

Drug development and improved treatment of rheumatoid arthritis (RA) may mean that the incidence of Felty's syndrome begins to decrease. One article reports a reduction in splenectomy for Felty's syndrome over the last 19 years. This may be related to improved disease management.²⁴

Document references

1. Felty AR; Chronic arthritis in the adult, associated with splenomegaly and leucopenia. A report of 5 cases of an unusual clinical syndrome. Bulletin of the Johns Hopkins Hospital, Baltimore, 1924, 35:16.
2. Balint GP, Balint PV; Felty's syndrome. Best Pract Res Clin Rheumatol. 2004 Oct;18(5):631-45. [abstract]
3. Wordsworth BP. Rheumatoid arthritis. Concise Oxford Textbook of Medicine. Chapter 10.2.
4. Keating RM; Felty Syndrome. eMedicine. Last updated December 2008.
5. Capsoni F, Sarzi-Puttini P, Zanella A; Primary and secondary autoimmune neutropenia. Arthritis Res Ther. 2005;7(5):208-14. Epub 2005 Aug 31. [abstract]
6. Chavalitdhamrong D, Molovic-Kokovic A, Iliev A; Felty's Syndrome as an initial presentation of Rheumatoid Arthritis: a case Cases J. 2009 Nov 18;2:206. [abstract]
7. Opeskin K, Burke M, Firkin F; Bone marrow lymphoid aggregates simulating histological features of non-Hodgkin's Pathology. 2005 Feb;37(1):82-4.
8. Wassenberg S, Herborn G, Rau R; Methotrexate treatment in Felty's syndrome. Br J Rheumatol. 1998 Aug;37(8):908-11. [abstract]
9. Mahevas M, Audia S, De Lastours V, et al; Neutropenia in Felty's syndrome successfully treated with hydroxychloroquine. Haematologica. 2007 Jul;92(7):e78-9.
10. Almoallim H, Klinkhoff A; Longterm outcome of treatment of Felty's syndrome with intramuscular gold: case J Rheumatol. 2005 Jan;32(1):20-6. [abstract]
11. Ishikawa K, Tsukada Y, Tamura S, et al; Salazosulfapyridine-induced remission of Felty's syndrome along with significant J Rheumatol. 2003 Feb;30(2):404-6. [abstract]
12. Sordet C, Gottenberg JE, Hellmich B, et al; Lack of efficacy of rituximab in Felty's syndrome. Ann Rheum Dis. 2005 Feb;64(2):332-3.
13. Lekharaju V, Chattopadhyay C; Efficacy of rituximab in Felty's syndrome. Ann Rheum Dis. 2008 Sep;67(9):1352.
14. British National Formulary; 58th Edition (September 2009) British Medical Association and Royal Pharmaceutical Society of Great Britain, London.
15. Ghavami A, Genevay S, Fulpius T, et al; Etanercept in treatment of Felty's syndrome. Ann Rheum Dis. 2005 Jul;64(7):1090-1.
16. Ish-Hurwitz S, Dovrish Z, Edelstein E, et al; Diffuse disseminated candidiasis in a patient with Felty's syndrome: a case Rheumatol Int. 2007 Nov;28(1):65-8. Epub 2007 Jun 19. [abstract]
17. Thomas DW, Munuswamy P, Adu-Poku K, et al; Candida albicans peritonitis in a patient with Felty's syndrome. J Clin Pathol. 2005 Apr;58(4):432-3. [abstract]
18. Makitie AA, Back L, Aaltonen LM, et al; Fungal infection of the epiglottis simulating a clinical malignancy. Arch Otolaryngol Head Neck Surg. 2003 Jan;129(1):124-6. [abstract]
19. Thorne C, Urowitz MB, Wanless I, et al; Liver disease in Felty's syndrome. Am J Med. 1982 Jul;73(1):35-40. [abstract]
20. Stock H, Kadry Z, Smith JP; Surgical management of portal hypertension in Felty's syndrome: A case report and J Hepatol. 2009 Apr;50(4):831-5. Epub 2009 Feb 12. [abstract]
21. Zakzook SI, Yunus MB, Mulconrey DS; Hyperviscosity syndrome in rheumatoid arthritis with Felty's syndrome: case Clin Rheumatol. 2002 Feb;21(1):82-5. [abstract]
22. Giuri S; (The ocular manifestations in Felty's syndrome) Oftalmologia. 1996 Jan-Mar;40(1):51-7. [abstract]
23. Gridley G, Klippel JH, Hoover RN, et al; Incidence of cancer among men with the Felty syndrome. Ann Intern Med. 1994 Jan 1;120(1):35-9. [abstract]
24. Ward MM; Decreases in rates of hospitalizations for manifestations of severe rheumatoid arthritis, 1983-2001. Arthritis Rheum. 2004 Apr;50(4):1122-31. [abstract]

Internet and further reading

• Burks EJ, Loughran TP Jr; Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty Blood Rev. 2006 Sep;20(5):245-66. Epub 2006 Mar 10. [abstract]

Acknowledgements