History

The disease has a slow, insidious and destructive progress. Remission and exacerbations are the rule. Patients commonly report with a long-standing history of severe RA. Infrequently, RA and FS might develop together.

Plain radiography will confirm the presence of a long history of active, severe erosive joint disease in patients with FS. Sometimes, patients might present in a phase of remission with no active symptoms of joint disease but extra-articular manifestations like skin or respiratory infection might be seen.

Rarely, a patient might present with acute, left upper abdominal pain occasioned by a splenic infarct or splenomegaly. Weight loss, loss of appetite, mild fever and fatigue are often experienced by patients. With time, patients learn to recognize an oncoming exacerbation from minor signs.

Signs and symptoms

Involvement of bilateral, symmetrical, peripheral joints like knees, ankles, wrists, metacarpophalangeal (MCP) and proximal interpahalangeal joints (PIP) is common. Axial joint involvement is uncommon. Joint disease is accompanied with pain, swelling, redness and tenderness. Joint deformities typical of long-standing RA, for example, boutonniere deformity, z-shaped deformity, etc might be present.

Extra-articular manifestations

Lymphadenopathy, anemia and splenomegaly or hepato-splenomegaly distinguish FS from RA [4]. Splenomegaly is the reason behind pancytopenia. Pleuritis, pulmonary fibrosis, episcleritis and Sjogren syndrome are often seen accompanying a severe neutropenia.

Rheumatoid nodules might be present on the skin along with signs of vasculitis like shin ulcers, periungual infarcts, mononeuritis multiplex and brownish hyperpigmentation on lower legs.

Complications

Occasionally, a patient might present with a complication of FS like a splenic rupture post-dating a spleen infarct or a life-threatening respiratory or skin infection. Hematemesis or vomiting of blood due to portal hypertension is another potentially fatal complication of FS.

• Splenomegaly

  […] arthritis, splenomegaly and neutropenia Splenomegaly-neutropenia-rheumatoid arthritis syndrome edit English Felty's syndrome syndrome that results in rheumatoid arthritis, splenomegaly and neutropenia Felty syndrome Rheumatoid arthritis with splenoadenomegaly [wikidata.org]

  […] of RA characterized by neutropenia and splenomegaly. [ncbi.nlm.nih.gov]

  Extra-articular manifestations Lymphadenopathy, anemia and splenomegaly or hepato-splenomegaly distinguish FS from RA. Splenomegaly is the reason behind pancytopenia. [symptoma.com]

• Massive Splenomegaly

  Splenectomy may be considered in those with massive splenomegaly or recurrent infections. [rheumaknowledgy.com]

  Ideally liver biopsy should be done but a diagnosis of nodular regenerative hyperplasia was assumed, as our patient had a clinical picture of rheumatoid arthritis with massive splenomegaly, pancytopenia, portal hypertension and with other potential causes [autoimmunediseases.imedpub.com]

  A spleen weight of 400-500 g indicates splenomegaly, while a weight of more than 1000 g is labelled massive splenomegaly. [emedicine.medscape.com]

• Anemia

  Felty, American physician, 1895-1963 a group of pathological changes that occurs with adult rheumatoid arthritis, characterized by splenomegaly, leukopenia, frequent infections, and sometimes thrombocytopenia and anemia. [medical-dictionary.thefreedictionary.com]

  Extra-articular manifestations Lymphadenopathy, anemia and splenomegaly or hepato-splenomegaly distinguish FS from RA. Splenomegaly is the reason behind pancytopenia. [symptoma.com]

  Fel·ty syndrome | \ ˈfel-tē- \ variants: or Felty's syndrome Medical Definition of Felty syndrome : a condition characterized by rheumatoid arthritis, neutropenia, and splenomegaly and often by weight loss, anemia, lymphadenopathy, and pigment spots on [merriam-webster.com]

  An acronym can be used to make recognizing this disease somewhat easier: S: Splenomegaly A: Anemia N: Neutropenia T: Thrombocytopenia A: Arthritis (rheumatoid) A complete blood count (CBC) can be done to diagnose anemia (normochromic, normocytic), thrombocytopenia [en.wikipedia.org]

  Another Felty syndrome mnemonic I’ve seen used (see below) includes anemia and thrombocytopenia. [firstaidteam.com]

• Fatigue

  Similar to FS, TB can present with fatigue, malaise, weight loss, and fever. [physio-pedia.com]

  Symptoms include: General feeling of discomfort ( malaise ) Fatigue Loss of appetite Unintentional weight loss Pale-looking skin Joint swelling, stiffness, pain, and deformity Recurrent infections Eye burning or discharge A physical exam will show: Swollen [nlm.nih.gov]

  Other people may display a number of symptoms, including: fatigue serious infections a fever weight loss discolored patches of skin Sometimes, people who have Felty’s syndrome may not have any symptoms. [healthline.com]

  Anemia Eye burning or discharge Symptoms of Felty syndrome mnemonic Fatigue Anorexia Weight loss Recurrent infections due to neutropenia (lung and skin infections are most common). L eft upper quadrant pain (due to splenomegaly or splenic infarcts). [medical-institution.com]

• Weight Loss

  Fel·ty syndrome | \ ˈfel-tē- \ variants: or Felty's syndrome Medical Definition of Felty syndrome : a condition characterized by rheumatoid arthritis, neutropenia, and splenomegaly and often by weight loss, anemia, lymphadenopathy, and pigment spots on [merriam-webster.com]

  Symptoms include: General feeling of discomfort ( malaise ) Fatigue Loss of appetite Unintentional weight loss Pale-looking skin Joint swelling, stiffness, pain, and deformity Recurrent infections Eye burning or discharge A physical exam will show: Swollen [nlm.nih.gov]

  Other times, they may have specific symptoms that occur with the syndrome, such as: eye discharge a burning feeling in the eyes fatigue weight loss joint pain, swelling, stiffness, and deformities a loss of appetite general discomfort infections pale [healthline.com]

  loss, strange skin rashes and mouth ulcers to name but a few. [feltyssyndrome.com]

  Similar to FS, TB can present with fatigue, malaise, weight loss, and fever. [physio-pedia.com]

• Loss of Appetite

  Symptoms include: General feeling of discomfort ( malaise ) Fatigue Loss of appetite Unintentional weight loss Pale-looking skin Joint swelling, stiffness, pain, and deformity Recurrent infections Eye burning or discharge A physical exam will show: Swollen [nlm.nih.gov]

  Symptoms are: 1.General feeling of discomfort (malaise) 2.Fatigue 3.Loss of appetite 4.Unintentional weight loss 5.Pale-looking skin 6.Joint swelling, stiffness, pain, and deformity due to RA 7.Recurrent infections due to neutropenia (lung and skin infections [amazon.fr]

  Symptoms Symptoms include: General feeling of discomfort (malaise) Fatigue Weakness in leg or arm Loss of appetite Unintentional weight loss Ulcers in the skin Joint swelling, stiffness, pain, and deformity Recurrent infections Red eye with burning or [mountsinai.org]

  Symptoms include: General feeling of discomfort (malaise) Fatigue Weakness in leg or arm Loss of appetite Unintentional weight loss Ulcers in the skin Joint swelling, stiffness, pain, and deformity Recurrent infections Red eye with burning or discharge [medlineplus.gov]

  Other symptoms of Felty syndrome include: Fatigue Loss of appetite Weight loss Pale skin Eye burning or discharge Treating Felty Syndrome “Treatment of Felty syndrome is treating the underlying disease [the rheumatoid arthritis] better,” says Goeckeritz [everydayhealth.com]

• Arthralgia

  Side effects included rare cases of thrombocytopenia, arthralgias, and development of cutaneous leukocytoclastic vasculitis. Side effects were dose dependent and resolved when treatment was discontinued. [ncbi.nlm.nih.gov]

  Some of the similar signs and symptoms include arthralgias, arthritis, anemia, neuropathy, vasculitis, and lymphoma. [physio-pedia.com]

  Case report A 17-year-old female with a 2-year history of erosive nodular seropositive RA followed Chinese herbal treatment for symptoms of repeated arthralgia in 2011. [spandidos-publications.com]

  Showing of 35 | Medical Terms Other Names Learn More: HPO ID 80%-99% of people have these symptoms Arthralgia Joint pain 0002829 Arthritis Joint inflammation 0001369 Autoimmunity Autoimmune disease Autoimmune disorder [ more ] 0002960 Immunodeficiency [rarediseases.info.nih.gov]

• Headache

  She also complains of a mild intermittent headache. Patient has chronic polyarticular pain, mostly on her left knee and ankles. [omicsonline.org]

  He denied chest pain, shortness of breath, palpitations, cough, headache, dizziness, nausea, vomiting, abdominal pain, bowel or urinary symptoms, weight or appetite changes. [casesjournal.biomedcentral.com]

  The patient denied having a cough, upper respiratory tract infection symptoms, headache, abdominal pain, or diarrhea. The patient reported having malaise, fatigue, and night sweats. [dovepress.com]

A thorough physical examination is mandatory to locate any unreported signs by the patient.

Laboratory studies

A complete blood count will reveal anemia, severe neutropenia and thrombocytopenia with leucopenia. Serum titers of RF, anti-nuclear antibodies (ANA) and anti-histone antibodies (AHA) are high.

Mild elevations are noted in alkaline phosphatase, erythrocyte sedimentation rate (ESR) and serum transaminases due to portal hypertension and nodular hyperplasia of liver. In about 77% of cases, perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) are also seen.

The significance of presence of ANA and p-ANCA in patients with FS is still not clear and it is doubtful they contribute to the disease itself either.

Histology

Samples might be obtained from the bone marrow and lymph nodes for histological studies. They will help rule out leukemia and large granular lymphocytosis (LGL). The bone marrow samples reveal normal megakaryocyte counts and myeloid hyperplasia. There is arrested growth of the immature cell lines in patients with FS.

Liver biopsy samples often reveal a nodular regenerative hyperplasia in FS. This is a result of portal hypertension due to splenomegaly. The condition is associated with portal fibrosis and might be complicated by an occluded portal venule due to a regenerative nodule.

Imaging

CT scan, ultrasound and radionuclide studies help to confirm the presence of splenomegaly and define its extent. They aid in assessing response to therapy in patients. Hepatomegaly might be noted on abdominal scans. Pulmonary fibrosis and pleurisy might be visible in chest CT scans and radiography.

Controlling the underlying RA is the first and best way of treating FS. Close involvement of a rheumatologist, hematologist and infectious disease specialist are important for successful outcome.

Complete cure isn’t possible yet, thus remission for longer durations is sought after. Remission and palliation of presenting symptoms are the aims of treatment.

There was a time when gold salts were the only treatment available for RA and FS. Now, immunosuppressive agents like methotrexate and cyclophosphamide are the mainstay of palliative therapy. Both are anti-neoplastic agents.

While methotrexate helps reduce inflammation and its signs, cyclophosphamide reduces B and T cell counts thereby increasing infection risk. The exact method of action of methotrexate in reducing inflammation is not known yet in low doses, it acts an anti-inflammatory agent, extensively in RA. It is used as the first line of treatment in RA and even FS along with folic acid to prevent adverse effects. The good effects might take 4-8 weeks to become visible.

Hematopoeitic growth factors or Granulocyte-Colony Stimulating Factors (G-CSF) like filigrastim and sargramostim are used to stimulate neutrophil production, maturation and activation. They increase the migration and cytotoxicity of mature neutrophils, helping antibiotics act better. Sargramostim especially stimulates cell division and maturation of early cell lines of myeloid and macrophage precursors.

A new class of medications called monoclonal antibodies has emerged in the recent years as an outfall of genetic engineering. These are chimeric murine or human immunoglobulins that are directed against the proteins that are involved in initiation of cell cycles.

Rituximab, a genetically manufactured human monoclonal antibody, is used as second line treatment in refractory cases of FS. It acts against the CD20 antigens of the normal and malignant B cells [5] [6]. Etanercept, infliximab and adalimumab are used to treat RA extensively for their anti-TNF-alpha (Tumor Necrosis Factor) properties but their use in FS is limited.

Splenectomy might be opted for in severe cases of neutropenia with no response to medical therapies. Occasionally, recurrent cutaneous ulceration and extrinsic hemolysis might need a splenectomy. Splenectomy hasn’t shown to correct neutropenia in all the cases and high rates of recurrence have been noted in patients. 80% patients noticed improvement in neutropenia post-splenectomy [7].

The prognosis for FS is poor given the low neutrophil counts causing repeated life-threatening infections. Skin and pulmonary infections are most common.

Extensive use of immunosuppressants for treating RA and FS further worsens the morbidity and mortality. A study from England observed that 5 out of 32 patients of FS died due to fulminant bronchopneumonia [8].

The exact cause of FS is not known but several risk factors have been implicated:

1. Long-standing rheumatoid arthritis (RA)
2. High titers of Rheumatoid Factor (RF positivity)
3. Extra-articular manifestations
4. Aggressive synovitis
5. Human Leucocyte antigen (HLA) – DR4 positivity

FS affects about 1-3% of RA patients after having arthritis for an average of 10-15 years. RA itself affects 1% of the population, making FS a rare diagnosis.

Men are affected in later years as compared to women. FS is rare in the African American population and in children. It is 3 times more prevalent in females, especially in their fifties [2] [3].

No significant international data is available about its prevalence in other countries. Also, since patients may be asymptomatic, even the data available might be an underreporting.

The exact pathophysiology of FS is unclear but underlying autoimmune mechanisms against neutrophil surface antigens are thought to be responsible.

A high incidence of infections might initiate a neutrophil response leading to histone deimination and chromatin expulsion from the cell.

Bacterial adjuvants and deiminated histones together with Neutrophil Extracellular chromatin Traps (NETs) are the most possible trigger for antibody production against these deiminated histones. These auto-antibodies further stimulate the neutrophils leading to a self-sustaining cycle causing repetitive depletion of neutrophils.

Studies have demonstrated high incidences of auto-antibodies against deiminated histones in FS patients.

There are no guidelines for prevention of Felty’s Syndrome

Felty’s syndrome (FS) was first identified in 1924 and named after its discoverer Augustus Roi Felty [1]. It is a triad of rheumatoid arthritis (RA), splenomegaly and neutropenia. 

Felty’s syndrome can lead to potentially fatal complications due to high chances of recurrent bacterial infections. It has been nicknamed ‘super rheumatoid’ by some, owing to the extreme joint affections seen in patients.

Felty’s Syndrome is a triad of enlarged spleen, low neutrophil counts and rheumatoid arthritis. It is most commonly seen in middle aged adults, especially in females in their fifth decade of life. It is commonly seen in people with rheumatoid arthritis of long standing.

The exact cause for it is unknown but auto-immune mechanisms have been found to play a strong role in initiating and worsening the condition.

The symptoms of rheumatoid arthritis are seen- joint pains, swelling, deformities of small joints of both hands and feet. Symptoms related to low neutrophil counts are recurrent fevers and infections and ulcers on legs. Vasculitis and splenomegaly related symptoms like skin hyperpigmentation, lymph node enlargements, spleen infarcts, portal hypertension, anemia, neutropenia and low platelet counts might be visible too.

Diagnosis is made with a series of blood tests to look for antibodies. Imaging studies may be done to look for organ enlargements and bone disorders.

Treatment involves medications that suppress the immune system and control inflammation due to it. Steroids and other molecules like methotrexate, haemotopoeitic growth factors are the chief drugs used for controlling Felty Syndrome.

Educating patients about the gravity of the condition, chances of recurrent infections and ensuring access to healthcare are the chief goals. A list of antibiotics for specific infections might be given to patients with instructions of contacting their physician at the first signs of an infection and starting the antibiotics after due confirmation. Patients should be taught how to prevent infections by adequate personal and home hygiene.

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. Goldberg J, Pinals RS. Felty syndrome. Semin Arthritis Rheum 1980; 10:52.
3. Sibley JT, Haga M, Visram DA, Mitchell DM. The clinical course of Felty's syndrome compared to matched controls. J Rheumatol 1991; 18:1163
4. Al-Ghamdi A, Attar SM. Extra articular manifestations of rheumatoid arthritis: a hospital based study. Ann Saudi Med. 2009 May-Jun; 29(3):189-93.
5. Tomi AL, Liote F, et al. One case of Felty’s Syndrome efficiently treated with rituximab. Joint Bone Spine. 2012 Dec;79(6):624-5.
6. Narvaez J, Domingo Domenech E, et al. Biological agents in the management of Felty’s Syndrome: a systematic review. Semin Arthritis Rheum. 2012 Apr;41(5):658-68.
7. Balint GP, Balint PV. Felty’s Syndrome. Best Pract Res Clin Rheumatol. 2004 Oct;18(5):631-45.
8. Campion G, Maddison PJ, Goulding N, James I, Ahern MJ, Watt I, et al. The Felty syndrome: a case-matched study of clinical manifestations and outcome, serologic features, and immunogenetic associations. Medicine (Baltimore). Mar 1990;69(2):69-80.