Felty Syndrome

 

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Original Editors - Students from Bellarmine University's Pathophysiology of Complex Patient Problems project.

Top Contributors - Abby Janszen, Shannon Stenger, Rucha Gadgil, Uchechukwu Chukwuemeka, WikiSysop, Kim Jackson, 127.0.0.1, Claire Knott, Lucinda hampton and Elaine Lonnemann  

Definition/Description

Felty Syndrome (FS), a rare complication of rheumatoid arthritis (RA), was first described by Dr. Augustus Felty in 1924. It is characterized by a triad of symptoms: seropositive RA with severe joint involvement, a low white blood cell count (neutropenia), and an enlarged spleen (splenomegaly). However, the triad is not required for diagnosis. Splenomegaly and severe joint involvement are not always present in some people with FS, and some people can even present with no symptoms. Neutropenia is the hallmark symptom of FS and is key for diagnosis. FS can be a potentially life-threatening, serious systemic condition due to its increased risk for infection during an immunosuppressed state of RA.

Prevalence

The prevalence of FS is an estimate 10 cases per 100,000 people. It is seen in about 1-3% cases of RA, making it a rare rheumatological disorder. 

FS is three times more common in females than males. However, early occurrence is more common in males. It more commonly affects the Caucasian population, and the mean age of those presenting with FS is between 50-70 years old.

Characteristics/Clinical Presentation

Aside from the classic triad of characteristics of FS, which are RA, neutropenia,  and splenomegaly, other signs and symptoms can also present themselves in this rare disorder, as well. Some of these other signs and symptoms include: 

• Painful, stiff, swollen joints (hands, feet, arms)
• Fever
• Weight loss
• Fatigue
• Skin discoloration (especially an abnormal brown pigmentation of the leg)
• Ulcers (especially on the lower leg)
• Enlarged liver (hepatomegaly)
• Possible anemia, thrombocytopenia, or vasculitis 

It should also be understood that splenomegaly is not always present in FS, and it could indicate other complications (see Associated Co-morbidities).   

                                                                                                                                                                                                                                                                                                                                                   

Associated Co-morbidities

Despite the associated signs and symptoms accompanying FS, other associated co-morbidities can occur, as well. Infections are common, especially due to neutropenia, and these infections primarily occur at the skin and pulmonary tracts. Nonetheless, neutropenia in FS can also lead to increased risk for cancers, especially Non-Hodgkins Lymphoma. Furthermore, hepatomegaly, lymphadenopathy, episcleritis, sicca syndrome, eyelid necrosis, pleuritic, neuropathy, portal hypertension, liver involvement, such as portal fibrosis or cirrhosis, and anemia can also arise from FS. 

Additionally, splenomegaly, one of the characteristics of FS, can indicate other complications, such as liver cirrhosis, brucellosis, visceral leishmaniasis, bacterial endocarditis, histoplasmosis, amyloidosis, and abdominal pain. 

Medications

Immunosuppressive agents and hematopoietic growth factors are two of the most common pharmacological treatments used to reduce mortality and prevent complications in FS. Glucocortoids and antineoplastics/monoclonal antibodies are also used in managing FS.

Medications Used in Managing Felty Syndrome

Immunosuppressive agents	Inhibit factors responsible for immune reactions
Methotrexate (Rheumatrex, Trexall)	Antineoplastic agent that is used as a immunosuppressant at lower doses; very effective in treating the RA piece of FS; antirheumatic effects take several weeks to become effective
Cyclophosphamide	Antineoplastic alkylating agent and immunosuppressive agent; increases risk of infection by reducing number of B and T cells
Hematopoietic growth factor	Stimulate production, maturation, and activation of neutrophils; increases migration and cytotoxicity of neutrophils
Filgrastim (Neupogen)	Manages infections that are not responding to antibiotics
Sargramostim (Leukine)	Increases granulocytes in 48-91% of patients with FS by stimulating division and maturation of early myeloid and macrophage precursor cells
Antineoplastics/Monoclonal Antibodies	Genetically engineered immunoglobulins that work against proteins involved in cell cycle initiation
Rituximad (Rituxan)	Genetically engineered antibody (immunoglobulin G1 kappa), which is directed against CD20 antigen of normal and malignant B cells

Evidence for the Use of Medications in Felty Syndrome

Low dose methotrexate (MTX)

• The most commonly used drug as the initial treatment 
• Interferes with interleukin-1 activity and leads to adenosine accumulation 
  

Corticosteroids

• Good initial response for those with FS 
• Long term use is a major issue due to increased risk of infection
• Second-line treatment modality 
  

Hydroxychloroquine

• Long lasting effect
• Increased the neutrophil count after a few days 
• Supported by a report of 2 cases of FS with severe neutropenia and methotrexate associated toxicity
  

B-cell depletion therapy with rituximab

• One case report demonstrated sustained remission, but rituximab was ineffective in 2 men with FS in a 6-mo follow up
• Another report with a 46 yo woman with 13 yr history of RA and newly developed FS who both failed to respond to treatment showed that a 12-mo therapy with rituximab resulted in a PMN response

Granulocyte colony-stimulating factor (G-CSF)

• Effective therapeutic modality in the management of severe neutropenia in FS 
• Supported by several case reports
• Some reports of complications developing from this medication
• G-CSF may be associated with flu-like Sx’s, exanthema, thrombocytopenia, hyperuricemia, and increased alkaline phosphatase
• One study of a patient with FS and profound neutropenia associated with recurrent infections showed that G-CSF significantly increased neutrophil count after 24 hrs
  

Diagnostic Tests/Lab Tests/Lab Values

Most often, FS is diagnosed based on the patient evaluation and history, the presence of RA, neutropenia, and splenomegaly. Severe RA joint involvement and splenomegaly are not always present in FS and are not necessary for diagnosis; however, these symptoms are common characteristics of FS. Neutropenia with an absolute neutrophil count of less than 1500/mm3 is necessary for diagnosis. Other tools for diagnosis are as follows:

Physical Exam:

• Palpate for swollen spleen
• Observe joints with evidence of RA
• Palpate for swollen lymph nodes
• Palpate for swollen liver

Lab Values/Tests:

• Low white blood cell count (less than 1500/mm3)
• Presence of rheumatoid factor (RF)
• Elevated Erythrocyte Sedimentation Rate (ESR) 
• Elevated serum immunoglobin levels
• Presence of Immunoglobin G autoantibodies can easily differentiate FS from RA 
• High titers of antibodies against cyclic citrullinated peptide (ACPA or anti-CCP) are expected in FS because of the strong association between ACPA and extra-articular manifestation of RA
• Antineutrophil cytoplasmic antibodies (ANCA) of atypical type can be (+) in 77% of patients with FS 
• Antinuclear antibodies (ANA), anti-perinuclear antibodies, and anti-keratin antibodies can be (+) in both FS and RA, but these are not sensitive or specific to be used for diagnosing FS
• Antihistone antibodies are detectable in 83% of those with FS, and the presence of this in a known case of RA is almost always indicative of FS

Diagnostic Tests:

• Ultrasounds, radionuclide studies, and computed tomography (CT) scans can illustrate splenomegaly
• Bone marrow aspiration and biopsy can be used for better assessment of the hematopoiesis; can rule out bone marrow involvement by other hematological or non-hematological diseases 
  

Etiology/Causes

There is currently no evidence for the exact cause of FS. However, both genetics and immunosuppressive drugs, used to treat previous aggressive and seropositive RA, tend to play a large role in its etiology. It is thought that genetics and the use of immunosuppressive drugs weakens the immune system, lowering the body's natural defenses and  allowing for an increased risk of infection. Research shows that about 86% of those who have FS are positive for HLA-DR4, which is a cell surface receptor antigen. More specifically, literature illustrates that the presence of two HLA-DRB1*04 alleles increases the susceptibility for extra-articular manifestations of RA and increases the chance of getting FS. Unfortunately, those who have the RA with extra-articular manifestations component of FS tend to have a worse prognosis and a higher risk for mortality. 

Systemic Involvement

Immune	Increased risk of infection due to neutropenia, increased risk of cancer, lymphadenopathy
Integumentary	Skin discolorations, ulcers, RA nodules
Hematological	Neutropenia, anemia, thrombocytopenia, vasculitis
Musculoskeletal	Painful, stiff, swollen joints (hands, feet, arms)
Hepatic	Enlarged liver, portal hypertension, portal fibrosis, cirrhosis
Splenic	Enlarged spleen
Ocular	Sicca syndrome, eyelid necrosis, episcleritis
Neurological	Neuropathy
Respiratory/pulmonary	Pleuritis

Medical Management (current best evidence)

Unfortunately, there is limited research that outlines effective treatment strategies for patients with FS. In FS, immunosuppressive agents, such as Methotrexate and Cyclophosphamide, and hematopoietic growth factors, such as Filgrastim and Sargramostim, are two of the most common ways for medical management. As stated in the Medications section, the immunosuppressive agents inhibit factors that cause immune reactions; whereas, the hematopoietic growth factors are responsible for stimulating production, maturation, and activation of neutrophils, along with increasing there migration and cytotoxicity. Low dose Methotrexate is oftentimes used for RA management; thus, it is the most commonly used medication to treat FS at its initial phase.

In addition to these medications, glucocortoids and antineoplastics/monoclonal antibodies are other pharmacological ways for the medical management of FS. In essence, these are genetically engineered immunoglobins that are designed to work against the proteins involved in cell cycle initiation. Specifically, the drug, Rituximad, is used for this purpose, in which it is directed against the CD20 antigen of normal and malignant B cells.

For more information of all medications used to treat FS, see medication section

As a last resort, a splenectomy is utilized, especially for those who have severe neutropenia (absolute neutrophil count of less than 1500/mm3) and frequent infections. A splenectomy has positive effects on treating various components of FS, such as anemia, thrombocytopenia, neutropenia, and chronic infections. Although most patients who undergo this surgery demonstrate initial improvement in their white blood cell count, neutropenia tends to reoccur in about 25% of the patient population. Thus, this surgery's long term value is unclear.

Physical Therapy Management (current best evidence)

Treatment for patients with FS is focused on addressing and controlling the presenting symptoms. Physical therapists are more involved with managing the pain, fatigue, and activity balance of the RA component of FS. RA should be treated as it would be in the absence of FS (e.g. bedrest, appropriate exercise, heat treatments, gold salts, nonsteroidal anti-inflammatory drugs (NSAIDS), penicillamine, etc.) (6)

In people with FS who present with RA and severe joint involvement, patient-centered physical therapy should be emphasized and implemented. The goal of patient-centered therapy is to is to formulate a self care plan for patients that consists of managing fatigue and balancing work/activities of daily living. This self care needs to involve both the physical therapist and the patient, and be something the patient is able to effectively do overtime. (Article Shan sent)

General Treatment Goals:

• Decrease pain and inflammation
• Increase ROM, strength, and endurance
• Educate on activity modulation and how to manage fatigue (self management)
• Joint protection
• Improve quality of life and independence

These goals can be achieved through stretching, aerobic exercise, resistance training, patient education, life style management, pain reducing modalities (heat, massage, ice, ultrasound, electrical stimulation), functional activities/ADL training, and joint protection strategies (education, splints, assistive devices, orthotics). (RA physiopedia page)

Aerobic and Resistance Training Guidelines:
The goal for the intensity of aerobic exercise should be moderate to hard (60-85% of maximum HR) and these exercises should be performed 3 days of the week for 30-60 minutes a day. These activities can be aquatic or land-based, such as swimming, walking, cycling, or aerobic class participation. Progressive adjustment of the intensity is recommended based on the patient's fatigue and pain level. (8)

The goal for strengthening exercises should be moderate to hard load (50-80% of a maximal voluntary contraction) and resistance training should be performed 2-3x/week. These exercises may be static or dynamic and can be body weight exercises or exercises using various types of equipment, such as resistance training equipment, pulley apparatus, dumbbells, or elastic bands. Progressive adjustment of the load is recommended based on the patient's fatigue and pain level. Joint protection is also key when performing these exercises by emphasizing proper body/lifting mechanics and by focusing on larger joints. (8)

Differential Diagnosis

• RA (see RA PhysioPedia Page)

RA is the main preceding condition and one of the main features of FS. Many of the signs and symptoms of RA are seen in FS, which can make it difficult to differentiate. RA is an immunologic disease that is chronic, affects the systemic systems, and causes inflammation in various joints. Like FS, women are more likely to have RA, and the HLA-DRB1 gene also have a component in developing this disease. Many of the signs and symptoms are very similar to FS; however, neutropenia is not as associated with RA as it is with FS. Neutropenia is one of the hallmark signs of FS.

• Amyloidosis

Characterized as a systemic disorder, Amyloidosis affects multiple systems in the body, such as the renal, cardiovascular, gastrointestinal, dermatological, and respiratory. It mainly targets the kidney and the heart, and can lead to neuropathy. The kidney can be enlarged, congestive heart failure can occur, along with an enlarged heart, irregular heartbeat, and murmurs. Unlike FS, where splenomegaly can occurs, Amyloidosis may affect the spleen, as well as the liver, but it is not as common. Similar to FS, arthropathies can also be seen in this disease, as well as neutropenia, specifically in primary Amyloidosis.

• T-cell large granular lymphocyte leukemia (TLGL)

Both TLGL and FS are from a single disease process, and about 25-30% of people with TLGL have RA as a proceeding complication. Although RA can be seen in TLGL, the arthritis and joint destruction is much milder than that of FS, and RF is not as common. Furthermore, neutropenia can occur in TLGL from neutrophil destruction. Additionally, extra-articular manifestations, leg ulcers, abnormal skin pigmentation, and hepatomegaly are not as common in TLGL as they are in FS.

• Systemic Lupus Erythematosus (SLE) (see SLE PhysioPedia Page)

SLE is an autoimmune rheumatic disease that is illustrated as inflammatory injury to the skin, joints, kidneys, heart, blood-forming organs, nervous system, and mucous membranes. Although the butterfly rash is the classic presentation to differentiate SLE from other diseases, like FS, it presents itself through arthralgias and arthritis. The arthralgias and arthritis of SLE can be seen especially in the hands, wrists, and knees, which is similar to the presentation of FS. Furthermore, fever, fatigue, neuropathy and anemia are also signs and symptoms that present similarly to FS.

• Cirrhosis

Cirrhosis is characterized by fibrosis and abnormal nodules on the liver, changing its structure. Some common signs and symptoms of cirrhosis that are similar to FS are hepatomegaly, abdominal pain, portal hypertension, fatigue, and weight loss.

• Myeloproliferative Disease

Myeloproliferative disease consists of hematologic cell proliferation, which can put the person at risk for developing acute leukemia. Since FS has a hematologic component, Myeloproliferative disease has similar presenting signs and symptoms as FS, such as fatigue, fever, weight loss, abdominal pain, swollen and painful joints, and splenomegaly.

• Non-Hodgkin Lymphoma (NHL) (see NHL PhysioPedia Page)

NHL are tumors or lymphomas that arise from lymphoid tissue. NHL has many similar clinical signs and symptoms as FS, which consist of fever, weight loss, increased risk of infection, fatigue, weight loss, splenomegaly, hepatomegaly, and abdominal pain.

• Sarcoidosis (see Sarcoidosis PhysioPedia Page)

This disease is characterized as a multisystem inflammatory, and like FS, fever and arthralgias are present. However, the inflammation manifests mostly in the lungs and intrathoracic lymph nodes, which makes Sarcoidosis present with more pulmonary issues.

• Sjogren Syndrome (see Sjogren Syndrome's PhysioPedia Page)

Sjögren syndrome is in the family of systemic chronic inflammatory diseases, and infiltrates of lymph in the exocrine organs characterize this syndrome. Sjogren’s has a very similar presentation to FS, which can make it difficult to differentiate. Some of the similar signs and symptoms include arthralgias, arthritis, anemia, neuropathy, vasculitis, and lymphoma. Furthermore, like FS, Sjogren’s, specifically secondary Sjogren’s, has connections to other rheumatic diseases, such as SLE and RA, which makes it hard to differentiate its manifestations as primary or secondary to the disorder. Finally, the medication Rituximab is a common treatment for this syndrome.

• Tuberculosis (TB) (see TB PhysioPedia Page)

TB is an infectious disease from bacteria. Similar to FS, TB can present with fatigue, malaise, weight loss, and fever. Also, Tuberculous arthritis can arise in this disease, but unlike FS, it typically involves only one joint, which affects the hip or knee most often, then the ankle, elbow, wrist, and shoulder.

Case Reports/ Case Studies

• Felty's Syndrome with hyperthyroidism: A Case Report and Literature Review (view article in ebscohost)
• A Case of Felty's Syndrome Associated with Skin Ulcers and Extranodal NK/T-cell Lymphoma (view article in ebscohost)
• A Case of Adult-onset Felty Syndrome in Juvenile Rheumatoid Arthritis (view article in ebscohost)
• Surgical Management of Portal Hypertension in Felty's Syndrome: A Case Report and Literature Review (view article in ebscohost)
• Diagnosis of Felty's Syndrome, distinguished from hematology cal neoplasm: A Case Report (view article in ebscohost)
• Felty's Syndrome as an initial presentation of Rheumatoid Arthritis: A Case Report (view artical on Biomed Central)
• Felty's Syndrome and Kala-azar: A challenge for the rheumatologist - (view article on PubMed)

Resources

• Genetic and Rare Diseases Information Center (GARD) - https://rarediseases.info.nih.gov/gard/8234/feltys-syndrome/resources/8
• National Organization for Rare Disorders - http://rarediseases.org/rare-diseases/felty-syndrome/
• The Arthritis Society - http://arthritis.ca/understand-arthritis/types-of-arthritis/felty-s-syndrome
• National Library of Medicine - https://www.nlm.nih.gov/medlineplus/ency/article/000445.htm

Recent Related Research (from Pubmed)

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References

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