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.
Lymphadenopathy, anemia and splenomegaly or hepato-splenomegaly distinguish FS from RA . Splenomegaly is the reason behind pancytopenia. Pleuritis, pulmonary fibrosis, episcleritis and Sjogren syndrome are often seen accompanying a severe neutropenia.
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.
A thorough physical examination is mandatory to locate any unreported signs by the patient.
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.
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.
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  . 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 .
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 .
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  .
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 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.