Introduction 

Felty syndrome (FS) is a sub-category, also known as an extra-articular manifestation, of rheumatoid arthritis (RA) first described as early as 1924 by its namesake, August Felty. Though rare, it is severe and is defined by three conditions experienced simultaneously, RA, neutropenia, and splenomegaly.

• RA is a long-term condition characterised by swelling, stiffness, and joint pain
• Neutropenia is a condition where a person's white blood cell count is lower than it should be, resulting in a weakened immune system
• Splenomegaly refers to when a person's spleen becomes enlarged and can be symptomatic of a broad range of other underlying conditions

Although FS is well-defined, its rarity and the intricacy in which its clinical presentations can manifest means it is still poorly understood. There is a large variance in the long-term outcomes of FS, as severity, treatment response, and associated complications, can differ significantly between patients. 

Below, this article will discuss the prognosis and long-term outcomes for patients diagnosed with FS.

Epidemiology and pathophysiology 

Epidemiology and pathophysiology simply refer to how common a disease is within a population and why, and the underlying reasons behind why a disease occurs within the body, respectively. 

FS is a rare disease, only appearing to affect 1-3% of patients with RA, and with the continued development of RA treatment, the prevalence of FS is declining. FS typically develops, on average, approximately 16 years after the initial onset of RA and is 3 times more likely to occur in those assigned female at birth (AFAB) than those assigned male at birth (AMAB).^1,2

Unfortunately, the pathophysiology is not clear, though the neutropenia is thought to be linked to defects in immune-mediated mechanisms, leading to inhibited neutrophil survival and proliferation.^1,3

Symptoms and diagnosis

The symptoms of RA will also be present in FS, therefore, patients may experience swelling, pain and stiffness in their joints, as well as more general symptoms, such as fatigue and weight loss. As neutropenia affects the immune system, patients may experience recurring infections, though it can also present asymptomatically (without symptoms). 

Diagnosis is generally confirmed by laboratory-based tests. Blood tests can reveal low neutrophil counts and the presence of rheumatoid factor (RF), which are indicators of FS.⁴ Additionally, imaging studies can reveal splenomegaly and joint conditions. 

One thing to be aware of is that large granular lymphocytic (LGL) leukaemia, sometimes referred to as “pseudo-Felty syndrome”, is a condition that presents similarly to FS, and thus it can be difficult for healthcare professionals to distinguish the two when seeking a diagnosis.¹ However, bone marrow biopsies can be useful in ruling out LGL leukaemia.⁴

Prognosis 

The prognosis can vary depending on the severity of the neutropenia, the response to treatment, and any complications that may arise. However, the severity of RA has improved with the introduction of disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, as a treatment option.² DMARDs are a class of drugs designed to treat inflammatory diseases, such as RA.

A five-year mortality rate of 36% has previously been reported, though this was before the advent of methotrexate.⁵ Unfortunately, more recent data is lacking regarding the prognosis of FS, though it can be said to have improved significantly thanks to the advanced treatment options now available.¹

Long-term outcomes

Due to complications from RA, and infections as a result of a weakened immune system due to neutropenia, the historical outcomes for FS were associated with high morbidity and mortality. Thankfully, outcomes have improved due to advances in treatment. However, long-term outcomes can still vary significantly, as the severity of the disease differs between patients, as does the response to treatment. 

Infection risk and management

A leading cause of morbidity and mortality in patients with FS is bacterial infection, the respiratory tract and skin can be especially vulnerable. Neutropenia is a condition that compromises your immune system, exposing patients to an increased risk of fatal infection, and the severity of potential infections correlates with the severity of neutropenia. Antibiotics can be used to treat infections as they arise, but careful monitoring and early intervention, as well as preventative actions, are crucial in the prevention, or subsequent management, of infection.¹ 

Response to treatment

The advent of DMARDs, such as methotrexate, has proven to be revolutionary and significantly improved the outcomes for patients with FS. Methotrexate in particular, though often used in conjunction with other DMARDs, is fundamental in the treatment FS. 

Biologic agents, (Biologics refer to a large class of medical drugs) such as rituximab, have demonstrated long-term efficacy in improving neutrophil count and neutropenia without the compromise of severe adverse side effects.⁶ 

Patients who respond well to the treatment options and are able to attain remission or reach low levels of disease, and thus have a lower risk of infection or other complications, commonly have a higher chance of a better long-term prognosis. 

Complications and comorbidities

As well as the risk of infection, patients can, unfortunately, develop other complications that affect their long-term outcomes. Immunocompromised patients are at risk of comorbidities, such as lymphoproliferative disorder.⁷ Patients with RA are also associated with a higher risk of osteoporosis and cardiovascular disease.^8,9 Prevention and management of complications and comorbidities require thorough and regular screening to ensure the optimisation of patient outcomes.

Survival rates

Infections and other complications are complicit in the historically low survival rates of FS. Although modern therapeutic approaches, including methotrexate, other DMARDs, and biologics, have contributed to decreasing the severity of extra-articular manifestations of RA, such as FS, an exact survival rate cannot be determined due to a lack of recent data.¹ Prior to the introduction of methotrexate, a 5-year survival rate was reported to be as low as 36%, though this will have improved.^1,5

Quality of life

There is evidence to suggest that there is no statistically significant difference in quality of life between patients with RA and an otherwise healthy population. Despite this, it does seem clear that increased levels of pain associated with RA and FS are associated with a decreased ability to participate in social activity, negative feelings regarding a person's own perception of their health, and a generally lesser ability to function physically.¹⁰

Unfortunately, the condition is chronic, which can have a significant negative psychological impact on patients. Effective management of RA symptoms, neutropenia, and any complications or comorbidities is essential in maintaining a patient's quality of life. Quality of life support should be approached holistically, emphasising physical rehabilitation and psychological and mental health support, as well as direct treatment of the disease. 

Future directions and research

There is continued ongoing research into FS, with an emphasis on uncovering the mechanisms behind the pathophysiology of the disease, improved criteria for effective diagnosis, and continued therapeutic advancements. 

New biologic agents are continually being developed and the role they could play in treatment is investigated. Other approaches include analysing potential disease susceptibility, and subsequent prognosis is being explored via genetic studies looking for biomarkers that may indicate a predisposition for the disease. 

Furthermore, there is research examining the long-term safety and efficacy of current treatment options.

Summary

Although Felty syndrome is rare, it is a severe extra-articular manifestation, or sub-category, of rheumatoid arthritis, characterised by rheumatoid arthritis, neutropenia, and splenomegaly. The implications of the disease regarding prognosis and long-term outcomes are, unfortunately, significant. 

With the advent of modern therapeutic therapies such as disease-modifying antirheumatic drugs, e.g. methotrexate, and biologic agents, prognosis and long-term outcomes have improved markedly. Still, there are many challenges to be faced; infections due to the immunocompromising effects of neutropenia remain a serious contributor to mortality in patients with Felty syndrome. The disease is also associated with complications and comorbidities, such as cardiovascular disease and osteoporosis.

The quality of life of patients with Felty’ syndrome can become compromised; the pain associated with Rheumatoid arthritis can impact a patient's physical functionality, and subsequent ability to participate in social events. The risk of infection due to immunocompromisation can weigh heavily on a patient's psyche, and in the event of infection, can also negatively affect quality of life. 

Continuing ongoing research, and taking a holistic approach to managing the disease, is crucial to improving positive outcomes and maintaining the quality of life for patients with Felty syndrome.