What are the causes of fever in adult lupus patients? How is fever associated with systemic lupus erythematosus (SLE) disease activity? Explore the mechanisms behind fever in lupus and the clinical manifestations.

Understanding Fever in Lupus Patients

Fever is a common manifestation of systemic lupus erythematosus (SLE), occurring in 36-86% of adult lupus patients. The variability in SLE disease manifestations is well recognized, with lupus activity ranging from mild to severe. Fever in lupus patients can be attributed to various factors, including lupus disease activity, infection, malignancy, or drug-related causes.

Mechanisms of Fever in Lupus

Normal body temperature is regulated by the thermoregulatory center in the anterior hypothalamus. Prostaglandin E2 (PGE2) is thought to be the proximal mediator of the febrile response, with elevated levels in the hypothalamus triggering an increase in the set point. This activates neurons in the vasomotor center, leading to vasoconstriction and increased heat production in the periphery.

Pyrogenic cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor (TNF), interleukin-6 (IL-6), and interferons (IFN-α, IFN-β, IFN-γ), are produced by activated macrophages and monocytes, and act directly on the hypothalamus to induce fever. Interestingly, fever itself appears capable of countering the release of these pyrogenic cytokines, suggesting a feedback mechanism.

In lupus, patients often have enhanced serum levels of IFN-α, which correlate with anti-double stranded DNA (anti-dsDNA) production and disease activity. A close correlation between serum IFN-α (but not IL-1 or TNF-α) and fever has been observed in untreated SLE patients, suggesting the potential involvement of IFN-α in fever pathogenesis.

Clinical Manifestations of Fever in Lupus

Fever in active SLE without infection typically presents with a peak temperature ranging from 38°C to 40.6°C and an intermittent pattern. Fever may be the only presenting symptom of SLE, as seen in patients with fever of unknown origin (FUO), where up to 5% are eventually diagnosed with lupus.

The differential diagnosis for fevers in lupus is broad, including lupus disease activity, infection, malignancy, or drug-related causes. Distinguishing the cause of fever can be challenging, as the initial clinical presentation of a patient with lupus is very similar to the acute febrile phase of an infection.

Fever and Lupus Disease Activity

Fever is an important disease activity indicator in lupus and is taken into account in the Modified Systemic Lupus Erythematosus Disease Activity Index (M-SLEDAI). The reported prevalence of fever attributed to SLE has declined over time, potentially due to the frequent use of nonsteroidal anti-inflammatory drugs.

In a large Canadian study, fever was found to typically present early in the disease course of lupus and was more common in Caucasian patients. The attribution of fever to SLE, however, requires the exclusion of other possible causes, as the initial presentation can mimic an acute febrile infection.

Cytokines and Fever in Lupus

Various cytokines, such as IL-1, IL-6, IL-17, and interferons, are dysregulated in SLE and play a role in the fever pathogenesis. IL-1 initiates the recruitment of immune cells and inflammation, while increased IL-6 and IL-17 serum levels have been associated with elevated anti-DNA levels.

IFN-γ, as well as T-cell-derived cytokines like IL-21 and IL-2, are also dysregulated in SLE. IL-17 induces the secretion of proinflammatory proteins, creating a positive feedback loop that leads to further IL-17 production.

Fever Management in Lupus Patients

Proper management of fever in lupus patients requires a thorough assessment to determine the underlying cause, whether it is due to lupus disease activity, infection, malignancy, or drug-related factors. Appropriate treatment strategies, which may include antibiotic therapy, immunosuppressive medications, or adjustments to existing treatments, should be implemented to address the specific etiology of the fever.

Conclusion

Fever is a common and important manifestation of systemic lupus erythematosus, occurring in a significant proportion of adult lupus patients. Understanding the mechanisms underlying fever in lupus, the association with disease activity, and the differential diagnosis is crucial for the effective management of this challenging clinical presentation.