What is the pathophysiology of fatigue in sarcoidosis?

Pathophysiology of Fatigue in Sarcoidosis

Fatigue in sarcoidosis is a complex multifactorial symptom affecting up to 90% of patients, significantly impairing quality of life, and often persisting even after remission of active granulomatous inflammation. 1

Underlying Mechanisms

The pathophysiology of sarcoidosis-associated fatigue (SAF) involves several interconnected mechanisms:

Primary Disease-Related Factors

• Persistent granulomatous inflammation: Even when clinical disease appears inactive, ongoing low-grade inflammation may contribute to fatigue
• Cytokine dysregulation: Pro-inflammatory cytokines (particularly TNF-α) likely play a significant role, as evidenced by improvement in fatigue with anti-TNF-α therapies 2
• Small fiber neuropathy (SFN): Often co-occurs with fatigue and may share underlying mechanisms

Secondary Contributing Factors

• Pulmonary dysfunction: Reduced lung function and gas exchange can contribute to fatigue
• Respiratory muscle weakness: Documented in sarcoidosis patients with fatigue, as evidenced by improvement with inspiratory muscle training 1
• Sleep disturbances: May occur independently of sleep apnea 3
• Neurocognitive effects: Direct CNS involvement or indirect effects of inflammation on brain function

Comorbid Conditions

Before diagnosing SAF, several other causes of fatigue must be ruled out:

• Diabetes mellitus
• Thyroid dysfunction
• Neuroendocrine disorders
• Mental disorders (especially depression)
• Obstructive sleep apnea
• Vitamin D deficiency (especially low 1,25-dihydroxy-cholecalciferol)
• Heart failure
• Neurologic disease 1

Clinical Significance

Fatigue in sarcoidosis:

• Is reported in up to 90% of patients 1
• Strongly correlates with decreased quality of life 4
• Often persists for years, even after apparent remission of inflammation 1
• Shows poor agreement between physician and patient assessment, highlighting the importance of using validated patient-reported outcome measures 1

Treatment Implications

The complex pathophysiology explains why:

• First-line anti-inflammatory treatments often have limited effect on fatigue 2
• Multiple treatment approaches may be needed:
  • Physical rehabilitation/exercise programs address deconditioning and respiratory muscle weakness 1
  • Neurostimulants (D-methylphenidate, armodafinil) may help with central components 1, 3
  • Anti-TNF-α therapies may benefit patients with ongoing inflammation 2

Clinical Pitfalls

1. Misattribution: Physicians often underestimate the severity and impact of fatigue compared to patients' self-assessment 1
2. Incomplete evaluation: Failing to rule out other causes of fatigue before attributing to sarcoidosis
3. Overlooking fatigue: Focus on organ involvement may lead to neglecting this quality-of-life-impairing symptom
4. Treatment resistance: Fatigue may persist despite apparent disease control, requiring specific targeted interventions

Understanding the complex pathophysiology of sarcoidosis-associated fatigue is essential for developing effective management strategies that address both the inflammatory disease process and its secondary effects on multiple body systems.