What is the differential diagnosis for extreme fatigue in a 24-year-old female with Crohn's disease treated with Skyrizi (Risankizumab) and hereditary angioedema?

Differential Diagnosis for Extreme Fatigue in a 24-Year-Old Female with Crohn's Disease on Skyrizi and Hereditary Angioedema

The differential diagnosis must prioritize Crohn's disease-related causes first, as fatigue affects 40-72% of IBD patients and is multifactorial, followed by medication effects, hereditary angioedema complications, and systemic causes common in young women. 1

Primary IBD-Related Causes

Active or Subclinical Crohn's Disease

• Subclinical inflammation remains the leading cause, as 30-50% of patients with inactive Crohn's disease still experience fatigue, and disease activity is a strong predictor of fatigue severity 1
• Check inflammatory markers (CRP, ESR) and fecal calprotectin to assess for subclinical disease activity, as raised inflammatory markers without bowel symptoms are reversible causes of fatigue 1, 2
• Consider imaging (CT/MR enterography) if inflammatory markers are elevated to assess bowel wall edema and disease extent 3

Nutritional Deficiencies from Malabsorption

• Iron deficiency with or without anemia is the most common and easily correctable cause—check complete blood count, serum ferritin, serum iron, and transferrin saturation 1, 2
• Vitamin B12 deficiency occurs frequently in Crohn's disease due to terminal ileal involvement or resection—measure serum B12 levels 1, 2
• Vitamin D deficiency correlates with muscle fatigue and self-reported fatigue in Crohn's disease patients—measure 25-OH vitamin D levels 1, 2
• Consider magnesium and IGF-1 levels, as low serum levels have been linked to muscle fatigue in Crohn's disease 1

Anemia from Chronic Blood Loss

• One-third of IBD patients suffer from recurrent anemia, which significantly contributes to fatigue 1
• Obtain hemoglobin and mean corpuscular volume (MCV) to guide further workup 2, 4
• Critical pitfall: Ferritin is an acute phase reactant and may be falsely normal or elevated despite true iron deficiency when CRP is elevated—do not rely on ferritin alone in the presence of inflammation 2

Medication-Related Causes

Skyrizi (Risankizumab) Effects

• Fatigue is a documented adverse reaction occurring in 2.5% of patients on Skyrizi versus 1.0% on placebo in psoriasis trials 5
• In Crohn's disease trials, subjects treated with Skyrizi experienced clinically meaningful improvement in fatigue (assessed by FACIT-F score) at Week 12, suggesting the medication typically reduces rather than causes fatigue 5
• However, individual responses vary—consider temporal relationship between Skyrizi initiation and fatigue onset 5

Polypharmacy and Drug Interactions

• Review all current medications including over-the-counter agents, supplements, and herbal products for fatigue-inducing effects 3
• Female gender and polypharmacy, particularly with neuropsychiatric drugs, are risk factors for medication-related fatigue in IBD 1

Hereditary Angioedema-Related Causes

HAE Disease Burden

• HAE itself causes substantial disease burden with unpredictable attacks that create cycles of stress, anxiety, and depression—all of which trigger further attacks and contribute to fatigue 6
• Patients with HAE experience continual emotional impairment and reduced quality of life between attacks despite full physical recovery 6
• Absenteeism and presenteeism increase stress and reduce productivity, compounding fatigue 6

HAE Medication Effects

• Review current HAE prophylactic medications for fatigue as a side effect 6

Psychological and Sleep-Related Causes

Depression and Anxiety

• Depression and anxiety are highly prevalent in IBD and are associated with fatigue, poor sleep quality, and poor health-related quality of life 1
• Fatigue and depression follow similar patterns in Crohn's disease, though they may not correlate directly with disease activity 7
• Screen using validated instruments, as these are leading causes of persistent fatigue 3

Sleep Disturbances

• Sleep disturbances are common in IBD and correlate strongly with fatigue severity in both active and inactive disease 1, 3
• Assess sleep quality using the Pittsburgh Sleep Quality Index (PSQI) 3
• Altered sleep patterns are significant predictors of chronic fatigue in IBD 4

Systemic Causes Common in Young Women

Thyroid Dysfunction

• Hypothyroidism is a common reversible cause of fatigue in young women—measure TSH and free T4 2, 3

Other Metabolic Disorders

• Obtain comprehensive metabolic panel including glucose, electrolytes, kidney function, and liver function tests 2

Chronic Fatigue Syndrome

• Consider if fatigue is debilitating, persistent for >6 months, not relieved by rest, and accompanied by myalgias, arthralgias, or postexertional malaise 8
• Diagnosis is primarily by exclusion with no definitive laboratory test 8

Recommended Diagnostic Algorithm

Initial Laboratory Assessment

1. Complete blood count with differential to assess for anemia 2, 4
2. Iron studies (serum ferritin, serum iron, transferrin saturation) 2
3. Inflammatory markers (CRP, ESR) to identify subclinical Crohn's activity 1, 2
4. Vitamin B12 and folate levels 2
5. 25-OH vitamin D level 1, 2
6. Thyroid function tests (TSH, free T4) 2, 3
7. Comprehensive metabolic panel 2

Extended Evaluation if Initial Workup Unrevealing

1. Fecal calprotectin to assess intestinal inflammation 1
2. Magnesium, zinc, copper, vitamin B6 levels 3
3. Sleep quality assessment using validated scales 3
4. Depression and anxiety screening using validated instruments 3
5. Formal fatigue quantification using visual analogue scale (0-10) or FACIT-F questionnaire 3

Imaging Considerations

• CT/MR enterography if inflammatory markers elevated or symptoms suggest active disease 3
• Abdominal imaging during attacks if gastrointestinal symptoms predominate, to evaluate for bowel wall edema 3

Critical Pitfalls to Avoid

• Do not attribute persistent fatigue to stress or depression without completing objective laboratory assessment first, as multiple reversible physiologic causes must be excluded 2
• Do not rely on ferritin alone when CRP is elevated, as it may be falsely normal despite true iron deficiency 2
• Do not assume fatigue correlates with disease activity—fatigue remains very common in patients with inactive Crohn's disease 1
• Do not pursue extensive imaging or invasive testing without specific clinical indicators beyond fatigue alone 3
• Recognize that fatigue severity does not correlate with disease activity markers in many conditions, so normal objective tests do not exclude significant pathology 3

Management Considerations Based on Findings

If Nutritional Deficiencies Identified

• Treat iron deficiency and anemia with appropriate supplementation—vitamin B12 and iron therapy are easily administered treatments 1, 3
• Supplement vitamin D if deficient 1, 2
• Repeat basic blood tests after 8-10 weeks if iron supplementation initiated, as ferritin levels may be falsely elevated immediately after iron infusion 2

If Subclinical Inflammation Present

• Optimize Crohn's disease therapy to achieve deeper remission, as anti-TNF therapy has been shown to reduce symptoms of fatigue 1

If Psychological Factors Identified

• Initiate psychological interventions including cognitive behavioral therapy or mindfulness-based programs, which show benefit for persistent fatigue 3
• Address sleep disturbances with cognitive behavioral therapy, which is first-line treatment for insomnia 3

Non-Pharmacological Interventions

• Recommend graded exercise programs, which have demonstrated positive effects on physical fatigue in IBD 1, 3
• Consider solution-focused therapy, which showed reduction in fatigue for up to 3 months in quiescent IBD 1