What are the likely causes of persistent fatigue, unintentional weight loss, and diffuse muscle aches that worsen at rest and improve with movement in an adult?

Differential Diagnosis: Persistent Fatigue, Weight Loss, and Muscle Pain Worse at Rest

The pattern of muscle pain that improves with activity and worsens at rest, combined with persistent fatigue and weight loss, strongly suggests inflammatory arthropathy (particularly axial spondyloarthropathy) or inflammatory bowel disease-related arthropathy, though malignancy, chronic inflammatory conditions, and metabolic disorders must be systematically excluded.

Key Diagnostic Features

The distinctive characteristic here is muscle/joint pain that paradoxically improves with movement and worsens with rest—this is pathognomonic for inflammatory arthropathy rather than mechanical or degenerative conditions 1.

Primary Considerations

Axial Spondyloarthropathy:

• Low back pain in adults under 45 years lasting more than 3 months that improves with exercise and is not relieved by rest is highly suggestive 1
• Pain worse in the latter part of the night with morning stiffness lasting more than 30 minutes 1
• This pattern warrants MRI scanning (sagittal images of cervicothoracic and thoracolumbar regions with T1 and STIR sequences, plus coronal/oblique sacroiliac joints) 1
• HLA-B27 testing, though less frequently positive in IBD-associated cases 1

Inflammatory Bowel Disease (IBD) with Extraintestinal Manifestations:

• Type 1 peripheral arthropathy affects fewer than five joints, often asymmetric, mainly weight-bearing lower limb joints 1
• Type 2 arthropathy involves more than five joints with symmetrical distribution, mainly upper limbs, and is independent of gut inflammation 1
• Associated systemic symptoms include fatigue and unintentional weight loss 1

Essential Workup

When Extensive Evaluation is Warranted

Moderate to severe fatigue with unintentional weight loss mandates comprehensive evaluation to exclude malignancy and other serious conditions 1, 2:

• Complete blood count to assess for anemia 1, 3
• Comprehensive metabolic panel 1
• Thyroid function tests (TSH, free T4) 1, 3
• Morning cortisol and ADTH to exclude adrenal insufficiency 1, 3
• Inflammatory markers (ESR, CRP) 1
• Iron studies, even if hemoglobin is normal 3
• Vitamin D and B12 levels 1, 3

Imaging Based on Clinical Suspicion

• MRI of spine and sacroiliac joints if axial spondyloarthropathy suspected 1
• Chest imaging and age-appropriate cancer screening given weight loss 1
• Colonoscopy if IBD suspected based on gastrointestinal symptoms 1

Additional Differential Considerations

Cachexia and Sarcopenia:

• Cachexia involves involuntary weight loss with ongoing skeletal muscle mass loss, associated with cancer, chronic heart failure, COPD, IBD, and chronic kidney disease 2
• Diagnostic criteria include weight loss >5% alone, or >2% if BMI <20 kg/m² or reduced muscle mass 2

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis:

• Post-exertional malaise is characteristic, where symptoms worsen after physical or cognitive exertion 4
• However, the improvement with activity described in this case argues against this diagnosis 4

Polymyalgia Rheumatica (in older adults):

• Bilateral shoulder and hip girdle pain and stiffness
• Typically worse in morning but improves throughout the day with movement
• Elevated inflammatory markers
• Dramatic response to low-dose corticosteroids

Critical Red Flags

The combination of unintentional weight loss with other symptoms demands urgent evaluation for metastatic disease or serious comorbidities 1:

• Weight loss >5% of body weight over 6 months 2
• Fatigue beginning after or worsening during the 6-12 month post-treatment period (if cancer history) 1
• Pain, pulmonary complaints, or other organ-specific symptoms 1

Management Approach

Immediate priorities:

1. Complete the diagnostic workup outlined above to identify treatable causes 3
2. Refer to rheumatology if inflammatory arthropathy suspected, as early diagnosis prevents long-term disability 1
3. Address pain with simple analgesia initially; NSAIDs are more effective but should be used cautiously 1

For inflammatory arthropathy:

• Control of intestinal inflammation (if IBD-related) through physiotherapy and simple analgesia 1
• Sulfasalazine, methotrexate, or anti-TNF therapy may be required for persistent symptoms 1
• NSAIDs can be used short-term if disease is in remission, but long-term use or use in active disease carries risk 1

Avoid these pitfalls:

• Do not dismiss the "better with activity" pattern as deconditioning—this is a hallmark of inflammatory conditions 1
• Do not delay rheumatology referral, as early intervention prevents irreversible disability in axial spondyloarthropathy 1
• Do not attribute all symptoms to fatigue without excluding malignancy when weight loss is present 1, 2