What other considerations should be included in the differential diagnosis?

Differential Diagnosis Considerations

When evaluating a patient with positive ANA (speckled pattern), elevated inflammatory markers, and musculoskeletal symptoms, you must systematically exclude infectious, malignant, and other autoimmune conditions before settling on a primary autoimmune diagnosis. 1

Critical Differential Diagnoses to Exclude

Infectious Etiologies

• Infectious osteomyelitis should be considered if the patient has systemic symptoms such as fever and chills, a presumable port of entry, solitary bone lesion, significantly elevated CRP or ESR, or bacteremia 2
• Tickborne rickettsial diseases (RMSF, ehrlichiosis, anaplasmosis) can present with fever, thrombocytopenia, leukopenia, and nonspecific symptoms that may mimic autoimmune disease—query regarding tick exposure, outdoor activities, and pet illness 2
• Sepsis must be excluded in patients with worsening clinical condition, altered mental status, and abnormal blood counts 2

Malignant Conditions

• Malignant bone tumors warrant consideration with unexplained weight loss, solitary bone lesion with rapid growth, cortical destruction, or perpendicular periosteal new bone formation on imaging 2
• Metastatic disease to liver or bone should be excluded through immunohistochemical panels (CK7, CK20, CDX2/SATB2, TTF1, and GATA3 in women) if imaging reveals suspicious lesions 2

Other Autoimmune and Inflammatory Conditions

Spondyloarthropathies

• Psoriatic arthritis should be considered with psoriasis (current, history, or family history in first-degree relatives), inflammatory articular disease, nail dystrophy, dactylitis, or juxta-articular new bone formation on hand or foot radiography 2
• Axial spondyloarthritis is suggested by inflammatory back pain, sacroiliitis, asymmetrical inflammatory arthritis, enthesitis, dactylitis, uveitis, inflammatory bowel disease, pain responsive to NSAIDs, family history, or HLA-B27 positivity 2

Rheumatoid Arthritis

• Rheumatoid arthritis remains in the differential despite negative anti-CCP, particularly with symmetrical polyarthritis of small joints, characteristic erosions, RF positivity, and elevated inflammatory markers 2

Inflammatory Myopathies

• Inflammatory myositis must be excluded through manual muscle testing of proximal, distal, and axial muscle groups, checking for true muscle weakness (not pain-limited movement), measuring CK, aldolase, AST/ALT, and LDH, and examining for dermatomyositis skin manifestations 3
• Immune checkpoint inhibitor-related myositis should be considered if the patient has any history of cancer treatment with immunotherapy 2, 3

Other Connective Tissue Diseases

• Sjögren's syndrome is compatible with speckled ANA pattern—assess for sicca symptoms (dry eyes, dry mouth), parotid gland enlargement, and consider anti-SSA/SSB antibodies 1
• Mixed Connective Tissue Disease presents with speckled ANA and overlapping features of multiple autoimmune conditions—consider anti-U1-RNP antibodies 1
• Undifferentiated Connective Tissue Disease often presents with positive ANA and nonspecific symptoms that don't meet criteria for specific autoimmune diagnoses 1

Metabolic and Degenerative Conditions

• Paget's disease should be considered with family history, pelvic or skull localization, raised alkaline phosphatase, deformities, characteristically mixed osteolytic and osteosclerotic appearance on imaging, and age of onset usually >50 years 2
• Osteomalacia presents with generalized bone pain and muscle weakness, low serum phosphate, elevated alkaline phosphatase, low 25-hydroxy-vitamin D, increased parathyroid hormone, and bone demineralization on imaging 2
• Osteoarthritis is suggested by older age at onset, history of strain or occurrence at dominant side, bony swelling, subchondral sclerosis or cysts, characteristic osteophytes, and joint space narrowing on imaging 2

Inflammatory Bowel Disease-Related Manifestations

• Inflammatory bowel disease with extraintestinal manifestations can present with arthritis and elevated inflammatory markers—consider if patient has gastrointestinal symptoms, and exclude infectious colitis, solitary rectal ulcer, psoriatic colitis, or chemical colitis 2

Factitious Disorders

• Factitious disorders should be considered as a differential diagnosis when patients present with variegated symptom presentations, self-inflicted injuries, unusual and protracted recoveries, frequent changes of treating physician, or symptoms that don't follow typical disease patterns 4

Key Clinical Pitfalls to Avoid

• Do not attribute all symptoms to a single diagnosis—overlapping conditions are common in autoimmune disease 1
• Do not delay rheumatology referral while waiting for additional test results, as early diagnosis and treatment of autoimmune conditions improves outcomes 1
• Recognize that normal CRP with elevated ESR can occur in certain autoimmune conditions and should not exclude inflammatory disease 1
• Consider temporal arteritis if patient has headache or visual disturbances—this requires urgent evaluation and potential temporal artery biopsy 2
• Failing to recognize cardiac involvement in myositis can be fatal—check for elevated cardiac biomarkers, abnormal ECG, or cardiac MRI findings 3