What is the likely diagnosis for an adult patient with a history of autoimmune or rheumatological disorders, presenting with polyarthritis, anemia, elevated Lactate Dehydrogenase (LDH) levels, and a positive anti-centromere antibody test?

Diagnosis: Limited Cutaneous Systemic Sclerosis (lcSSc) with Possible Overlap Syndrome

The combination of positive anti-centromere antibody, polyarthritis, anemia, and elevated LDH most strongly suggests limited cutaneous systemic sclerosis (lcSSc), potentially with an overlap syndrome involving rheumatoid arthritis or another connective tissue disease. 1, 2

Primary Diagnostic Considerations

Limited Cutaneous Systemic Sclerosis (Most Likely)

• Anti-centromere antibodies (ACA) are the hallmark serologic marker of lcSSc, occurring in 50-80% of cases and generally indicating a better prognosis compared to diffuse cutaneous systemic sclerosis 1, 2, 3
• The presence of polyarthritis in this context is consistent with the "15% rule" where approximately 1 in 6 patients with systemic sclerosis have inflammatory arthritis 1
• Anemia is a common systemic manifestation of connective tissue diseases, including systemic sclerosis 1
• Elevated LDH can reflect tissue damage and cellular turnover associated with systemic sclerosis, particularly with organ involvement 1

Overlap Syndromes (Important Differential)

• 3% of systemic sclerosis cases overlap with rheumatoid arthritis, and the concurrence of RA with lcSSc has been well-documented 1, 4
• When inflammatory arthritis is present in a patient with positive ACA, testing for rheumatoid factor and anti-citrullinated peptide antibody should be performed 1
• Systemic sclerosis can overlap with other connective tissue diseases including SLE, dermatomyositis, polymyositis, and Sjögren syndrome 1

Essential Immediate Workup

Autoantibody Panel

• Complete extractable nuclear antibody (ENA) panel including anti-Sm, anti-RNP, anti-SSA/Ro, anti-SSB/La, anti-Scl-70 (topoisomerase-1), and anti-Jo-1 to identify potential overlap syndromes 1
• Rheumatoid factor and anti-citrullinated peptide antibody to evaluate for RA overlap 1
• Anti-dsDNA and complement levels (C3, C4) if SLE overlap is suspected 1

Organ-Specific Screening

• High-resolution CT of the chest to screen for interstitial lung disease (ILD), as patients with systemic sclerosis are at high risk, particularly those with anti-topoisomerase-1 antibodies 1
• Pulmonary function tests including DLCO to establish baseline respiratory function 1
• Echocardiography, NT-proBNP, and 6-minute walking distance to screen for pulmonary arterial hypertension (PAH), which is a serious late complication in ACA-positive patients with longer disease duration 1, 2
• Liver function tests including alkaline phosphatase, as primary biliary cholangitis occurs in 8% of lcSSc cases, usually in those positive for anti-centromere antibodies 1, 2

Additional Laboratory Studies

• Complete blood count to characterize the anemia (hemolytic vs. anemia of chronic disease) 1
• Comprehensive metabolic panel including renal function 1
• Thyroid function tests, as autoimmune thyroid disease is the most common concurrent autoimmune condition with systemic sclerosis 1
• Direct Coombs test if hemolytic anemia is suspected 1

Critical Clinical Features to Assess

Systemic Sclerosis Manifestations

• Raynaud's phenomenon (present in virtually all lcSSc patients) 1, 2
• Skin thickening limited to distal extremities (hands, forearms, feet, legs, face) 1
• Digital ulcers or pitting scars 1
• Telangiectasias 1, 2
• Esophageal dysmotility symptoms (dysphagia, reflux) 1, 2
• Calcinosis 1

Arthritis Characteristics

• Distribution and pattern of joint involvement (symmetric small joint involvement suggests RA overlap) 1, 4
• Presence of joint erosions on imaging 1
• Morning stiffness duration 1

Management Priorities

Immediate Interventions

• Establish regular blood pressure monitoring (home and clinic) to screen for scleroderma renal crisis, particularly in early disease 1, 2
• Initiate proton pump inhibitors if esophageal symptoms are present 2
• Consider hydroxychloroquine if overlap features are present 5

Multidisciplinary Referrals

• Immediate rheumatology referral for disease-modifying therapy and comprehensive management 1, 2
• Pulmonology consultation if ILD is detected on screening 1
• Cardiology evaluation if PAH screening is abnormal 1, 2
• Hepatology referral if liver function tests suggest primary biliary cholangitis 1, 2

Important Caveats and Pitfalls

Diagnostic Considerations

• Anti-centromere antibodies are not 100% specific for CREST/lcSSc—they can occur in other conditions including seronegative polyarthritis, SLE with digital vasculitis, and Raynaud's phenomenon alone 6, 7
• Only 16.4% of ACA-positive patients carry a clinical diagnosis of CREST syndrome, meaning ACA presence mandates thorough evaluation for the full spectrum of systemic sclerosis and related conditions 7
• Anti-Scl-70 and anti-centromere antibodies are mutually exclusive and represent two distinct forms of scleroderma with different courses and prognoses 8

Monitoring Strategy

• Screen for depression, which is elevated in patients with chronic diseases including systemic sclerosis 1, 2
• Perform bone density scanning, as osteoporosis is increased in systemic sclerosis 1, 2
• Monitor for nutritional deficiencies if malabsorption develops from gastrointestinal involvement 1, 2
• Address cardiovascular risk factors including hypertension, diabetes, hyperlipidemia, and smoking cessation 1, 2

Malignancy Screening

• Anti-RNA polymerase III antibodies (not anti-centromere) increase malignancy risk, but age-appropriate cancer screening should still be performed as per local guidelines 1