In a patient with a negative anti‑neutrophil cytoplasmic antibody (ANCA) screen, undetectable myeloperoxidase (MPO) and proteinase‑3 (PR3) antibodies, and markedly elevated anti‑Saccharomyces cerevisiae IgA (27 U/mL) and IgG (81 U/mL) antibodies, what is the most appropriate next diagnostic and therapeutic step?

Diagnostic Interpretation: Elevated Anti-Saccharomyces cerevisiae Antibodies with Negative ANCA

These laboratory results indicate inflammatory bowel disease (IBD), specifically Crohn's disease, not ANCA-associated vasculitis, and the next step is gastroenterology referral for colonoscopy with ileoscopy and biopsy to confirm the diagnosis.

Laboratory Result Interpretation

ANCA-Associated Vasculitis is Excluded

• The negative ANCA screen with undetectable MPO (<1) and PR3 (<1) antibodies effectively rules out ANCA-associated vasculitis (AAV) as the primary diagnosis 1
• High-quality antigen-specific immunoassays for both MPO-ANCA and PR3-ANCA are the recommended primary screening method, and both are negative in this case 1, 2
• While approximately 10% of true AAV patients can be ANCA-negative, this occurs primarily in limited respiratory tract disease or renal-limited vasculitis, not in the absence of clinical vasculitis symptoms 1, 2
• The combination of negative ANCA by both screening and antigen-specific testing makes AAV highly unlikely unless there is compelling clinical evidence of small-vessel vasculitis 1

Anti-Saccharomyces cerevisiae Antibodies Point to Crohn's Disease

• Markedly elevated ASCA IgA (27 U/mL, normal <20) and ASCA IgG (81 U/mL, normal <20) are highly suggestive of Crohn's disease, where ASCA positivity reaches 70% 3
• ASCA antibodies are a well-established serological marker specifically for Crohn's disease, not ulcerative colitis 3
• The dual positivity of both IgA and IgG ASCA increases diagnostic specificity for Crohn's disease 3

Alternative Diagnoses with ASCA Positivity

• Primary sclerosing cholangitis (PSC) shows 53% ASCA prevalence, but this typically occurs with concomitant IBD 3
• AMA-negative primary biliary cirrhosis demonstrates 44% ASCA prevalence, though this is associated with elevated serum IgA levels 3
• ASCA in autoimmune liver disease correlates with enhanced mucosal immunity but is not a primary diagnostic marker 3

Recommended Diagnostic Workup

Immediate Next Steps

• Refer to gastroenterology for colonoscopy with ileoscopy and mucosal biopsies to confirm Crohn's disease, looking specifically for skip lesions, transmural inflammation, and non-caseating granulomas 3
• Obtain inflammatory markers (ESR, CRP) to assess disease activity 4
• Check complete blood count for anemia and thrombocytosis commonly seen in active IBD 3
• Assess nutritional status including albumin, vitamin B12, folate, and vitamin D levels 3

Additional Serological Testing if Needed

• Consider perinuclear ANCA (p-ANCA) testing, which can be positive in 50-70% of ulcerative colitis cases but is less specific and not diagnostic 3
• Fecal calprotectin can help differentiate IBD from irritable bowel syndrome if the diagnosis remains uncertain 3

Clinical Correlation Required

Symptoms Suggesting Crohn's Disease

• Chronic diarrhea (often with blood or mucus), abdominal pain (particularly right lower quadrant), weight loss, and perianal disease 3
• Extraintestinal manifestations including arthritis, uveitis, erythema nodosum, or pyoderma gangrenosum 3
• Oral aphthous ulcers and perianal fistulas or abscesses 3

Symptoms That Would Suggest Vasculitis Despite Negative ANCA

• Pulmonary-renal syndrome with alveolar hemorrhage, rapidly progressive glomerulonephritis with red cell casts, or mononeuritis multiplex would warrant tissue biopsy even with negative ANCA 1, 2
• Systemic vasculitis symptoms including palpable purpura, necrotizing skin lesions, or deep-seated facial pain with nasal crusting would require further vasculitis evaluation 1

Critical Pitfall to Avoid

• Do not pursue ANCA-associated vasculitis workup or initiate immunosuppressive therapy for vasculitis based solely on these laboratory results without clinical evidence of small-vessel vasculitis 1
• The presence of ASCA antibodies in the absence of ANCA positivity and vasculitis symptoms should redirect the diagnostic focus toward inflammatory bowel disease, not vasculitis 3
• Approximately 60% of patients with positive ANCA testing do not have vasculitis, particularly with low-medium titers, but this patient has negative ANCA, making vasculitis even less likely 5