From the Guidelines
In a patient with fever, fatigue, myalgias, and a positive MPO antibody test despite an extensive negative workup, additional testing should focus on evaluating for ANCA-associated vasculitis, particularly microscopic polyangiitis (MPA). I recommend obtaining a comprehensive renal assessment including urinalysis with microscopy, urine protein-to-creatinine ratio, and serum creatinine to assess for glomerulonephritis, as suggested by the KDIGO 2024 clinical practice guideline for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis 1. Chest imaging with high-resolution CT is essential to evaluate for pulmonary involvement such as alveolar hemorrhage or interstitial lung disease. Complete blood count should be checked for anemia or leukocytosis, and inflammatory markers (ESR, CRP) should be measured. Tissue biopsy from an affected organ (typically kidney, lung, or skin) is the gold standard for diagnosis, as recommended by the EULAR recommendations for the management of primary small and medium vessel vasculitis 1. Additional autoimmune serologies including anti-GBM antibodies, ANA, and complement levels may help rule out overlapping conditions. Nerve conduction studies should be considered if there are neurological symptoms suggesting mononeuritis multiplex. These tests are crucial because MPO-ANCA positivity strongly suggests small vessel vasculitis, and early diagnosis allows for prompt initiation of immunosuppressive therapy to prevent organ damage, as these conditions can progress rapidly despite initially subtle presentations. It is also important to note that a positive biopsy is strongly supportive of vasculitis, and waiting for a kidney biopsy to be performed or reported should not delay starting immunosuppressive therapy, especially in patients who are rapidly deteriorating, as stated in the KDIGO 2024 guideline 1. The EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis also emphasize the importance of determining ANCA for classification of patients with medium-and small-vessel vasculitis in clinical trials 1. Overall, a comprehensive approach to diagnosis and management is necessary to improve outcomes in patients with ANCA-associated vasculitis.
From the Research
Additional Testing Considerations
In a patient with fever, fatigue, and myalgias, but no other findings after an extensive workup, and a positive Myeloperoxidase (MPO) antibody test, the following additional testing should be considered:
- Renal function tests and urinalysis to evaluate for potential renal involvement, as MPO-ANCA-associated glomerulonephritis can occur 2, 3, 4
- Immunofluorescence microscopy and electron microscopy to investigate the presence of immune complexes and electron-dense deposits in the glomerular basement membrane 2, 4
- Testing for other autoantibodies, such as IgG subclass, to determine the presence of secondary membranous nephropathy 2, 4
- Evaluation for gastrointestinal tract disorders, infections, and other connective tissue disorders, as these conditions can be associated with MPO-ANCA positivity 3
- Consideration of Schnitzler's syndrome, a rare clinical entity characterized by intermittent urticarial rash, fevers, arthralgias, myalgias, and monoclonal gammopathy, in the differential diagnosis of fever of unknown origin 5
- Assessment for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a chronic and potentially debilitating disorder, using the 2015 National Academy of Medicine diagnostic criteria 6
Key Findings to Guide Additional Testing
- The presence of MPO-ANCA positivity in patients without primary systemic vasculitis highlights the need for careful clinical correlation and confirmatory tissue diagnosis 3
- The coexistence of other types of glomerulonephritis, especially membranous nephropathy, should be considered in patients with MPO-ANCA-associated vasculitis 2, 4
- A comprehensive history, cardiopulmonary, neurologic, and skin examinations can help guide the workup and diagnosis of fatigue 6