Anti-neutrophil cytoplasmic autoantibody (ANCA) testing is useful for the early diagnosis of ANCA-associated vasculitis (AAV) in patients with central nervous system symptoms, allowing for timely treatment and a better prognosis, but a positive ANCA test could also mean several things besides vasculitis, a review study reports.
About 5-15 percent of AAV patients have several central nervous system-related symptoms, which usually are a sign of long-established disease and considered an alarming manifestation. However, the diversity of neurological symptoms poses a diagnostic challenge for physicians, delaying treatment and contributing to disease progression, or even death.
Investigators from the Zhejiang University in China have now summarized the current evidence on central nervous system involvement in AAV, including what is known about the disease mechanism, clinical presentation, auxiliary testing, differential diagnosis, and treatment.
The review study, “Central Nervous System Involvement in ANCA-Associated Vasculitis: What Neurologists Need to Know,” was published in Frontiers in Neurology.
Caused by the excessive production of ANCAs, AAV is characterized by inflammation of the small blood vessels in the nose, sinuses, throat, lungs, and kidneys. The inflammatory process can also affect nerves, skin, and joints. When AAV is suspected, a thorough examination of systemic symptoms should be performed.
“Timely recognition and diagnosis of AAV is important, since the progressive disease can be dramatically mitigated by prompt use with steroid and other immunosuppressive agents,” the investigators wrote.
AAV patients may experience headaches, ischemic infarction, intracranial bleeding, seizures, neuropsychiatric disorders, confusion, and altered consciousness. Cognitive decline has also been reported in 30 percent of cases.
Nonetheless, the most common central nervous system manifestation is localized inflammatory thickening of the dura mater — the protective outer layer that surrounds the brain and spinal cord — detected by brain magnetic resonance imaging (MRI) and computed tomography (CT).
There are different types of ANCAs, the most frequent being antibodies against the proteinase-3 (PR3) or the myeloperoxidase (MPO) proteins. Studies suggest that ANCA subtypes influence the pattern and severity of central nervous system involvement. PR3-ANCA has been linked to more severe damage and disease progression, while MPO-ANCA seems to be related more to limited disease development.
Diagnosis of AAV must be based on clinical, blood, radiographic, and pathological evidence. Exams include MPO- and PR3-ANCA testing, complete blood count, autoimmune plus endocrine-related molecular analysis, brain imaging, and biopsy.
“In patients with established AAV, new-onset neurologic deficits with abnormal radiological and cerebrospinal fluid (CSF) findings are suggestive of [central nervous system] involvement,” the team noted. CSF is the liquid that surrounds and protects the brain and the spinal cord.
Although positive ANCA testing is indicative of vasculitis, further examination is required for an accurate diagnosis.
Likewise, a negative ANCA test does not mean there is no vasculitis because the negative laboratory result might be due to the test’s limited sensitivity, common in the early stage of disease without generalized organ damage. For these cases, experts recommend a biopsy of the affected organ.
“Overall, current thinking holds that ANCA levels alone are helpful but not sufficient to determine relapse or reflect disease activity, and ANCA testing is not recommended to guide clinical decisions on treatment,” the researchers said.
The gold standard for AAV diagnosis is tissue analysis, typically using samples from kidney and skin. Nonetheless, a negative biopsy does not exclude AAV, since disease-related lesions are not evenly distributed throughout the organ.
Doctors must also be aware of ANCA-positive conditions with neurological manifestations where ANCA does not play a direct role in disease mechanism. Some of these conditions include rheumatoid arthritis, systemic lupus erythematosus, Behçet syndrome, tuberculosis, human immunodeficiency virus, and lymphoma.
AAV treatment consists of two phases: remission induction and remission maintenance, depending on the disease stage. The remission-induction regimen includes high-dose glucocorticoids and cyclophosphamide.
About eight to 12 weeks after starting treatment, patients typically go into remission, meaning they are free of disease activity. Once remission is reached, maintenance treatment — low-dose glucocorticoids and an oral immunosuppressive agent such as azathioprine, methotrexate, mycophenolate mofetil, or Rituxan (rituximab) — should be started and continued for at least 24 months to prevent further relapses.
In patients who are unresponsive to treatment, experts should perform clinical reassessment and therapy optimization.
“Continued attempts are needed to validate the utility of ANCA specificity in classifying [central nervous system] manifestations, guiding treatment decisions, and predicting prognosis,” the researchers concluded.