Novel Use of Biomarkers Proposed for Rheumatoid Meningitis Diagnosis

The presence of anticyclic citrullinated peptide (anti-CCP), immunoglobulin M rheumatic factor (IgM RF), and chemokine ligand 13 (CXCL-13) in cerebrospinal fluid (CSF) are potential biomarkers that can be used to diagnose rheumatoid meningitis, a rare extra-articular manifestation of rheumatoid arthritis. This is according to a case study presented in Frontiers in Neurology.

After 4 months of intermittent frontal headache, nausea, and disturbances in gait and balance, a 62-year-old woman was admitted to the hospital. The patient had a 3-year history of seropositive RA (IgM RF- and anti-CCP-positive) and had been treated with leflunomide, infliximab, methotrexate, and salazopyrine entabs within the previous year.

Brain magnetic resonance imaging (MRI) was performed due to chronic headache. According to the researchers, MRI results showed “patchy interhemispheric pachy- and leptomenigeal enhancement adjacent to the parietal- and occipital lobes.” Signs of inflammation were found with blood tests, including high levels of IgM RF, anti-CCP, and interleukin-2 receptor, as well as C-reactive protein and erythrocyte sedimentation rate.

An analysis of the patient’s CSF showed a mononuclear pleocytosis and elevated protein level; subsequent CSF cultures did not indicate the growth of bacteria, Borrelia antibodies, or viral or bacterial PCR.

The patient began to exhibit sporadic confusion, delusions, and fever. CSF reexamination showed continuous mononuclear pleocytosis, high immunoglobulin G index, and the presence of oligoclonal bands, indicating inflammation. To investigate the possibility of systemic inflammation, a whole-body fluorodeoxyglucose positron emission tomography scan/computed tomography scan was performed, which showed cerebral cortex hypermetabolism and right medial lobe infiltrate of the lung.

Following the suspicion of rheumatoid meningitis as the cause, the clinicians analyzed undiluted CSF that showed moderately positive IgM RF, strongly positive anti-CCP, and CXCL-13. Chronic inflammation of CD138 positive plasma cells was confirmed through meninges biopsy.

“Based on the (i) MRI findings with patchy meningeal enhancement, (ii) high titer of IgM-RF and anti-CCP in CSF, and (iii) histopathological chronic inflammation of meninges with plasma cells and rheumatic nodules, the diagnosis of [rheumatoid meningitis] was established.”

The patient was treated with a high-dosage of methylprednisolone — 750 mg plus 1000 mg plus 1000 mg on 3 consecutive days — followed by oral tapering to the current methotrexate dose. In the following weeks, the patient was treated with rituximab 100 mg intravenous repeated at 14 days. Following this therapy, CSF levels of IgM RF, anti-CCP, and CXCL-13 “decreased accordingly,” per the researchers.

“Clinical neurological manifestations are often nonspecific, and duration and manifestations of RA [are] unreliable,” the researchers wrote, noting that among the cases of rheumatoid meningitis published since 2010, 34% had no history of RA prior to rheumatoid meningitis diagnosis.

“Until now, there are no known [rheumatoid meningitis] biomarkers in CSF, and meningeal biopsy is required for definite diagnosis,” the researchers added. “No clear guideline for treatment of [rheumatoid meningitis] exists.”

They concluded, “In this case, anti-CCP level in CSF was strongly positive and a crucial element in both diagnosing [rheumatoid meningitis] and monitoring treatment response…We show a novel clear response of anti-CCP to the treatment of [rheumatoid meningitis].”

Reference
Nissen MS, Nilsson AC, Forsberg J, et al. Use of cerebrospinal fluid biomarkers in diagnosis and monitoring of rheumatoid meningitis [published online June 26, 2019]. Front Neurol. doi: 10.3389/fneur.2019.00666