Intracranial rheumatoid nodules: a rare localization of rheumatoid arthritis

Excerpt

Rheumatoid arthritis (RA) is an auto-immune disease that most commonly manifests as a chronic inflammatory arthritis, though systemic inflammatory disease and extra-articular manifestations occur in up to 40 percent of the patients [1]. RA may present as pain and fatigue, osteopenia, vasculitis, Sjögren’s syndrome, episcleritis, scleritis, pericarditis, myocarditis, anemia, and many others [1]. Rheumatoid nodules are described only sporadically. These rheumatoid nodules are usually found subcutaneously; only rarely they are demonstrated in the lungs and in other organs [2, 3]. We report a unique case of intracranial localization of rheumatoid nodules. A 64-year-old female was referred to the neurology department in 2019 with complaints of ageusia and anosmia for several months. The patient had been diagnosed with seropositive RA (with elevated anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF)) since 2006. She was being treated with leflunomide (a disease-modifying antirheumatic drug (DMARD)) since 2007, and with leflunomide, etanercept and corticosteroids since 2011. She suffered from pain in her hands and arms, as well as from an extensive joint disease in both shoulders. Several rheumatoid noduli had been described since 2019, localized in the lungs with central necrotic cavitation and necrosis, more pronounced in the right lung (Fig. 1A). Clinical examination showed normal cranial nerves. The finger–nose test and heel–knee test showed mild ataxia and dysmetria, bilaterally. Plantar reflex test caused downward response of the right hallux, and an equivocal response at the left side. Otherwise, neurological examination was unremarkable. CCP was > 340 U/mL (N < 7); RF was not tested; her RF concentration one year before was 110 kIU/L (N < 14). The electroencephalography was normal. Visual evoked potentials showed bilaterally normal P100 latencies. Magnetic Resonance Imaging (MRI) of the brain showed four irregular noduli situated intra-axially in the periphery of the anterior half of the left temporal lobe with significant perilesional edema (Fig. 1B, C, D). The imaging results most likely resembled glioblastoma multiforme. Therefore, a tissue biopsy was obtained. There were necrotic aspects with an atypical infiltration which did not confirm a glioblastoma or other primary or secondary cerebral neoplastic disease. The differential included several inflammatory and infective diseases. A tuberculoma was less probable as there were no risk contacts, Ziehl–Neelsen staining and PCR for Mycobacterium tuberculosis on the biopsy sample, and Mantoux tuberculin sensitivity test returned negative as well. Because the absence of oral or genital aphthosis, characteristic skin manifestations, vascular or ocular lesions and a negative pathergy test (nonspecific hypersensitivity skin reaction) neuro-Behçet’s disease was very unlikely. Fungal infection was less likely after Gorcott and PAS with diastase staining turned out negative. Furthermore, Epstein–Barr virus (EBV)-associated vasculitis, brain abscesses, and B-cell-non-Hodgkin lymphoma were considered in the differential, but neither of them were supported by clinical, pictorial, and laboratory findings. The first tissue biopsy failed to assess whether granulomatous formation was present given the limited sample size. As control MR imaging showed progressive disease at the left temporal lobe, it was decided to get an open biopsy by surgical resection. This additional pathology examination showed granulomatous changes in the brain parenchyma, most likely due to rheumatoid arthritis (Fig. 2A, B). The administration of leflunomide was omitted as this drug is considered to play a possible role in granulomatous formations; instead rituximab was initiated [3]. Rheumatoid nodules are related to a more impactful phenotype and have a more adverse prognosis. Intracranial rheumatoid nodules have sporadically been reported in literature and may mimic cerebral tumors, some with multiple localizations, as in this patient [2, 4]. Takahashi reported on a female who initially did not present with any neurological symptoms and who presented with a lesion that seemed to shrink after additional treatment for her RA. After a relapse, she was lethargic, and reported hearing loss in the right ear, and presented with a mild limb ataxia [2]. A more recent case by Tokdemir and co-workers described a 45-year-old male who had suffered from seropositive RA for five years and was referred to hospital with an one-week history of right-sided facial paralysis, left hemiparesis and headache due to a large mass-like lesion extending from mesencephalon to the right hippocampus and basal ganglia [2]. Extensive nodulosis in the lungs under leflunomide may occur [3]. However, the leflunomide-associated formation of specific intracranial rheumatoid nodules has not been reported thus far. The exact pathogenesis of noduli formation by this DMARD remains unsolved. Other anti-inflammatory drugs that are likewise associated with an increased risk of rheumatoid nodules include azathioprine, methotrexate, and anti-TNF drugs such as etanercept. In other patients, the immunomodulatory therapy with leflunomide can result in immunosuppression and may be, thus, a significant parameter in the pathogenesis of brain abscesses, another rare cause of pseudotumoral lesions in RA patients [5]. Rheumatoid nodules are associated with a more aggressive disease course. Intracranial noduli formation, although very rare, should be kept in mind when RA patients present with neurological complaints. We report the first case that suggests leflunomide-associated formation of specific intracranial rheumatoid nodules.

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