Deciphering neurological symptoms in ANCA-associated vasculitis, uncontrolled disease or a complication of therapy

Withdrawing and withholding further immunosuppression in AAV patients with PML can result in a better- than-expected outcome. Mirtazipine can be considered to facilitate PML control. PML can occur after rituximab (and other immunosuppressants) in AAV patients but may be less common than in SLE patients treated with rituximab. A 74-year-old male presented with a three-month history of cough, dyspnea on exertion, arthralgias, constitutional symptoms and bilateral foot drop. His initial blood work indicated a normocytic anaemia, raised C-reactive protein (CRP), microscopic haematuria, along with a positive proteinase 3 (PR3) ANCA antibody. He was diagnosed with PR3 ANCA-associated vasculitis (AAV) with a microscopic polyangiitis phenotype, causing a mononeuritis multiplex. He was initially treated with intravenous methylprednisolone followed by prednisolone and six doses of intravenous cyclophosphamide. Despite the combination of glucocorticoid and cytotoxic therapy, a rise in inflammatory markers (CRP 89 mg/l) occurred with recurrence of constitutional symptoms and new sensory changes in his lower extremities suggesting active disease. A CT PET scan excluded malignancy and infection and he was re-pulsed with three doses of methylprednisolone therapy and given two 1 g doses of rituximab. Despite this combination, our patient had ongoing constitutional symptoms and elevation of his CRP, he therefore commenced low dose azathioprine 75 mg daily for ongoing active disease. Seven months after initial diagnosis, he was in remission with improvement in his peripheral neurological symptoms. On the morning the patient was scheduled for his first six-month maintenance dose of rituximab he complained of dysarthria and unsteady gait, which had progressed over one month. Physical examination revealed cerebellar signs. His rituximab dose was postponed and an urgent brain MRI indicated bilateral cerebellar white matter hyperintensities (Fig. 1). Lumbar puncture indicated elevated cerebrospinal fluid (CSF) protein with normal CSF glucose and no lymphocytes. CSF bacterial culture, herpes simplex virus type 1 and 2, varicella-zoster virus and enterovirus PCR were negative. CSF John Cunningham (JC) virus PCR was positive. Disease course and therapy (A) Timeline of CRP and ANCA titre from initial diagnosis to AAV remission. (B) Graph of lymphocyte count from diagnosis to 18 months after PML diagnosis. (C) Brain MRI axial FLAIR images indicating hyperintensity in the left cerebellar hemisphere that extends to the left middle cerebellar peduncle (white arrow) and a mild hyperintensity in the right cerebellar hemisphere (red arrow), suggestive of PML. Disease course and therapy (A) Timeline of CRP and ANCA titre from initial diagnosis to AAV remission. (B) Graph of lymphocyte count from diagnosis to 18 months after PML diagnosis. (C) Brain MRI axial FLAIR images indicating hyperintensity in the left cerebellar hemisphere that extends to the left middle cerebellar peduncle (white arrow) and a mild hyperintensity in the right cerebellar hemisphere (red arrow), suggestive of PML. The combination of subacute neurological symptoms with typical brain MRI findings and a CSF PCR positive for JC virus in an immunosuppressed patient led to the diagnosis of progressive multifocal leukoencephalopathy (PML). At diagnosis, our patient’s rituximab and azathioprine were discontinued. He was maintained on prednisolone 5 mg daily and his lymphocyte count improved over three months from 0.31 to 0.96 ×109/l. Despite withdrawing azathioprine, our patient had initial progression of his neurological symptoms with swallowing difficulties necessitating a thickened fluid diet, dysphonia and he became wheelchair bound. He was therefore initiated on mirtazapine 45 mg daily. Four months after initial diagnosis, his neurological symptoms and brain MRI imaging improved. Thirty months after diagnosis he has remained neurologically stable with normal swallowing, ongoing dysarthria and able to walk. Alongside this, his AAV has remained in remission with a negative PR3 ANCA, CRP <4 and normal lymphocyte count 1.36 ×109/l, with re-emergence of low-level circulating CD20 B-cells post rituximab. AAV is a multi-organ autoimmune condition characterized by necrotizing small vessel vasculitis associated with antibodies to myeloperoxidase (MPO) or proteinase 3 (PR3) [1]. Without immunosuppressive therapy, severe AAV has a mortality rate of 90%; however, advances in immunosuppressive therapy over the past four decades have led to remission in up to 90% of patients [2]. Remission induction in AAV is achieved with a combination of glucocorticoid and immunosuppressive therapy, including cyclophosphamide, rituximab, methotrexate or mycophenolate. Despite these advances, there is a subset of patients who present with refractory disease that does not respond to glucocorticoids and immunosuppression. In these cases, combination therapy is often initiated, with evidence for rituximab as an effective agent in refractory/relapsing disease [3, 4]. Rituximab is a chimeric monoclonal antibody that causes CD20 B-cell depletion, which is approved treatment for remission induction and maintenance in AAV. While repeat rituximab dosing is highly efficacious for remission maintenance in AAV, it is also associated with infectious complications including PML, a condition with significant morbidity and mortality. PML results from reactivation of JC virus, which infects oligodendrocytes and astrocytes causing demyelination of white matter in the brain. JC virus is a ubiquitous virus that the majority of the population have been exposed to, but only causes PML in immunosuppressed patients [5]. Risk factors for PML include lymphoproliferative disorders, HIV, solid organ transplants, inflammatory conditions such as SLE, and immunosuppressive agents. The incidence of PML with rituximab varies based on the underlying condition, with a 1/4000 risk in SLE and 1/100000 risk in rheumatoid arthritis [5]. In two previously reported AAV patients who developed PML in association with rituximab, both had a significant burden of preceding immunosuppressive therapy, suggesting that cumulative immunosuppressive burden is a risk factor for PML development [6]. PML presents with subacute progression of hemispheric and posterior fossa neurologic symptoms, including hemiparesis, dysphasia, agnosia, ataxia, visual disturbance and seizures. The gold standard for a diagnosis of PML is a brain biopsy; however, a diagnosis of PML can also be made with a typical clinical syndrome, characteristic brain MRI findings and positive CSF JC virus PCR [7]. The prognosis associated with PML is poor, with up to a 50% mortality in patients with rheumatoid arthritis who received rituximab. The mainstay of therapy in PML is stopping immunosuppressive therapy. The principal therapy for PML in this context is withdrawal of immunosuppression, in the hope that reconstitution of the immune repertoire will restore immunological surveillance of the brain. Additional therapeutic options for PML include the prevention of JC virus entry into oligodendrocytes and astrocytes by blocking 5-HT2A receptors with mirtazapine, which has been associated with improved outcomes [8]. Unfortunately, anti-viral therapy with mefloquine and cidofovir have not been shown to be effective [8]. PML is a rare but devasting complication of immunosuppressive therapy. Here, we report the third case in the literature of an AAV patient who developed PML in association with rituximab therapy. His main risk factor was combination immunosuppressive therapy. This case highlights the fine balance of immunomodulatory therapy in attaining disease remission along with the risk of infectious complications. Previous reports of PML associated with rituximab in hematologic malignancies and rheumatoid arthritis have indicated a high mortality rate. However, thus far our patient has done well, likely due to early withdrawal of azathioprine with early improvement of lymphopenia, alongside the introduction of mirtazapine. This indicates the importance of prompt diagnosis and urgent intervention. With the increasing use of monoclonal antibody therapy in AAV patients, PML is an important complication that all health practitioners should be aware of. The authors would like to thank the patient for his consent to publish this manuscript. This work was supported by the NIHR Cambridge BRC. Funding: This paper forms part of the supplement entitled ‘EUVAS Cambridge Vasculitis Course Case-Base Supplement’. This supplement is supported by the University of Cambridge. Disclosure statement: The authors have no conflicts of interest to declare. The data underlying this article will be shared on reasonable request to the corresponding author.

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