Characteristics and treatment response of patients
A total of twelve patients were treated with anakinra (Table 1). The clinical diagnoses were primary progressive multiple sclerosis (PPMS) (Patient 1), granulomatosis with polyangiitis (GPA) (Patient 2), ADEM (Patients 3, 4, and 5), NORSE (Patients 6 and 7), seronegative autoimmune encephalitis (Patient 8), autoimmune meningitis (Patient 9), methotrexate-necrotizing leukoencephalopathy (Patient 10), Japanese B encephalitis (JBE) (Patient 11), and sporadic Creutzfledt-Jakob disease (CJD) (Patient 12). Brain biopsy was performed for seven patients (Patients 1, 2, 3, 5, 8, and 12), and three patients (Patients 1, 2, and 3) showed CAIR, defined by prominent CD68-positive macrophage/microglial infiltration. All the patients were refractory to previous immunotherapies (Table 1).
Anakinra treatment showed clear responses in four patients (Patients 1, 2, 3, and 4). In particular, all the patients with biopsy proven CAIR (Patient 1, 2, and 3) had favorable outcomes for anakinra. Patient 1 with PPMS showed dramatic improvement of gait and magnetic resonance imaging (MRI) lesions during anakinra treatment, but the disease recurred after switching anakinra to azathioprine (Figure 1A and C). Patient 2 was diagnosed with GPA and was unresponsive to previous immunotherapies, but anakinra had great efficacy in improving the clinical symptoms and MRI lesions (Figure 1B and C). Patients 3 and 4 who were diagnosed with ADEM also showed good responses to anakinra, and the clinical course and pathology of patient 3 have been previously described as a case report. However, the other eight patients (Patients 5, 6, 7, 8, 9, 10, 11, and 12) showed unclear responses to anakinra treatment. Representative cases with very good responses to anakinra are described below.
Adverse events were reported in two patients (Patients 6 and 9). Patient 6 experienced mild neutropenia without fever. Patient 9 showed delirium during anakinra, resulting in the treatment discontinued.
Case 1 (Patient 1)
A 29-year-old female was referred to our clinic due to progressive gait disability (Figure 1A and C). She was previously healthy, but after delivery, she complained of gait disturbance with a tingling sensation in both legs, urinary retention, and fecal incontinence, worsening over a year. On the neurologic examination, she was alert with full orientation but could not walk without assistance, scoring EDSS of 6.5, mRS of 4, and CASE of 3. Brain MRI revealed T2 high signal intensities in the bilateral subcortical and periventricular white matter, middle cerebellar peduncle, and cerebellum (Figure 1 C). A cerebrospinal fluid (CSF) test showed mild leukocytosis with a high immunoglobulin G (IgG) index (8/μL white blood cells [WBCs], 100% leukocytes, 47 mg/dL protein, and 3.04 IgG index) and oligoclonal band (Type 3) (Table 1). Extensive laboratory evaluations of infection, autoimmune diseases, and malignancy were all negative, and empirical steroid treatment also failed. Therefore, a brain biopsy was performed, revealing CD68-positive microglia/macrophage infiltration with a few scattered CD3-positive T-cells (Figure 1A). She was clinically diagnosed with PPMS, in which no treatment was available and ocrelizumab was not regionally approved. Empirical immunotherapies, including IVIg, rituximab, tocilizumab, and tofacitinib, were ineffective.
Because the pathological findings indicated CAIR, anakinra treatment was sympathetically applied with the patient’s consent at four and half years from disease onset. The treatment was very effective. Her symptoms improved dramatically, allowing her to perform daily activities and walk without any assistance, scoring EDSS of 2, mRS of 2, and CASE of 1. The brain lesions on MRI also disappeared during five months of treatment (Figure 1C). Anakinra treatment continued for 5 months without any side effects. However, after switching anakinra to azathioprine for maintenance treatment due to cost issues, the clinical symptoms and MRI lesions recurred in one month (Figure 1C), and she again continued anakinra afterward.
Case 2 (Patient 2)
A 51-year-old male was transferred to our hospital due to an altered mentality (Figure 1B and C). He previously suffered from chronic rhinitis with conjunctivitis. His symptoms started with headache and fever, and within a week, he experienced a rapid cognitive decline with memory loss to a point where he could not even recognize his own writing. On the neurologic examination, he was drowsy and disoriented to time and place with severe memory impairment, scoring CASE of 12, mRS of 5, and mini-mental status exam (MMSE) of 19. An initial CSF test showed leukocytosis with elevated protein (172/µL WBCs, 23% poly, 55% leukocytes, 22% others, and 85 mg/dL protein), and brain MRI revealed T2 lesions in the bilateral medial temporal lobes and basal ganglia with leptomeningeal enhancement (Figure 1C). Extensive evaluation of infectious etiologies (viral, fungal, bacterial, and mycobacterium), autoantibody-mediated diseases, and malignancy was negative. Because high-dose corticosteroids followed by serial immunotherapies, including IVIg, rituximab, and tocilizumab, were ineffective, a brain biopsy was performed and revealed chronic granulomatous and suppurative vasculitis with diffuse infiltration of CD68-positive macrophages (Figure 1B).
To target CAIR caused by GPA, we treated the patient with anakinra after ten weeks of disease onset and continued for two weeks. The patient responded very well to the treatment, showing rapid improvement of the symptoms. He recovered a CASE of 0 and mRS of 1 with minimal memory impairment, and the T2 lesions in the mesial temporal lobes also clearly decreased with no more leptomeningeal enhancement (Figure 1C). He returned to daily life without recurrence while taking oral prednisolone and azathioprine maintenance.