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Intrathecal administration of rituximab—an anti-CD20 monoclonal antibody—is emerging as a promising therapeutic strategy for B cell lymphomas of the central nervous system (CNS).1 2 The rationale for administering rituximab directly into the cerebrospinal fluid (CSF) stems from the need to achieve optimal therapeutic concentrations within the intrathecal compartment. Rituximab, in fact, has a high molecular weight and only 0.1%–0.5% of its plasmatic concentrations crosses the ‘blood-brain barrier’ (BBB) after intravenous infusion.1 In addition, despite inducing prolonged depletion of circulating B lymphocytes, systemic rituximab does not affect malignant B cells in CNS lymphomas.2 Hypertrophic pachymeningitis (HP) is the most frequently encountered CNS manifestation of IgG4-related disease (IgG4-RD), a fibroinflammatory condition of unclear aetiology.3 The intrathecal synthesis of IgG4 in patients with IgG4-related hypertrophic pachymeningitis(RHP) and the clinical improvement after rituximab in patients with systemic involvement, support a pathogenic role of B lymphocytes.4–6 Among IgG4-RD manifestations, however, IgG4-RHP stands out for a certain resistance to intravenous rituximab raising the possibility that systemic administration might not be as effective on putative pathogenic B cells residing in inflammatory niches within the CNS.4 Here, we report the first case of IgG4-RHP treated with intrathecal rituximab.
A young adult patient was admitted in April 2015 for rapidly progressive frontal headache and complete visual loss on the right eye. Imaging studies of the head and neck revealed diffuse pachymeningitis with bone erosions, thickening of the nasal septum, hard palate tumefaction, and bilateral optic neuritis; neuro-ophthalmological examination reported asymmetrical signs of optic nerve fibre atrophy (right >left) with loss of colour vision and complete depression of the visual field on the right eye (figure 1 and see online supplementary figure e1). Laboratory and CSF analyses at the time of admission are reported in online supplementary figure e1. Mimicking autoimmune, neoplastic and infectious conditions were excluded by ad hoc serological and CSF studies. Additional CSF analyses revealed oligoclonal IgG bands, and increased concentrations of total IgG, IgG1 and IgG4 antibodies. Brain and meningeal biopsies showed storiform fibrosis, lymphoplasmacytic infiltration, 100 IgG4+ plasma cells/HPF, and an IgG4+/IgG+ plasma cells ratio >40%, consistent with a diagnosis of IgG4-RD (see online supplementary figure e2).3 The patient was treated with three daily pulses of 1 g intravenous methylprednisolone followed by oral prednisone (1 mg per kg of body weight daily in the first month before tapering). In August 2015, given the bilateral progression of the optic nerve atrophy and the unchanged meningocortical MRI findings, two infusions of 1 g rituximab were administered 15 days apart. In December 2015 the patient was admitted for generalised seizures. The IgG Index was slightly improved but brain MRI was grossly unchanged; circulating plasmablasts, a biomarker of IgG4-RD activity, increased again;6 visual defect was stable but optic neuropathy further deteriorated bilaterally (figure 1 and see online supplementary figure e1). Due to the active and severe inflammation in the intrathecal compartment, we decided to administer rituximab directly into the CSF, after obtaining patients' informed consent and ethical approval. In February and March 2016, intrathecal rituximab was infused according to protocols adopted for CNS lymphomas.1 Briefly, after premedication and removal of 8 mL of CSF, we injected 40 mg of methylprednisolone (diluted in 2 mL of saline) followed by 25 mg of rituximab (Mabthera diluted in 6 mL of saline 0.9%) directly through lumbar puncture. Notably, plasmablasts were expanded in the peripheral blood before the first intrathecal infusion (see online supplementary figure e1). In March 2016, before the second intrathecal rituximab, visual function improvement was reported by the patient and confirmed by a neuro-ophthalmological evaluation. Optic neuropathy stabilised in both eyes. Brain MRI showed a reduction in meningeal inflammation and a marked amelioration of the cerebral oedema (figure 1). Intrathecal synthesis of IgG, IgG1 and IgG4 further decreased. CD19+ and CD20+ B cells were depleted both in the CSF and in the peripheral blood. Circulating plasmablasts decreased from 2490 cells/mL to 340 cells/mL (see online supplementary figure e1). In September 2016, 6 months after the second intrathecal rituximab, brain MRI findings showed progressive improvement. A neuro-ophthalmological evaluation described an additional mild amelioration of visual function bilaterally with normalisation of colour vision (figure 1). At the last available follow-up (March 2017), meningeal thickening, visual field and circulating plasmablasts were stable, thus requiring no additional treatments.
The efficacy of intrathecal rituximab in the present case of IgG4-RHP is supported by clinical observations, radiological data and immunological studies. One month after the first infusion we observed a rapid improvement in both MRI findings and visual function, a result that was not accomplished during the previous year of systemic immunosuppressive treatments. In addition, CD20+ lymphocytes in the CSF swiftly decreased, suggesting that therapeutic concentrations of the monoclonal antibody were efficiently delivered beyond the BBB. Interestingly, depletion of circulating CD20+ and CD19+ B cells was also observed, indicating a rapid recirculation of rituximab from the CSF to the peripheral compartment. It is difficult, however, to discriminate whether B cell depletion in the CSF was a direct effect of intrathecal rituximab or was secondary to B cell depletion in the peripheral blood and impaired recruitment into the CNS. Our hypothesis is that both scenarios likely concurred because maturation of naive CD20+ B cells—the preferential target of rituximab—is known to occur in peripheral lymph nodes as well as in tertiary lymphoid organs within inflamed tissues.3 4 Indeed, tertiary lymphoid structures rich in CD20+ B lymphocytes—the precursors of antibody secreting plasma cells—were found in the leptomeninges of our patient (see online supplementary figure e2). Yet, initial improvement of the blood-CSF barrier damage was already observed after intravenous rituximab suggesting that peripheral B cells contributed, at least in part, to intrathecal inflammation.
The effector mechanisms by which intrathecal rituximab depleted B cells into the CSF and ameliorated inflammation within the CNS of our patient remain, however, unknown. On one hand, complement and antibody-dependent cytotoxicity might have concurred in lysing CSF CD20+ B lymphocytes.1 2 On the other hand, CSF depletion of B cells might have significantly disrupted B-T cells interactions within tertiary lymphoid organs in the meninges, thus preventing antigen presentation to T cells, intrathecal T cell activation and perpetuation of the inflammatory process.7
In conclusion, here we report the first case of non-neoplastic inflammatory pachymeningitis and optic neuritis related to IgG4-RD treated with intrathecal rituximab. Intrathecal rituximab might represent a valid and safe therapeutic approach for patients with organ-threatening manifestations of IgG4-RD due to meningeal involvement poorly responsive to systemic immunosuppressive therapies.
The authors are grateful to Prof. Fabio Ciceri and Dr. Raffaella Milani (Hematology and Bone Marrow Transplant Unit - IRCCS San Raffaele Scientific Institute, Milan, Italy), and to Dr. Luisa Roveri (Department of Neurology - IRCCS San Raffaele Scientific Institute, Milan, Italy) for helpful discussion.
ED-T and CC contributed equally.
Contributors ED-T, CC and EBC conceived the study and wrote the article. LA, SG, SB-M, EB, GP, ML, MC, MrT, MaT, MoT, SA contributed to patient clinical care, data collection and interpretation. PM and LD provided significant advice and supervision, drafting a significant portion of the manuscript. All authors approved the final version of the manuscript. ED-T and CC contributed equally as first authors.
Funding This work was supported by “Fondazione Italiana per la Ricercasull’Artrite” (FIRA Onlus 2014) and by the “Collegio Ghislieri” (Pavia).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.