Intrathecal rituximab for IgG<sub>4</sub>-related hypertrophic pachymeningitis

Della‐Torre, Emanuel; Campochiaro, Corrado; Cassione, Emanuele Bozzalla; Albano, Luigi; Gerevini, Simonetta; Bianchi-Marzoli, Stefania; Bozzolo, Enrica; Passerini, Gabriella; Lanzillotta, Marco; Terreni, Mariarosa; Callea, Marcella; Trimarchi, Matteo; Mortini, Pietro; Tresoldi, Moreno; Acerno, Stefania; Dagna, Lorenzo

doi:10.1136/jnnp-2017-316519

Cited by 32 publications

(17 citation statements)

References 7 publications

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“…[33][34][35][36][37] Rituximab is also highly effective in patients with IgG 4 -RD, a primarily fibrotic disorder in which the relevance of autoantibodies and T cells to fibrosis is still being explored. 5,38 Our recent studies have implicated antibodies to galectin-3 in a subset of patients with IgG 4 -RD, and others have identified autoantibodies to a recombinant truncated form of laminin 511, but definitive proof of a pathogenic role of these antibodies has not yet been demonstrated. 39,40 Similarly, our studies have revealed expansions of CD4 1 CTLs in patients with IgG 4 -RD, as well as secretion of profibrotic cytokines and potential induction of apoptosis by these cells, but conclusive evidence that they drive fibrosis has not yet been obtained.…”

Section: Discussionmentioning

confidence: 99%

B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease

Della‐Torre

Rigamonti

Perugino

et al. 2020

Journal of Allergy and Clinical Immunology

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Background: IgG 4-related disease (IgG 4-RD) is a fibroinflammatory condition marked by rapid clinical improvement after selective depletion of B lymphocytes with rituximab. This feature suggests that B cells might participate in fibrogenesis and wound healing. Objective: In the present work we aimed to demonstrate that B lymphocytes contribute directly to tissue fibrosis in patients with IgG 4-RD. Methods: Total circulating CD19 1 B lymphocytes, naive B cells, memory B cells, or plasmablasts from patients with IgG 4-RD were cultivated with human fibroblasts. Profibrotic soluble factors and collagen production in cocultures were assessed by using ELISAs and Luminex assays. RNA sequencing and quantitative RT-PCR were used to assess fibroblast activation in the presence of B cells, as well as induction of profibrotic pathways in B-cell subsets. Relevant profibrotic and inflammatory molecules were confirmed in vitro by using functional experiments and on IgG 4-RD tissue sections by using multicolor immunofluorescence studies. Results: B cells from patients with IgG 4-RD (1) produced the profibrotic molecule platelet-derived growth factor B and stimulated collagen production by fibroblasts; (2) expressed enzymes implicated in extracellular matrix remodeling, such as lysyl oxidase homolog 2; (3) produced the chemotactic factors CCL4, CCL5, and CCL11; and (4) induced production of these same chemokines by activated fibroblasts. Plasmablasts expressed sets of genes implicated in fibroblast activation and proliferation and therefore represent cells with intrinsic profibrotic properties. Conclusion: We have demonstrated that B cells contribute directly to tissue fibrosis in patients with IgG 4-RD. These unanticipated profibrotic properties of B lymphocytes, particularly plasmablasts, might be relevant for fibrogenesis in patients with other fibroinflammatory disorders and for woundhealing processes in physiologic conditions.

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Section: Discussionmentioning

confidence: 99%

B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease

Della‐Torre

Rigamonti

Perugino

et al. 2020

Journal of Allergy and Clinical Immunology

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“…Systemic administration might not be as effective on putative pathogenic B cells residing in inflammatory niches within the CNS. Intrathecal rituximab was reported to be effective (52).…”

Section: Discussionmentioning

confidence: 99%

“…Three steroid-refractory HP patients treated with RTX for 4 weeks showed clinical improvements and exhibited prominent decreases in dural thickness (61). Thus, RTX has been suggested to be a second-line therapy for steroid-refractory HP, especially for IgG4-RD (52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65).…”

Section: Discussionmentioning

confidence: 99%

Hypertrophic Pachymeningitis in a Southern Chinese Population: A Retrospective Study

Xiao

2020

Front. Neurol.

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Aims: To investigate the causes, clinical characteristics, imaging features, and therapeutic implications of hypertrophic pachymeningitis (HP) in a southern Chinese population. Methods: We retrospectively analyzed 48 patients with HP with different causes from 1 January 2006 to 31 December 2018. Clinical manifestation, laboratory findings, and neuroimaging results were evaluated in all HP patients. Results: The mean age at onset was 50 ± 12 years. The most common diagnosis was idiopathic HP (67%), followed by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (15%), tuberculous meningitis (8%), viral meningitis (6%), and bacterial meningitis (4%). Headache was the most common symptom. The most frequently changed laboratory finding was elevated erythrocyte sedimentation rate (ESR). Imaging was characterized by cerebral or spinal dura mater enhancement in MRI scan with contrast. Enhancements were mainly located in the posterior fossa for idiopathic HP; frontal, parietal, and occipital lobes for ANCA-related HP; and posterior fossa for tuberculous-associated HP. Diffuse enhancement was found in most cases, except for tuberculous-associated HP. Glucocorticoid or immunosuppressive treatment was applied in most cases. Conclusions: The etiology of HP varied among patients, with idiopathic HP being the most common. MRI showed enhancement of the dura mater, which differed according to different etiologies. Glucocorticoid or immunosuppressive agents were the primary drugs for treatment.

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“…B cell depletion also improves tissue fibrosis in IgG4-RD by directly targeting a subset of B lymphocytes with pro-fibrotic properties involved in fibroblast activation and recruitment of inflammatory cells 4142. Rituximab was effective when administered either as two 1 g infusions 15 days apart (rheumatological protocol) or in four weekly 375 mg/m 2 infusions (hematological protocol), as well as at lower doses (single 1 g infusion) in a few reports 138139. However, although rituximab has been administered in more than 200 patients with IgG4-RD worldwide, the best dosage and timing of administration remain to be defined, and some drawbacks are emerging that are similar to those observed in hematological settings and other autoimmune disorders.…”

Section: Management Of Igg4 Related Diseasementioning

confidence: 99%

Advances in the diagnosis and management of IgG4 related disease

Lanzillotta

Mancuso

Della‐Torre

2020

BMJ

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172

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IgG4 related disease was recognized as a unified disease entity only 15 years ago. Awareness of IgG4 related disease has increased worldwide since then, and specialists are now familiar with most of its clinical manifestations. Involvement of the pancreato-biliary tract, retroperitoneum/aorta, head and neck, and salivary glands are the most frequently observed disease phenotypes, differing in epidemiological features, serological findings, and prognostic outcomes. In view of this multifaceted presentation, IgG4 related disease represents a great mimicker of many neoplastic, inflammatory, and infectious conditions. Histopathology remains key to diagnosis because reliable biomarkers are lacking. Recently released classification criteria will be invaluable in improving early recognition of the disease. IgG4 related disease is highly treatable and responds promptly to glucocorticoids, but it can lead to end stage organ failure and even death if unrecognized. Prolonged courses of corticosteroids are often needed to maintain remission because the disease relapses in most patients. Rapid advancement in our understanding of the pathophysiology of IgG4 related disease is leading to the identification of novel therapeutic targets and possible personalized approaches to treatment.

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Intrathecal rituximab for IgG₄-related hypertrophic pachymeningitis

Cited by 32 publications

References 7 publications

B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease

B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease

Hypertrophic Pachymeningitis in a Southern Chinese Population: A Retrospective Study

Advances in the diagnosis and management of IgG4 related disease

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Intrathecal rituximab for IgG4-related hypertrophic pachymeningitis

Cited by 32 publications

References 7 publications

B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease

B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease

Hypertrophic Pachymeningitis in a Southern Chinese Population: A Retrospective Study

Advances in the diagnosis and management of IgG4 related disease

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Intrathecal rituximab for IgG₄-related hypertrophic pachymeningitis