Treatment of IgG4-related pachymeningitis in a patient with steroid intolerance: The role of early use of rituximab

Highlights

• Steroids are the treatment of choice for patients with IgG4-related diseases.

• In patients with IgG4-related pachymeningitis, response to MTX can be suboptimal.

• Rituximab has been shown to be effective in patients with IgG4-related pachymeningitis.

• Early RTX treatment should be considered in patients with IgG4-related pachymeningitis.

Abstract

IgG4-related pachymeningitis is a serious inflammatory condition that can present with symptoms of mass effect and focal deficits. The first-line therapy is steroids and second-line is chemotherapy (methotrexate, azathioprine, etc.). We describe a patient with IgG4-related pachymeningitis in whom steroid use was contraindicated and methotrexate was ineffective. During the course of treatment, the patient presented to the emergency department with receptive and expressive aphasia, slurred speech, right-sided neglect, and loss of sensation. After a single infusion of rituximab and anticonvulsants, her symptoms resolved. Our unique case suggests that patients with IgG4-related pachymeningitis might benefit from early initiation of rituximab.

Introduction

Although initially reported in cases of Type I autoimmune pancreatitis, IgG4-related disease, an inflammatory condition, has recently been implicated in a wide range of pathologies. The disease is a “great mimicker” of numerous disorders. Seemingly unrelated medical conditions including, but not limited to, Riedel's thyroiditis, idiopathic tubulointerstitial nephritis, autoimmune pancreatitis, and inflammatory aortic aneurysm are now known to be part of the IgG4-related disease spectrum (Stone et al., 2012). IgG4-related disease typically exhibits pathological characteristics of IgG4⁺ plasma cell-rich lymphoplasmacytic infiltrate, storiform fibrosis, as well as mild to moderate eosinophilia and obliterative phlebitis (Kamisawa et al., 2015, Mahajan et al., 2014, Perez Alamino et al., 2013, Stone et al., 2012). While the pathophysiology of the disease is not fully understood, involvement of cytokine imbalances, T helper cells, and T regulatory cells has been proposed (Akitake et al., 2010, Detlefsen et al., 2008, Kanari et al., 2010, Miyoshi et al., 2008, p. 4; Suzuki et al., 2010). Descriptive studies have found an imbalance of T helper type 2 cells (Th2) with overproduction of Th2 derived cytokines in affected tissue from patients with IgG4-related disease (Akitake et al., 2010, Kanari et al., 2010, Suzuki et al., 2010). Cytokine imbalances may underlie the allergic manifestations of IgG4-related disease (Kamisawa et al., 2009). Other studies have implicated that an increase in transforming growth factor β driven by T regulatory cells may lead to development of fibrosis in late disease (Detlefsen et al., 2008, Miyoshi et al., 2008). Historically, the first cases of IgG4-related disease were described over 100 years ago; however, a clear description and nomenclature did not get formulated until the last 10 years. IgG4-related pachymeningitis is a rare fibroinflammatory condition affecting the dura mater, resulting in neurological symptoms such as headaches, cranial nerve palsies, visual problems, motor weakness, numbness, sensorineural hearing loss, and less commonly, seizures (Lu et al., 2014, Wallace et al., 2013). Histologically, it is characterized by the predominance of IgG4-positive plasma cells and CD4 + T lymphocytes. Disease progression and response to treatment are best monitored with serial imaging, although recent studies have also demonstrated that analysis of IgG and IgG4 production in cerebrospinal fluid are safe potential diagnostic and monitoring tools (Della-Torre et al., 2014, Della-Torre et al., 2013, Li et al., 2015). Despite the recent increase in the number of confirmed cases of IgG4-related pachymeningitis, no consensus on its optimal treatment has yet been reached. Steroids are currently the first-line treatment followed by other immunosuppressants, such as methotrexate, mycophenolate mofetil, and finally, rituximab, which although expensive, has been shown to be most effective (Bosco et al., 2013, Ebbo et al., 2012, Hyun et al., 2014, Khosroshahi et al., 2015, Khosroshahi et al., 2012, Khosroshahi et al., 2010, Moss et al., 2012). We describe a patient with IgG4-related pachymeningitis in whom steroids were contraindicated. Treatment with methotrexate did not show any clinical or radiological response and as a result, the patient experienced a significant exacerbation of her symptoms that may have been prevented with early institution of rituximab treatment.