Autoimmune Sequelae Following Rituximab Therapy

A Review of the Literature and Potential Immunologic Mechanisms

Anna E. Kersh, MD, PhD; Ron J. Feldman, MD, PhD

Disclosures

J Clin Rheumatol. 2018;24(8):427-435. 

In This Article

Results

A review of the literature revealed 33 case reports of new autoimmune disease along with 2 personal cases that developed in patients receiving rituximab therapy (Table 1). The autoimmune reactions were most commonly observed in the skin and pulmonary system, although manifestations in the central nervous system (CNS), gastrointestinal tract, and joint synovium were also reported. Patient age and sex, as well as duration of primary disease and previous treatments prior to rituximab therapy, are summarized in Table 1. In addition, the time from starting rituximab treatment to onset of symptoms of the novel autoimmune disease is reported, as well as therapies given concomitantly with rituximab treatment. Women (n = 22) and men (n = 13) were affected, and the ages of individuals ranged from 16 months to 84 years (Table 1). Onset of symptoms after starting rituximab ranged from 2 weeks to 3 years. Patients carrying a diagnosis of non-Hodgkin lymphoma, B-cell lymphoma, or Waldenstrom macroglobulinemia (totaling n = 13 patients) received no prior therapies before starting rituximab. The remaining patients (n = 20) had undergone a range of immunosuppressive treatment regiments including corticosteroids, tumor necrosis factor α (TNF-α) inhibitors, methotrexate, cyclosporine, cyclophosphamide, mycophenolate mofetil, dapsone, and intravenous immunoglobulin. After development of disease, there was a difference in how extensively the reports detailed treatments administered and therapeutic response (Table 2). Treatments after development of rituximab-induced autoimmune disease included immune-suppressing medications, ranging from topical corticosteroids (for psoriasis) to systemic corticosteroids as the most commonly given treatment with various adjuvant therapies based on the disease site and discretion of treating physicians. For the cases of autoimmune skin disease, 4 cases improved with the use of topical therapies alone,[6,11–13] whereas 6 cases required systemic immunosuppressive therapies (no report of treatment in 1 case[9]). Of the 13 reports of lung disease, 9 cases required treatment with systemic corticosteroids (Table 2),[15,16,18–22] 3 cases resolved without treatment or with "supportive" measures,[17,19] and 1 case resulted in death secondary to respiratory failure.[19] Only 7 reports clearly stated that rituximab therapy was discontinued, 12 reports described limited rituximab therapy with no mention of repeat treatment, 8 cases attempted repeat rituximab therapy, and 5 cases did not indicate whether rituximab therapy was discontinued (Table 2). Three cases, 2 of psoriatic reactions and 1 case of RA, reported recurrence of symptoms with repeat rituximab therapy.[10,11,13,29] The majority of cases did not report peripheral B-lymphocyte counts at diagnosis of autoimmune disease (n = 28), and those that did used CD19, CD20 or simply "B-cell markers" to quantify B lymphocytes. Low or absent peripheral B-cell counts were reported in 5 cases,[6,13,24,25] whereas elevated levels of peripheral B cells were also reported (personal observations). Of note, tissue biopsy, cerebrospinal fluid (CSF) examination, and bronchoalveolar lavage revealed an absence of tissue-infiltrating B cells in several cases,[17,24–27] although there was an increase in lung-infiltrating CD19+ B lymphocytes in others.[16]

The autoimmune processes that developed were associated with varying mechanisms of pathogenesis with roles for regulatory B cells (Bregs), autoreactive CD4 and CD8 T cells, increased cytokine release, and innate immune system through the inflammasome.

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