Effect of low-dose rituximab treatment on autoimmune nodopathy with anti-contactin 1 antibody

Abstract

Background: Autoimmune nodopathy with anti-contactin-1 (CNTN1) responds well to rituximab instead of traditional therapies. Although a low-dose rituximab regimen was administered to patients with other autoimmune diseases, such as myasthenia gravis and neuromyelitis optica spectrum disorders, and satisfactory outcomes were obtained, this low-dose rituximab regimen has not been trialed in anti-CNTN1-positive patients.

Methods: Anti-CNTN1 nodopathy patients were enrolled in this prospective, open-label, self-controlled pilot study. A cell-based assay was used to detect anti-CNTN1 antibodies and their subclasses in both serum and cerebrospinal fluid. Clinical features were evaluated at baseline, 2 days, 14 days, and 6 months after single low-dose rituximab treatment (600 mg). The titers of the subclasses of anti-CNTN1 antibody and peripheral B cells were also evaluated at baseline, 2 days, and 6 months after the rituximab regimen.

Results: Two patients with anti-CNTN1 antibodies were enrolled. Both patients had neurological symptoms including muscle weakness, tremor, sensory ataxia, numbness and mild nephrotic symptoms. In the field of neurological symptoms, sensory ataxia markedly improved, and the titer of anti-CNTN1 antibody as well as CD19+ B cells decreased only two days following low-dose rituximab treatment. Other neurological symptoms improved within two weeks of rituximab treatment. At the 6-month follow-up, all neurological symptoms steadily improved with steroid reduction, and both the anti-CNTN1 antibody titer and CD19+ B cells steadily decreased. No adverse events were observed after this single low-dose rituximab treatment.

Conclusions: We confirmed the clinical efficacy of low-dose rituximab by B cell depletion in autoimmune nodopathy with anti-CNTN1 antibody. This rapid and long-lasting response suggests that low-dose rituximab is a promising option for anti-CNTN1 nodopathy.

Keywords: anti-CNTN1 antibodies; antibody titer; autoimmune nodopathy; low-dose rituximab; treatment outcome.

Figure 1

Detection of anti-CNTN1 antibodies (A–D) Detection of anti-CNTN1 antibodies in serum of patient 2. (A) 1:10 positive anti-CNTN1 IgG1 antibodies (arrow); (B) 1:320 positive anti-CNTN1 IgG2 antibodies (arrow); (C) Negative anti-CNTN1 IgG3 antibodies; (D) 1:3200 positive anti-CNTN1 IgG4 antibodies (arrow); (E–H) Detection of anti-CNTN1 antibodies in CSF of patient 1. (E) Negative anti-CNTN1 IgG1 antibodies; (F) Negative anti-CNTN1 IgG2 antibodies; (G) Negative anti-CNTN1 IgG3 antibodies; (H) 1:1 positive anti-CNTN1 IgG4 antibodies (arrow); (I–K) Double-immunofluorescence of murine teased fibers with serum sample of the patient. Seropositive of serum from patient 1 (green) (arrow). Antigen was in the paranodal region as the serum antibody merged well to HEK293 cells transfected with human NF155/NF186 plasmids (yellow) (arrow). Scale bars = 100 μm (A–H); Scale bars = 50 μm (I–K). CNTN1 = contactin-1; CSF, cerebrospinal fluid; NF155/NF186, neurofascin-155/neurofascin-186.

Figure 2

Nerve biopsy findings in anti-CNTN1-positive autoimmune nodopathy (A) MDC (arrow) and slightly reduced myelinated fibers in patient 1; (B) Myelin ovoids (black arrow), clusters of regenerating nerve fibers (white arrow), and thinly myelinated fiber (arrowhead) though semithin toluidin blue staining in patient 1; (C) No obvious subperineurial edema or lymphocytic infiltration in patient 1; (D) Large spaces observed between the terminal loops and the axolemma under electron microscopy (arrow) in patient 1. Scale bars = 50 μm (A, C); Scale bars = 10 μm (B); Scale bars = 500 nm (D). CNTN1, contactin-1; MDC, myelin digestion chamber;