High Relapse Rate in Anti-CASPR2 Disease: Implications for Prolonged Immunotherapy

Anti-contactin-associated protein-like 2 (CASPR2) disease-previously considered a subtype of anti-voltage-gated potassium channel (VGKC-complex) encephalitis-is a relatively new disease entity, and information on long-term outcomes and relapses is limited. We investigated long-term clinical outcomes and factors associated with higher relapse rates. In addition, we compared different treatment strategies.

In this nationwide observational cohort study, patients with anti-CASPR2 disease were included. Clinical data were collected at diagnosis and during follow-up, both retrospectively and prospectively.

Forty-four patients with anti-CASPR2 disease were included (42 male patients [96%]; median age at onset 66 years [interquartile range (IQR) 61-71; range 40-86]). The median follow-up time was 55 months (IQR 38-78; range 8-200). Sixty percent of the patients experienced at least one relapse. Most patients experienced similar but fewer symptoms during relapse(s). However, new symptoms could occur during a relapse episode, mainly involving the peripheral nervous system. The median time to relapse was 10.5 months (IQR 6-14; range 3-58). Twelve of the 44 patients were diagnosed with cancer, with 3 cancers identified only at relapse. We found significantly higher anti-VGKC-complex concentrations at diagnosis (p = 0.043) and a higher occurrence of seizures (p = 0.041) in relapsing patients. In 94%, a clear correlation was observed between anti-VGKC-complex concentrations and the clinical status (59% decrease from diagnosis to post-treatment stage, 122.5% increase during the first relapse). In our total cohort, tapering with oral steroids seemed effective in reducing relapses during administration (annual relapse rate [ARR] 0.12) but did not prevent relapses beyond the taper. Second-line therapy also appeared effective (ARR 0.09) while steroid-sparing agents provided limited benefits (ARR 0.22). In patients prone to relapse, repeated courses of rituximab seem necessary to prevent further relapses (hazard ratio 26.33, p < 0.0005 in post-second-line treatment group; ARR 0.09 vs 0.81).

The relapse rate in anti-CASPR2 disease is much higher than previously reported. In patients prone to relapse, (repeated) courses of rituximab appear to be most effective in preventing future relapses beyond acute therapy and tapering with oral steroids. Anti-VGKC-complex concentrations in serum can aid in monitoring of relapses and disease course in most of the patients. It is recommended to repeat tumor screening when patients relapse.

This study provides Class IV evidence that, in anti-CASPR2 disease, prolonged immunotherapy is associated with reduced relapse rates.