Use of Acthar GEL for MS Exacerbations During Natalizumab Induction and Maintenance

Background: Natalizumab is a humanized recombinant monoclonal antibody interfering with the interaction of VLA-4 with its natural ligand VCAM-1 and fibronectin. Reduced extravasation of T and B cells through the bloodbrain barrier results, which creates an attenuated CNS inflammatory response. Natalizumab's contraindications include simultaneous use of immunosuppressive agents including methylprednisolone, which may increase risk of PML. ACTHar gel represents an alternative medication for MS exacerbations. Because the mechanisms of action of ACTHar gel are believed to encompass melanocortin receptor activation, immunomodulation is potentiated with direct anti-inflammatory effects and immune effector cell modulation.

Objectives: Discuss safety and novel mechanism of action of ACTHar gel in the treatment of multiple sclerosis exacerbations during the concurrent use of natalizumab.

Methods: Subjects who participated included MS patients (n=8) enrolled in the Touch Program and treated with natalizumab from three months to four years. Baseline EDSS scores ranged from 2.5-6.5. Clinical exacerbations were treated with a ten day course of ACTHar gel. In addition to Touch Program parameters, patients were evaluated with monthly blood work, monthly neurologic examinations, lumbar punctures performed yearly and following ACTHar administration, and annual MRI scans. CSF immunologic profiles, JC virus DNA PCR probes in whole blood, urine, and CSF, STRATIFY-1 JCV antibody testing, and NABs to natalizumab during and after exacerbations were obtained.

Results:  Three patients demonstrated JC seropositivity conversion (STRATIFY-1) and one demonstrated JCV DNA, PCR probe conversion in urine. JCV DNA PCR probes remained negative in whole blood and CSF of all patients enrolled in the study. Multiple natalizumab NAB testings were negative. Exacerbations occurred early and late in the course of natalizumab treatment and included: optic neuritis, ataxia, and worsening myelopathy. No pseudoexacerbations were noted.  EDSS scores improved following ACTHar gel administration. ACTHar gel side effects were minimal and included transient pedal edema. Stable parameters in CSF immunologic profiles, JCV DNA PCR in whole blood and CSF, and MRI study vectors were noted even in ACTHar treated patients even after four years of natalizumab use.

Conclusions: Treating MS exacerbations while on natalizumab can be difficult. Immunosuppressive agents are contraindicated. Based on our findings, ACTHar gel represents a safe and effective alternative medication. Because ACTHar induces endogenous production of cortisol and has direct effects on relapses via melanocortin receptors, the effects may be immunomodulatory rather than immunosuppressive, mitigating potential risk of PML. Future large scale studies appear warranted to confirm our findings.