Why does this not come as a surprise to all and sundry, the report of a potentially harmful infection following immunosuppressive treatment, but this time from the new kid on the block, ocrelizumab (Ocrevus). Not to sound cliched, but if you hadn’t seen this one coming, well then the rest is history.
Risk is all about perception; what is reasonable for one person is unacceptable for another. Society, is inherently risk averse, directed by a set criteria for risks and risk mitigation. But in the land of MS, have we taken a risk too far?
Dudek et al., burst our safety bubble with the report of a case of HSV-2 encephalitis in Germany, with normal MRI head scan. The individual is 61 years old with secondary progressive MS; relapsing-remitting in 1997, secondary-progressive course in 2005 and treated with mitoxantrone until mid 2015. Ocrelizumab was started towards the end of 2018 (so this developed on ocrelizumab). Roughly 4 weeks after the second course of ocreluzimab he experienced a focal seizure involving the right arm. A subsequent CSF examination revealed an increased cell count, predominantly lymphocytes (WCC 559/ul; 546/ul mononuclear cells), and PCR positivity for HSV-2. Aciclovir was started, as well as anti-epileptics with recovery. A follow-up CSF examination revealed normalization of the cell count and drop in HSV-2 copy numbers to 1206 copies/ul. The CD19 lymphocyte level was 15.9% after the first dose of ocrelizumab and had dropped to 5% at the time of infection.
Ocrelizumab is a recombinant humanized monoclonal antibody directed against CD20-expressing B-cells; it results in antibody-dependent cellular cytolysis following cell surface binding to B lymphocytes (see figure above). In RRMS trials 58% of ocrelizumab treated individuals experienced one or more infections compared to 52% with Rebif; in PPMS trial 70% of ocrelizumab treated individuals experienced one or more infections compared to 68% on placebo (dummy tablet).
“In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in OCREVUS-treated patients than in REBIF-treated patients, including herpes zoster (2.1% vs. 1.0%), herpes simplex (0.7% vs. 0.1%), oral herpes (3.0% vs. 2.2%), genital herpes (0.1% vs. 0%), and herpes virus infection (0.1% vs. 0%). Infections were predominantly mild to moderate in severity. There were no reports of disseminated herpes. In the placebo-controlled (PPMS) clinical trial, oral herpes was reported more frequently in the OCREVUS-treated patients than in the patients on placebo (2.7% vs 0.8%)” (Genentech prescribing information).
As ocrelizumab is relatively new (FDA approval March 2017, EMA Jan 2018), long-term data is sadly lacking. It is important to note that unlike other DMTs, following the first infusion of ocrelizumab B cell counts are reduced within 2 weeks and remain at a low level throughout the treatment. B cells recover to baseline/lower limit of normal only 2.5 years after discontinuation in 90% of individuals.
Given that HSV-2 encephalitis is a serious outcome and that the MRI head scan is likely to be normal (possibly because of the lack of inflammatory response that results in the FLAIR abnormality on MRI), the safest scenario maybe to investigate for subclinical HSV in the CSF prior to starting ocrelizumab.
HSV-2-encephalitis in a patient with multiple sclerosis treated with ocrelizumab.
Here, we report the case of a 61-year-old man (K.H.) with secondary progressive multiple sclerosis, who suffered from HSV-2-encephalitis under treatment with ocrelizumab. First symptoms of a relapsing–remitting multiple sclerosis occurred in 1997. In November 2005 he developed a secondary progressive course, and hence next year the diagnosis of that type of multiple sclerosis was established. He had developed left-sided spastic hemiparesis and neurogenic bladder dysfunction. Despite treatment with mitoxantrone until May 2015 he developed spastic tetraparesis and in 2017 dysarthria. In September 2018 ocrelizumab was started with an initial dose of 300 mg and a second dose of 300 mg at the end of the month. Against spasticity he had received 4-aminopyridine for several years and triamcinolon intrathecally once a year. No other immunosuppressive or immunomodulatory drugs were applied between the termination of mitoxantrone and the start of ocrelizumab. The last treatment with triamcinolon was 3 months before the first administration of ocrelizumab. Nevertheless, he was unable to walk and his left arm was almost plegic. About 4 weeks after the second application of ocrelizumab he developed severe headache and the following day a bilateral clonic seizure with movements mainly of the right arm.