Q&A 71: Failing natalizumab - ocrelizumab or AHSCT?

Ocrelizumab is at about the same efficacy level as natalizumab. As this patient is not doing well on natalizumab we would tend to escalate to the next level.

Case study:

I am a 47-year-old male diagnosed with MS in September 2018 (EDSS 4.5). In mid-2017, I first noticed problems with my left eye but attributed them to my nearsightedness. By mid-2018, I began having issues with my big right toe, which started twitching. Shortly afterwards, I experienced severe cramps in my right leg, mild difficulty walking and clonus in my right foot.

The first MRI revealed four lesions in the brain (one affecting my left eye), one of which showed contrast enhancement, and five lesions in the cervical spine, none of which enhanced with contrast. Oligoclonal bands were positive in my spinal fluid.

In January 2019, I began treatment with intravenous natalizumab and was switched to subcutaneous in June 2022). By July 2019, there was some improvement. However, by late 2019, my hands started becoming stiff in the mornings, I developed myoclonus throughout my body, and my arms became weak. Tingling sensations and paresthesia were constant companions.

An MRI from June 2020 unfortunately showed new lesions in the cervical spine, as well as enlarged lesions and a small lesion in the thoracic spine. The MRI from November 18, 2020, revealed a new lesion at C3. I frequently dealt with myoclonus, extremely vivid reflexes in all extremities, and sensory disturbances. I was never wholly symptom-free and have had many courses of steroids with moderate success since my diagnosis. However, I never experienced severe relapses with paralysis.

In June 2023, an MRI revealed an enlarged lesion at C7. Last summer, I again experienced severe cramps in my right leg and received 6g of methylprednisolone. This led to temporary improvement, and I could walk several km with the help of diazepam.

The last two MRIs of the spine in January 2025 revealed enlarged and more pronounced lesions throughout the cervical spine segment. The brain MRI remained stable, but black holes were detected. No iron rim lesions were observed.

My questions:

1. My neurologist mentioned that the smouldering component might now be predominant in my case due to the presence of slowly expanding lesions, though he also suggested that the lesions could have formed as part of the relapse in the summer of 2023. As a result, he proposed a corticosteroid pulse, which I had a few days ago. Initially, there was a brief improvement, but after a day, my condition returned to its previous state.

If the smouldering component truly predominates, what should I do therapeutically? There seem to be no medications available for this. Tolebrutinib or other BTKs are still not available.

2. My neurologist and I are considering switching from natalizumab to ocrelizumab, as new lesions under Tysabri are not a good sign. Another MS expert has also recommended ocrelizumab, as it is presumably more effective in preventing a rebound after stopping natalizumab than ofatumumab. Is this switch sensible? Ocrelizumab, however, is not effective against smouldering MS.

3. I could access all available medications, including AHSCT, in Europe. Would AHSCT be a better option than ocrelizumab?

4. By switching to ocrelizumab, would I jeopardise the possibility of transitioning to BTK inhibitors later?

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Prof G’s answer

Q1. My neurologist mentioned that the smouldering component might now be predominant in my case due to the presence of slowly expanding lesions, though he also suggested that the lesions could have formed as part of the relapse in the summer of 2023. As a result, he proposed a corticosteroid pulse, which I had a few days ago. Initially, there was a brief improvement, but after a day, my condition returned to its previous state.

If the smouldering component truly predominates, what should I do therapeutically? There seem to be no medications available for this. Tolebrutinib or other BTKs are still not available.

My first reaction is, why is this patient unresponsive to natalizumab? ……