What if a patient with multiple sclerosis has an acute relapse, but standard treatment with methylprednisolone does not bring any improvement? As it stands, the guidelines recommend a second cycle of double-dose steroids. A German study has now shown that visual, motor and sensory abilities are better preserved through immunoadsorption – an important finding for updating current guidelines. 
Significant progress has been made over the past 20 years in the long-term immunomodulatory treatment of multiple sclerosis. However, the same cannot be said for the treatment of acute relapses, explain Steffen Pfeuffer, MD, and his colleagues at the University of Münster in the Journal of Neuroinflammation. Current practice still involves the administration of high-dose intravenous methylprednisolone, 1000 mg per day for 3-5 consecutive days.
However, approximately 25% of patients respond insufficiently to this first cycle. Therefore, the guidelines recommend a second double-dose cycle. Only if this second cycle results in no improvement is immunoadsorption (a form of apheresis) offered as an alternative.
A separator divides plasma and cells
Immunoadsorption is an extracorporeal procedure that removes (auto)antibodies and immune complexes to treat autoimmune diseases or solid organ transplant rejection. Plasma is continuously separated from the cellular components of blood and passed through an adsorber which binds pathogenic substances. Thus, it is “cleaned” and can be put back into circulation.
Immunoadsorption has already proven to be a lifeline when methylprednisolone failed. Studies in patients with a clinically isolated syndrome or relapsing-remitting multiple sclerosis have produced response rates of up to nearly 90%. However, a disadvantage is that it is an invasive method as it requires a central venous catheter. The costs are also relatively high.
The mechanisms of action also differ:
Methylprednisolone almost exclusively targets T lymphocytes by inducing apoptosis.
In contrast, immunoadsorption with tryptophan ligand removes soluble immunoglobulins such as IgG and IgM.
So how does immunoadsorption compare to a double-dose second cycle of methylprednisolone in terms of safety and effectiveness? The knowledge would be relevant for the guidelines, but such a comparison has not been made to date.
The disease had not yet progressed much
Pfeuffer and his team have now made this comparison using a prospective observational study. The study involved 42 patients with multiple sclerosis from the Department of Neurology at the University Hospital of Münster, Germany, all of whom were still quite young (average age 35) and in the early stages of their disease. The patients had previously received a first cycle of 1000 mg of methylprednisolone for an acute flare, but without significant success.
Of these, 26 received a new cycle of methylprednisolone, but this time at 2000 mg per day for five consecutive days. This was accompanied by prophylaxis against gastric ulcers, venous thrombosis and osteoporosis.
Sixteen patients were assigned to tryptophan column immunoadsorption: six sessions in 1 week, in addition to anticoagulation with unfractionated heparin.
A battery of blind tests
Two neurologists examined the patients before immunoadsorption or the second cycle of methylprednisolone, respectively, then at discharge and once 3 months later, without receiving information on the type of treatment the patients received. The Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite Test (MSFC), and SF36 questionnaire to assess health-related quality of life were used for assessment.
Patients also underwent electrophysiology tests, including visual evoked potentials and somatosensory evoked potentials. To gather information on immunological changes, cellular components of blood were determined by flow cytometry and soluble factors by serum analyses.
The analysis revealed the significant advantages of immunoadsorption over a second, higher dose methylprednisolone pulse – not only directly after the respective treatments, but also at follow-up assessment.
Probability of a favorable outcome calculated
At discharge, the odds ratio for a complete or moderate response was 11 in favor of immunoadsorption. This means that patients on immunoadsorption were 11 times more likely to obtain this positive result than the reference group on steroids. In other words: The symptoms completely improved in 19% of these patients, and then not all in such a large proportion. While for methylprednisolone the corresponding values were 4% and 62%. Moderate symptom relief was experienced by the remaining participants.
During the evaluation 3 months later, the researchers were mainly interested in the number of completely cured patients. At this point, a patient was 103 times more likely to belong to the higher group if he had undergone immunoadsorption. In the methylprednisolone group, 50% were still non-responders, against none on immunoadsorption.
The authors also consider it noteworthy that it took longer for relapse to occur after immunoadsorption than after methylprednisolone administration: a median of 104 days versus 88 days. The most common symptom of relapse was optic neuritis.
Performance scales indicate severity of disability
EDSS scores did not differ significantly at discharge between each group, but immunoadsorption produced better values at follow-up. In contrast, MSFC scores were significantly more favorable at both appointments. Similarly, the information provided by the patients in the SF36 questionnaire suggested a better quality of life with immunoadsorption.
Flow cytometry revealed a profound reduction in B cells following immunoadsorption (from 253/µL to 148/µL) closely correlated with clinical improvement, the researchers found. The number of B cell-bound cytokines also dropped.
The researchers therefore assume that the reduction of B lymphocytes and the modulation of their function is an essential mechanism of action for immunoadsorption. In contrast, methylprednisolone had only minimal effects on these cell populations.
Even with measurements of electrical activity in fast-conductive sensory nerve fibers (somatosensory evoked potentials), the immunoadsorption group fared much better, at least in the follow-up assessment.
Improvement could also be detected in biomarkers
The level of neurofilament light chains (NfL) in serum decreased significantly with immunoadsorption, but not with methylprednisolone. The structural protein NfL constitutes a main component of the cytoskeleton of neurons. Since degradation of myelin sheaths is associated with axonal degeneration, the amount of NfL in serum increases. Therefore, the protein is well suited as a marker to monitor multiple sclerosis therapy, progression and relapses.
Immunoadsorption is also more favorable in terms of safety results. At least one adverse event occurred in 14 out of 16 patients, and most commonly these were hypocalcemia and hypotension. However, the jugular central venous catheter was dislocated in two patients, and displacement of the catheter from a jugular vein to an inguinal vein was unavoidable in two other patients. In one case, catheter-associated sepsis developed and required treatment with vancomycin.
Some serious side effects
Methylprednisolone therapy proved to be more critical. Under this therapy, the 26 patients developed adverse effects, most often hyperglycemia, sleep disturbances, tachycardia, hypokalemia and arterial hypertension. Sixteen patients required temporary insulin and potassium substitution. Four patients developed anxiety states and clinically significant affective disorders.
One patient suffered liver damage and an otherwise healthy 26-year-old suffered from osteomyelitis of the left hip with subsequent sepsis, which required hip replacement surgery.
Three patients developed acute psychosis, but in two of them it regressed a few days after stopping the steroid. However, the other patient had to be admitted to a psychiatric clinic and treated with long-term antipsychotics.
Concerning these complications, the authors summarize: “The safety of methylprednisolone is debatable, whereas for immunoadsorption, the use of the central venous catheter requires the greatest caution.
“Generally, both treatments visibly altered cytokine networks. It is unknown whether cytokine levels were affected by immune cell modulation. In the context of immunoadsorption, they were simply removed from circulation by non-specific binding to tryptophan columns,” the scientists write.
Simply immunoadsorption instead of double steroid?
Since 9 of the 26 patients treated with methylprednisolone recovered only partially despite two cycles, they also underwent immunoadsorption afterwards. It should be noted here that the two cycles of methylprednisolone before immunoadsorption hindered clinical recovery and the reduction in NfL values was also weaker.
As a cause of the limited efficacy of immunoadsorption, Pfeuffer and colleagues postulated that high-dose methylprednisolone modulates the blood-brain barrier and protein distribution in the blood. Since immunoadsorption was also carried out relatively late in these patients, the “window of time” in which modulation of the immune system leads to relief of neurological deficits may also have already closed.
“In view of these results, it is worth asking whether, in the case of relapses of steroid-refractory MS with deficits relevant to daily life, immunoadsorption should follow directly instead of the second corticosteroid therapy currently recommended”, has said Ralph Gold. , MD, PhD, director of the University Clinic for Neurology in Bochum, Germany, in a report. “The results of the study could therefore influence guidelines for the treatment of escalating acute relapse MS.”
1. Pfeuffer S, et al: J Neuroinflammation (online) September 7, 2022
This content originally appeared on The German edition of Medscape.
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