This pilot open label study investigated the safety and preliminary efficacy of using IVIG over a 6-month period for treatment of MSA. IVIG treatment was well tolerated. Post-treatment functional assessment showed promising improvement of many areas of daily living activities. IVIG infusions were acutely associated with increase in blood pressure, but post-treatment orthostatic hypotension did not change significantly. Imaging studies have shown brain and cerebellar atrophy.
No serious AEs occurred as a result of the total 42 IVIG infusions. Previously reported AEs associated with IVIG, such as renal failure and thromboembolic events, did not occur in our cohort. Minor AEs are common with IVIG treatment and range from 2% to 25% per infusion
]. The most commonly reported AE’-associated with Privigen® is headache, which occurs in 65% of patients
]. No headaches were observed in our group. Skin reaction occurs rarely with IVIG. In our study two subjects developed pruritic rash and they withdrew for safety reasons. It is likely that rash in one subject was not related to IVIG because it persisted beyond 3 months after the last infusion, and then it was reassociated with a food allergy. The most common AE in our study was elevated BP, which occurred in all of the subjects. This appears to be an MSA-specific effect of IVIG or Privigen® since, to our knowledge, this is the first study reporting transient elevation of the BP due Privigen® infusions. Previous studies utilizing Privigen® observed infusion induced hypotensive reactions
]. However a transient BP elevation was reported with other IVIG preparations. In our cohort, elevated BP declined when the infusion rate was slowed down, or position changed from supine to semi recumbent or sitting or both. Allowing a subject to void was another effective maneuver to reduce BP.
The mechanisms leading to IVIG-induced BP elevation are unclear. BP changes were typically observed minutes after starting infusions rendering the effect of volume expansion unlikely. It also is unlikely that sensitization to IVIG plays a role in BP elevation because BP elevation occurred during the first infusion in six of seven participants. Possible mechanisms include the effect of a yet-to-be-determined substance in IVIG or a specific substance in Privigen®. Possible candidates are cytokines, vasoactive substances or other proteins, or L-prolin that is unique to Privigen®. MSA patients can have denervation hypersensitivity that can render them more sensitive to vasoactive substances in Privigen®. It is of interest to elucidate Privigen®-induced mechanisms of BP elevation given that, in general, treatment of hypotension in MSA can be difficult.
CRP as a marker of systemic inflammation did not change significantly following IVIG treatment. The main reason why the expected reduction of CRP was not observed in our trial was the fact that two subjects experienced viral infection at the final visit that increased CRP dramatically. Without these 2 subjects, the mean CRP would be reduced at the end of the trial compared to baseline.
Because a biomarker of MSA is not available, the UMSARS was chosen as a proxy for the disease stage. At present, UMSARS is the best instrument for evaluation of disease severity and disease progression
]. Baseline UMSARS scores in our study are similar to those of a progressive observational study by the North American MSA Group of 67 patients
]. In that study the average increases of the UMSARS score for part I and part II were equal to 3.1 and 4.5 points over 12 months. However, the European MSA study group
] showed a faster progression of MSA as indicated by the increase in UMSARS-I by 6.7 points and UMSARS-II by 9.6 points over 12 months. In our study, group averages showed decreases in the part I and part II scores. These results are encouraging, given that current therapies for MSA are only symptomatic.
This pilot trial was open label and therefore a placebo effect cannot be ruled out. Investigators who evaluated the UMSARS (PN, PR) were not blinded to the intervention, and so the rating could be biased. Only a larger placebo-controlled double-blinded study can effectively delineate the role of IVIG in the treatment of MSA. However, Privigen® appears to have a profound immediate effect on BP, as discussed above. This fact can complicate the blinding of future studies since BP responses to infusions can distinguish the interventions from placebo. On the other hand, there was no significant difference in systemic BP on UMSARS-III based on a comparison of screening rating and the final visit rating suggesting that hypertensive effect of Privigen® is transient and therefore theoretically should not “mask” the putative disease-modifying effect. This fact is important to consider since what appears to be a slowing of disease progression could be due to symptomatic drug affect.
The effect of IVIG on MSA remains to be clarified. The present study design was based on the assumption that brain inflammation contributes to MSA. Furthermore, IVIG enters the central nervous system only if the blood brain barrier (BBB) is disrupted
]. Although measurement of the extravasation of IVIG was never performed in MSA, BBB is impaired in MSA
] including at basal ganglia and at similar areas that show activation of microglia
]. However, it is not clear whether the disruption of blood brain barrier is necessary for IVIG to be effective with MSA. Alternatively, IVIG could exhibit its effect on systemic modulation of the immune system.
The imaging portion of the study showed significant differences in particular brain areas of MSA subjects as compared with controls. Our results are similar to those of previous studies
]. Our MSA patients had reduced gray matter volume mainly in cerebellum and putamen and increased in hippocampus. White matter volume was increased in frontal lobe, putamen, cerebellum and hippocampus. The significance of the increase of the white matter remains unclear. It may simply reflect that proportionally more gray matter was lost than true enlargement of the white matter.
We also compared volumes before and after the treatment 8 months apart. There was no significant difference in any of the analyzed variables. Previous studies
] showed interval progression in atrophy of brain tissue. For example, annualized rates of atrophy of MSA, parkinsonian variant, are 1.0% for the whole brain (controls 0.4%) but can be as high as 4.5% in the pons (controls 0.2%) or 3.2% in cerebellum (controls 0.3%). In our study, the volumes did not change between the pre- and post-treatment evaluations. However, our imaging comparison interval was shorter (8 months versus 1 year). These findings are also encouraging but need to be validated in larger studies with longer follow up.