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A pilot study comparing treatments for severe attacks of neuromyelitis optica spectrum disorders: Intravenous methylprednisolone (IVMP) with add-on plasma exchange (PLEX) versus simultaneous ivmp and PLEX
Division of Neurology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, 10700, ThailandMedicine Department, Nan Hospital, Nan, 55000, Thailand
Division of Neurology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, 10700, ThailandDivision of Neurology, Department of Medicine, Bumrungrad International Hospital, Bangkok, 10110, Thailand
Added-on PLEX in steroid non-responder is commonly conducted for NMOSD attack.
•
A prospective study between IVMP added-on PLEX and simultaneous IVMP+PLEX was done.
•
Both methods, preferable simultaneous therapy, showed benefit in acute NMOSD attack.
•
Simultaneous IVMP+ PLEX therapy should be inspired in acute severe attack of NMOSD.
Abstract
Background
: Our previous retrospective study demonstrated that NMOSD patients with an acute attack who did not respond to IVMP alone, however, showed further significant improvement after treatment with PLEX at 6 month-follow-up.
Objective
: To compare the efficacy between treatments with intravenous methylprednisolone (IVMP) with subsequent add-on plasma exchange (PLEX) and a combination of simultaneous IVMP and PLEX in neuromyelitis optica spectrum disorders (NMOSD) patients with a severe acute attack.
Method: We conducted a prospective, randomized, controlled, pilot study of the treatments for a severe acute attack in NMOSD patients.
Results
: There were eleven AQP4-positive NMOSD patients in the study. One received only IVMP, five received IVMP with subsequent add-on PLEX treatment, and the other five received simultaneous IVMP and PLEX treatment. The attacks comprised myelitis (57.1%) and optic neuritis (42.9%). Both treatments with IVMP followed by subsequent add-on PLEX when needed (not-respond to IVMP treatment) and a combination treatment of simultaneous IVMP+PLEX from the outset showed clinical improvement measured by EDSS at 6 months follow-up, compared to those at the attacks (p-value = 0.07 in IVMP add-on PLEX group and p-value = 0.05 in IVMP+PLEX group), respectively. Although, a trend of a better outcome stratified by EDSS toward early PLEX initiation with IVMP+PLEX treatment was observed at 6 months follow-up, however not significantly.
Conclusion
: Early treatment with PLEX should be encouraged especially in NMOSD with a severe acute attack.
Neuromyelitis optica spectrum disorders (NMOSD) is an inflammatory disease of the central nervous system (CNS) characterized by severe optic neuritis (ON) and transverse myelitis (TM). The aquaporin-4 (AQP-4) antibody is an autoantibody directed against AQP-4, a water channel highly expressed on the foot processes of astrocytes in the CNS (
Despite unclear evidence-based medicine studies, administration of high-dose intravenous methylprednisolone (IVMP; 1 g daily for 3–7 consecutive days) (
) is typically the initial treatment given to reduce disease severity at the time of the NMOSD attacks in order to restore neurological function. However, in some cases, this first-line treatment is not sufficient to reduce the inflammatory process, and another strategy needs to be used, most notably, PLEX (
Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the writing committee of the american society for apheresis: the seventh special issue.
), which assign category II to neuromyelitis optica, PLEX is accepted as the second-line therapy for acute steroid-refractory NMOSD. Since the widely used steroid treatment usually fails to control severe attacks, specific add-on treatments have to be considered in order to limit the residual impairment. Given that a strong humoral response is a characteristic of NMOSD physiology, one might assume PLEX to be particularly well adapted to severe NMOSD relapses (
) has demonstrated a favorable response to this treatment modality, but no published study has compared PLEX to IVMP in a severe acute attack of NMOSD.
Our previous retrospective study demonstrated that NMOSD patients with an acute attack who did not respond to IVMP alone, however, showed further significant improvement after treatment with PLEX at 6 month-follow-up (
). We, therefore, performed a prospective comparison study between treatments with intravenous steroid with an add-on PLEX (IVMP add-on PLEX) if deemed necessary and a combination of simultaneous intravenous steroid and PLEX (IVMP + PLEX) in NMOSD patients with a severe acute attack.
2. Materials and methods:
2.1 Patients and study design
We performed a prospective, randomized, controlled, pilot study of the treatment for patients who were diagnosed with an acute severe NMO attack within 30 days of the onset of symptoms. All of the patients were admitted for treatments and follow-up at Siriraj Hospital, Bangkok, Thailand between January 2016 and December 2018. All patients were included in the study if they were 1) 18 years or older, 2) meeting the criteria for NMOSD (International Consensus Diagnostic Criteria, 2015) (
), 3) having a severe NMOSD attack based on our definition and 4) having at least 6 months of follow - up after the treatment. Patients were excluded if they had 1) a period of fewer than 90 days from the last NMOSD attack, 2) a previous treatment with an intravenous steroid within the last 30 days, 3) a severe or uncontrolled infection, and 4) hemodynamic instability.
Patients who were eligible for the study were randomized by using the research randomizer website
to either arm of the treatment, with IVMP add-on PLEX or IVMP + PLEX. IVMP add-on PLEX was defined as a treatment regimen with IVMP 1 g/D for 7 consecutive days and then subsequently centrifugal PLEX was given only if a patient was not responding to the IVMP treatment as per our previous definition used (
); the assessment was made on day 7 after the first day of IVMP initiation. IVMP + PLEX was defined as a treatment regimen with a combination of simultaneous IVMP 1 g/D for 7 consecutive days and centrifugal PLEX method. PLEX was performed on alternate days for 5 sessions, starting on the first day of IVMP treatment, with 1 liter of total plasma volume exchanged for a similar volume of 5% albumin. We obtained data regarding baseline characteristics of the patients including documented relapses and neurological examinations, radiographic data, treatment details during their hospitalization and follow-up outpatient visits, and adverse events (Fig. 1).
Fig. 1Flow diagram of the patients with NMOSD who were eligible for the inclusion criteria. IVMP; intravenous methylprednisolone, NMOSD; neuromyelitis optica spectrum disorders, PLEX; plasma exchange * VA improved by 2 lines of the Snellen chart but patient refuse to have PLEX done.
) less than 6, which cannot be explained by other causes.
2. Hemodynamic instability or respiratory failure that cannot be explained by other causes than NMOSD attack.
To exclude pseudorelapse, all relapses must last at least 24 h in the absence of fever or infection and must be confirmed by gadolinium enhancing lesion on neuroimaging and/or ophthalmologic examination before entering into the study.
2.1.2 Definition of non-responders
The responses of IVMP in the IVMP add-on PLEX were assessed at day 7 after the first day of initiation of IVMP treatment. A non - responder was defined as any of the following was met:
For a TM attack, a non - responder was defined as having no improvement of at least 1 grade of MRC Scale for Muscle Strength (
For an ON attack, a non - responder was defined as having no improvement in visual acuity > 2 lines of the near chart vision with a baseline visual acuity ≥ 0.025 or 1 step better if the baseline visual acuity was worse than counting fingers (
For attacks at other locations, a non - responder was defined as having no clinical improvement or getting worse of the symptoms as evaluated by the clinicians.
2.1.3 Outcome measurements
We recorded the clinical parameters at several times points, namely at baseline, at the nadir of the attacks, day 7 after the attack onset, at the time of discharge and at 1-, 3 - and 6 - month follow - up visits. EDSS and the changes of EDSS (ΔEDSS) were displayed as the mean of the difference between each time point of EDSS score and the nadir EDSS score. A change in EDSS over time was calculated intra-individually for each patient at different time points.
The primary outcome was an improvement of the EDSS score of at least one point at any time of follow-up visits. We also documented a change of MRC Scale for Muscle Strength in a severe TM attack, a change of log MAR (
All statistical analyses were carried out using SPSS Statistics for Windows, version 18 (SPSS Inc., Chicago, IL, USA). The patients’ data were presented as mean ± SD, median with minimum and maximum values, frequency, and percentage. Categorical variables were compared using the chi-squared test. Continuous variables were compared using the t-test or Mann–Whitney U test. Predictive factors of response were determined by logistic regression analysis. The results were expressed as odds ratio (OR), 95% confidence intervals (CI), and P values. After the number of univariate predictive factors had been determined, a forward stepwise selection was carried out to determine the appropriate multivariate model. Factors selected for the multivariate model were those found significant in the univariate model.
3.1 Standard protocol approvals, registration and patient consents
The study's protocol was approved by the Siriraj Institutional Review Board 671/2558 (EC4) and registered for Thai Clinical Trials Registry with TCTR identification number TCTR20160314002. All patients gave written inform consent.
4. Results
There were 11 NMOSD patients with a severe acute attack eligible in this pilot study. One with severe ON attack received only IVMP treatment and improved by 2 lines of the Snellen chart (20/100) on day 7 but did not want to have PLEX; therefore, she was omitted in the analysis for the outcome measurements. Another five received treatment with IVMP add-on PLEX after meeting the definition of non-responders, and the other five patients received IVMP + PLEX regimen. All were Thai women with the mean age at the attack of 37.9 ± 14.7 years. The majority of the patients had an attack centered at the spinal cord (57.1%), followed by the optic nerve (42.9%). None presented with severe brainstem attack. All of the patients were AQP4 serology positive. Sixty-seven percent of the IVMP add-on PLEX group and 60% of the IVMP+PLEX group received immunosuppressant. The mean nadir EDSS score at the time of the attacks seemed to be higher in the group of IVMP+PLEX, but not significantly different (EDSS 7.2 in IVMP+PLEX vs 6.7 in IVMP add-on PLEX group, p = 0.67). The median interval time from the clinical attack to the first day of IVMP initiation and those to the first day of PLEX initiation were 8 days and 10.5 days for the IVMP add-on PLEX group and 5 days and 5 days for the IVMP+PLEX group, respectively. The IVMP+PLEX group had a more severe motor disability when having a severe acute TM attack and a worse visual disturbance when having a severe ON attack, compared to those of the IVMP add-on PLEX group. The IVMP+PLEX group seemed to have an older age at onset and age at attack, higher frequency of TM attacks and concomitant with type 2 DM, and worse EDSS prior to the attack than those of IVMP add-on PLEX group. Both had no significant differences in sex distribution, AQP4 status, duration of the disease, and annual relapse rate prior to an attack event. The IVMP add-on PLEX group tends to have more patients with autoimmune disease and the presentation with simultaneous TM and ON than those of IVMP+PLEX group (Table 1).
Table 1Demographic characteristics
IVMP added on PLEX (*n = 5)
IVMP+PLEX (n = 5)
P-value
Age at onset, years; mean ± SD
37.40 ± 18.95
40.40 ± 12.07
0.74
Age at attack, years; mean ± SD
45.40 ± 15.69
48.60 ± 13.57
0.77
Female, n (%)
5 (100)
5 (100)
1.00
Concomitant diseases, n (%)
Diabetes mellitus
0 (0)
1 (25)
0.341
Hypertension
0 (0)
0
-
Dyslipidemia
0 (0)
0
-
Malignancy
0 (0)
0
-
Autoimmune disease
2# (40)
0
0.17
Duration of the disease, months; median (range)
79 (22–240)
77 (3–300)
0.98
Interval from clinical attack to the first day of IVMP initiation, days; median (range)
8 (3–13)
5 (4–21)
0.23
Interval from clinical attack to the first day of PLEX initiation, days; median (range)
10.5 (8-17)
5 (5-11)
0.02
Patients were receiving immunosuppressant, n (%)
4 (66.7)
3 (60)
0.59
Azathioprine
1 (25)
3 (100)
0.07
Mycophenolate mofetil
2 (50)
0 (0)
0.145
Prednisolone
1 (25)
0 (0)
0.341
AQP4-seropositivity, n (%)
5 (100)
5 (100)
-
Location of the attacks, n (%)
Spinal cord
2 (40)
3 (60)
0.44
Optic nerve
1 (20)
1 (20)
1.0
Brainstem
0
0
-
Cerebral
0
0
-
Multifocal involvement
0
0
-
ON+TM
2 (40)
1 (20)
0.549
Annualized relapse rate (ARR) prior to attack; median (min–max)
3 (1-14)
3 (0-4)
0.50
Pre-attack, median (range)
EDSS
1 (0–8)
2.5 (0–8)
0.775
mRS
1 (0–5)
1 (0–5)
0.14
EDSS at attack, median (range)
8 (0–8)
8 (3.5–8)
0.489
mean
6.7
7.2
0.67
omitted 1 patient who had only IVMP and denied PLEX, #Systemic lupus erythematosus, EDSS; Expanded Disability Status Scale, IVMP; intravenous methylprednisolone, PLEX; plasma exchange, mRS; modified Rankin Scale, MRC; Medical Research Council (MRC) Scale for Muscle Strength.
In both groups, the EDSS scores at discharge were not significantly improved compared to EDSS at the attacks. The IVMP add-on PLEX group showed an improvement occurred at 1 month after the attack (∆EDSS = - 0.5), with further improvement being demonstrated at 3 months and 6 months after the attack (∆EDSS = −0.9 and −1.2, respectively) whereas the IVMP+PLEX group demonstrated a similar pattern, with a faster improvement being demonstrated at 1month, 3 months and 6 months, respectively (∆EDSS = −0.80, −1.4 and −1.8, respectively). Comparing between the two groups, there were no statistically significant differences in their mean EDSS changes at any time point. Nevertheless, both treatment regimens showed significant EDSS improvement at 6 months follow-up compared to the EDSS at the attack (p-value = 0.07 in IVMP add-on PLEX group and p-value = 0.05 in IVMP+PLEX group, respectively) (Fig. 2A).
Fig. 2(A) Comparison of the changes in EDSS scores in patients with NMOSD between the treatment with IVMP add- on PLEX and IVMP+PLEX groups at different time points At 6 months follow up, both treatment showed significant improvement, measured by the change in EDSS compared to EDSS at attack (P-value=0.07 for IVMP add-on PLEX group and P-value= 0.05 for IVMP+PLEX group, respectively) EDSS; Expanded Disability Status Scale, IVMP add-on PLEX; intravenous methylprednisolone followed by subsequent plasma exchange when not respond to steroid treatment, IVMP+PLEX; simultaneous intravenous methylprednisolone with plasma exchange, NMOSD; neuromyelitis optic spectrum disorders. (B) Comparison of the changes in motor rating score (MRC) in patients with NMOSD between the treatment with IVMP add- on PLEX and IVMP+PLEX groups at different time points At 6 months follow up, both treatment showed significant improvement, measured by the change in MRC compared to MRC at attack (P-value=0.03 for IVMP add-on PLEX group and P-value= 0.05 for IVMP+PLEX group, respectively) EDSS; Expanded Disability Status Scale, IVMP add-on PLEX; intravenous methylprednisolone followed by subsequent plasma exchange when not respond to steroid treatment, IVMP+PLEX; simultaneous intravenous methylprednisolone with plasma exchange, MRC; motor rating scale, NMOSD; neuromyelitis optic spectrum disorders. (C) Comparison of the changes in the log MAR score between the treatment with IVMP add- on PLEX and IVMP+PLEX groups at different time points At 6 months follow up, neither treatment showed significant improvement, measured by logMAR score compared to log MAR score at attack (P-value=0.78 for IVMP add-on PLEX group and P-value= 0.39 for IVMP+PLEX group, respectively). IVMP add-on PLEX; intravenous methylprednisolone followed by subsequent plasma exchange when not respond to steroid treatment, IVMP+PLEX; simultaneous intravenous methylprednisolone with plasma exchange, LogMAR; Logarithm of the Minimum Angle of Resolution, NMOSD; neuromyelitis optic spectrum disorders.
For NMOSD patients presented with severe acute TM attacks, the IVMP+PLEX group had more severe levels of disability with a mean MRC grade of 0.67 compared to those with MRC score of 2.0 in the IVMP add-on PLEX group. The MRC grade of the IVMP add-on PLEX group remained the same at the discharge then improved by a mean of 0.5 at 1 month after the attack and subsequently rose to 2.0 and 2.5 at the 3- and 6-months follow-up whereas the mean MRC improvement in the IVMP+PLEX group improved by 0.67 at the discharge then climbing to 1.67, 3.67, and 4.5 at the 1-, 3-, and 6-months follow-up period. At 6 months follow-up, subjects in the IVMP+PLEX group tended to demonstrate greater improvement in their motor strength than those in the IVMP add-on PLEX group, however not statistically significant (∆MRC = 2.50 for the IVMP add-on PLEX group vs 4.5 for the IVMP+PLEX group; P-value = 0.12). Both treatment groups had significant motor improvement, measured by an improvement of MRC, at 6 months compared to MRC at the attack (p-value = 0.03 in IVMP add-on PLEX group and p-value = 0.05 in IVMP+PLEX group, respectively) (Fig. 2B).
Moving on to the log MAR scale for a severe acute ON attack, there was initially slow visual improvement, then it continued to have a faster recovery after 3 months in the group received IVMP +PLEX regimen. Even visual improvement in the IVMP add-on PLEX group seemed to be observed at the beginning, it declined its efficacy after 3 months. However, at 6 months, neither group showed significant visual improvement, measured by the LogMAR compared to the LogMAR at attack (p-value = 0.78 in IVMP add-on PLEX group and p-value = 0.39 in IVMP+PLEX group, respectively). The IVMP+PLEX group tended to have a more favorable visual outcome at 6 months follow-up, although not significantly (∆logMAR = −0.1 for the IVMP add-on PLEX vs −1.4 for the IVMP+PLEX group; P-value = 0.22) (Fig. 2C).
At 6 months follow-up, NMOSD patients with a severe attack who received IVMP+PLEX showed a higher proportion (80%) of those with clinical improvement measured by EDSS scores, compared to EDSS at the attack, than those received treatment with IVMP add-on PLEX (60%), although not significantly (OR 2, 95% CI, 0.125–31.97, P = 0.545). Two-fifth of the subjects in the IVMP add-on PLEX group and one-fifth of those with IVMP+PLEX treatment had improved their EDSS scores to equal or below their baseline EDSS scores at 6 months follow-up (Table 2). Responses of each patient in both groups measured by EDSS at a different time point were displayed in Fig. 3A and B.
Table 2The proportion of EDSS improvement at 6-months follow-up of the patient with NMOSD with severe acute attack in each treatment regimen.
Treatment EDSS at 6months
IVMP added on PLEX (n = 5)
IVMP+PLEX (n = 5)
p-value
EDSS score improvement (vs EDSS at attack)
3 (60%)
4 (80%)
0.545
EDSS ≤ pre-attack EDSS
2 (40%)
1 (20%)
0.637
IVMP add-on PLEX; intravenous methylprednisolone followed by subsequent plasma exchange when not respond to steroid treatment, IVMP+PLEX; simultaneous intravenous methylprednisolone with plasma exchange, NMOSD; neuromyelitis optic spectrum disorders.
Fig. 3Outcome response measured by EDSS of individual NMOSD patient with severe acute attack in each group of the treatment at different time points IVMP add-on PLEX; intravenous methylprednisolone followed by subsequent plasma exchange when not respond to steroid treatment, IVMP+PLEX; simultaneous intravenous methylprednisolone with plasma exchange, NMOSD; neuromyelitis optic spectrum disorders.
If we categorized patients by level of disability measured by EDSS into 4 groups; EDSS 0–2.5 = minimal disability, EDSS 3–5 = mild disability, EDSS 5.5–7 = moderate disability, and EDSS >7 = severe disability, we found patients receiving IVMP+PLEX treatment had a higher frequency of who had severe disability at the attack than those receiving IVMP add-on PLEX (60% vs 50%). Both groups of the patients showed a decrement of EDSS score after the treatment compared to nadir EDSS at the attack. The shifting status from severe disability level (EDSS >7) to a lesser degree of disability level was found more often and earlier in those receiving IVMP+PLEX group, although no statistical significance (Fig. 4).
Fig. 4Distribution of disability level categorized by EDSS scores at different time points of each treatment regimen. IVMP add-on PLEX; intravenous methylprednisolone followed by subsequent plasma exchange when not respond to steroid treatment, IVMP+PLEX; simultaneous intravenous methylprednisolone with plasma exchange, NMOSD; neuromyelitis optic spectrum disorders.
Corresponding to other measurements, mRS also showed a trend of better mobility in favor the group treated with IVMP+PLEX, however not significant.
4.2 MRI findings
The length of the spinal lesions were 6 and 15 VBs for TM attacks and 4 and 7 VBs for ON+TM presentation in the IVMP add-on PLEX group and 6, 7, 7 VBs for TM attacks vs 4VBs for ON+TM presentation in the IVMP+PLEX group, respectively. The optic involvement revealed lesion about half of optic nerve length in the former and longer than half including chiasm lesion in the latter. However, these was no association between the outcome measurement and MRI findings at the attack location.
4.3 Relapse rate after treatment
In our clinic, we initiate both oral prednisolone (OPN) + immunosuppressant, if no contraindication, after seropositive NMOSD diagnosis is made. OPN will taper off within 3–6 months and maintain with immunosuppressant.
During the 6-month period following treatment, 3 out of the 11 patients relapsed; 2 relapses occurred in the IVMP add-on PLEX group with the average time to relapse of 3.2 months whereas the other in the IVMP+PLEX group had a relapse 2 months after discontinuation of the immunosuppressive drug.
4.4 Treatment-related adverse events
There were 15 adverse events related to the treatment from a total of 8 patients. One had an accidental arteriovenous fistula (6.7%) from double lumen insertion and needed closure surgery. One developed an episode of transient hypotension (6.7%) during PLEX treatment but was stabilized after intravenous crystalloid replacement. There were 6 incidents of hypofibrinogenemia without clinical bleeding (40%), 2 incidents of hypocalcemia with muscle cramp (13.33%), 3 incidents of asymptomatic hypocalcemia PLEX (20%), 1 case of steroid-induced hyperglycemia (6.67%), and 1 case of deep venous thrombosis (6.67%).
5. Discussion
Our pilot study comparing the two treatment regimens for a severe acute attack of NMOSD demonstrated that each treatment either with IVMP followed by subsequent PLEX when needed (not-respond to IVMP treatment) or a combination treatment of simultaneous IVMP+PLEX from the outset resulted in clinical improvement measured by EDSS at 6 months follow-up, compared to those at the attacks (p-value = 0.07 in IVMP add-on PLEX group and p-value = 0.05 in IVMP+PLEX group, respectively). However, there were no statistically significant differences in the EDSS outcomes between the two groups at the 1-, 3- and 6-month follow-ups. While high dose corticosteroid mainly affects the inflammatory cascade and control of vascular integrity (
Efficacy of methylprednisolone pulse therapy for acute relapse in Japanese patients with multiple sclerosis and neuromyelitisoptica: a multicenter retrospective analysis -1. Whole group analysis.
), PLEX treatment is not only removing pathologic AQP4 antibody but also complementing cytokines and other inflammatory mediators, the main contributors to the pathogenesis of NMOSD (
Clinical efficacy of plasmapheresis in patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels.
). As a consequence, the earlier treatment with PLEX for a severe acute attack of NMOSD may have more benefit and provide a greater improvement than a delayed PLEX. Moreover, the previous study (
) showed a better disability outcome of NMOSD patients with acute TM attacks if they received PLEX within 2–3 weeks after the attack onset compared to those who had a delayed treatment. Our study had a short interval from clinical attack to PLEX initiation with an average of 10.5 days in the IVMP add-on PLEX group and 5 days in the IVMP+PLEX group. One study demonstrated that the amount of prednisolone removed by PLEX was less than 1% of the administered prednisolone dose and the changes in pharmacokinetic values for prednisolone attributable to PLEX were minimal so that supplemental dosing of prednisolone following PLEX appears unnecessary (
). Therefore, we assume that an early combination treatment with simultaneous IVMP and PLEX would have a synergistic effect and may give a greater improvement on disability outcome of NMOSD patients with severe acute attacks. Since our study had early judgment for PLEX treatment in both treatment groups with only 6 days different, it may be difficult to see a significantly different outcome between the two groups. A trend of a better outcome stratified by EDSS toward early PLEX initiation in the group receiving IVMP+PLEX treatment was observed at 6 months follow-up, however not significantly.
Although a greater improvement in favor of IVMP+PLEX was observed both in the group of patients with severe acute TM attacks and in the group of severe acute ON attacks, it was more obviously seen in the former group since the beginning of the treatment than in the latter group which can be obviously detected 6 months later. These findings were corresponding to the previous study showing a lesser benefit after PLEX treatment in ON attack compared to TM attack (
We also found a trend of faster recovery and a better improvement in disability level assessed by EDSS range and mRS in patients receiving IVMP+PLEX treatment than those received IVMP add-on PLEX treatment.
), we found only minor adverse events, except one with AV-fistula, occurred during catheter insertion, however, was manageable. The adverse events could be ameliorated with peripheral techniques assessment for Apheresis, however, it is not yet widely used in our institute. Nevertheless, the expecting benefit from PLEX treatment for NMOSD patients with severe attacks would overcome the risk from PLEX procedure.
Our previous retrospective study showed a trend of having a better outcome in NMOSD patients with acute attacks when PLEX was added on to patients who did not respond to IVMP treatment, similar to what we do in routine clinical practice (
). This present study was different from the previous one that it was a prospective study, comparing the common practice with add-on PLEX to steroid-unresponsive NMOSD patients with an acute attack and the combination of simultaneous IVMP and PLEX, focusing only on a severe acute attack. Although the result of the study did not show a significant difference between the two treatments, a trend of favoring the combination IVMP+PLEX treatment over IVMP add-on PLEX was observed. Whether the combination of simultaneous of IVMP and PLEX could be utilized as the first-line therapy for AQP4-seropositive NMOSD patients with a severe clinical attack needed further evaluation.
Our study has several limitations. Firstly, this is a pilot study with only a small number of patients. Secondly, we have no standard clinical outcome measurements or biomarkers to monitor the recovery of NMOSD patients other than EDSS, log MAR, MRC, and mRS. Future study and upcoming surrogate markers for an acute attack in NMOSD patients should guide our decision for the appropriate time to initiate PLEX and also the regimens.
6. Conclusion
Our randomized, controlled trial demonstrated that both IVMP add-on PLEX treatment and IVMP+PLEX treatment showed benefits in decreasing disability outcomes of NMOSD patients with severe acute attacks and a trend favoring the combination of simultaneous IVMP+PLEX treatment.
Funding
This work was supported by the Siriraj Hospital, Mahidol University, funding number R015937004
Dr. Songthammawat has nothing to disclose. Dr. Srisupa - Olan has nothing to disclose. Dr. Siritho has received funding for travel and speaker honoraria from Merck Serono, Pacific Healthcare (Thailand), Menarini (Thailand), Biogen Idec, UCB (Thailand), Eisai Inc, Sanofi-Aventis and Novartis. Dr. Kittisares has nothing to disclose. Dr. Jitprapaikulsan has received funding for travel and speaker honoraria from Novartis, Thailand, Bayer Schering Pharma, Easai Inc, Merck Serono, Thailand, Pfizer Pharamaceutical company, Sanofi-Aventis, outside the submitted work; Dr. Satukijchai: has received funding for travel and received speaker honoraria from Merck Serono, Eisai Inc, Sanofi-Aventis and Novartis. Dr. Prayoonwiwat has received funding for travel and received speaker honoraria from Bayer Schering Pharma, Eisai Inc, UCB, Thailand, Merck Serono, Pfizer Pharmaceutical Company Limited, Novartis, Sanofi-Aventis.
Acknowledgments
We are grateful to Wanichada Kosolthammakorn, M.T.; Natakorn Sangnumpong, B.Sc.; Leatchai Wachiruttamungkur, M.Sc.; Nopwan Siwasiriyanont, M.Sc.; Laddawan Champa, M.Sc.; Montira Engchuan, NS. for their technical support.
Clinical efficacy of plasmapheresis in patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels.
Efficacy of methylprednisolone pulse therapy for acute relapse in Japanese patients with multiple sclerosis and neuromyelitisoptica: a multicenter retrospective analysis -1. Whole group analysis.
Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the writing committee of the american society for apheresis: the seventh special issue.
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