Relapse management in multiple sclerosis (MS), although not clinically indicated in every case, provides symptomatic relief, which is particularly important when symptoms affect function. We review the evidence and practical applications for 3 relapse treatment modalities: 1) corticosteroids, 2) intravenous immunoglobulin (IVIg), and 3) therapeutic apheresis (TA).
Corticosteroids
Mechanism of Action
High-dose corticosteroids are generally the first line of treatment for MS relapse. Corticosteroids shorten relapse duration and improve symptoms by suppressing the immune system and reducing inflammation in the central nervous system through several pathways, including suppressing the production of proinflammatory cytokines and chemokines; inducing the production of anti-inflammatory cytokines; reducing the migration of inflammatory cells, such as leukocytes, into the central nervous system; stabilizing mast cell membranes, thus preventing them from releasing inflammatory mediators; and inhibiting the production of prostaglandins and other inflammatory mediators. In addition, corticosteroids are immunosuppressants, inhibiting the proliferation and inducing the apoptosis of lymphocytes, which may help prevent further relapses.1,2
Dosage
The optimal dosage and regimen of corticosteroids for an acute MS relapse have been debated. The Optic Neuritis Treatment Trial (ONTT; NCT00000146) was a large randomized controlled trial that compared the efficacy of 3 different treatments for optic neuritis (ON): high-dose intravenous methylprednisolone ([IVMP] Solu-Medrol; Pfizer, New York, NY) (1 g/day for 3 days) followed by oral prednisone taper (1 mg/kg/d for 11 days), oral prednisone alone (1 mg/kg/d for 14 days), and placebo. The primary outcome was visual acuity at 6 months. The results of the ONTT showed that high-dose IVMP followed by oral prednisone accelerated visual recovery compared with placebo. Participants in the 2 corticosteroid groups had no significant difference in visual acuity at 6 months, however. Low-dose oral prednisone alone was no better than placebo in terms of visual recovery and was associated with an increased risk of recurrent ON. In addition, those treated with IVMP followed by the oral taper had a temporarily reduced risk of a second demyelinating attack leading to a diagnosis of MS when compared with those who received a placebo or low-dose oral corticosteroids alone. Given these results, acute MS relapse is typically treated with 3 to 5 days of IVMP.3
Based on findings from the ONTT, there is no role for oral prednisone alone in standard doses. However, an oral prednisone dose of 1250 mg, which is equivalent to 1 g IVMP, is an option that is appealing to individuals because of convenience and cost. A bioavailability study comparing a single dose of IVMP with high-dose oral prednisone demonstrated that the area under the curve (a measure of the total amount absorbed) was similar between the groups. The study represented indirect evidence that an equivalent dose of oral prednisone has similar bioavailability to IVMP.4 A randomized clinical trial5 compared the efficacy and safety of high-dose oral methylprednisolone vs IVMP for treatment of MS relapses at 4 weeks. Oral corticosteroids were not inferior to IVMP in improving Expanded Disability Status Scale (EDSS) scores. On MRI, there were no significant differences seen in those taking either oral methylprednisolone or IVMP in the number and volume of gadolinium-enhancing (Gd+) lesions or the number of new or enlarged T2 lesions.5 This study was supported by a multicenter noninferiority trial6 in which 199 individuals were randomized to receive 1 g of oral methylprednisolone vs IVMP within 15 days of symptomatic onset. The primary outcome—the proportion of individuals who had at least 1-point improvement in the most affected score on the Kurtzke Functional System Scale—was met. The rate of adverse events was similar, except for insomnia, which was more frequent in the oral methylprednisolone group.6 If high-dose oral prednisone is used, a dose of 1250 mg every other day for 3 days is commonly used. A sucrose permeability test showed a similar incidence of gastric mucosal injury with 1250 mg of oral prednisone vs 1 g of intravenous Solu-Medrol (Pfizer, New York NY). The sucrose permeability test was previously shown to be a sensitive and specific test for gastric mucosal damage.7
In the ONTT, IVMP was followed by an oral prednisone taper. Another study8 compared the efficacy of IVMP followed by an oral prednisone taper with IVMP alone in treating MS relapses. Examining a cohort with similar EDSS at baseline and relapse confirmation, there was no difference between the 2 groups at 3, 6, and 12 months after relapse. Thus, an oral prednisone taper after IVMP for a confirmed MS relapse does not hasten or improve neurologic recovery at 1 year, and stopping a short course of high-dose corticosteroids without tapering is safe.8
Potential Complications
Because side effects of corticosteroids are typically related to dose and duration, the best practice is to use them for the shortest time possible to avoid long-term side effects, such as insulin resistance, osteoporosis, adrenal insufficiency, opportunistic infections, cataract formation, cardiovascular events, and more.9 In the short term, there are several recommendations to combat corticosteroids side effects. Corticosteroids can cause severe hyperglycemia, and it is recommended individuals undergo diabetic teaching and start sliding-scale insulin when on these high doses. To avoid gastrointestinal toxicity, individuals can take a proton pump inhibitor or an H2 blocker. For insomnia, sleep aids can be prescribed. Although short-term corticosteroids courses (<3 months) are less likely to contribute to bone thinning, individuals can supplement with vitamin D and calcium. Corticosteroids may also lead to electrolyte shifts, which can cause an elevation in blood pressure and edema. Low sodium and high potassium intake, and a diet avoiding simple carbohydrates is advised, which can also help mitigate weight gain attributable to water retention and excessive appetite. Although corticosteroids can suppress the immune system and increase the risk of infection, antibiotic prophylaxis is not recommended unless corticosteroids are taken for more than 4 weeks.9
Alternative
Acthar gel (adrenocorticotropic hormone [ACTH] gel; Mallinckrodt, St. Louis, MO) is an alternative to high-dose corticosteroids for the treatment of acute MS relapse in individuals who do not respond to or cannot tolerate corticosteroids. ACTH stimulates the adrenal cortex to produce cortisol in response to stress, acting as an agonist for several melanocortin receptors (MCRs). Binding of ACTH to MC2R (melanocortin 2 receptor) accounts for its steroidogenic effect; the strong affinity of ACTH to all MCRs (MC1R [melanocortin 1 receptor] through MC5R [melanocortin 5 receptor]) accounts for its immunomodulatory effect. This effect involves modulating T and B lymphocytes and macrophages; reducing proinflammatory cytokines, inflammatory nitric oxide, and adhesion molecules; and producing anti-inflammatory interleukin-10.10,11
ACTH was first used to treat MS relapses in the 1960s, when an ad hoc committee arising from a symposium designed a protocol to evaluate ACTH vs placebo in MS relapse management. Short-term, high-dose ACTH showed a small but significant improvement in the rate of recovery when compared with placebo. No major complications or severe side effects were encountered with the use of ACTH or placebo gel under the conditions of this study.12 The efficacy of ACTH was hypothesized to be attributable to its corticotropic effects, leading to increased interest and later acceptance of high-dose corticosteroids for treatment of MS exacerbations. A double-blind randomized controlled study13 examined the efficacy of IVMP vs intramuscular ACTH in the treatment of acute MS relapse and found no difference in relapse recovery rate or outcome between the 2 treatments. Although the benefits are similar, corticosteroids are typically favored over ACTH in MS relapse because of lower cost, greater convenience, and broader availability.
Intravenous Immunoglobulin
IVIg is an established first-line therapy for several neurologic immune-mediated diseases, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy relapses and maintenance. However, in MS, the utility of IVIg for relapse management or maintenance therapy is limited.
Mechanism of Action
IVIg is thought to exert its actions by 2 main proposed mechanisms: F(ab’)-dependent mechanisms, involving blockade of cell–cell interactions that are mediated by cell-surface receptors; and Fc-dependent pathways, involving blockade of complement.14 IVIg preparation contains other substances that have an immunomodulatory effect, such as soluble cytokine inhibitors, soluble CD4, and major histocompatibility complex class II molecules, and various sugars.15
The mechanisms of action of IVIg might not be uniform in all types of autoimmune diseases. In individuals with active MS, multiple immunologic mechanisms are thought to be at play, including an increased number of activated proinflammatory T cells (T helper 1 [Th1]), a reduced number of regulatory T cells, and an increased number of B cells producing immunoglobulin G antibodies against myelin proteins. IVIg has the potential to restore the balance of Th1 and T helper 2 (Th2) cells and inhibits the formation of antibody/complement complexes.16
Clinical Data on IVIg in MS
Studies investigating IVIg in acute MS relapse management yielded conflicting results. In a double-blind trial performed by Roed and colleagues,17 68 individuals with acute ON were randomized to IVIg (0.4 g/kg/day) or placebo infusions given on days 0, 1, 2, 30, and 60. There was no difference in visual function measures (ie, contrast sensitivity, color vision, visual acuity [VA], visual evoked potential measurements) or MRI findings (ie, Gd+ lesions) at any time during follow-up over 6 months.17 In an open-label controlled study, Tselis and colleagues18 treated 23 individuals with severe ON (VA of 20/400 or worse) refractory to high-dose corticosteroids with IVIg within 3 months of ON onset. In the IVIg-treated group, VA of 20/30 or better was observed in 78% of the individuals, vs 12.5% in the control group (n=24). The authors acknowledged several limitations to the study: the VA of the population being studied showed no improvement at 3 months, which is atypical for most individuals with MS; a nonrandomized study design; and use of only VA as an end point to measure visual function. Given the atypical nature of ON, the positive outcomes of IVIg in the treatment group might suggest an alternate etiology, such as myelin oligodendrocyte glycoprotein–associated demyelination, considering recent evidence.18 A small study by Elovaara and colleagues19 found that IVIg treatment (n=12) was noninferior to IVMP treatment (n= 5) of an acute MS relapse, clinically and radiologically. The study showed a significant reduction in the volumes of T2, FLAIR, and Gd+ lesions as well as in the number of Gd+ lesions over a period of 3 weeks after treatment in the IVIg group only, whereas MRI results in the IVMP group were unchanged. The small sample size is a limitation. The efficacy of IVIg in combination with IVMP has been analyzed in 2 studies, which did not demonstrate superiority of the combination over IVMP alone.20,21
Potential Complications
IVIg is well tolerated. Most of the side effects, such as flushing, headache, malaise, fever, chills, fatigue, and lethargy, are transient and mild. However, some rare side effects, including renal impairment, thrombosis, arrhythmia, chemical meningitis, hemolytic anemia, and transfusion-related acute lung injury, are more serious. Risk factors should be assessed. Premedicating with antihistamines and corticosteroids and slowing the infusion rate can help mitigate these adverse effects.22
Therapeutic Apheresis in Multiple Sclerosis
Historical Background
TA was first used in 1914 to separate blood cells from plasma in uremic dogs. In 1959, TA was used to treat macroglobulinemia. In the mid-1980s, the technique was introduced for the treatment of neurologic diseases.23
TA encompasses several techniques that “take away with force” (from the Latin aipheresis) different blood components. In the literature, the terms plasmapheresis and plasma exchange are used interchangeably, albeit incorrectly: there is no plasma replacement in plasmapheresis, and in plasma exchange, plasma usually is replaced with a colloid or a combination of colloid with crystalloid (most commonly albumin and normal saline) solution—rarely plasma.23 Immunoadsorption, unavailable in the United States, involves removing selectively harmful antibodies and immune complexes while leaving the other blood products intact.24
Mechanism of Action
Removal from plasma of pathogenic antibodies and immune complexes in autoimmune diseases, medications (such as natalizumab), and accumulated substances (such as in hypertriglyceridemia and Refsum disease), and control of hyperviscosity associated with lymphoproliferative disorders, are some of the obvious mechanisms of action of TA. There is no scientific agreement on its immunomodulatory effects, however. There is some indirect evidence that removal of immune complexes results in upregulation of complement receptors on the surface of red blood cells and reversal in splenic blockade in individuals with systemic lupus erythematosus, resulting in an accelerated clearance of immune complexes by red blood cells and spleen. A Th2 to Th1 deviation, a decrease in B cells, and an increase in suppressor T-cell function were observed in small case series of individuals treated with TA in conjunction with immunosuppressants, precluding generalization of findings. There is no compelling evidence that TA had a therapeutic benefit on cytokines, soluble cytokine receptors, or adhesion molecules when explored in different pathologic states. It is fair to conclude that the strong science behind TA is lacking beyond its original aipheresis role.23
Clinical Data on TA in MS
In 1999, the results of the first and only randomized, sham-controlled, crossover trial that enrolled individuals with different inflammatory demyelinating diseases were published. In this trial,25 individuals with severe targeted neurologic deficits (TND) (ie, coma, aphasia, acute and severe cognitive impairment, hemiplegia, paraplegia, quadriplegia) who failed a dose of corticosteroid of 7 mg/kg/day for 5 days were randomized to receive 7 sessions of TA or sham exchange. The primary outcome measured was moderate or marked improvement of the TND. On day 14, those individuals who did not meet the primary endpoint crossed over to the other group. Secondary outcomes included a change in EDSS score and different scales used to rate the TND. By the end of a 2-week course of TA, 42.1% of the individuals met the primary outcome. Other secondary outcomes showed trends in favor of efficacy.25 Based on these findings, the American Academy of Neurology and the American Society for Apheresis concluded that TA is probably effective and should be considered a second-line therapeutic option for acute MS relapses that fail to respond to high-dose corticosteroids.26,27 In 2016, Schimrigk and colleagues28 published the results of an observational multicenter study of 147 individuals from Germany treated with tryptophan immunoadsorption (mean of 5.4 sessions). All individuals had relapsing forms of MS, and 136 received a mean dose of 8±4.5 g of corticosteroids. The primary outcome was a moderate to marked improvement in EDSS score and at least a 10% improvement in best-corrected VA in the ON subgroup immediately before and after immunoadsorption. This outcome was met by 71.4% and 84% (ON subgroup) of individuals.28
The beneficial effect of TA on severe ON (VA of 20/200 or worse) of mixed demyelinating etiologies were retrospectively confirmed by Chen et al. Almost 80% of 357 individuals with ON treated with TA recovered to a VA of 20/40 or better. Predictors of response to TA in this study are reviewed below.29
Predictors of Clinical Response
Factors that could modulate treatment response (eg, age, sex, number of exchanges, EDSS score at index event, symptom response to TA, disease duration predating TA, time from index events, optimal response time to TA) were examined in cohorts of variable sizes. The results were not uniform. Llufriu and colleagues30 retrospectively reviewed the TA treatment response of 41 individuals with inflammatory demyelinating disease. At the time of discharge, 39% were considered treatment responders based on EDSS improvement, and 63% had experienced treatment response by 6 months after TA. Predictors of treatment response at 6 months were earlier inception of TA and improvement at discharge. Age, sex, severity of neurologic deficit before attack or TA onset, site of involvement, number of exchanges, or concomitant medication were not associated with outcome.30 Conversely, in the study by Chen et al, older age of onset, severe vision loss of counting fingers at nadir, and delay to PLEX were associated with a worse visual outcome despite treatment with TA.29
In another study, Magaña and colleagues31 undertook an exploratory analysis of the clinical (n=153 individuals) and imaging (brain=114, spine=85) features associated with a favorable response within 6 months of TA in individuals with inflammatory demyelinating disease. Treatment success was defined as moderate or marked functional improvement in at least 1 TND 6 months after TA; 59% of the individuals met this outcome. Response to treatment was observed by a median of 4 days and 3 exchanges and EDSS score improved from 8 to 4. Predictors of response to TA in this study included ring-enhancing lesions, mass effect, and perilesional edema.31
A study of 118 patients with MS analyzed predictors of response to TA in corticosteroid-resistant relapses. Contrast enhancement, younger age of onset, earlier treatment initiation, lower EDSS, and a relapsing MS course were associated with a mild-to-marked improvement in the final EDSS within 6 months of TA.32
Potential Complications
TA is generally safe. Catheter-associated complications, such as local or systemic infection, thrombosis, pulmonary embolism, pneumothorax, and hemothorax, have occurred. Heparin-induced thrombocytopenia has been reported. Manageable adverse events include anaphylactoid reaction (with fresh frozen plasma replacement), paresthesia secondary to the use of citrate anticoagulant and resulting in hypocalcemia (corrected by adding calcium), hypofibrinogenemia, and transient hypotension, with lightheadedness and nausea. Transient hypotension does not occur with immunoadsorption.23
Conclusions
Data on MS disease-modifying therapies are robust, but the literature on MS relapse management is scarce. There is good evidence of the equivalence of high-dose oral to intravenous corticosteroids on clinical and imaging measures. A survey of MS neurologists on their high-dose oral corticosteroids prescribing practices would be interesting. Corticosteroids remain the cornerstone of relapse management, although the dosages used in clinical practice are highly empiric. TA is an effective treatment for severe relapse management, but the available literature is underwhelming and heterogeneous in terms of measured endpoints. There is no indication for IVIg in relapse management; its use must be individualized, and the benefits must be weighed against the scarcity of the product. The mechanism of action of TA and IVIg in MS remains an undeveloped area in need of further immunologic research.
