Efficacy of Glucocorticoid Therapy in Different Types of Multiple Sclerosis Progression

Abstract

Multiple sclerosis (MS) is an autoimmune disease, affecting the central nervous system that causes significant disability and healthcare burden. Pulse-dosage corticosteroid therapy (GCT) remains the mainstay of treatment of exacerbations of multiple sclerosis. A total of 98 patients were examined, including 28 patients with relapsing-remitting MS (24 women and 4 men) and 70 patients with secondary progressive MS (57 women and 13 men). The number of GCT therapy courses in 98 patients at all disease stages totalled 536: 98 in RR MS (9 at debuts and 89 at RRS) and 438 in SP MS (11 at debuts, 178 at RRS and 249 at SPS). The efficacy of repeated courses of GCT therapy in patients with RR and SP MS was evaluated at different stages of the disease progression: debut in RR and SP MS, RRS in RR and SP MS and SPS in SP MS, including retrospective analysis. Important conclusions have been made about complex systemic reorganisation at different stages of relapsing-remitting and secondary-progredient types of MS, efficiency of GCT in different types of MS and stages of pathological process and about influence of GTC on the prognosis of the disease.

1. Introduction

The modern algorithm of multiple sclerosis (MS) treatment includes management of exacerbations with glucocorticoids (GCT), immunotherapy with MS disease-modifying drugs (MS DMDs), symptomatic therapy to eliminate various clinical disease manifestations and adaptive strategies to develop a set of rehabilitation measures to reduce the degree of disability [1, 2, 3, 4, 5, 6, 7, 8].

First-line drugs that manage MS exacerbations are GCTs (prednisolone, methylprednisolone), whose clinical effect is due to their immunosuppressive, anti-inflammatory and anti-oedematous action. GCTs have a wide spectrum of therapeutic action, influencing immune reactions in various ways: by lymphocytolysis, by accelerating the catabolism of immunoglobulins, by reducing the production of pro-inflammatory cytokines (interleukins-1, −6, −8 and tumour necrosis factor-alpha (TNF-α), by suppressing the transcription and enhancing the degradation of genes controlling the synthesis of interleukin-2, which is central to the development of the immune response, by improving axonal conduction, and by stabilising the permeability of the blood-brain barrier (BBB). Recent studies point to the ability of GCTs to inhibit the formation of ‘black holesʼ (sites of neuronal death) and prevent the development of brain atrophy. The discovered effects of GCTs prevent early persistent disability by slowing the development of brain atrophy, which is accompanied by a steady accumulation of residual neurological deficit [9, 10, 11].

Hormonal therapy in MS is important not only as a factor suppressing the autoimmune process but also as a type of substitution therapy due to the development of glucocorticoid deficiency, which changes immunological reactivity towards increased allergic manifestations and contributes to the demyelination process. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) system in MS is caused by reduced functional activity of GCT receptors and results in impaired immunoreactivity of the body. At the same time, the experience of using GCTs in MS accumulated over many decades has not solved a series of problems related to their administration. There is no consensus on adequate dosages, regimens, methods and duration of administration taking into account the severity of exacerbations, expediency of prescription in the debut and evaluation of the efficacy of GCT therapy in isolated use and in combination with other alternative treatment methods. Frequent administration of inadequate hormone regimens by increasing the daily dose of the drug at the next exacerbation contributes to the suppression of the HPA system and the development of steroid addiction, which leads to persistent hormone-dependent forms and further progression of the process [1, 3, 12].

A breakthrough in this field occurred in recent decades thanks to the implementation of highly effective pulse therapy with methylprednisolone (Metypred, Solu-Medrol) for the management of relapses in the relapsing-remitting (RR) type of MS progression. The drug has a significant advantage over prednisolone due to the presence of a methyl group capable of penetrating the cell membrane and binding to intracellular receptors. Solu-Medrol (Metypred) is administered in high doses (up to 1000 mg) by intravenous drip for 5–7 days. The effect of the drug in the process of restoration of central nervous system (CNS) functions affected by demyelinating processes is maintained for 1.5 months due to a powerful anti-inflammatory and anti-oedematous action, leading to a significant reduction in brain volume and normalisation of BBB permeability [1, 8, 13, 14].

2. Rationale

Until recently, the spectrum of therapeutic measures in the secondary progredient (SP) type of MS progression was forcefully limited to the use of cytostatics, which cause a significant number of complications in case of long-term treatment [15, 16]. Due to the therapeutic effects of GCTs, the sceptical attitude to their prescription in SP MS was reconsidered because, unlike RR MS, SP MS is characterised by an unfavourable prognosis because of the progression of the process leading to the accumulation of neurological deficit and persistent disability. It is proved that in this disease type, degenerative-axonal lesions are combined with autoimmune inflammatory changes of varying severity. Despite a different temporal algorithm of the inflammatory process development and significant differences between these MS types, which are manifested by clinical-immunological and clinical-morphological dissociations (‘iceberg phenomenonʼ according to C. Poser), the activity of the demyelinating process at the secondary progression stage (SPS) in SP MS can be comparable with the activity of relapses in RR MS. Therefore, timely and adequate administration of GCTs at early stages of SP MS, that is. at the debut and at the beginning of the relapsing-remitting stage (RRS), can delay further progression of the process. This statement is the evidence-based justification for the use of active immunosuppressive GCT therapy in this category of patients at all stages of the disease progression [1, 5, 17].

3. Aim of the study

To evaluate the comparative efficacy of hormonal glucocorticoid pulse therapy and to develop an algorithm of differential administration at different stages of relapsing-remitting and secondary-progredient types of multiple sclerosis.

4. Materials and methods

The study was conducted at the Department of Autoimmune and Degenerative Pathology of the Nervous System at the Multiple Sclerosis Centre of the State Enterprise ‘Institute of Neurology, Psychiatry and Narcology of the National Academy of Medical Sciences of Ukraineʼ (SE INPN NAMS of Ukraine).

The study involved clinical neurological and statistical research methods. The clinical neurological method included retrospective analysis of the disease progression from the manifestation of clinical symptoms in each patient and dynamic neurological examination during periods of relapses and remissions at the RRS in RR MS and during progression and stabilisation at the SPS in SP MS. Statistical processing of the data was carried out using the ‘Statgraphʼ statistical software package with a defined number of patients (n), mean index value (M) and the standard deviation of the index (m).

A total of 98 patients were examined, including 28 patients with RR MS (24 women and 4 men) and 70 patients with SP MS (57 women and 13 men).

The number of GCT therapy courses in 98 patients at all disease stages totalled 536: 98 in RR MS (9 at debuts and 89 at RRS) and 438 in SP MS (11 at debuts, 178 at RRS and 249 at SPS).

The efficacy of repeated courses of GCT therapy in patients with RR and SP MS was evaluated at different stages of the disease progression: debut in RR and SP MS, RRS in RR and SP MS and SPS in SP MS, which are of strategic importance for the final prognosis of the disease. The following clinical parameters were considered at different stages of RR and SP MS: age at onset, disease duration, age and severity of debuts, duration of remission after debut, duration of RRS, number and severity of relapses at RRS, mean relapse rate (MRR) at RRS, duration of SPS at the end of the study, progression variants at SPS, duration of remissions (stabilisation) after the first and before the last GCT course in RR and SP MS, progression rate in RR and SP MS, dynamics of EDSS disability scale scores after the first and before the last GCT course in RR and SP MS [18, 19, 20].

5. Results

At the time of evaluation of GCT treatment efficacy, the age of patients and disease duration in RR MS were significantly lower than in SP MS (p < 0.05), whereas the age of debut in the two disease types was not significantly different (Table 1).

Parameter	RR (n = 28)	SP (n = 70)
Mean age	39.2 ± 2.0^1	45.9 ± 2.5^1
Mean disease duration	9.5 ± 1.2^2	19.8 ± 2.3^2
Mean age at onset	29.5 ± 2.1	27.6 ± 2.0

Table 1.

Age, disease duration and age at onset in RR and SP MS (years), M ± m.

Notes: n, number of patients; M, mean value; m, standard deviation; ¹p < 0.05 – significant differences in age between RR and SP MS; ²p < 0.05 – significant differences in disease duration between RR and SP MS.

The pattern of debut severity in RR and SP MS was alternating, mild debuts were predominant in RR and moderate debuts were predominant in SP MS. Accordingly, a comparative assessment of debut severity between the two types of disease showed a significant predominance of mild debuts in RR and moderate debuts in SP MS; severe debuts were rare in all patients with almost equal incidence (Table 2).

Parameter	RR (n = 28)		SP (n = 70)
	abs. value	%	abs. value	%
Mild debuts	16	57.2 ± 9.3^1	19	27.5 ± 7.4^1
Moderate debuts	10	35.7 ± 9.0^2	44	62.5 ± 8.1^2
Severe debuts	2	7.1 ± 4.8	7	10.0 ± 5.1

Table 2.

Debuts of varying severity in RR and SP MS, M ± m.

Notes: n, number of patients; M, mean value; m, standard deviation; ¹p < 0.05 – significant differences in the frequency of mild debuts between RR and SP MS; ²p < 0.05 – significant differences in the frequency of moderate debuts between RR and SP MS.

GCT pulse therapy at the debut stage was performed in only 21 (21.4%) of 98 patients, including in 9 (32.1 ± 8.8)% of 28 with RR and in 12 (17.1 ± 4.5)% of 70 with SP MS. Such a low percentage, especially in patients with future SP MS (2 times less), was due to untimely diagnosis of MS (Table 3).

			Percentages
Parameter	RR (n = 28)		SP (n = 70)
	abs. value	%	abs. value	%
After GCT administration in RR	9	32.1 ± 8.8	—	—
Without GCT administration in RR	19	67.9 ± 8.8	—	—
After GCT administration in SP	—	—	12	17.1 ± 4.5
Without GCT administration in SP	—	—	58	82.9 ± 4.5

Table 3.

GCT pulse therapy at the debut stage in patients with RR and SP MS, M ± m.

Notes: n – number of patients; M – mean value; m – standard deviation.

The experience of GCT administration proved its high efficacy in mild and moderate debuts, especially in RR MS. The first course of the GCT therapy resulted in rapid and significant regression of neurological symptoms and full clinical remission. In the group of patients with severe debuts, which were extremely rare, especially in RR MS, the recovery from debuts was prolonged and accompanied by minimal regression of neurological deficit with the outcome of incomplete clinical remission despite GCT administration.

Despite the high efficacy of the first GCT therapy course, no significant differences in the duration of remission after the debut were found in patients with RR and SP MS, whereas this parameter was significantly higher in patients with SP MS without GCT administration (Table 4).

		Percentages
Parameter	RR (n = 28)	SP (n = 70)
After GCT administration	3.5 ± 1.3	5.7 ± 2.8
Without GCT administration	2.6 ± 0.8^1	6.2 ± 2.9^1

Table 4.

Duration of remission after debut depending on the administration of the first GCT therapy course in RR and SP MS, М ± m.

Notes: n – number of patients; M, mean value; m, standard deviation; ¹p < 0.05 – significant differences in the duration of remission after debuting in SP MS without GCT administration.

The specific features of the RRS (duration, frequency and severity of relapses and neurological deficit accumulation rate) play a key role in triggering the process of RRS to SPS transformation. The implementation of this process requires a complex selective structural reorganisation of clinical indicators at RRS, among which the severity of relapses is of particular significance. An increase in the frequency of severe relapses during the RRS is a trigger that accelerates the RRS to SPS transformation [19, 21].

According to its duration, RRS was divided into short (2 to 5 years), moderate (5 to 8 years) and long (more than 8 years). The average duration of RRS at the background of repeated hormonal therapy courses was (6.8 ± 0.8) years in RR MS and (10.4 ± 3.9) years in SP MS. Thus, at the time of pulse therapy efficacy evaluation, the duration of RRS was shorter (p > 0.05) in RR MS than in SP MS due to the incomplete nature of the relapse process and indicated the absence of an immediate threat of its transformation into SPS.

Neurological symptoms during exacerbation periods at the RRS affected the leading functional systems with predominance of pyramidal and cerebellar syndromes. As a rule, relapses of different severity (mild, moderate and severe) alternated in the vast majority of patients as the RRS progressed. Mild relapses were characterised by rapid rates of clinical symptom development, short duration (no more than 3–4 weeks), mono- or oligosyndromic symptoms with minimal signs of rapidly regressing neurological deficit. In moderate relapses, oligo- or polysyndromic symptoms prevailed with the formation of moderate neurological deficit and its subsequent regression at moderate rates (up to 2 or more months). In severe relapses, pronounced polysyndromic symptoms developed and their partial regression occurred at a slower rate (within 3 or more months), as a rule with the outcome of short and incomplete clinical remissions.

19 of 28 patients with RR MS and 47 of 70 patients with SP MS were first administered GCT therapy at the RRS. As a consequence, all patients with RR MS and 59 of 70 patients with SP MS received GCT therapy at the debut or at the RRS. The other 11 patients with SP MS first received hormonal therapy at the SPS due to the absence of the RRS.

A total of 267 GCT therapy courses were administered at the RRS in both patient groups: 89 courses for RR MS (72 for moderate relapses and 17 for severe relapses) in 67.8% of patients and 178 courses for SP MS (104 for moderate relapses and 74 for severe relapses) in 84.3% of patients. The mean number of courses per patient was 3.1 for RR MS and 3.0 for SP MS.

Thus, hormonal therapy at the RRS covered the vast majority of patients with moderate to severe relapses. In mild relapses, patients did not receive GCT therapy despite a significant proportion of this subgroup having radiological activity based on MRI. Violation of the protocol, according to which hormonal therapy is recommended for all relapses regardless of their severity, led to an increase in the frequency and severity of relapses, accumulation of residual neurological deficits, shortened RRS duration and increased risk of RRS transformation into secondary progression.

The total number of relapses at the RRS in all patients at the background of repeated courses of GCT therapy was 505, including 139 (27.5%) in RR MS and 366 (72.5%) in SP MS. The average number of relapses per patient was 4.9 in RR MS and 6.3 in SP MS. The prevalence of relapses at the RRS in patients with SP MS indicates a more unfavourable development of the process and can serve as one of the clinical markers of probable RRS to SPS transformation.

The analysis of the frequency of relapses of different severity (mild, moderate, severe) showed no significant differences between RR and SP MS. During the entire RRS in the two types of disease progression, the relapses of moderate severity prevailed with the same incidence; mild relapses were more frequent in RR MS (p > 0.05); severe relapses prevailed in SP MS (p > 0.05). A significant predominance of moderate over severe and mild over severe relapses was observed in RR MS. In turn, moderate relapses were significantly more frequent than mild or severe relapses in SP MS (Table 5).

		Percentages
Relapse severity at the RR stage	RR (n = 28)	SP (n = 59)
Mild	35.9 ± 9.1^2	28.8 ± 5.9^3
Moderate	51.9 ± 9.4^1	49.1 ± 6.5^3,4
Severe	12.2 ± 6.2^1,2	22.1 ± 5.4^4

Table 5.

Severity of relapses at the relapsing-remitting stage (RRS) in RR and SP MS at the background of repeated GCT therapy courses, М ± m.

Notes: n, number of patients; M, mean value; m, standard deviation; ¹p < 0.05 – significant differences in the incidence of moderate and severe relapses in RR MS; ²p < 0.05 – significant differences in the incidence of mild and severe relapses in RR MS; ³p < 0.05 – significant differences in the incidence of mild and moderate relapses in SP MS; ⁴p < 0.05 – significant differences in the incidence of moderate and severe relapses in SP MS.

The mean relapse rate (MRR – the ratio of the number of relapses to the RRS duration) was not significantly different between the studied patient groups and was 0.9 ± 0.1 for RR MS and 1.1 ± 0.2 for SP MS (MRR for each patient ranged from 0.1 to 2.8). Decreasing MRR (<1.0) indicated infrequent relapses and longer RRS duration, increasing MRR (>1.0) was associated with more frequent relapses and shorter RRS duration (Table 6).

		Percentages
MRR	RR (n = 28)	SP (n = 70)
<1.0	0.6 ± 0.3	0.5 ± 0.1^1
>1.0	1.5 ± 0.9	1.6 ± 0.7^1

Table 6.

Mean relapse rate at the relapsing-remitting stage in RR and SP MS at the background of repeated GCT therapy courses, М ± m.

Notes: n, number of patients; M, mean value; m, standard deviation; ¹p < 0.05 – significant difference between MRR <1.0 and MRR >1.0 in SP MS.

Relapses were significantly more frequent in SP MS with MRR > 1.0 than with MRR < 1.0, whereas there was just a trend between these two parameters in RR MS (р > 0.005) (Table 6).

The clinical effect under the influence of GCT therapy courses was characterised by differentiated regression of neurological deficit. This led to conditional distinction between ‘well-controlledʼ and ‘poorly controlled ʼ symptoms in each functional system. In the pyramidal syndrome, spastic tonus disorders were primarily subject to reverse development, while recovery of leg strength depended on the severity of paresis. In the cerebellar-atactic syndrome, ‘well-controlledʼ symptoms included a decrease in the amplitude of horizontal nystagmus and shakiness when walking, as well as an improvement in the performance of the finger-nose test. Performance of the patellofemoral test and static ataxia in the Romberg test were much less frequently subject to reverse development. The regression of sensory disorders was differentiated and depended on their nature. The most ‘well-controlledʼ symptoms were disorders of pain sensitivity and astereognosis, whereas normalisation of proprioceptive and temperature sensitivity was slow and, as a rule, partial. In stem disorders, vestibular syndrome, vertical nystagmus and facial muscle dysfunctions as a result of facial nerve damage were more often subjected to significant regression; less frequently, various oculomotor disorders were observed. Sphincter disorders, depending on the degree of their decompensation, were usually subject to partial regression with significant individual differences.

Thus, the analysis of GCT pulse therapy efficacy indicates that a ‘dissociation syndromeʼ with selective and differentiated regression of clinical symptoms in separate functional systems was developed during RRS at relapses of varying severity in patients with RR and SP MS.

The process of RRS to SPS transformation occurred as the efficacy of hormonal therapy decreased and proceeded at different rates in different patients. At the time of assessment of GCT treatment results in 70 patients with SP MS, the average duration of SPS was (7.2 ± 1.4) years (ranging from 3 to 17 years).

The number of GCT therapy courses at SPS in 70 patients with SP MS was 249, which on average corresponded to 3.5 courses per patient. There were no significant differences in the average frequency of courses during RRS and SPS in SP MS (3.0 and 3.5, respectively).

Clinical analysis of the SPS identified the main variants and rates of progression, which indicate its complex structural and functional organisation and are of strategic importance for further disease development and prognosis.

Three main variants of progression have been identified: steady, proceeding without clinically marked stabilisation periods; relapsing, in the form of abrupt exacerbations, resembling relapses, recovery from which was accompanied by stabilisation periods of different duration; and progressive, representing an alternation of the periods of slow progression of neurological symptoms and stabilisation of different duration [7, 20, 21].

The first two variants (steady and relapsing), usually unfavourable, are characterised by the development of gross and persistent polysyndromic neurological symptoms, absence or relative rarity of dissociation syndromes and a high progression rate. As a result of such development, a deep disability degree and therapeutic resistance to GCT therapy of varying degrees are developed. The progressive variant of progression is more favourable in comparison with the first two and is characterised by the absence of gross neurological deficit, higher efficacy of pathogenetic therapy, longer period of residual working ability and better sociopsychological adaptation. The nature of further progression was determined not only by the variants but also by the intensification rates of neurological symptoms – rapid, moderate and slow. In rapid rates, steady and relapsing variants or their alternation prevail; in moderate and especially slow rates, progressive variants prevail.

The analysis of clinical features of the SPS revealed interdependence between the MRR at RRS and variants of secondary progression. The most favourable progressive variant of progression (40.0 ± 5.8) %, which prevailed in patients with MRR <1.0, was the most frequent (Table 7).

Parameter	SP MS (n = 70)
	abs. value	%
Progressive variant	28	40.0 ± 5.8^1,2
Relapsing variant	17	24.3 ± 4.5^1,3
Steady variant	21	30.0 ± 5.4^4
Alternation of different variants	4	5.7 ± 2.8^2,3,4

Table 7.

Progression variants in SP MS.

Notes: n, number of patients; M, mean value; m, standard deviation; ¹p < 0.05 – significant differences between progressive and relapsing variants of progression; ²p < 0.05 – significant differences between progressive variant and alternation of different variants of progression; ³p < 0.05 – significant differences between relapsing variant and alternation of different variants of progression; ⁴p < 0.05 – significant differences between steady variant and alternation of different variants of progression.

The second most frequent variant of progression was the most unfavourable one, that is. steady (30.0 ± 5.4) %, which occurred in one half of the patients at MRR > 1.0, and in the second half at the SPS development, which followed remission after the debut, bypassing the RRS. The relapsing variant, which has an intermediate position between the previous variants in terms of its prognostic significance, was observed in (24.3 ± 4.5) % of patients. In this category of patients, MRR < 1.0 and MRR > 1.0 were almost equally frequent. Very rarely, in (5.7 ± 2.8) % of cases, alternation of different variants of progression throughout the course of SPS was observed (Table 7).

When assessing GCT treatment efficacy in RR and SP MS at the beginning (after the first course) and at the end (before the last course), the following parameters were taken into account: mean remission duration (MRD) and (or) stabilisation duration, the dynamics of scores on the EDSS disability scale and the rate of progression.

In RR MS, a comparative assessment of MRD was performed after the first and before the last GCT course at the end of the study when the RRS was not completed and there was no immediate risk of transformation into SPS. The studies showed a significant prevalence of MRD after the first course – (2.8 ± 0.8) years (ranging from 6 months to 10 years) versus the last course – (1.5 ± 0.2) years (ranging from 4 months to 3 years).

In SP MS, the MRD or stabilisation duration during the SPS was significantly longer (1.8 ± 0.5) years (ranging from 3 months to 5 years) after the first course than before the last course (1.0 ± 0.1) years (ranging from 2 months to 2 years). A comparative analysis of this parameter between the two disease types, a tendency towards predominance after the first course and a significant predominance before the last course was noted in patients with RR MS.

The prevalence of MRD at the initial stages of the disease and its significant decrease at the end of the study despite repeated courses of hormonal therapy indicates the depression of the HPA system with the development of steroid addiction, which in some patients leads to the depletion of adaptation-compensatory processes and increased risk of transformation into SPS.

The above finding is supported by the increased degree of neurological deficit according to the EDSS disability scale in the two disease types. In RR MS, the mean disability score was (2.1 ± 1.1) points (ranging from 1.0 to 3.0 points) after the first course of GCT therapy and (3.5 ± 0.7) points (ranging from 2.0 to 4.5 points) before the last course. In SP MS, the EDSS score was (3.1 ± 0.4) points (ranging from 2.8 to 5.0 points) after the first course and (6.0 ± 0.9) points (ranging from 5.5 to 7.0 points) before the last course at the end of the study. Comparative analysis of the mean EDSS score after the first and before the last course of GCT therapy shows a deepening of neurological deficit, especially in patients with SP MS at the SPS (p < 0.05).

The negative dynamics of EDSS scores corresponds to such an integral indicator as the rate of progression (the sum of the difference of scores on the EDSS disability scale between the first and before the last GCT course for each patient in relation to the total number of patients), which was 1.1 in RR MS and 2.3 in SP MS.

Based on the findings, criteria for the efficacy of GCT treatment in RR and SP MS were developed. High (61.0 ± 9.2) % and moderate (39.0 ± 9.2) % efficacy was obtained for RR MS, and moderate (30.0 ± 5.4) %, low (30.0 ± 5.4) % and no (40.0 ± 5.8) % efficacy was obtained for SP MS.

With high efficacy of GCT therapy, the risk of transformation into SPS was considered minimal, and the MRR was less than 1.0. The treatment process in these patients was accompanied by a decrease in the duration of debuts and complete clinical remission after the debut. At the background of increasing RRS duration, mild (more often) and moderate (less often) short or mid-duration relapses, complete remissions between relapses with minimal residual neurological deficit (EDSS not more than 2.0 points), long-term preservation of full (more often) or partial (less often) working ability prevailed. With moderate efficacy, patients with RR MS were not at immediate risk of transformation to SPS either (with MRR values of less than 1.0 (more often) and more than 1.0 (less often)). However, despite repeated courses of GCT therapy, the course of the RRS was less favourable in contrast to patients with high treatment efficacy. This was manifested by an increase in the duration of the debut, predominance of incomplete clinical remissions after the debut, an increase in the frequency of relapses of moderate severity during the RRS, a gradual increase in neurological deficit (EDSS from 2.0 to 3.0 points) in remissions between relapses and partial loss of working ability (Table 8).

Parameter	RR (n = 28)		SP (n = 70)
	abs. value	%	abs. value	%
High	17	61.0 ± 9.2	—	—
Moderate	11	39.0 ± 9.2	21	30.0 ± 5.4
Low	—	—	21	30.0 ± 5.4
No efficacy	—	—	28	40.0 ± 5.8

Table 8.

GCT therapy efficacy in RR and SP MS.

Notes: n, number of patients; M, mean value; m, standard deviation.

Differences in MRD in patients with high and moderate efficacy after the first and before the last GCT course were not significant. Low rate of progression (1.1) correlated with insignificant negative dynamics of EDSS disability score between the first and before the last GCT course (from 2.1 ± 1.1 to 3.5 ± 0.7), which was mainly attributed to patients with moderate efficacy.

In SP MS, there was no high efficacy at the background of repeated courses of GCT therapy. Moderate efficacy was obtained in patients with MRR < 1.0 and MRR > 1.0, whose clinical symptoms at the background of GCT therapy were characterised by incomplete remissions after the management of debuts of different severity and duration, development of the RRS of different duration, against which moderate relapses prevailed. After transformation into SPS, which occurred at a slow pace, progressive (more often) or relapsing (less often) variants of progression were predominant with neurological deficit (< 6.0 points on the EDSS scale) and partial or complete loss of working ability (Table 8).

Low efficacy was characterised by the development of a short RRS after the management of severe or moderate long-term debuts and incomplete and short-term remission. During the RRS, there was a regular tendency to more frequent and more severe relapses (MRR > 1.0) with a steady accumulation of neurological deficit. As a result, there was an inevitable transformation into SPS, occurring in the form of relapsing (more often) or steady (less often) variants of progression with persistent neurological deficit (from 5.5 to 6.5 points on the EDSS scale) and complete loss of working ability.

There was no efficacy in some patients with MRR > 1.0. In part of these patients, RRS was absent and SPS developed immediately after a prolonged and severe debut. This category of patients was characterised by a steady variant of progression that developed rapidly, high scores (more than 6.5 on the EDSS scale) with profound disability and complete loss of working ability (Table 8). The comparison of treatment results with the nature of prognosis depending on the disease type indicates that patients with an uncertain prognosis are characterised by moderate treatment efficacy, whereas an unfavourable prognosis prevails in patients with low or no efficacy.

6. Discussion of results

The conducted study indicate that hormonal therapy was the most effective in patients with RR MS. Under the influence of repeated courses of GCT therapy, high and moderate efficacy of treatment was achieved in the form of positive dynamics of most clinical parameters. At different stages of RR MS, there was a rapid and complete regression of the leading syndromes in the debuts, completeness and duration of remission after the debut increased, the number of patients with MRR <1.0 rose, the duration of the RRS increased, the frequency and severity of relapses decreased and minimal neurological deficit was preserved at the background of low progression rate. As a result of the above reorganisation, the duration of the RRS was prolonged and the immediate risk of RRS to SPS transformation was averted.

In SP MS, hormonal therapy was less effective and was assessed according to three gradations as moderate, low or no efficacy. With moderate efficacy, the SPS developed later after the onset of the disease compared to low efficacy. In this process, which was accompanied by a complex structural rearrangement of the leading clinical indicators, the duration of remission after the debut increased, the number of patients with MRR >1.0 decreased, the duration of the RRS increased against the background of reduced number of severe relapses, and there was a slow accumulation of neurological deficit. The positive dynamics of these parameters under the influence of GCT treatment were partial and differentiated, and despite significant individual differences, led to the development of a progressive variant of progression, which has a more favourable prognostic value.

In patients with low or no efficacy of GCT therapy, recovery from debuts was prolonged and accompanied by minimal regression of neurological deficit and short remission after the first attack. The duration of the RRS was shorter and the frequency of severe relapses was higher than in the group of patients with moderate efficacy. This led to an increase in the number of patients with a high MRR, steady accumulation of neurological deficit, increased rate of progression and rapid development of the SPS, whose structure is dominated by unfavourable variants of progression (steady and relapsing).

The analysis of the dynamics of clinical symptoms at different stages of RR and SP MS under the influence of repeated courses of GCT therapy indicates that the treatment efficacy is closely related to the nature of the disease prognosis. It is known that, in the overwhelming majority of patients, RR MS has a favourable character. However, a variety of variants should be distinguished in RR MS, differing in their clinical course and prognostic significance. Thus, the presence of clinical markers indicating the risk of transformation into SP MS leads to treating the current prognosis in RR MS as uncertain. Progredient types of disease, including SP MS, are usually characterised by a rapid accumulation of neurological deficit due to the progression of the process with the development of a high degree of disability and an unfavourable prognosis in the vast majority of patients. However, a relatively ‘benignʼ or uncertain, variant of prognosis should also be distinguished in SP MS, which is characterised by longer RRS, progressive variant of progression with long periods of stabilisation, slow accumulation of neurological deficit and positive response to various methods of pathogenetic therapy (GCT, MS DMDs, etc.). Consequently, the prognosis, as an expected result of the previous course of the demyelinating process, depends on the clinical interpretation of the entire disease pattern, including retrospective analysis of disease stages [7, 20, 22, 23].

Clinical and mathematical analysis for the evaluation of the studied indicators in different types of MS resulted in the development of clinical criteria for different prognosis variants: favourable and uncertain for RR MS and unfavourable and uncertain for SP MS [23, 24, 25].

A comparison of treatment results with the prognosis in RR MS indicates a favourable prognosis with high efficacy and an uncertain prognosis with moderate efficacy of repeated courses of GCT. In SP MS, uncertain prognosis prevailed in patients with moderate efficacy, while low or no efficacy under the influence of GCT treatment suggested an unfavourable prognosis.

7. Conclusions

1. Under the influence of repeated courses of GCT therapy, clinical parameters undergo a complex systemic reorganisation at different stages of relapsing-remitting and secondary-progredient types of MS.

2. As a result of retrospective analysis of the dynamics of clinical parameters occurring in the course of relapsing-remitting and secondary-progredient MS, criteria for the efficacy of hormonal GCT therapy were developed: high and moderate efficacy for the relapsing-remitting type; moderate, low and no efficacy for the secondary-progredient type.

3. Treatment efficacy in repeated GCT courses is closely associated with the nature of prognosis (favourable, unfavourable, uncertain) obtained as a result of clinical and mathematical analysis of indicators characterising different types of MS. In the relapsing-remitting type, high efficacy prevailed for the favourable prognosis, and moderate efficacy prevailed for the uncertain prognosis; in the secondary-progredient type, moderate efficacy correlated with the uncertain prognosis, and low or no efficacy correlated with the unfavourable prognosis.

4. High efficacy of GCT therapy in patients with relapsing-remitting MS with a favourable prognosis was characterised by complete clinical remissions after the debut, predominance of mild short relapses at the relapsing stage, minimal neurological deficit, low progression rate, long-term preservation of working ability and minimal risk of transformation into the secondary-progredient type. With moderate efficacy of GCT therapy in patients with an uncertain prognosis, the probability of transformation into the secondary-progredient type increased due to decreased compensatory reserves of the body. In this process, the duration of debut and the prevalence of incomplete clinical remissions after debut increased. At the relapsing-remitting stage, relapses of moderate severity prevailed against the background of a gradual increase in neurological deficit with partial loss of working ability.

5. In the secondary-progredient type, the efficacy of treatment with repeated courses of GCT was significantly lower than in the relapsing-remitting type, but the process of transformation of the relapsing-remitting stage into secondary progression occurred at different rates and was characterised by significant individual differences. In the case of an uncertain prognosis, moderate efficacy prevailed, which led to a decrease in the number of severe relapses against the background of increased duration of the relapsing-remitting stage and the development of a more favourable progressive variant of progression. The unfavourable prognosis was characterised by low or no efficacy. These subgroups of patients showed no positive dynamics of most clinical parameters at all stages of the disease. As a result, a steady or recurrent variant of progression, a pronounced neurological deficit, and a high degree of disability were developed.

6. The expediency of timely administration of and treatment with repeated courses of GCT pulse therapy in patients with relapsing-remitting MS with a favourable and uncertain prognosis and in patients with the secondary-progredient type with an uncertain prognosis has been proved. In case of low efficacy in patients with secondary-progredient MS type and an unfavourable prognosis, it is necessary to develop new approaches to the MS treatment strategy.

Abbreviations

SP	secondary progredient type
HPAS	hypothalamic-pituitary-adrenal system
GCT	glucocorticoids
BBB	blood-brain barrier
MS DMDs	multiple sclerosis disease-modifying drugs
MS	multiple sclerosis
RR	relapsing-remitting type
RRS	relapsing-remitting stage
MRD	mean remission duration
MRR	mean relapse rate
CNS	central nervous system
SPS	secondary progression stage