Oral versus intravenous steroid therapy for relapses in patients with multiple sclerosis: an updated meta-analysis of six randomized controlled trials

Luo, Wenjing; Han, Min; Wei, Chunying; Liu, Bo; Du, Yi

doi:10.5935/MedicalExpress.2017.02.01

Brasil

Español English

REVIEW • MedicalExpress (São Paulo, online) 4 (2) • Mar-Apr 2017 • https://doi.org/10.5935/MedicalExpress.2017.02.01 copy

Oral versus intravenous steroid therapy for relapses in patients with multiple sclerosis: an updated meta-analysis of six randomized controlled trials

TERAPIA ORAL VERSUS INTRAVENOSA PARA RECAÍDAS DE PACIENTES COM ESCLEROSE MÚLTIPLA: UMA METANÁLISE ATUALIZADA DE SEIS ENSAIOS CLÍNICOS RANDOMIZADOS

Authorship SCIMAGO INSTITUTIONS RANKINGS

PURPOSE:

To systematically evaluate whether oral steroids can be used with the same efficacy and safety in comparison with the intravenous regimen for treatment of multiple sclerosis relapses.

METHOD:

We searched Medline, Embase and Cochrane Library and systematically reviewed articles comparing outcomes of oral versus intravenous steroids for acute relapses in patients with a clinically definite diagnosis of multiple sclerosis.

RESULTS:

Six articles with 414 participants in total were analyzed. Five of the included trials reported the proportion of patients experiencing improvement in Expanded Disability Status Scale after receiving either oral or intravenous methylprednisolone treatment at four weeks; the pooled results showed that there was no statistically significant difference (OR 0.96; 95% CI 0.60, 1.54; p=0.86) between treatments. Three trials reported the detailed results of adverse events, indicating the two treatments appear to be equally safe. Two trials revealed that there was no significant difference in gadolinium enhancement activity on magnetic resonance imaging. One trial showed that the mean area under the concentration-time curve (AUC) at 24 and 48 hours did not differ between groups.

CONCLUSION:

No significant differences were found in terms of clinical (benefits and adverse events), radiological and pharmacological outcomes in multiple sclerosis relapses in patients after oral or intravenous steroids treatment. Our meta-analysis provides evidence that oral steroid therapy is not inferior to intravenous steroid therapy. Thus oral administration may be a favorable substitute for intravenous medication of multiple sclerosis relapses.

KEYWORDS:
Multiple sclerosis; relapses; methylprednisolone; meta-analysis

Studies	Adequate sequence generation?	Allocation concealment?	Blinding?	Incomplete out-come data addressed?	Free of selective reporting?	Free of other bias?	Risk of bias
Alam 1993¹⁴14 Alam SM, Kyriakides T, Lawden M, Newman PK. Methylprednisolone in multiple sclerosis: a comparison of oral with intravenous therapy at equivalent high dose. J Neurol Neurosurg Psychiatry. 1993;56(11):1219-20. DOI: 10.1136/jnnp.56.11.1219 https://doi.org/10.1136/jnnp.56.11.1219...	unclear	unclear	yes	unclear	unclear	unclear	unclear
Barnes 1997¹⁵15 Barnes D, Hughes RA, Morris RW, Wade-Jones O, Brown P, Britton T, et al. Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet 1997;349(9056):902-6. DOI: 10.1016/S0140-6736(96)06453-7 https://doi.org/10.1016/S0140-6736(96)06...	yes	yes	yes	yes	unclear	yes	low
Morrow 2004¹⁶16 Morrow SA, Stoian CA, Dmitrovic J, Chan SC, Metz LM. The bioavailability of IV methylprednisolone and oral prednisone in multiple sclerosis. Neurology. 2004;63(6):1079-80.	unclear	unclear	unclear	unclear	unclear	unclear	unclear
Martinelli 2008¹⁷17 Martinelli V, Rocca MA, Annovazzi P, Pulizzi A, Rodegher M, Martinelli Boneschi F, et al. A short-term randomized MRI study of high-dose oral vs intravenous methylprednisolone in MS. Neurology. 2009;73(22):1842-8. DOI: 10.1212/WNL.0b013e3181c3fd5b. https://doi.org/10.1212/WNL.0b013e3181c3...	yes	no	unclear	yes	yes	yes	potentially high
Ramo-Tello 2014¹⁸18 Ramo-Tello C, Grau-Lopez L, Tintore M, Rovira A, Ramió i Torrenta L, et al. A randomized clinical trial of oral versus intravenous methylprednisolone for relapse of MS. Mult scler. 2014;20(6):717-25. DOI: 10.1177/1352458513508835. https://doi.org/10.1177/1352458513508835...	yes	yes	yes	yes	yes	yes	low
Le Page 2015¹²12 Le Page E, Veillard D, Laplaud DA, Hamonic S, Wardi R, Lebrun C, et al. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. Lancetet al. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. Lancet. 2015;386(9997):974-81. DOI: 10.1016/S0140-6736(15)61137-0. https://doi.org/10.1016/S0140-6736(15)61...	yes	yes	yes	yes	yes	yes	low

Reference	Interventions	Outcomes
Alam, 1993¹⁴14 Alam SM, Kyriakides T, Lawden M, Newman PK. Methylprednisolone in multiple sclerosis: a comparison of oral with intravenous therapy at equivalent high dose. J Neurol Neurosurg Psychiatry. 1993;56(11):1219-20. DOI: 10.1136/jnnp.56.11.1219 https://doi.org/10.1136/jnnp.56.11.1219...	OMP^* * OMP=oral methylprednisolone; group: 500mg/d of oral MP as five 100mg tablets with 100mL of placebo intravenously for 5 days IVMP^† † IVMP=intravenous methylprednisolone; group: 500mg/d of intravenous MP in 100mL of saline solution with five placebo tablets for 5 days	1.Proportion of patients with improvement on EDSS^‡ ‡ EDSS=Kurtzke’s expanded disability status scale; at day 28 2.Proportion of patients with improvement on EDSS at day 5 3.Adverse event rates
Barnes 1997¹⁵15 Barnes D, Hughes RA, Morris RW, Wade-Jones O, Brown P, Britton T, et al. Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet 1997;349(9056):902-6. DOI: 10.1016/S0140-6736(96)06453-7 https://doi.org/10.1016/S0140-6736(96)06...	OMP group: 48 mg/d x 7 days,then 24 mg/d x 7 days,finally 12mg/d x 7 days IVMP group: 1000mg/d of intravenous MP in 100 mL of a 5% dextrose solution for 3 days	1.Proportion of patients with improvement on EDSS at 4 weeks 2.Median EDSS at 0-1 weeks,0-4 weeks,0-12 weeks,0-24 weeks and over all area under the curve 3.Median ambulatory index at 0-1 weeks,0-4 weeks,0-12 weeks,0-24 weeks and over all area under the curve 4.Median arm index at 0-1 weeks,0-4 weeks,0-12 weeks,0-24 weeks and over all area under the curve 5.Proportion discharged from hospital at week 1 and week 4 6.Adverse event rates
Morrow 2004¹⁶16 Morrow SA, Stoian CA, Dmitrovic J, Chan SC, Metz LM. The bioavailability of IV methylprednisolone and oral prednisone in multiple sclerosis. Neurology. 2004;63(6):1079-80.	OMP group: 1250mg of oral prednisone IVMP group: 1000mg/d of intravenous MP in 100 mL of 0.9% sodium chloride	1.Mean absorption of steroid absorption by liquid chromatography/mass spectrometry at 1, 2, 4, 8, 24 and 48 hours following treatment 2.Mean area under the curve for absorption by liquid chromatography/mass spectrometry at 1, 2, 4, 8, 24 and 48 hours following treatment
Martinelli 2008¹⁷17 Martinelli V, Rocca MA, Annovazzi P, Pulizzi A, Rodegher M, Martinelli Boneschi F, et al. A short-term randomized MRI study of high-dose oral vs intravenous methylprednisolone in MS. Neurology. 2009;73(22):1842-8. DOI: 10.1212/WNL.0b013e3181c3fd5b. https://doi.org/10.1212/WNL.0b013e3181c3...	OMP group: 500mg of oral MP × 2/day for 5 days IVMP group: 1000mg/d of intravenous MP for 5 days	1.Number of gadolinium-enhancing lesions on MRI^§ § MRI=magnetic resonance imaging. 1 week after steroid treatment 2.Number of gadolinium-enhancing lesions on MRI 4 weeks after steroid treatment 3.Proportion of patients with improvement on EDSS at 1 week 4.Proportion of patients with improvement on EDSS at 4 weeks 5.Adverse event rates
Remo-Tello 2014¹⁸18 Ramo-Tello C, Grau-Lopez L, Tintore M, Rovira A, Ramió i Torrenta L, et al. A randomized clinical trial of oral versus intravenous methylprednisolone for relapse of MS. Mult scler. 2014;20(6):717-25. DOI: 10.1177/1352458513508835. https://doi.org/10.1177/1352458513508835...	OMP group: 1250mg of oral MP 3 days+intravenous placebo IVMP group: 1000mg/d of intravenous MP for 3 days+oral placebo	1.Proportion of patients with improvement on EDSS of at least one poin at 1 week,4 weeks and 12 weeks 2.Number and volume of new and persistent T1 gadolinium-enhancing lesions on MRI at 1 week and 4 weeks 3.Number and volume of new and persistent? T2 lesions on MRI at 1 week and 4 weeks 4.Adverse event rates
Le Page 2015¹²12 Le Page E, Veillard D, Laplaud DA, Hamonic S, Wardi R, Lebrun C, et al. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. Lancetet al. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. Lancet. 2015;386(9997):974-81. DOI: 10.1016/S0140-6736(15)61137-0. https://doi.org/10.1016/S0140-6736(15)61...	OMP group: 1000mg of oral MP for 3 days IVMP group: 1000mg/d of intravenous MP for 3 days	1.the proportion of patients who decrease of at least one point in most affected score on EDSS by day 28 2.the proportion of patients who decrease of at least one point in most affected score on EDSS by day 180 3.Adverse event rates

Outcomes	# of studies	Numbers assessed	OR (95% CI) or Mean Difference (95% CI)	Heterogeneity	P-value
Improvement on EDSS^‡ ‡ EDSS=Kurtzke’s expanded disability status scale. at 1 week^* * a random-effects model was used.	2	85	0.49 [0.05, 5.12]	0.06	0.55
Improvement on EDSS at 6 months	1	170	1.01 [0.49, 2.09]	-	0.98
Relapse rate (0-6 months)	1	80	0.21 [-0.06, 0.48]	-	0.13
Relapse rate (year 1)	1	80	0.34 [-0.13, 0.81]	-	0.15
Relapse rate (year 2)	1	80	0.21 [-0.16, 0.58]	-	0.27
Overall relapse rate (2 years study period)	1	80	0.28 [-0.08, 0.64]	-	0.13
Proportion relapse free at 2 years	1	80	0.77 [0.28, 2.08]	-	0.60
Patients improved by at least 1 point on the most affected functional system scale without retreatment with methylprednisolone (4 weeks)	1	172	1.03 [0.49, 2.19]	-	0.94
Patients improved by at least 1 point on the most aff ected functional system (irrespective of retreatment) (4 weeks)	1	172	0.51 [0.18, 1.48]	-	0.22
Patients fully recovered from the relapse (4 weeks)	1	172	0.80 [0.44, 1.47]	-	0.47
Patients fully recovered from the relapse (6 months)	1	170	0.99 [0.51, 1.93]	-	0.98
Relapse-free patients (6 months)	1	170	0.94 [0.46, 1.91]	-	0.86
Proportion with gadolinium enhancing lesions at week 1	2	85	0.57 [0.24, 1.38]	0.72	0.21
Proportion with gadolinium enhancing lesions at week 4	2	85	0.68 [0.28, 1.67]	0.67	0.40
Mean change in gadolinium enhancing lesions on MRI ^§ § MRI=magnetic resonance imaging between weeks 0 and 1	2	85	-0.30 [-1.02, 0.43]	0.32	0.42
Mean change in gadolinium enhancing lesions on MRI between weeks 0 and 4	2	85	-0.26 [-1.48, 0.96]	0.63	0.67
Mean percentage reduction in gadolinium positive MRI lesions weeks 0-1	2	85	-0.01 [ -0.30, 0.29 ]	0.09	0.96
Mean percentage reduction in gadolinium positive MRI lesions weeks 0-4	2	85	-0.02 [ -0.24, 0.21 ]	0.97	0.89

Outcome	Oral MP Group	Intravenous MP Group	Odds Ratio in Favour of Outcome in Oral MP Group(95% CI )	P value
Headache	90/125	76/123	1.59 [0.93, 2.71]	0.09
Anxiety	53/145	49/143	1.11 [0.68, 1.81]	0.69
Euphoria^* * a random-effects model was used.	18/125	15/123	1.42 [0.31, 6.54]	0.66
Depressed mood	6/25	2/24	3.47 [0.63, 19.28]	0.15
Fatigue	3/25	4/24	0.68 [0.14, 3.43]	0.64
Insomnia	105/145	83/143	2.09 [1.22, 3.56]	0.007
Dysgeusia^* * a random-effects model was used.	100/145	97/143	1.48 [0.48, 4.58]	0.50
Stomach pain	10/25	6/24	2.00 [0.59, 6.79]	0.27
Epigastric pain	43/100	45/99	0.91 [0.52, 1.58]	0.73
Nausea	38/125	41/123	0.87 [0.51, 1.49]	0.62
Diarrhea	25/125	19/123	1.38 [0.71, 2.66]	0.34
Cutaneous rash	40/145	39/143	1.01 [0.60, 1.71]	0.96
Edema	2/25	3/24	0.61 [0.09, 4.01]	0.61
Palpitations	45/125	34/123	1.47 [0.86, 2.52]	0.16
Gastric pyrosis	6/20	5/20	1.29 [0.32, 5.17]	0.72
Hypertension	2/20	1/20	2.11 [0.18, 25.35]	0.56
Hypertrichosis	1/20	2/20	0.47 [0.04, 5.69]	0.56
Hiccup	1/20	0/20	3.15 [0.12, 82.16]	0.49
Hyperglycemia	0/20	1/20	0.32 [0.01, 8.26]	0.49
Hot flashes	63/100	58/99	1.20 [0.68, 2.13]	0.52
Agitation	42/100	29/99	1.75 [0.97, 3.15]	0.06
Vomiting	14/100	12/99	1.18 [0.52, 2.70]	0.69
Chest pain	18/100	13/99	1.45 [0.67, 3.15]	0.35

Mavera Edições Técnicas e Científicas Ltda Rua Professor Filadelfo Azevedo, 220, Cep: 04508-010, tel: (11) 3051 3043 - São Paulo - SP - Brazil
E-mail: medicalexpress@me.net.br

Acompanhe os números deste periódico no seu leitor de RSS

[1] E-mail: duyi@gxmu.edu.cn