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Intravenous immunoglobulin versus intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy: a randomised controlled trial Eduardo Nobile-Orazio, Dario Cocito, Stefano Jann, Antonino Uncini, Ettore Beghi, Paolo Messina, Giovanni Antonini, Raffaella Fazio, Francesca Gallia, Angelo Schenone, Ada Francia, Davide Pareyson, Lucio Santoro, Stefano Tamburin, Roberta Macchia, Guido Cavaletti, Fabio Giannini, Mario Sabatelli, for the IMC Trial Group*
Summary Background Intravenous immunoglobulin (IVIg) and corticosteroids are effective as initial treatment in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but little is known about the comparative risk– benefit profile of their long-term use in this disease. We compared the efficacy and tolerability of 6-month therapy with IVIg versus that with intravenous methylprednisolone. Methods We did a multicentre, randomised, double-blind, placebo controlled, parallel-group study in patients with CIDP. We assessed efficacy and tolerability of IVIg (0·5 g/kg per day for 4 consecutive days) and intravenous methylprednisolone (0·5 g in 250 mL sodium chloride solution per day for 4 consecutive days) given every month for 6 months. Eligible patients had to be in an active or stationary phase of the disease. Allocation to treatment was centrally managed with a computer-generated, 1:1 randomisation scheme with a sequential block size of four. All patients and assessors were unaware of the treatment assignment. After therapy discontinuation, patients were followed up for 6 months to assess relapses. The primary outcome was the difference in the number of patients discontinuing either therapy owing to inefficacy or intolerance. Secondary endpoints included the difference in the proportion of patients experiencing adverse events or worsening after therapy discontinuation. This study is registered with EUDRACT, number 2005-001136-76. Findings 45 patients (24 IVIg, 21 intravenous methylprednisolone) completed the study; one was excluded for inappropriate inclusion. More patients stopped methylprednisolone (11 [52%] of 21) than IVIg (three [13%] of 24; relative risk 0·54, 95% CI 0·34–0·87; p=0·0085). When adjusted for sex, age, disease duration, comorbidity, modified Rankin scale and ONLS scores at enrolment, and previous treatment with IVIg and steroids, the difference between the two groups remained significant (odds ratio 7·7, 95% CI 1·7–33·9; p=0·0070). Reasons for discontinuation were lack of efficacy (eight in the methylprednisolone group vs three in the IVIg group), adverse events (one in the methylprednisolone group), or voluntary withdrawal (two in the methylprednisolone group). Two patients on IVIg died during follow-up after the 6-month assessment. The proportion of patients with adverse events did not differ between the intravenous methylprednisolone group (14 [67%] of 21) and the IVIg group (11 [46%] of 24; p=0·1606). After therapy discontinuation, more patients on IVIg worsened and required further therapy (eight [38%] of 21) than did those on methylprednisolone (none of ten; p=0·0317). Interpretation Treatment of CIDP with IVIg for 6 months was less frequently discontinued because of inefficacy, adverse events, or intolerance than was treatment with intravenous methylprednisolone. The longer-term effects of these treatments on the course of CIDP need to be addressed in future studies. Funding Kedrion.
Introduction Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic progressive or relapsing neuropathy,1,2 with a prevalence ranging from 0·8 to 8·4 per 100 000 people.3,4 CIDP is often disabling with over 50% of patients having temporary disability and about 10% eventually becoming persistently disabled or dying because of the disease.5 The cause of CIDP remains unknown, but there are data supporting an immune pathogenesis.6 These data have led to the use of immune therapies, the efficacy of which has reinforced the hypothesis of an autoimmune origin. A few www.thelancet.com/neurology Vol 11 June 2012
randomised trials and several uncontrolled studies on a large series of patients have shown the efficacy of corticosteroids, plasma exchange, and intravenous immunoglobulin (IVIg) in CIDP.7–9 Two randomised trials on a small population of patients showed a comparable short-term efficacy of IVIg and oral corticosteroids10 and of IVIg and plasma exchange.11 Little is known about the efficacy of these therapies over the long term. In a large randomised trial, IVIg was more efficacious than placebo for 6 months and possibly up to 12 months,12,13 whereas a similar chance of remission was seen over 12 months with the use of either daily oral corticosteroids or pulsed
Lancet Neurol 2012; 11: 493–502 Published Online May 10, 2012 DOI:10.1016/S14744422(12)70093-5 See Comment page 478 *Members listed at end of paper Milan University, IRCCS Humanitas Clinical Institute, Rozzano, Milan, Italy (Prof E Nobile-Orazio MD, F Gallia MD); AOU S Giovanni Battista, Turin, Italy (D Cocito MD); Niguarda Ca’ Granda Hospital, Milan, Italy (S Jann MD); University G d’Annunzio, SS Annunziata Hospital, Chieti, Italy (Prof A Uncini MD); Mario Negri Institute, Milan, Italy (E Beghi MD, P Messina MSc); Rome University Sapienza, Sant’Andrea Hospital, Rome, Italy (G Antonini MD); San Raffaele Scientific Institute, INSPE, Milan, Italy (R Fazio MD); Genoa University, San Martino Hospital, Genoa, Italy (A Schenone MD); Umberto I Policlinico, Rome, Italy (A Francia MD); IRCCS Neurological Institute Carlo Besta, Milan, Italy (D Pareyson MD); Federico II University, Naples, Italy (Prof L Santoro MD); Pederzoli Clinic, Verona University, Peschiera del Garda ,Verona, Italy (S Tamburin MD); Kedrion, Castelvecchio Pascoli, Lucca, Italy (R Macchia MSc); Milan Bicocca University, San Gerardo Hospital, Monza, Italy (G Cavaletti MD); Siena University, Policlinico Le Scotte, Siena, Italy (F Giannini MD); and Catholic University, Policlinico Gemelli, Rome, Italy (M Sabatelli MD) Correspondence to: Prof E Nobile-Orazio, Department of Translational Medicine, University of Milan, 2nd Neurology, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089, Rozzano, Milan, Italy
[email protected]
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high-dose dexamethasone.14 The comparative efficacy and tolerance of IVIg or corticosteroids over this period remains unclear. We compared the efficacy and tolerability of 6-month therapy with IVIg or intravenous methylprednisolone in patients with CIDP.
Methods Patients For the study protocol see http://www.humanitas.it/hur/ cms/attivita_e_progetti/aree_di_ attivita/neuroriabilitativa/index. html
In this multicentre, randomised, double-blind, placebo controlled, parallel-group study, patients with CIDP were enrolled from 14 Italian neurological centres. Patients were eligible if they were at least 18 years of age, had definite typical CIDP according to the European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) criteria,15 had some disability (scoring 2 or more on either the overall neuropathy limitation scale [ONLS]16 or the modified Rankin scale17), were in an active or stationary phase but not in remission compared with the last available assessment, and were without improvement in the ONLS and modified Rankin scale scores between the screening and inclusion visits. Patients were excluded if they had atypical CIDP,15 a diagnosis of multifocal motor neuropathy,18 or other underlying causes including diabetes and IgM monoclonal gammopathy with antibodies to myelinassociated glycoprotein or to sulfatides. Patients were also excluded if they had concurrent medical disorders preventing treatment or assessment, history of psychiatric disorders, abnormalities on chest radiography, or ocular hypertension. On entry to the trial, patients should not have had known contraindications to steroids (heart failure, cataract, psychosis, uncontrolled
46 patients assessed for eligibility
1 excluded 1 had received high-dose intravenous corticosteroids 2 months before
45 patients randomised
21 patients allocated to intravenous methylprednisolone
11 patients shifted during treatment phase 6 at 0–15 days 1 at 15 days to 1 month 2 at 1 month to 2 months 2 at 2 months to 3 months
21 included in intention-to-treat analysis 10 included in per-protocol analysis
Figure 1: Trial profile
494
24 patients allocated to IVIg
3 patients shifted during treatment phase 1 at 0–15 days 2 at 15 days to 1 month
24 included in intention-to-treat analysis 21 included in per-protocol analysis
hypertension, gastric ulcer) or to IVIg (renal insufficiency, allergy to IVIg, IgA deficiency). Patients should not have taken IVIg in the previous 8 weeks or corticosteroids in the previous 3 months at a dose higher than 25 mg on alternate days or 12·5 mg daily. Lower doses were accepted but must not have changed in the previous 3 months. Patients with a documented lack of response to a previous course of an effective dose of steroids (intravenous methylprednisolone 0·5 g for 3 days or oral corticosteroids at a dose comparable to 1 mg/kg per day of prednisone for at least 1 month) or to IVIg 2 g/kg were also excluded. Concurrent immune therapy was accepted if not changed in the previous 12 months. Ongoing or planned pregnancy was an exclusion criterion. CSF analysis was not required, but patients were excluded if they had increased concentrations of cells in their CSF (higher than 10 per mL). All patients gave written informed consent before inclusion and were allowed to withdraw their consent at any time during the study. The study is registered under the EUDRACT number 2005-001136-76 and was approved by the ethics committees of all the participating centres.
Randomisation and masking Allocation to treatment was stratified by centre and centrally managed with a computer-generated, 1:1 randomisation scheme with a sequential block size of four. For each patient the treatment was prepared by a pharmacist or nurse, who had no further role in the study, in a different room or in the pharmacy of the hospital separate from where the patient was treated. Trial drugs were transferred in identical masked bottles marked with the patient’s identification number to the trial nurse, who was masked to treatment allocation. Patients, their families, and investigators were masked to treatment assignment.
Procedures Patients were randomly assigned to receive in 1:1 proportion either IVIg (IgVena, Kedrion, Italy) at the daily dose of 0·5 g/kg for 4 consecutive days and intravenous steroid placebo (250 mL of sodium chloride solution) or daily intravenous methylprednisolone 0·5 g in 250 mL of sodium chloride solution for 4 consecutive days and IVIg placebo (the equivalent volume of 10% maltose solution). Each patient was treated every 28 days (within 3 days) for 6 months. After 6 months, therapy was discontinued and patients followed up for a further 6 months for deterioration (worsening by at least one point in the ONLS or modified Rankin scale score), in which case they resumed the therapy at the discretion of the treating physician. During the 4 days of therapy, patients received either omeprazole or another gastroprotective agent, while oral antihistaminic drugs were added at the discretion of the treating neurologist. www.thelancet.com/neurology Vol 11 June 2012
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Patients were screened within 30 days before enrolment with medical assessments including measurement of blood pressure and body weight, electrocardiography, and chest radiographs, a complete neurological assessment, nerve-conduction measurement on a minimum of eight motor and six sensory nerves, routine laboratory tests, and measurement of intraocular tension. For each patient the treating neurologist chose the two most relevant motor nerves to test for the diagnosis of CIDP, according to the EFNS/PNS criteria15 for demyelination. Severity of neuropathy was graded with the modified Rankin scale and the ONLS. After enrolment, patients were assessed by an unmasked treating neurologist, who followed up the patient, checked the side-effects of therapy and laboratory tests, and decided whether to change therapy, and by a masked neurologist, who undertook all the periodic assessments and was unaware of assigned treatment, side-effects reported by the patients, and results of laboratory tests. Electrophysiological studies were done by a physician who was masked to treatment. Patients were assessed before (month 0) and 15 days after the first therapy, then every month before each therapy course and 1 month after the last therapy (month 6). Patients were subsequently assessed every 2 months until month 12. Patients who did not improve by at least one point on the ONLS or modified Rankin scale scores after the first two courses of therapy at the 2-month visit were allowed to shift to the alternative therapy. Patients not tolerating the first therapy or who worsened by at least one point in the ONLS or modified Rankin scale scores after use of the first therapy were shifted to the alternative therapy. Each periodic assessment included several investigations: a general assessment with an enquiry about side-effects; neurological assessment; ONLS score (range 0 to 12, healthy to unable to perform any purposeful movement with arms and legs [0 to 5 in the arms and 0 to 7 in the legs]);16,19 modified Rankin scale score (range 0 to 5, healthy to severely disabled);17 Medical Research Council sum score on 12 muscles (range 0 to 60, most impaired to healthy);20 inflammatory neuropathy cause and treatment (INCAT) sensory sum score (range 0 to 20, healthy to severe sensory loss);21 vibratory sensation at index finger and toe measured with the Rydell tuning fork (range 0 to 8 at each site, most impaired to healthy); grip strength measured with the Martin vigorimeter; and timed 10-m walk. An early version of the Rotterdam nine-task handicap scale (nine tasks, plus a task on economic autonomy; each item scored 0=unable, 1=partially able or able with help, 2=independent, total score 0 to 20)10,22 and short-form 36 quality-of-life scale23 were assessed at baseline and 15 days, and 2, 6, and 12 months after starting therapy. A complete nerve conduction assessment, similar to that www.thelancet.com/neurology Vol 11 June 2012
done at enrolment and including the two most relevant nerves for the diagnosis of CIDP, was done after 6 months, and the two most relevant motor nerves were also assessed before and 15 days after therapy. Routine laboratory tests were done at study entry, 15 days after therapy, before the second and fourth course of therapy, and 1 month after the sixth course. Blood pressure was measured after each infusion and intraocular tension was reassessed after 3 months and 6 months of therapy. The primary outcome was the difference in the proportion of patients discontinuing treatment with IVIg or intravenous methylprednisolone during the 6 months of therapy because of side-effects, intolerance, or inefficacy (absence of improvement after 2 months or worsening after 15 days). Several secondary outcomes were assessed: the change of assessment scores after 15 days, 2 months, and 6 months of therapy compared
Men Women
Intravenous methylprednisolone (n=21)
Intravenous immunoglobulin (n=24)
15
15
6
Age (years)
9
66 (39–79)
54 (19–83)
14
13
7
11
CIDP Progressive Relapsing Disease duration (years)
6 (0–29)
ONLS
4 (2–9)
4 (0–12) 3 (2–5)
Modified Rankin score
3 (2–5)
2 (1–4)
Previous therapy Intravenous immununoglobulin Steroids
7
15
10
14
Concurrent immune therapy Azathioprine
0
3
Methotrexate
1
0
Low-dose steroids Patients with comorbidities
3
2
15*
11†
Data are number or median (range). CIDP=chronic inflammatory demyelinating polyradiculoneuropathy. ONLS=overall neuropathy limitations scale. *Including controlled hypertension in 12 patients and cardiopathy in two patients. †Including controlled hypertension in six patients and cardiopathy in one patient.
Table 1: Baseline demographics and clinical characteristics
Intravenous methylprednisolone (n=21)
Intravenous immunoglobulin (n=24)
Risk difference (95% CI)
Relative risk (95% CI)
p value
15 days
6 (29%)
1 (4%)
0·24 (0·03–0·45) 0·75 (0·56–0·99)
0·0389
2 months
9 (43%)
3 (13%)
0·30 (0·05–0·55)
0·65 (0·44–0·97)
0·0406
6 months* 11 (52%)
3 (13%)
0·40 (0·15–0·65) 0·54 (0·34–0·87)
0·0085
Data are number (%) unless otherwise stated, risk difference, or relative risk (95% CI). *Primary outcome.
Table 2: Cumulative treatment failures
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with baseline; the proportion of patients worsening by at least one point in the ONLS or modified Rankin scale score during the 6 months after therapy discontinuation; the difference in the time to worsening after therapy discontinuation; the difference in the proportion of patients without limitation on the ONLS (ie, with scores 0 or 1, with 1 not in the lower limbs) and modified 1·0
Survival probability
0·8
0·6
0·4
Rankin scale (ie, with scores 0 or 1) at the end of 6 months; the change of negative phase amplitude of proximal and distal compound muscle action potentials, motor conduction velocity, and distal latencies and in the number of nerves with conduction block among the two representative motor nerves after 15 days and 6 months of therapy; the proportion of patients unresponsive to the first therapy who improved after the alternative therapy; the proportion of patients experiencing adverse events during therapy; and the change on nerve conduction studies before and after 6 months of therapy (these data will be analysed separately). An independent data safety monitoring board was not deemed to be necessary since both therapies are currently used in clinical practice and unexpected adverse events were deemed unlikely to occur.
0·2 Intravenous immunoglobulin Intravenous methylprednisolone 0 Baseline 0·5* 1 2 3 (randomisation) Time (months) Number at risk Intravenous immunoglobulin 24 24 23 21 21 Intravenous methylprednisolone 21 21 15 14 12
Statistical analysis 4
5
6
21 10
21 10
21 10
Figure 2: Time to failure occurrence (actuarial method) Product-limit survival estimates with number of patients at risk and 95% CIs (shaded areas). *0·5 months=15 days.
Intravenous methylprednisolone (n=21)
Intravenous immunoglobulin (n=24)
p value
Modified Rankin score Enrolment
3 (2–5)
2 (1–4)
15 days
2 (1–5)
2 (0–4)
·· 0·1742
2 months
2 (0–5)
2 (0–3)
0·1413
6 months
2 (0–5)
2 (0–3)
0·0228
p value*
0·0220
0·0006
0·3542†
Enrolment
4 (2–9)
3 (2–5)
15 days
4 (1–9)
3 (0–8)
0·1506
2 months
4 (0–9)
3 (0–5)
0·0388
ONLS
6 months
3 (0–9)
2 (0–5)
0·1322
p value*
0·0582
6·1 mmol/L) were defined according to normative standards.25,26 †In one of the two patients the adverse event occurred after the patient had shifted to the alternative therapy. ‡Adverse event leading to therapy discontinuation. §Adverse events occurred after the patient had shifted to the alternative therapy.
Table 5: Patients with adverse events
significantly differ between the methylprednisolone group (1·62, 95% CI 1·12–2·26) and IVIg group (0·75, 0·45–1·18; p=0·0724). Both groups had a similar number of abnormal laboratory tests at the end of the study (data not shown). www.thelancet.com/neurology Vol 11 June 2012
Discussion Treatment of CIDP with IVIg for 6 months was less frequently discontinued because of inefficacy, adverse events, or intolerance than was treatment with intravenous methylprednisolone. Assessment scores showed that responses tended to be more favourable in the IVIg group, possibly reflecting the different drop-out rate in the two groups; however, these data should be interpreted with caution because of the large number of comparisons for which no adjustment was made. The small sample size prevented further assessment of treatment efficacy and safety in patient subgroups. The most important limitation of the study was the imbalance of some baseline characteristics in the two treatment arms. Patients treated with intravenous methylprednisolone tended to be older and have more functional impairments than did patients treated with IVIg. Additionally, more patients in the IVIg group than in the methylprednisolone group had previously received IVIg. Since failure to respond to IVIg (and steroids) was an exclusion criterion, this might have affected the results by the exclusion of non-responsive patients. However, the multivariable models accounted for these imbalances at least for the primary outcome and, with the adjusted estimates, the two groups were still different in the primary outcome. The inclusion of non-treatmentnaive patients might limit the extent to which the results can be generalised to previously untreated patients. However, our results could be applicable to treatment of patients in an active or stationary phase of the disease with significant disability, without contraindication to steroids or IVIg, and who have not failed to respond to one of the treatments (panel). The dose and regimen of the steroids used in this study could also be questioned. We used monthly pulse intravenous methylprednisolone, because this regimen allowed us to mask the treatment of patients in the hospital with the same type of intravenous regimen used for IVIg. Compared with intravenous methylprednisolone, oral prednisolone therapy would have been continued at home and would have required the preparation of a different oral placebo. In addition, we gave intravenous methylprednisolone for 4 consecutive days in the same way as IVIg administration. This made the two regimens identical for the patient and the nurse. Corticosteroids are effective in patients with CIDP when prescribed orally,27 and the dose of 60 mg per day of prednisolone is usually thought to correspond with a monthly dose of 1350 mg intravenous methylprednisolone. In the prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT) study, the pulse dose of oral dexamethasone of 160 mg per month was used, equivalent to 850 mg intravenous methylprednisolone.14 The dose of intravenous methylprednisolone used in our study (0·5 g per day for 4 consecutive days) was in the range of doses used in other trials in patients with 499
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Panel: Research in context Systematic review We searched the Cochrane Neuromuscular Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library for studies (March, 2012), Medline for studies published between 1960 and April, 2012, and Embase for studies published between 1980 and April, 2012, with the search terms “steroids”, “corticosteroids”, “prednisone”, “prednisolone”, “methylprednisolone”, “dexamethasone”, “high dose intravenous immunoglobulin”, “IVIg”, “immunoglobulins”, “azathioprine”, “methotrexate”, “interferon”, “cyclosporin”, “rituximab”, “cyclophosphamide”, “alentuzumab”, “mycophenolate”, “immune therapy”, “chronic inflammatory demyelinating polyradiculoneuropathy” or “polyneuropathy” or “polyradiculopathy, “CIDP, “polyneuropathy”, “neuropathy”, and “polyneuritis”. We also hand-searched relevant journals and the reference lists of included papers. We included randomised trials and open-label trials assessing the effects of steroids, high-dose IVIg and immune therapies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). All trials were assessed for methodological quality and were judged to assess the risk of bias for sequence generation, allocation concealment, masking, incomplete outcome data, selective outcome reporting, from low (low risk of bias), high (high risk of bias), and unclear (unclear or unknown risk of bias). A few randomised trials have shown the efficacy of steroids, plasma exchange, and IVIg in CIDP.7–9 Long-term efficacy of IVIg12,13 and corticosteroids14 has also been reported. IVIg and oral corticosteroids were reported to have similar efficacy over the short term,10 but little is known about their comparative efficacy over the long term. Interpretation We showed that treatment of CIDP with IVIg for 6 months was less frequently discontinued because of inefficacy, adverse events, or intolerance than was treatment with intravenous methylprednisolone. Future studies should assess whether the longer-term efficacy of intravenous methylprednisolone compared with IVIg has an effect on the chronic course of CIDP.
inflammatory neuropathies, including Guillain-Barré syndrome (eg, intravenous methylprednisolone 0·5 g per day for 5 consecutive days in addition to IVIg),28 and with CIDP (intravenous methylprednisolone 1 g per day for 3–5 consecutive days followed by maintenance infusions of 1 g per week for a month and subsequent tapering doses for 1–2 years).29 A few reports on a small series of patients described a similar efficacy when steroids were prescribed in pulsed monthly doses or daily regimens,29–31 and a randomised trial14 showed comparable efficacy of standard oral prednisolone and pulsed, high-dose, monthly oral dexamethasone over 6 months. In some of these studies pulsed corticosteroids were associated with fewer adverse events than daily oral steroids.29–31 However, the high dose of intravenous methylprednisolone used in our study might explain the non-significant higher rate of adverse events in the methylprednisolone group than in the IVIg group. In a short-term trial,10 IVIg and oral prednisolone had the same efficacy after 2 weeks of therapy. We did not find a significant difference in the degree of improvement between IVIg and intravenous methylprednisolone even after 6 months of therapy, but more patients were able to continue therapy with IVIg than with 500
methylprednisolone. However, the early shift of therapy by patients treated with methylprednisolone who deteriorated or did not improve after 2 months excluded patients who might have later improved as indicated by the PREDICT study, in which the median time to improvement in the pulsed dexamethasone group was 17 weeks.14 Our study also showed that, when efficacious and tolerated, intravenous methylprednisolone was associated with fewer relapses than IVIg after discontinuation of therapy. Similar long-term efficacy of corticosteroids was reported in six of ten patients treated with pulsed high-dose dexamethasone who sustained improvement for 6 months after therapy discontinuation.31 Additionally, the follow-up of the PREDICT study showed that the median time to relapse after therapy discontinuation ranged from 11·0 months for oral prednisolone to 17·5 months for pulsed dexamethasone.32 The longer efficacy of corticosteroid than that of IVIg after discontinuation could be relevant to the long-term treatment of CIDP. Most patients with CIDP require long-term therapy, facing the inconveniences of repeated infusions and high costs related to IVIg or of side-effects often associated with the prolonged use of corticosteroids.33 These inconveniences have led to the use of immunosuppressive agents in CIDP,34 the efficacy of which has not been confirmed in randomised studies.19,35–37 Whether the high dose of corticosteroids used in our study delayed progression compared with IVIg or induced longer remission will be clarified by a follow-up study. These factors, together with the lower cost of intravenous methylprednisolone, might favour the choice of this drug as initial treatment for patients with CIDP. On the one hand, long-term use of IVIg was less frequently discontinued because of inefficacy, adverse events, or intolerance than was treatment with intravenous methylprednisolone. On the other hand, methylprednisolone induced a longer-term remission than did IVIg. Whether the latter difference might also affect the chronic course of the disease remains to be clarified. Contributors EN-O, EB, DC, MS, and AS were members of the IMC study steering committee and contributed to the conception and design of the study and the preparation of the final protocol. EN-O, DC, SJ, AU, GA, RF, FG, AS, AF, DP, LS, ST, GC, FG, and MS contributed to data. RM helped in the preparation of the study protocols and verified the completeness of the submitted data. PM and EB did the statistical analysis. EN-O and EB analysed and assessed the results of the study and contributed to the development of the first draft and subsequent revisions of the Article. All authors critically reviewed and approved the final version. Immunoglobulin Methylprednisolone for CIDP (IMC) trial group Eduardo Nobile-Orazio, Francesca Gallia (Milan University, IRCCS Humanitas Clinical Institute, Rozzano, Milan, Italy), Dario Cocito, Ilaria Paolasso (Department of Neuroscience, AOU S Giovanni Battista, Turin, Italy), Stefano Jann, Luisa De Toni Franceschini (Department of Neuroscience, Niguarda Ca’ Granda Hospital, Milan, Italy), Antonino Uncini, Francesca Notturno (Department of Neuroscience and Imaging,
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G d’Annunzio University, SS Annunziata Hospital, Chieti, Italy), Giovanni Antonini, Alessandro Clemenzi (Department of Neurology, Mental Health and Sensory Organs, University of Rome Sapienza, Sant’Andrea Hospital, Rome, Italy), Raffaella Fazio, Francesca Bianchi (Department of Neurology, San Raffaele Scientific Institute , INSPE Milan, Italy), Angelo Schenone, Elisabetta Fiorina (Department of Neuroscience, Ophtalmology and Genetics, Genoa University, San Martino Hospital, Genoa, Italy), Ada Francia, Simona Pontecorvo (Department of Neurology, Umberto I Policlinico, Rome, Italy), Davide Pareyson, Chiara Marchesi (Central and Peripheral Degenerative Neuropathy Unit, IRCCS Carlo Besta Neurological Institute, Milan, Italy), Lucio Santoro, Fiore Manganelli (Department of Neurology, Federico II University, Napoli, Italy), Stefano Tamburin, Maria Luigia Praitano (Neurology Unit, Pederzoli Clinic, Peschiera del Garda, Verona University, Verona, Italy), Guido Cavaletti, Marialuisa Piatti (Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy), Fabio Giannini, Giuseppe Greco (Department of Neurological, Neurosurgical and Behavioural Sciences, Siena University, Policlinico Le Scotte, Siena, Italy), Mario Sabatelli, Marco Luigetti (Department of Neurology, Catholic University, Policlinico Gemelli, Rome, Italy), Ettore Beghi, Paolo Messina (Laboratory of Neurological Disorders, Mario Negri Institute for Pharmacological Research, Milan, Italy), Roberta Macchia, Chiara Guarnieri, Bruno Fiorentino (Medical Affairs, Kedrion SpA, Castelvecchio Pascoli, Lucca, Italy). Conflicts of interests EN-O served on the Immunoglobulin in Neurology Advisory Board of CSL Behring and as ad-hoc consultant for Baxter, Laboratoire Français du Biofractionnement, and Kedrion, and lectured for Talecris. EN-O and DC have received travel grants to attend scientific meetings from Baxter, Grifols, Kedrion, and Novartis. SJ and LS have received travel grants to attend scientific meetings from Grifols and Kedrion. AU, FG, AF, DP, GC, and FG have received travel grants to attend scientific meetings from Kedrion. GA has received travel grants to attend scientific meetings from Baxter, CSL Behring, and Kedrion. RF received has received travel grants to attend scientific meetings from Baxter, Grifols, and Kedrion. AS has received travel grants to attend scientific meetings from Biofutura, Grifols, Kedrion, and Lilly. ST and MS have received travel grants to attend scientific meetings from Grifols. EB served on the advisory board of Viropharma and lectured for UCB-Pharma, Sanofi-Aventis, Eisai, and GSK. EB’s institution has received grants from Sanofi-Aventis, Janssen, and Eisai. RM is an employee of Kedrion. PM declares no conflicts of interest. References 1 Hahn AF, Hartung H-P, Dyck PJ. Chronic inflammatory demyelinating polyradiculoneuropathy. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy, 4th edn. Philadelphia: Elsevier, 2005: 2221–53. 2 Vallat J-M, Sommer C, Magy L. Chronic inflammatory demyelinating polyradiculoneuropathy: diagnostic and therapeutic challenges for a treatable condition. Lancet Neurol 2010; 9: 402–12. 3 Kusumi M, Nakashima K, Nakayama H, et al. Epidemiology of inflammatory neurological and inflammatory neuromuscular diseases in Tattori Prefecture, Japan, Psychiatry. Clin Neurosci 1995; 49: 169–74. 4 Laughlin RS, Dyck PJ, Melton LJ, et al. Incidence and prevalence of CIDP and the associations with diabetes mellitus. Neurology 2009; 73: 39–45. 5 Lunn MPT, Manji H, Choudhary PP, et al. Chronic inflammatory demyelinating polyradiculoneuropathy: a prevalence study in south east England. J Neurol Neurosurg Psychiatry 1999: 66: 677–80. 6 Hughes RAC, Allen D, Makowska A, Gregson NA. Pathogenesis of chronic inflammatory demyelinating polyradiculoneuropathy. J Peripher Nerv Syst 2006; 11: 30–46. 7 Eftimov F, Winer JB, Vermeulen M, et al. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2009; 1: CD001797. 8 Mehndiratta MM, Hughes RAC. Corticosteroids for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2002; 1: CD002062.
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Mehndiratta MM, Hughes RAC, Agarwal P. Plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2004; 3: CD003906. Hughes RAC, Bensa S, Willison HJ, et al, and the Inflammatory Neuropathy Cause and Treatment (INCAT) group. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001; 50: 195–201. Dyck PJ, Litchy WJ, Kratz KM, et al. A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 1994; 36: 838–45. Hughes RA, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized placebo-controlled trial. Lancet Neurol 2008; 7: 136–44. Merkies IS, Bril V, Dalakas MC, et al. Health-related quality-of-life improvements in CIDP with immunoglobulin IV 10%: the ICE study. Neurology 2009; 72: 1337–44. van Schaik IN, Eftimov F, van Doorn PA, et al. Pulsed high-dose dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind randomised controlled trial. Lancet Neurol 2010; 9: 245–53. Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst 2005; 10: 220–28. Graham RC, Hughes RA. A modified peripheral neuropathy scale: the overall neuropathy limitation scale. J Neurol Neurosurg Psychiatry 2006; 77: 973–76. Bamford JM, Sandercock PA, Warlow CP, Slattey J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1989; 20: 828. Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of multifocal motor neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst 2006; 11: 1–8. RMC Trial Group. Pilot randomised controlled trial of methotrexate for chronic inflammatory demyelinating polyradiculoneuropathy (RMC trial). Lancet Neurol 2009; 8: 158–164. Kleyweg RP, van der Meché FG, Schmitz PI. Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barré syndrome. Muscle Nerve 1991; 14: 1103–09. Merkies ISJ, Schmitz PIM, van der Meché FGA, van Doorn PA, for the European neuropathy Cause and treatment Group. Psychometric evaluation of a new sensory scale in immune-mediated polyneuropathies. Neurology 2000; 54: 943–49. Merkies IS, Schmitz PI, Van Der Meché FG, et al. Psychometric evaluation of a new handicap scale in immune-mediated polyneuropathies. Muscle Nerve 2002; 25: 370–77. Ware JE Jr, Sherbourne CD. The MOS 36-item short form health survey (SF-36): I: conceptual framework and item selection. Med Care 1992; 30: 473–83. McCrone P, Chisholm D, Knapp M, et al. Cost-utility analysis of intravenous immunoglobulin and prednisolone for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Eur J Neurol 2003; 10: 687–94. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003; 42: 1206–52. The Expert Committee on the diagnosis and classification of diabetes mellitus. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003; 26: 3160–67. Dyck PJ, O’Brien PC, Oviatt KF, et al. Prednisone improves chronic inflammatory demyelinating polyradiculoneuropathy more than no treatment. Ann Neurol 1982; 11: 136–14. van Koningsveld R, Schmitz PI, Meché FG, et al. Effect of methylprednisolone when added to standard treatment with intravenous immunoglobulin for Guillain-Barré syndrome: randomised trial. Lancet 2004; 363: 192–96.
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Comment
First-line treatment for CIDP: a new piece of the puzzle Published Online May 10, 2012 DOI:10.1016/S14744422(12)70101-1
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Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disease of peripheral nerves that can cause substantial disability for long periods of time.1 The primary goal in treating chronic diseases should be a sustained clinically meaningful improvement or remission without long-term treatment. The potential benefits of corticosteroids and intravenous immunoglobulin (IVIg) for patients with CIDP have been known for a long time.2,3 More recently, corticosteroids and IVIg were shown to be efficacious in the long-term, and remissions were shown to be induced after a relatively short treatment regimen with corticosteroids.4,5 Whether IVIg induces remissions has not been proven. An urgent question is what the optimum first-line treatment is for patients with CIDP. In one head-to-head comparison in which the shortterm benefits were addressed, no difference was shown between a single course of 2·0 g/kg IVIg and 6 weeks treatment with oral prednisolone starting with 60 mg a day with subsequent tapering.6 Few studies of CIDP have been done on which the choice of treatment can be based, which explains the
large treatment variations. Therefore, the study by Eduardo Nobile-Orazio and colleagues7 reported in this issue of The Lancet Neurology is timely. In this study, IVIg and intravenous methylprednisolone therapy were both given for 6 months. Patients more often discontinued intravenous methylprednisolone (11 [52%] of 21) than IVIg (three [13%] of 24) therapy because of inefficacy or adverse events (relative risk 0·54, 95% CI 0·34–0·87; p=0·0085), but patients who responded to intravenous methylprednisolone did not require any other therapy for the next 6 months. The results showed that the magnitude of improvement in neurological deficit (modified Rankin, Rotterdam, and short-form 36 scores, overall neuropathy limitation scale [ONLS] score, Medical Research Council sum score, grip strength, inflammatory neuropathy cause and treatment sensory sum score, and timed 10-m walk) was similar between the two treatment groups but that the percentage of patients responding to IVIg (88% [21 of 24]) was higher than the percentage of patients responding to intravenous methylprednisolone (48% [ten of 21]). Previous studies showed a much more rapid improvement after IVIg than after corticosteroids.2,8 The time to improvement after corticosteroid treatment is at least several months but could be much longer.5,9 At 15 days and 2 months, six and nine patients, respectively, had already dropped out of the intravenous methyprednisolone group because of worsening after treatment or failure to improve. This period could be too early for intravenous methylprednisolone to have an effect in many patients. The imbalance in the baseline characteristics might also have offset methylprednisolone in the comparison: patients in the intravenous methylprednisolone group were about one point more disabled on the modified Rankin scale and the OLNS. The dose of methylprednisolone in this study (2·0 g per month) is high compared with doses used in previous studies of corticosteroids.5,9–11 The proportion of patients improving by at least one point in the ONLS or modified Rankin score on pulsed intravenous methylprednisolone is in the same range as found in the prednisolone versus dexamethasone for chronic inflammatory demyelinating polyradiculopathy trial (PREDICT), in which pulsed highdose dexamethasone was compared with prednisolone.5 This finding could mean that higher dosing such as that www.thelancet.com/neurology Vol 11 June 2012
Comment
used in the study by Nobile-Orazio is not necessary and will only lead to more adverse events, which could be an explanation for the high dropout rate at 15 days in the intravenous methylprednisolone group. Another problem might have been that more patients in the IVIg group were treated with IVIg previously and thus were known to be responsive to this treatment. Therefore, the design of the study could have underestimated the efficacy of intravenous methylprednisolone. Nevertheless, the study shows that if a rapid improvement is needed (eg, because of severe disability), IVIg is the first choice therapy. Nobile-Orazio and colleagues’ study7 has important clinical implications. As said before, in patients with a chronic disease, remission should be the goal of therapy and transient side-effects or discomfort should be weighted against this treatment goal. On the basis of this goal, given the data from this study and the PREDICT study, one could argue that a patient without contraindications for corticosteroids should be started on pulsed high-dose intravenous methylprednisolone or dexamethasone for 6 months. About half of patients will respond to this treatment and remain in remission. The other half, who do not improve or who deteriorate on intravenous methylprednisolone, can safely be switched to IVIg and most will improve on this treatment. Nine of 11 patients in Nobile-Orazio and colleagues’ study7 were taken off intravenous methylprednisolone within 2 months and the adverse events were similar between the two groups, making this strategy safe and the time on corticosteroids relatively short. Costs, convenience, and patient autonomy are other factors that should be taken into account when choosing between IVIg and corticosteroids. No reliable predictors of response exist for either treatment and this should be an important area of research. Combining IVIg and pulsed high-dose
corticosteroids for 6 months could combine the best of both worlds: fast recovery and induction of remission. This combination requires a new study. Yet another piece of the jigsaw puzzle has been added, but there are many more to go. Ivo N van Schaik Department of Neurology, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD, Amsterdam, Netherlands
[email protected] I have received departmental honoraria for serving on scientific advisory boards and a steering committee for CSL-Behring. 1
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Lunn MPT, Manji H, Choudhary PP, Hughes RAC, Thomas PK. Chronic inflammatory demyelinating polyradiculoneuropathy: a prevalence study in south east England. J Neurol Neurosurg Psychiatry 1999; 66: 677–80. Eftimov F, Winer JB, Vermeulen M, de Haan RJ, van Schaik IN. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2009; 1: CD001797. Mehndiratta MM, Hughes RAC. Corticosteroids for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2002; 1: CD002062. Hughes RA, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol 2008; 7: 136–44. van Schaik IN, Eftimov F, Van Doorn PA, et al. Pulsed high dose dexamethasone treatment versus standard prednisolone treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): a double-blind randomised controlled clinical trial (PREDICT study). Lancet Neurol 2010; 9: 245–53. Hughes RA, Bensa S, Willison HJ, et al. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001; 50: 195–201. Nobile-Orazio E, Cocito D, Jann S, et al. Intravenous immunoglobulin versus intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy: a randomised controlled trial. Lancet Neurol 2012; published online May 10. DOI:10.1016/S1474-4422(12)70093-5. Latov N, Deng C, Dalakas MC, et al. Timing and course of clinical response to intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy. Arch Neurol 2010; 67: 802–07. Muley SA, Kelkar P, Parry GJ. Treatment of chronic inflammatory demyelinating polyneuropathy with pulsed oral steroids. Arch Neurol 2008; 65: 1460–64. Lopate G, Pestronk A, Al-Lozi M. Treatment of chronic inflammatory demyelinating polyneuropathy with high-dose intermittent intravenous methylprednisolone. Arch Neurol 2005; 62: 249–54. Dyck PJ, O’Brien P, Oviatt KF. Prednisone improves chronic inflammatory demyelinating polyradiculoneuropathy more than no treatment. Ann Neurol 1982; 11: 136–41.
Reducing the risk of recurrent stroke in patients with AF Previous stroke or transient ischaemic attack (TIA) is the most powerful independent predictor of stroke in patients with atrial fibrillation (AF), with an annual rate of subsequent stroke of between 6% and 10% per year in the absence of anticoagulation.1–3 The time interval from the most recent stroke or TIA is inversely related to stroke rate, but previous stroke or TIA occurring in the past 1–3 years still confers a high (>5% per year) risk www.thelancet.com/neurology Vol 11 June 2012
of stroke.4 The rate seems to be lower for patients with AF and previous TIA versus those with AF and previous stroke, but it is still substantial, and the responses to anticoagulation are similar for patients with both types of brain ischaemia.5 The absolute reduction in stroke provided by anticoagulation for patients with AF and previous stroke is larger than that of any other medical intervention for stroke prevention.6
Published Online May 8, 2012 DOI:10.1016/S14744422(12)70096-0 See Articles page 503
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