Immunomodulatory treatment other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy

  • Review
  • Intervention

Authors


Abstract

Background

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disease causing progressive or relapsing and remitting weakness and numbness. It is probably due to an autoimmune process. Immunosuppressive or immunomodulatory drugs would be expected to be beneficial. This review was first published in 2003 and has been most recently updated in 2013.

Objectives

We aimed to review systematically the evidence from randomised trials of immunomodulatory and immunosuppressive agents other than corticosteroids, immunoglobulin and plasma exchange for CIDP.

Search methods

On 9 July 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register (July 2012), CENTRAL (2012, Issue 6 in The Cochrane Library), MEDLINE (January 1977 to July 2012), EMBASE (January 1980 to July 2012), CINAHL (January 1982 to July 2012) and LILACS (January 1982 to July 2012). We contacted the authors of the trials identified and other disease experts seeking other published and unpublished trials.

Selection criteria

We sought randomised and quasi-randomised trials of all immunosuppressive agents such as azathioprine, cyclophosphamide, methotrexate, ciclosporin, mycophenolate mofetil, and rituximab and all immunomodulatory agents such as interferon alfa and interferon beta, in participants fulfilling standard diagnostic criteria for CIDP.

Data collection and analysis

Two authors independently selected trials, judged their risk of bias and extracted data. We wanted to measure the change in disability after one year as our primary outcome. Our secondary outcomes were change in disability after four or more weeks (from randomisation), change in impairment after at least one year, change in maximum motor nerve conduction velocity and compound muscle action potential amplitude after one year and for those participants who were receiving corticosteroids or intravenous immunoglobulin, the amount of this medication given during at least one year after randomisation. Participants with one or more serious adverse events during the first year was also a secondary outcome.

Main results

Four trials fulfilled the selection criteria, one of azathioprine (27 participants), two of interferon beta-1a (77 participants in total) and one of methotrexate (60 participants). The risk of bias in the two trials of interferon beta-1a for CIDP and the trial of methotrexate was assessed to be low but bias in the trial of azathioprine was judged high. None of these trials showed significant benefit in the primary outcome (measured only in the methotrexate study) or secondary outcomes selected for this review. Severe adverse events occurred no more frequently than in the placebo groups for methotrexate and interferon beta-1a, but participant numbers were low. There was no adverse event reporting in the azathioprine study.

Authors' conclusions

The evidence from randomised trials does not show significant benefit from azathioprine, interferon beta-1a or methotrexate but none of the trials was large enough to rule out small or moderate benefit. The evidence from observational studies is insufficient to avoid the need for randomised controlled trials to discover whether these drugs are beneficial. Future trials should have improved designs, more sensitive outcome measures and longer durations.

Resumen

Antecedentes

Tratamiento inmunorregulador distinto de los corticosteroides, la inmunoglobulina o el recambio plasmático, para la polirradiculoneuropatía desmielinizante inflamatoria crónica

La polirradiculoneuropatía desmielinizante inflamatoria crónica es una enfermedad que causa debilidad muscular y pérdida de la sensibilidad progresivas o recurrentes y remitentes. Probablemente se deba a un proceso autoinmune. Se esperaría que los fármacos inmunosupresores o inmunomoduladores fueran beneficiosos.

Objetivos

El objetivo fue revisar de manera sistemática las pruebas en ensayos aleatorios de fármacos citotóxicos e interferones, aparte de los corticosteroides, la inmunoglobulina y el recambio plasmático, para la polirradiculoneuropatía desmielinizante inflamatoria crónica.

Estrategia de búsqueda

Se hicieron búsquedas en el registro de ensayos del Grupo Cochrane de Enfermedades Neuromusculares (Cochrane Neuromuscular Disease Group) (mayo 2010), Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL) (The Cochrane Library, número 2), MEDLINE (enero 1977 hasta mayo 2010), EMBASE (enero 1980 hasta mayo 2010), CINAHL (enero 1982 hasta mayo 2010) y en LILACS (enero 1982 hasta mayo 2010). Se estableció contacto con los autores de los ensayos identificados y a otros especialistas en la enfermedad en busca de otros ensayos publicados y no publicados.

Criterios de selección

Se buscaron ensayos aleatorios y cuasialeatorios de todos los agentes inmunosupresores como azatioprina, ciclofosfamida, metotrexato, ciclosporina A, micofelonato mofetilo y rituximab y de todos los agentes inmunomoduladores, como interferón alfa e interferón beta, en participantes que cumplieran con criterios estándar de diagnóstico para la polirradiculoneuropatía desmielinizante inflamatoria crónica.

Obtención y análisis de los datos

Dos autores, de forma independiente, seleccionaron los ensayos, juzgaron su calidad metodológica y extrajeron los datos. Se deseaba medir los cambios en la discapacidad luego de un año como resultado primario. Nuestros resultados secundarios fueron el cambio en la discapacidad luego de cuatro semanas o más (desde la asignación al azar), el cambio en el deterioro luego de al menos un año, el cambio en la velocidad de conducción máxima de los nervios motores y la amplitud del potencial de acción muscular compuesto luego de un año y, para los participantes que estaban recibiendo corticosteroides o inmunoglobulina intravenosa, la cantidad administrada de dicha medicación durante al menos un año después de la asignación al azar. Otro resultado secundario fueron los participantes con uno o más eventos adversos graves durante el primer año.

Resultados principales

Cuatro ensayos cumplieron con los criterios de selección, uno de la azatioprina (27 participantes), dos del interferón beta1a (77 participantes en total) y uno del metotrexato (60 participantes). Ninguno de estos ensayos demostró beneficios significativos en el resultado primario o los resultados secundarios seleccionados para esta revisión.

Conclusiones de los autores

Las pruebas de los ensayos aleatorios no muestran beneficios significativos de la azatioprina, el interferón beta1a o el metotrexato aunque ninguno de los ensayos fue suficientemente amplio como para descartar un beneficio pequeño o moderado. Las pruebas de los estudios observacionales son insuficientes para evitar la necesidad de ensayos controlados aleatorios para descubrir si estos fármacos son beneficiosos. Los ensayos futuros deben tener diseños mejorados, medidas de resultado más sensibles y duraciones más largas.

Traducción

Traducción realizada por el Centro Cochrane Iberoamericano

Plain language summary

Immunomodulatory treatment other than corticosteroids, immunoglobulin and plasma exchange for CIDP

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an uncommon disease that causes weakness and numbness of the arms and legs, which can be progressive or have a relapsing and remitting course. It is due to inflammation which damages the insulating sheaths (myelin) around individual nerve fibres. In severe cases the actual nerve fibres themselves are affected. The underlying cause is thought to be an autoimmune response in which immune cells are misdirected against the myelin components. Cochrane systematic reviews have presented evidence that some treatments do help. These are corticosteroids, plasma exchange (in which the abnormal plasma portion of the blood is replaced with a substitute) and intravenous infusions of human immunoglobulin (antibodies). However, benefit from these treatments is often absent, inadequate, or short-lived, lasting only a few weeks. Other treatment options include cytotoxic 'chemotherapy-like' drugs, which kill the harmful immune cells, and drugs that regulate the immune system, such as interferons. High quality evidence that these treatments work is sparse and there have only been four randomised trials that we have been able to identify. One tested the cytotoxic drug azathioprine for nine months involving 27 participants. The second tested the immune regulating drug interferon beta-1a involving 10 participants, with each treatment period lasting 12 weeks. Neither trial showed a significant result but neither was large enough to detect even moderate benefit. The third trial was a double-blind randomised trial of interferon beta-1a including 67 participants for 32 weeks. The fourth was a double-blind placebo controlled trial of methotrexate involving 60 participants for 40 weeks. These latter two trials again did not show significant benefit from methotrexate or interferon beta-1a and were still not large enough to detect or rule out minor or moderate benefit. Not all of the studies reported outcomes that might be considered relevant to drug response or patients. There was no significant bias in the conduct and reporting of the two trials of interferon beta-1a and the trial of methotrexate but there was high risk of bias in the trial of azathioprine. Observational studies of these and other drugs, including the cytotoxic drugs cyclophosphamide, ciclosporin, mycophenolate, rituximab, and alemtuzumab, peripheral blood stem cell transplantation and the immune regulating drug interferon alfa, have been performed but are of insufficient quality to determine whether any of these drugs are beneficial.

Laički sažetak

Imunomodulacijsko liječenje izuzev kortikosteroida, imunoglobulina i plazmafereze za liječenje kronične upalne demijelinizirajuće poliradikuloneuropatije (CIDP)

Kronična upalna demijelinizirajuća poliradikuloneuropatija (CIDP) je rijetka bolest koja uzrokuje slabost i utrnulost ruku i nogu, koji mogu biti progresivni ili se pojavljivati u obliku razdoblja pogoršanja i smirenja (relapsi i remisije). To se događa zbog upale koja oštećuje izolacijske ovojnice (mijelin) oko pojedinih živčanih vlakana. U teškim slučajevima pogođena su i sama živčana vlakna. Smatra se da je temeljni uzrok autoimuni odgovor organizma u kojem su imune stanice pogrešno usmjerene protiv komponenti mijelina. Drugi Cochrane sustavni pregledi prikupili su dokaze koji potvrđuju da neki postupci liječenja mogu biti korisni za liječenje te bolesti. To su kortikosteroidi, plazmafereza (u kojoj se abnormalni dio plazme iz krvi zamijeni nadomjestkom) i intravenske infuzije ljudskog imunoglobulina (antitijela). Međutim, ti postupci liječenja pacijentima često ne pomažu, nisu prikladni ili učinak traje krtko, odnosno traje samo nekoliko tjedana. Ostale mogućnosti liječenja uključuju citotoksične lijekove kao što je kemoterapija, koji ubijaju štetne imunološke stanice, te lijekove koji reguliraju imunološki sustav, kao što su interferoni. Rijetki su dokazi visoke kvalitete koji potvrđuju učinkovitost tih postupaka liječenja, a provedena su samo četiri randomizirana kontrolirana ispitivanja koja smo uspjeli pronaći u ovom Cochrane sustavnom pregledu. Jedno ispitivanje citotoksičnog lijeka azatioprina tijekom devet mjeseci uključivalo je 27 sudionika. Drugo ispitivanje je analiziralo lijek koji regulira imunološki sustav interferon beta-1a, a uključivalo je 10 sudionika, uz svaki period liječenja u trajanju od 12 tjedana. Niti jedno ispitivanje nije pokazalo značajan rezultat, i niti jedno nije bilo dovoljno veliko kako bi potvrdilo čak i umjerenu korist. Treće ispitivanje je bilo dvostruko slijepo randomizirano kontrolirano ispitivanje interferona beta-1a, koje je uključivalo 67 sudionika tijekom 32 tjedna. Četvrto je ispitivanje bilo dvostruko slijepo placebo kontrolirano ispitivanje metotreksata koje je uključivalo 60 sudionika tijekom 40 tjedana. Te dvije studije ponovo nisu pokazale značajnu korist od metotreksata ili interferona beta-1a, a također nisu bile dovoljno velike da otkriju ili isključe manju ili umjerenu korist. U tim znanstvenim radovima nisu opisani svi rezultati dobiveni iz studija koji bi se mogli smatrati relevantnim za odgovor lijeka ili za pacijente. Nije bilo značajne pristranosti u vođenju i prikazivanju podataka u studijama o interferonu beta-1a i ispitivanju metotreksata, ali je uočen veliki rizik od pristranosti u ispitivanju azatioprina. Opservacijska ispitivanja ovih i drugi lijekovi, uključujući citotoksične lijekove ciklofosfamid, ciklosporin, mikofenolat, rituksimab i alemtuzumab, transplantacija matičnih stanica periferne krvi, te lijek za regulaciju imunološkog sustava - interferon alfa, provedena su, ali su nedovoljne kvalitete kako bi potvrdila da je bilo koja od ovih terapija korisna.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Jasna Safić
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Laienverständliche Zusammenfassung

Andere immunmodulatorische Behandlungen als Kortikosteroide, Immunoglobin und Plasmaaustausch bei CIDP

Die chronische entzündliche demyelinisierende Polyneuropathie (CIDP) ist eine seltene Erkrankung, bei der es zu Muskelschwäche und Taubheitsgefühlen der Arme und Beine kommt. Sie kann progressiv oder schubförmig verlaufen. Sie wird wahrscheinlich durch eine Entzündung der Nervenfaserummantelung oder in schweren Fällen der Nervenfasern selbst verursacht. Es wird angenommen, dass eine autoimmune Reaktion bei der Immunzellen gegen Bestandteile der Nervenfaserummantelung fehlgeleitet werden diese Krankheit verursacht. In Reviews von Cochrane wurde Evidenz vorgestellt, die zeigt, dass manche Therapien helfen können. Hierzu gehören Kortikosteroide, Plasmatausch (in der die abnorme Plasmamenge im Blut durch einen Ersatz ausgetauscht wird) und intravenöse Gabe von menschlichem Immunoglobulin (Antikörper). Jedoch ist der Nutzen dieser Behandlungen oft nicht vorhanden, unpassend oder zu kurz, da er nur wenige Wochen andauert. Andere Behandlungsmethoden beinhalten zytotoxische Medikamente (ähnlich einer Chemotherapie), die die schädigenden Immunzellen abtöten, oder Medikamente die das Immunsystem regulieren, wie z.B. Interferone. Qualitativ hochwertige Evidenz zur Wirksamkeit dieser Behandlungen ist selten und nur vier randomisierte, kontrollierte Studien wurden gefunden. Eine testete das zytotoxische Medikament Azathioprine über neun Monate bei 27 Patienten. Eine zweite Studie testete über 12 Wochen das immunregulierende Medikament Interferon Beta-1a an zehn Patienten. Keine der Studien zeigte signifikante Ergebnisse und keine war groß genug um einen moderaten Nutzen zu entdecken. Die dritte Studie war eine doppelt verblindete, randomisierte Studie mit Interferon Beta-1a mit 67 Teilnehmern über 32 Wochen. Die vierte war eine doppelblinde, placebokontrollierte Studie von Methotrexat mit 60 Teilnehmern über 40 Wochen. Die beiden letztgenannten Studien haben auch keinen signifikanten Nutzen von Methotrexat oder Interferon Beta-1a gezeigt. Beide waren nicht groß genug, um einen kleinen oder moderaten Nutzen zu erkennen oder auszuschließen. Nicht alle Studien berichteten Endpunkte, die für das Ansprechen auf das Medikament oder die Patienten relevant sein könnten. Es gab keinen signifikanten Bias in der Durchführung und Berichterstattung der beiden Studien zu Interferon Beta-1a und der Studie zu Methotrexat, aber es gab ein hohes Risiko für Bias in der Studie zu Azathioprin. Beobachtungsstudien über diese und anderen Medikamente, einschließlich der Zytostatika Cyclophosphamid, Cyclosporin, Mycophenolat, Rituximab und Alemtuzumab, Transplantation von Blutstammzellen und des immunregulierenden Medikaments Interferon Alfa, wurden durchgeführt, sind aber von unzureichender Qualität, um festzustellen, ob ein Nutzen von einem der Medikamente ausgeht.

Anmerkungen zur Übersetzung

Koordination durch Cochrane Schweiz

Summary of findings(Explanation)

Summary of findings for the main comparison. Methotrexate compared to placebo for CIDP
  1. 1 The high rate of responders in the placebo group reduced the power of the trial to detect an effect of methotrexate.
    2 Participants in the two groups received different dosages of IVIg or corticosteroids which risked confounding this comparison.

Methotrexate compared to placebo for CIDP
Patient or population: patients with CIDP
Settings: hospital
Intervention: methotrexate
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Placebo Methotrexate
Participants able to reduce corticosteroid or IVIg dose by more than 20%
Follow-up: mean 40 weeks
44 per 100 53 per 100
(18 to 100)
RR 1.21
(0.4 to 3.7)
59
(1 study)
⊕⊕⊕⊝
moderate 1
This was the primary outcome in the trial although not specified as a primary outcome in the review
Change in disability after 26 or more weeks
Overall Neuropathy Limitation Scale. Scale from: 0 to 12.
Follow-up: mean 40 weeks
The mean change in disability after 26 or more weeks in the control groups was
0 points
The mean change in disability after 26 or more weeks in the intervention groups was
0 higher
(0 to 0 higher)
 59
(1 study)
⊕⊕⊝⊝
low 2
No significant difference
Change in disability after 26 or more weeks
Amsterdam Linear Disability Scale. Scale from: 0 to 100.
Follow-up: mean 40 weeks
The mean change in disability after 26 or more weeks in the control groups was
-0.48
The mean change in disability after 26 or more weeks in the intervention groups was
0.47 lower
(3.62 lower to 1.87 higher)
 59
(1 study)
⊕⊕⊝⊝
low
No significant difference
Serious adverse events 3 per 100 11 per 100
(1 to 100)
RR 3.56
(0.39 to 32.23)
59
(1 study)
⊕⊕⊕⊕
high
Significantly more serious adverse events with methotrexate
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; CIDP: chronic inflammatory demyelinating polyradiculoneuropathy
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Interferon beta-1a compared to placebo for CIDP

Summary of findings 2. Interferon beta-1a compared to placebo for CIDP
  1. 1 There was a high rate of responders in the placebo group which reduced the power to detect an effect of IFN beta-1a.
    2 There were no serious adverse events in the control group but RevMan software automatically makes a correction to allow calculation of a RR.

Interferon beta-1a compared to placebo for CIDP
Patient or population: CIDP
Settings: hospital
Intervention: interferon beta-1a
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Placebo Interferon beta-1a
Participants who completed the study and did not restart IVIg therapy after IVIg withdrawal
Follow-up: median 32 weeks
47 per 100 47 per 100
(25 to 89)
RR 1
(0.54 to 1.88)
49
(1 study)
⊕⊕⊕⊝
moderate 1
This was the primary outcome in the trial although not specified as a primary outcome in the review
Serious adverse eventsSee comment2See comment RR 4.5
(0.25 to 80.05)
67
(1 study)
⊕⊕⊕⊕
high
0 of 22 in the control and 4 of 45 with IFN beta-1a had serious adverse events
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; CIDP: chronic inflammatory demyelinating polyradiculoneuropathy; IVIg: intravenous immunoglobulin; IFN: interferon
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disease causing progressive or relapsing and remitting weakness and numbness. Its minimum prevalence is at least one or two cases per 100,000 of the population and may be as high as 8.9 per 100,000 (Lunn 1999; Mygland 2001; Chio 2007; Laughlin 2009). Its clinical course is variable and unpredictable. In a population based study, 13% of 46 patients in the South East Thames region of England required aid to walk and 54% were receiving medical treatment on the prevalence date (Lunn 1999). A similar study done by in the same region in 2008 found that 76.2 % of 84 patients had needed treatment at some time and 31.7% of 41 patients could not walk independently (Mahdi-Rogers, 2008).

Chronic inflammatory demyelinating polyradiculoneuropathy began to emerge as a syndrome separate from Guillain-Barré syndrome (an acute paralysing disorder usually due to acute inflammatory demyelinating polyradiculoneuropathy) with the description of recurrent steroid responsive neuropathy by Austin in 1958 (Austin 1958).The description of larger series of patients (Dyck 1975; Prineas 1976; McCombe 1987; Barohn 1989) led to a clearer clinical picture and eventually an arbitrary definition (Ad hoc 1991). This definition has been widely used and was the basis of the diagnostic criteria in the first issue of this review although it has been criticised as too restrictive, excluding patients who are considered by the authors of case series to have a clinical condition identical with CIDP (Saperstein 2001; Koski 2009). Other criteria have been published including less restrictive criteria agreed by a consensus committee (EFNS/PNS 2010) which we have accepted in recent updates of this review.

A number of conditions that are forms of, or resemble, CIDP require special consideration. The duration of the onset phase in CIDP is more than eight weeks while that of Guillain-Barré syndrome (GBS) is less than four weeks. Some cases of CIDP have an acute onset like GBS or are subacute (Hughes 1992; Oh 2003; Ruts 2005; Ruts 2010). Guillain-Barré syndrome itself may recur on one or sometimes several occasions (Kuitwaard 2009). While some relapses are acute and easily recognisable as Guillain-Barré syndrome, others may be subacute or chronic and these cases are difficult to distinguish from CIDP. For this reason we would have included patients with recurrent GBS in this review, but noted in which studies they were included: we are not aware of any that were. A form of asymmetrical sensory and motor neuropathy with persistent conduction block, the Lewis-Sumner syndrome (Lewis 1982; Saperstein 1999; Viala 2004), has been recognised as a distinct subgroup of CIDP which differs from other cases in the persistence of the conduction block at individual sites over long periods. We would have included such cases in this review if they had been included in trials. However, the syndrome of multifocal motor neuropathy with conduction block is a pure motor syndrome which differs from CIDP in its response to steroids and might differ in its response to other agents (EFNS/PNS 2010). Consequently, multifocal motor neuropathy has been excluded from this review and a separate review has been published (Umapathi 2009). By contrast, in the sensory form of CIDP there is electrophysiological evidence of motor involvement (Oh 1992). We therefore regarded this as a form of CIDP and would have included such patients. We would also have included variants with cranial nerve or upper limb onset or involvement (Thomas 1996), distal or proximal and distal involvement (Katz 2000; Saperstein 2001), and subclinical (magnetic resonance imaging) evidence of central nervous system involvement (Ormerod 1990; Waddy 1989).

There has been debate as to whether patients with the clinical features of an acquired demyelinating neuropathy and a systemic disease, such as cancer, diabetes mellitus and systemic lupus erythematosus and other connective tissue diseases should be included as having CIDP (Ad hoc 1991; EFNS/PNS 2006; EFNS/PNS 2010). To confine this review to as homogeneous a group as possible, we would have excluded such cases where the results were available separately from the whole trial. About 10% of patients with an acquired demyelinating neuropathy have a serum paraprotein (Kelly 1981). About half such patients have an IgM paraprotein in which the paraprotein is an autoantibody directed against carbohydrate epitopes on myelin associated glycoprotein, other myelin proteins and glycolipids. This condition and some of the other paraprotein associated demyelinating neuropathies have different underlying pathology and presumably pathogenesis. Consequently, treatments for all paraprotein associated demyelinating neuropathies will be left for other reviews to consider. A Cochrane review of immunotherapy for IgM (Lunn 2006) and another for IgG and IgA paraprotein-associated demyelinating neuropathy have been published (Allen 2007).

Although not proven, CIDP is generally considered to be an autoimmune disease caused by either humoral or cell-mediated immunity directed against myelin or Schwann cell antigens which have not been identified (Koller 2005). Consequently, various forms of immunotherapy have been tried in its treatment. A Cochrane systematic review of corticosteroid treatment concluded that the one randomised controlled trial (RCT) identified gave only weak support for the conventional view that such drugs are beneficial (Mehndiratta 2002). In a recent RCT of high-dose monthly oral dexamethasone versus standard prednisolone treatment for CIDP, 10 of 24 in the dexamethasone group and 6 of 16 in the prednisolone group (odds ratio 1·2, 95% CI 0·3 to 4·4) went into remission after 12 months (van Schaik 2010). Two RCTs have reported that plasma exchange is more effective than sham exchange (Dyck 1986; Hahn 1996a). A Cochrane systematic review concluded that plasma exchange does produce benefit but this is short-term and may be followed by rebound worsening (Mehndiratta 2004). A Cochrane systematic review of five trials (Vermeulen 1993; Hahn 1996b; Thompson 1996; Mendell 2000; Hughes 2008) including a total of 235 participants concluded that a single course of intravenous immunoglobulin (IVIg) significantly reduces disability and weakness (Eftimov 2009). One RCT showed that 3-weekly treatment with IVIg has a sustained effect for at least 24 weeks (Hughes 2008) and another has shown that plasma exchange has similar efficacy to IVIg (Dyck 1994). A trial comparing oral prednisolone with IVIg showed slightly but not significantly more benefit from IVIg (Hughes 2001). Since corticosteroids have serious long-term side effects, such as hypertension, osteoporosis, diabetes mellitus and obesity, and both plasma exchange and IVIg are expensive, require hospitalisation and have only short-term benefits, there is a need for more effective, longer lasting treatment regimens.

In response to the need for better treatments many neurologists have tried treating patients with immunosuppressive and immunomodulatory agents that have been found useful in rheumatoid arthritis, other connective tissue diseases and renal transplant rejection, including azathioprine, interferon beta (IFNb), cyclophosphamide, ciclosporin, methotrexate, etanercept, alemtuzumab, rituximab and autologous peripheral blood stem cell transplantation (PBSCT). When this review was first published in 2003 only one small RCT of azathioprine combined with prednisone compared with prednisone alone (Dyck 1985) and another of interferon beta-1a (Hadden 1999) had been published. The topic of immunosuppressive and immunomodulatory agents for CIDP has regularly been the subject of non-systematic reviews (Hahn 2005; Koller 2005; Léger 2005; Nobile-Orazio 2005; van Doorn 2005; Saperstein 2008) but we know of no other systematic review. This review aims to provide the best evidence about such immunomodulatory treatment for CIDP. It was updated in 2013 to include the latest evidence.

Objectives

The objective is to review systematically all randomised and quasi-randomised trials of immunosuppressive and immunomodulatory agents for CIDP, except corticosteroids, intravenous immunoglobulin and plasma exchange which are covered in other Cochrane reviews.

Methods

Criteria for considering studies for this review

Types of studies

We included all randomised and quasi-randomised trials of immunosuppressive and immunomodulatory agents for CIDP, except corticosteroids, intravenous immunoglobulin and plasma exchange. Quasi-randomised trials are those trials in which treatment allocation was intended to be random but might have been biased (for example alternate allocation or allocation according to the day of the week).

Types of participants

We included results from participants of all ages who fulfilled criteria which approximated to the definition of probable CIDP by an American Academy of Neurology ad hoc committee (Ad Hoc 1991) or the Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society (EFNS/PNS 2005) which were updated in 2010 (EFNS/PNS 2010). Briefly, these criteria require progressive weakness with an onset phase lasting more than eight weeks due to polyradiculoneuropathy, fulfilment of strict criteria for a demyelinating neuropathy, and the absence of significant central nervous system involvement or alternative causes. For the reasons described in the background we included patients with cranial nerve or upper limb onset, proximal and distal or distally predominant weakness, symmetrical or asymmetrical involvement, and sensory predominant deficit but not multifocal motor neuropathy. We did not include patients with cancer, connective tissue diseases, or IgM paraprotein with antibodies to myelin associated glycoprotein.

Types of interventions

We included all immunosuppressive agents such as azathioprine, cyclophosphamide, methotrexate, ciclosporin, mycophenolate mofetil, etanercept, rituximab and alemtuzumab, immunomodulatory agents such as interferon alfa (IFNa) and interferon beta (IFNb) and autologous PBSCT. We did not include corticosteroids, plasma exchange or IVIg. We also included studies of combinations of these interventions or of these interventions with corticosteroids, plasma exchange or IVIg where the objective of the study was to evaluate the effectiveness of cytotoxic drugs or IFNs.

Types of outcome measures

The outcomes used in the review were pre-specified in the initial review protocol but in more recent updates of the review, disability scales validated for CIDP such as the ONLS are preferred to the Modified Rankin Scale, a generic disability scale, which was the foremost disability scale in earlier versions.

Primary outcomes

Change in disability at least one year after randomisation measured by a disability scale designed and validated for CIDP treatment trials such as the Inflammatory Neuropathy Cause and Treatment (INCAT) scale (Hughes 2001), the Overall Disability Status Score (ODSS) (Merkies 2002), Overall Neuropathy Limitations Scale (ONLS) (Graham 2006) (Appendix 1) or Rasch-built Overall Disability Scale (R-ODS) scale (van Nes 2011) or, failing that, a validated generic disability scale such as the Modified Rankin Scale (van Swieten 1988)(Appendix 2).

A disability outcome was selected as the primary outcome on the grounds that a patient-centred outcome is more relevant to patients' and healthcare purchasers' needs than a measure of impairment or neurophysiology. One year was chosen as the period for measurement of outcome on the grounds that the risk, expense and inconvenience of cytotoxic agents and interferons would not be worthwhile unless improvements lasted for at least 12 months. However, none of the trials of immunomodulatory drugs in CIDP have lasted as long as one year so we have reported change in disability at 26 or more weeks as the primary outcome since the 2010 update of the review.

Secondary outcomes
  1. Change in disability four or more weeks after randomisation measured by the Modified Rankin Scale, ONLS or a similar disability scale.

  2. Change in impairment at least one year after randomisation measured by an impairment scale similar to the Mayo Neuropathy Impairment Scale (NIS) (Dyck 2005).

  3. Change in maximum motor nerve conduction velocity (MNCV) and compound muscle action potential (CMAP) amplitude one year after randomisation. Where more than one nerve was studied the average of all the nerves studied was to be used.

  4. For those participants who were receiving corticosteroids or IVIg, the amount of this medication which was given during at least one year after randomisation.

  5. Participants with one or more serious adverse events during the first year after randomisation. A serious adverse event is one that is life-threatening, requires or prolongs hospitalisation, is severely or permanently disabling, or is a new malignancy.

These outcomes are not eligibility criteria for this review, but are outcomes of interest within the included studies.

Search methods for identification of studies

Electronic searches

On 9 July 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2012, Issue 6 in The Cochrane Library), MEDLINE (January 1977 to July 2012), EMBASE (January 1980 to July 2012), LILACS (January 1982 to July 2012) and CINAHL Plus (January 1982 to July 2012).

Electronic strategies

The detailed search strategies are in the appendices: CENTRAL (Appendix 3), MEDLINE (Appendix 4), EMBASE (Appendix 5), LILACS (Appendix 6) and CINAHL (Appendix 7).

Searching other resources

We contacted the authors of the trials identified and other disease experts seeking other published and unpublished trials.

Data collection and analysis

Two authors (MM-R and RACH) checked the titles and abstracts of the articles identified by the search and then extracted data using a specially designed form, assessed the risk of bias of the selected trials and decided upon inclusion independently. If there had been disagreement, we would have reached agreement by discussion and adjudication by the third author. We assessed the risk of bias of the included trials using the methods described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008, current version Higgins 2011).

Although there were two trials of IFNb-1a the efficacy outcomes were different. If there had been similar outcomes we would have calculated a weighted treatment effect across trials using the Cochrane statistical package Review Manager (RevMan) (RevMan 2008) or equivalent statistical software (e.g. Stata). We would have expressed results as risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcome measures and differences between means with 95% CIs for continuous outcomes. In the event that our preferred outcomes had not been available but others were available for more than one trial we would have used whatever outcomes were available to calculate a weighted treatment effect across trials. We would have tested the results for heterogeneity across trials. If heterogeneity had been found, we would have undertaken sensitivity analyses by repeating the calculation after omitting the trials which had low scores on individual risk of bias items and we would have reported 95% CIs obtained using random-effects estimation.

If the data had allowed we would also have tested the effect of interventions in the subgroups mentioned in Types of participants.

Results

Description of studies

Results of the search

The search on 9 July 2012 found 345 papers in MEDLINE, 122 in EMBASE, 14 in LILACS, 14 in the Cochrane Neuromuscular Disease Group Specialized Register and 61 in CENTRAL but no new trials. Previous searches had identified four trials (Dyck 1985; Hadden 1999; Hughes 2010; RMC 2009). 

Additional relevant observational studies have been included in the Discussion.

Included studies

We included four trials, one of azathioprine, one of methotrexate, and two of the immunomodulatory drug IFNb. We will describe these in turn but more details are available in Characteristics of included studies.

The first trial (Dyck 1985) compared 14 adult participants randomised to azathioprine 2 mg/kg and prednisone with 13 participants treated with prednisone alone. The trial had a parallel group design and treatment lasted nine months. The observers and participants were not blinded. There were multiple explicit outcome criteria but none were stipulated as primary. Follow-up data were not available for one azathioprine and prednisone participant and three prednisone alone participants. There were no significant differences after four or nine months in any of 16 variables including the NIS, other measures of impairment, motor nerve conduction parameters and cerebrospinal fluid protein concentration.

The second trial (Hadden 1999) compared interferon beta-1a (IFNb-1a) with placebo in a cross-over design. Ten adult participants with treatment resistant CIDP were randomised to receive IFNb-1a (Rebif, Serono) 11 μg subcutaneously thrice weekly for two weeks and then 22 μg thrice weekly for ten weeks or a similar appearing placebo. After a four-week wash out period they were started on the opposite treatment to that which they had received during the first treatment period. The primary outcome measure was a clinically significant improvement in at least three of the following measurements:

five disability scales:

  • one grade in the Ambulation Index;

  • one grade in the upper limb subscale of the Guy's Neurological Disability Scale;

  • >4 units in the expanded Medical Research Council (MRC) sum score;

  • at least 2 points on the Hammersmith Motor Ability Scale;

  • at least 10 points on the Functional Independence Measure;

two impairment scales:

  • >20% from baseline on the time taken to remove and replace the pegs from a board in the nine-hole peg test;

  • >20% from baseline value (and >2 seconds) in the time taken to walk 10 metres;

and one quality of life scale:

  • at least 33 points on the EuroQoL visual analogue scale.

If the participant worsened on any of these measures, then improvement had to be observed on two more measures than the number that had worsened. Only one participant fulfilled the criteria proposed for the primary outcome measure in the IFNb-1a treatment period and two in the placebo treatment period. The secondary outcome measures were the changes in the same measurements and in parameters of motor nerve conduction in the median nerves. The only statistically significant difference was a trivial one point improvement in the median of the functional independence measure in the placebo treatment period compared with no change in the IFNb-1a treatment period.

The third trial (Hughes 2010) compared the effect of intramuscular IFNb-1a with placebo in a double blind, placebo controlled, parallel group, dose ranging study. Sixty-seven IVIg-dependent patients were randomised, 45 to different doses of intramuscular IFNb-1a and 22 to placebo. Participants received two intramuscular injections of IFNb-1a or placebo weekly for 32 weeks. There were five treatment groups: IFNb-1a 30 μg weekly and placebo, IFNb-1a 60 μg weekly and placebo, IFNb-1a 30 μg twice weekly, IFNb-1a 60 μg twice weekly, and placebo twice weekly. At the end of week 16 of the trial, IVIg was stopped. IVIg was restarted if the participant had a clinical relapse, which was defined as a two point deterioration on the MRC sum score and one functional disability grade on Overall Disability Sum Score, or study termination at 32 weeks. The primary outcome was the total IVIg dose (g/kg) administered in the 16 weeks after the 16 week visit.

The fourth trial (RMC 2009) was a randomised, double blind, parallel group, placebo controlled trial of methotrexate in CIDP patients who had previously responded to and were still receiving corticosteroids or IVIg. Sixty participants were randomised to receive oral methotrexate or placebo (starting at 7.5 mg weekly increasing to 10 mg weekly after four weeks and 15 mg weekly after eight weeks) both with folic acid 5 mg twice weekly for 40 weeks. After 16 weeks (15 weeks if on three or five times weekly IVIg and 14 weeks if on seven times weekly IVIg), corticosteroids or IVIg were reduced, subject to satisfactory progress, at a rate of 20% of the baseline dose every four weeks. The primary outcome was the percentage change in mean weekly dose of corticosteroids or IVIg during the last four weeks, usually from week 37 to week 40, compared with week one to four. Secondary disability outcomes were changes in disability measured in two ways and at two times, the Amsterdam Linear Disability Score (ALDS), ranging from 0, which is death, to 100, indicating fully able (Holman 2004) and the ONLS (Graham 2006), measured from baseline to week 16 and to week 40. The secondary impairment measures were the changes in the expanded (to include the first dorsal interosseus and extensor hallucis longus) MRC sum score from baseline to week 16 and to week 40.

Risk of bias in included studies

See Figure 1. Three trials were at low risk of bias (RMC 2009; Hadden 1999; Hughes 2010). The fourth trial (Dyck 1985) was at high risk of bias because of lack of allocation concealment, lack of blinding and unexplained dropouts.

Figure 1.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Effects of interventions

See: Summary of findings for the main comparison Methotrexate compared to placebo for CIDP; Summary of findings 2 Interferon beta-1a compared to placebo for CIDP

Azathioprine

Dyck 1985

None of the outcomes specified for this review were provided since the trial only lasted nine months and there was no measure of disability. However, two outcomes approximated to two of the specified secondary outcomes:

1. Change in impairment at least one year after randomisation measured by an impairment scale similar to the Mayo Neuropathy Disability Scale (Dyck 2005).

After nine months there was a median improvement of 29 points (range 49 points worse to 84 points better) in the azathioprine and prednisone treated participants compared with 30 points worse (range 20 points worse to 104 points better) in the prednisone alone group.

2. Change in maximum MNCV and CMAP amplitude one year after randomisation.

After nine months the median maximum MNCV and CMAP amplitude of the ulnar, median and peroneal nerves showed small changes after nine months in both groups of participants. The changes were not clinically significant. The mean changes of all the nerves tested could not be computed from the published data.

As stated above, there were no significant differences after four or nine months in any of the other measures of impairment reported by the authors (See Characteristics of included studies). Adverse events were not reported.

Methotrexate

RMC 2009

Only the following outcomes from those desired for this review were provided.

Primary outcome

1. Change in disability 26 or more weeks after randomisation measured by the ONLS or a similar disability scale

All analyses were adjusted for age, baseline score and baseline corticosteroid or IVIg dose. At the end of the trial (approximately 40 weeks) there was no significant change in activity limitation (disability) measured with the ONLS or ALDS. The median change of ONLS was 0 (interquartile range -1 to 0) in the methotrexate group and 0 (interquartile range -0.75 to 0) in the placebo. The mean change from baseline ALDS score of the methotrexate group was -0.66 (4.25) and placebo -0.48 (2.40). The mean change from the baseline ALDS score of the methotrexate group was -0.47 (95% CI -3.62 to 1.87) points less than that of the placebo group, adjusting for ALDS score at baseline, baseline IVIg or corticosteroid dose per week per kg and age. These changes in disability might have been confounded by the reduction in the corticosteroid or IVIg doses required by the protocol.

Secondary outcomes

  1. Change in disability four or more weeks after randomisation measured by the ONLS or a similar disability scale.

The ONLS and ALDS were also measured at the mid-trial visit (approximately 16 weeks). There was no significant change in limitations (disability) measured with the ONLS, the median change being 0 (interquartile range -1 to 0) in both the methotrexate and placebo groups. The mean change from baseline ALDS score of the methotrexate group was 1.51 (SD 2.71) and placebo -0.42 (SD 2.51). The mean improvement from the baseline ALDS score of the methotrexate group was 1.79 (95% CI 0.12 to 3.05) points more than in the placebo group adjusting for ALDS score at baseline, baseline IVIg or corticosteroid dose per week per kg and age. Since this scale ranges from 0 which is death to 100 indicating fully able, such a small change is unlikely to be clinically significant.

2. Participants with one or more serious adverse events during the first year after randomisation. There were three participants in the methotrexate group and one in the placebo with one or more serious adverse events, RR 3.56 (95 % CI 0.39 to 32.23) (Analysis 1.1).

More results are given in Summary of findings for the main comparison and Discussion.

Interferon beta-1a

Hadden 1999

This was a cross-over trial with treatment periods of only 12 weeks. The only outcomes stipulated for this review were:

Secondary outcomes

  1. Change in disability four or more weeks after randomisation measured by the Modified Rankin Scale or a similar disability scale. The median improvement in the combined upper and lower limb components of the Guy's Neurological Disability Scale was 0.5 grades (interquartile range 1.8 grades better to zero grade change) in the IFNb-1a treatment period and 0.5 grades (interquartile range 1.8 grades better to 1.0 grade worse) in the placebo treatment period.

  2. Participants with one or more serious adverse events during the first year after randomisation. There were no serious adverse events during either treatment period.

Hughes 2010

Only the following outcome measures from those desired for this review were provided:

Secondary outcome

  1. Participants with one or more serious adverse events during the first year after randomisation. There were four participants in the IFNb-1a group and none in the placebo group with one or more serious adverse events, RR 4.50 (95 % CI 0.25 to 80.05) (Analysis 2.1).

More results are given in Summary of findings 2 and Discussion.

Discussion

Since there are only four randomised trials included in this review, we have considered observational studies as well. No robust method exists for identifying and reviewing such studies systematically. The relevant literature discovered in our search is not very large and we have referenced and described briefly case reports and series which gave the number of participants treated with individual immunosuppressive agents and the number who have been deemed by the authors to have improved. We do not claim to have discovered all such reports or series and the criteria for diagnosis and improvement and completeness of follow-up have often not been reported even in those to which we have referred. Any conclusions from these data require extreme caution in interpretation.

Azathioprine

Azathioprine is a broad-spectrum immunosuppressive agent and is probably the one most commonly used in CIDP. The trial by Dyck and colleagues (Dyck 1985) described above is the only controlled trial and did not detect a significant effect on any of the 16 outcomes tested by the authors or on the outcomes that we had selected for this review. However, the trial was small and lacked power to detect or exclude any but very large treatment effects. Furthermore, it only tested a dose of 2 mg/kg of azathioprine whereas a dose of 2.5 mg/kg or sometimes 3.0 mg/kg has been used in other conditions such as multiple sclerosis and Crohn's disease (BDMSATG 1988). The trial also only continued treatment for nine months whereas in a similar trial in myasthenia gravis a treatment effect did not become evident until after 12 months (Palace 1998). Consequently it would be premature to draw conclusions about the efficacy of azathioprine from this trial alone (Dyck 1985) .

The trial did not mention the occurrence of side effects from azathioprine but azathioprine may cause nausea, vomiting, diarrhoea and allergic reactions including rash, which prevent its continuation in about 10% of participants. It also causes leucopenia, altered liver function, increased susceptibility to infection and a theoretical risk of neoplasia (Confavreux 1996; Kissel 1986). A large retrospective cohort study of immunosuppressive agents in autoimmune ocular disease did not show increased incidence of neoplasia in patients treated with antimetabolites such as azathioprine, methotrexate and mycophenolate mofetil after 17316 person years (Kempen 2009).

Azathioprine is less expensive than most immunosuppressive drugs. The annual cost of giving 150 mg daily for a year is about GBP 101 (125 euros) (BNF 2012). To this cost must be added the costs of monitoring haematological and liver function, which is required for as long as treatment is continued, and the costs of side effects caused by the drug. However, if the drug is effective it might result in savings because of reduced healthcare costs arising from the disability which CIDP causes and especially from the reduced usage of IVIg, which is one of the preferred treatments for CIDP (Eftimov 2009), and corticosteroids which are a major cause of disabling, and therefore expensive, side effects.

Uncontrolled observations from case reports and case series in the literature provide little information about the value of azathioprine in CIDP. In 1981 Dalakas et al. (Dalakas 1981) described azathioprine taken as a 3 mg/kg single daily dose as their immunosuppressive drug of choice (see Table Summary of observational studies of azathioprine). They considered that a clinical effect could be detected in between one and 12 weeks. They reported improvement in three of four steroid resistant CIDP patients to almost 90% to 95% of normal. They also considered that azathioprine has a steroid sparing action in patients who responded to steroids. Seven of a series of 92 patients with CIDP were treated with azathioprine and four improved by at least one point on a six-point disability scale (McCombe 1987). In a series of 59 treated patients, Barohn 1989 reported that 56 (95%) responded to immunosuppressive treatment which started with prednisone and then included azathioprine in the event of a relapse or poor response; the number who received azathioprine was not stated. Simmons 1995 followed up 69 patients, of whom 50 were being treated and eight were receiving azathioprine: they did not state how effective they thought azathioprine was being. Monaco et al. (Monaco 2004) state their own experience that low doses of azathioprine (1 mg/kg) and prednisolone (0.25 to 0.5 mg/kg) prevent relapses, in particular in patients who have responded poorly to IVIg, but do not give figures to support this impression. In a disease with a relapsing remitting course and a drug that has a slow onset of action, conclusions are particularly difficult to draw from anecdotal observations. A retrospective Italian multicentre study of 158 CIDP patients treated with immunosuppressive drugs included 77 patients treated with azathioprine of whom 21 were reported to improve (Cocito 2011).

Summary of observational studies of azathioprine

Series Dose Duration Total Improved Notes
Dalakas 19813 mg/kg dailyNot stated43Corticosteroid resistant patients
McCombe 1987Not statedNot stated74 
Cocito 2011100 to
200 mg daily
≥12 months7721Italian retrospective study
All studies  8828 

Cyclophosphamide

Cyclophosphamide is an alkylating agent that can be given orally or by intravenous injection. Four patients who were worsening despite treatment with corticosteroids had sustained improvement when given oral cyclophosphamide 50 to 150 mg daily for two to nine months (Prineas 1976). Dalakas and colleagues (Dalakas 1981) reported that oral cyclophosphamide 2 mg/kg was beneficial in the one patient in whom they tried it. McCombe et al. (McCombe 1987) described benefit in four of five patients but did not mention the dose or route. Bouchard and colleagues (Bouchard 1999) described the treatment of 36 patients using in turn, depending on response, corticosteroids, IVIg, plasma exchange and finally oral cyclophosphamide 2 mg/kg daily for six to 12 months. Three patients who had not responded to previous agents also failed to respond to this cyclophosphamide regimen. Brannagan and colleagues (Brannagan 2002) gave high dose cyclophosphamide to four patients with CIDP that had responded inadequately to other treatments. The dose was 200 mg/kg over four days accompanied by a forced diuresis and the drug mesna to prevent haemorrhagic cystitis. All four patients improved in functional status and had their other treatment stopped. Complications included alopecia in four, infections, transient amenorrhoea, transient renal failure, heart failure, mucositis and diarrhoea. In a follow-up study of the same four and one additional patient after a median 2.9 years, four of five showed improvements in the Modified Rankin score, four of five improved more than two points on the MRC sum score and three of five had increases in summed CMAP amplitudes of more than 1.0 mV (Gladstone 2005). The largest series is that of Good 1998 who treated 15 patients with intravenous pulses of 1 g/m2 monthly for a maximum of six months with careful precautions to avoid dehydration and premedication to reduce nausea. Twelve patients showed marked improvement, 11 improving to normal. Three did not improve and one worsened. Six patients had minor side effects and two alopecia. None developed haematuria, prolonged bone marrow depression or neoplasia, all of which are feared side effects of high dose cyclophosphamide. Additional side effects are increased susceptibility to infection and ovarian failure. The results in these case series strongly suggest but do not prove treatment benefit. The risk of serious side effects puts many patients and their neurologists off using this drug.

Summary of observational studies of cyclophosphamide

Series Dose Duration No. of patients No. improved Notes
Prineas 197650 to 150 mg daily2 to 9 months44 
Dalakas 19812 mg/kg dailyNot stated11 
McCombe 1987Not statedNot stated54 
Bouchard 19992 mg/kg daily6 to 12 months30Refractory to other treatments
Brannagan 2002200 mg/kg daily4 days44 
Gladstone 2005Not statedMedian 2.9 years54Follow up of Brannagan 2002 included the 4 patients in Brannagan and one additional patient (Brannagan 2002)
Good 19981 g/m2 monthlyMaximum 6 months151211 improving to normal
Cocito 20111 g/m2 iv monthly,
or 2 mg/kg oral daily
≥12 months135Italian retrospective study
All studies  5034 

Ciclosporin

Another drug, which has been used quite frequently in CIDP, is ciclosporin, which particularly inhibits the proliferation of T cells. One patient improved on ciclosporin but developed irreversible renal failure as a side effect (Kolkin 1987). Another patient improved when treated with the combination of plasma exchange and ciclosporin but treatment had to be discontinued because of a rise in serum creatinine (Hefter 1990). The largest series comes from Sydney (Barnett 1998; Hodgkinson 1990) where 19 patients with CIDP were treated but five had a paraprotein which excluded them from consideration in this review. At the beginning of their series they used a high dose, 10 mg/kg daily, reduced to 8 mg/kg daily after one month and 5 mg/kg daily after three months, but later they reduced the starting dose to 3 to 7 mg/kg and the maintenance dose to 2 to 3 mg/kg. All 14 patients without a paraprotein improved either with a reduction in disability by at least one grade or by a reduction in the annual relapse rate. Of the 19 patients, 11 had side effects, nephrotoxicity in four, hypertension in four, nausea in three, oedema in three and hirsutism in four. The side effects were less with lower doses. In a North American series, three of eight patients improved (Mahattanakul 1996). In a Japanese series, all of seven patients with CIDP inadequately controlled by other agents including corticosteroids and IVIg improved following treatment with oral ciclosporin 5 mg/kg daily to keep the trough plasma concentration between 100 and 150 ng/ml. All seven patients had improvements in disability measured with the Modified Rankin scale and increases in grip strength within three months. None had side effects attributed to ciclosporin (Matsuda 2004). Five patients were treated with ciclosporin 3 mg/kg daily adjusted to keep the trough plasma concentration between 100 and 150 ng /ml: four improved, including one who had failed to respond to intravenous cyclophosphamide (Odaka 2005). Three of 12 patients treated with ciclosporin improved in the Cocito 2011 retrospective study. These series suggest but do not prove that ciclosporin is also beneficial in CIDP: there is no doubt that it causes potentially serious side effects, especially renal failure.

Summary of observational studies of ciclosporin

Series Dose Duration No. of patients No. improved Notes
Hefter 1990Not statedNot stated11Combination of ciclosporin and plasma exchange
Kolkin 1987Not statedNot stated11 
Barnett 1998; Hodgkinson 199010 to 8 mg/kg daily after 1 month and 5 mg/kg daily after 3 months but later 3 to 7 mg/kg and then maintained at 2 to 3 mg/kgNot stated191411 had side effects
Mahattanakul 19963 to 5 mg/kg dailyNot stated83 
Matsuda 20045 mg/kg dailyNot stated77Trough dose maintained at 100 to 150 ng/ml
Odaka 20053 mg/kg dailyNot stated54Trough dose maintained at 100 to 150 ng/ml
Cocito 2011100 to 300 mg daily≥12 months123Italian retrospective study
All studies  5333 

Tacrolimus

Tacrolimus (FK506), which is related to ciclosporin, has only been used in one published patient in whom it appeared beneficial (Ahlmén 1998).

Sirolimus

We have not found any reports of the use of sirolimus (rapamycin) in CIDP.

Methotrexate

Methotrexate is one of the favoured disease modifying agents in treatment of rheumatoid arthritis but until recently there were no reports of its use in CIDP. It is a folate inhibiting drug which is well tolerated for long periods and is reasonably safe when used in low weekly oral doses of about 15 to 20 mg/kg. A consecutive series of 10 patients with inadequate responses to other agents was treated with oral methotrexate 10 to 15 mg weekly for at least 32 weeks. Five reported symptomatic benefit and seven had increased MRC sum scores indicating increased strength. However, none showed improvements in the ODSS, indicating that improvements were modest (Fialho 2006). The results of this study, the excellent tolerability of methotrexate and its efficacy in rheumatoid arthritis motivated the RMC trial (RMC 2009).

The design of the RMC trial (RMC 2009) was a double blind randomised parallel group trial of methotrexate versus placebo. Some of the results have been reported in the Description of studies above. In the authors' own analysis of its primary outcome, the results were dichotomised into non-responders (reduction of corticosteroid or IVIg dose by 20% or less) and responders (reduction of corticosteroid or IVIg dose by more than 20%). There were 14 responders out of 27 (52%) in the methotrexate group and 14 of 32 (44%) in the placebo group; the RR of being a responder in the methotrexate group was 1.18 (95 % CI 0.69 to 2.02) more than in the placebo group which is not significant. The average change from baseline in the expanded MRC sum score, graded out of 80, for participants in the methotrexate group at the mid trial visit improved by 2.05 (95% CI -0.21 to 4.32) points more in the methotrexate group than the placebo group. Although the trial did not show significant benefit, mild or moderate significant benefit could not be excluded because of problems inherent in the trial. These included especially the high proportion of responders in the placebo group, the complexity of the trial design and the subjective component to the decision about dose adjustment on which the primary outcome depended.

In the Italian retrospective study, only two of 12 patients treated with 7.5 to 15 mg weekly responded (Cocito 2011). There has been one case report of the use of a higher dose (20 mg weekly) of methotrexate in a CIDP patient refractory to conventional treatment. In this report, there was a 14-point improvement in MRC sum score and three times weekly IVIg was stopped after eight months on methotrexate 20 mg weekly. The improvement was sustained and prednisolone dose was reduced from 50 mg on alternate days to 10 mg on alternate days (Diaz-Manera 2009).

Mycophenolate mofetil

Mycophenolate mofetil is becoming popular as an alternative to azathioprine and ciclosporin in prevention of rejection of renal transplants and has been used in eight published series of CIDP patients. Chaudhry et al. treated three patients with CIDP with 1000 mg twice daily and one improved (Chaudhry 2001). Mowzoon et al. reported two patients, both of whom improved (Mowzoon 2001). According to an abstract report, three of six CIDP patients improved with mycophenolate (Radziwill 2006). In two CIDP patients, it was possible to reduce the amount of IVIg being used by 50% without any deterioration in their condition (Benedetti 2004). By contrast there was no improvement in any of four patients in another consecutive series (Umapathi 2002). Gorson et al. treated 12 patients with CIDP and in the group as a whole there was no significant improvement in average impairment or disability compared with baseline. However three patients did improve significantly (Gorson 2004). In another series, eight patients received mycophenolate mofetil (mean dose 2 g/day; median duration 15.2 months): all eight improved and their average (SD) NIS score increased from a baseline of 72.3 (35) to 37.8 (37) (P < 0.001) after treatment. Six of these eight patients either stopped corticosteroids or IVIg or reduced their doses and frequency by ≥50% (Bedi 2010). Three of 12 patients in the Cocito 2011 series improved with mycophenolate.

Summary of observational studies of mycophenolate

Series Dose Duration No. of patients No. improved Notes
Chaudhry 20011000 mg twice dailyNot stated31 
Mowzoon 2001Not statedNot stated22 
Radziwill 2006Not statedNot stated63 
Benedetti 2004Not statedNot stated22It was possible to reduce the amount of IVIg being used by 50% without any deterioration in patients' condition
Umapathi 2002Not statedNot stated40 
Gorson 2004Not statedNot stated123In the group as a whole there was no significant improvement in average impairment or disability compared with baseline
Bedi 20102 g dailymedian 15.2 months88All 8 patients had improved impairment scores and 6 either stopped corticosteroids or IVIg or reduced their doses and
frequency by ≥50%.
Cocito 20111 to 2 g daily≥12 months123Italian retrospective study
All studies  4922 

Etanercept

The tumour necrosis factor-α antagonist etanercept is beneficial in rheumatoid arthritis. Three of 10 patients with treatment-resistant CIDP were considered to gain significant benefit from it (Chin 2003). However, there are also reports of GBS, multifocal motor neuropathy and CIDP developing in patients being treated with tumour necrosis factor inhibitors for other conditions (Hamon 2007; Lozeron 2009; Alshekhlee 2010).

Rituximab

Rituximab, a chimeric (mouse/human) monoclonal antibody against CD20+ B lymphocytes, beneficial in lymphoma and rheumatoid arthritis, has been used in small series of patients with paraproteinaemic demyelinating neuropathy with modest benefit in some patients. A randomised controlled trial of its use in IgM anti-myelin-associated glycoprotein demyelinating neuropathy showed benefit in some patients (Dalakas 2006; Dalakas 2009). In CIDP, it was reported to have been beneficial in 12 of 17 patients in published case reports and small series (see Table of Summary of observational studies of rituximab). A recent email survey of international experts reported benefit from rituximab in 12 of 20 patients (Lunn 2009). The reports of Lunn 2009 and Cocito 2011 have been omitted from the Table of Summary of observational studies of rituximab since there may have been overlap with the case reports and series already included in the table. The patients in whom rituximab was reported to be beneficial often had other autoimmune disease or haematological disease. The table did not include patients who had simultaneous treatment with other agents, such as one with associated non-Hodgkin lymphoma co-treated with cyclophosphamide, doxorubicin and prednisone and then etoposide (Kasamon 2002) or those with IgM paraproteinaemia such as four reported by (Kilidireas 2006).

Summary of observational studies of rituximab

SeriesDoseDurationNo of patientsNo improvedNotes
Bodley-Scott 2005700 mg every 3 weeks7 courses11Self-report
Briani 2004; Benedetti 2008; Benedetti 2011375 mg m2weekly4 weeks1063 patients with IgM paraprotein in these series were excluded
D'Amico 2012375 mg m2weeklynot stated11 
Gorson 2007375 mg/m2 weekly4 weeks21 
Knecht 2004375 mg/m2 weekly7 months11With associated Evans syndrome
Münch 2007375 mg/m2 weekly4 weeks11With type 2 diabetes
Sadnicka 20111 g every 2 weeks2 doses11With Morvan's syndrome and myasthenia gravis
Total  1712 

Interferons

Interferon beta

Interferon beta (IFNb) is a naturally occurring cytokine, which downregulates inflammatory responses and has been shown to reduce relapse frequency and blood-brain barrier leakage in multiple sclerosis. IFN-b1a is a recombinant protein manufactured in mammalian cells that exactly replicates human IFNb. An apparently beneficial effect was reported in one patient with treatment resistant CIDP (Choudhary 1995). In a prospective open study, four patients with moderately severe CIDP received a six month course of IFN-b1a 22 μg thrice weekly for three weeks and then 44 μg thrice weekly for 8.5 to 10.3 months (Kuntzer 1999). There was no statistically significant benefit: two patients showed moderate improvement and one relapsed on treatment with IFN-b1a alone. When the treatment was combined with IVIg, improvement did occur but this might have been due to the known beneficial effect of IVIg. Martina and colleagues (Martina 1999) reported benefit in an open study from IFNb-1a 22 μg thrice weekly in one patient with pure motor CIDP as well as three with the related condition of multifocal motor neuropathy. The encouraging anecdotes led to the first randomised trial described in this review (Hadden 1999). Its negative result has to be considered in the context of the facts that the patients were resistant to other treatments, only received treatment for 12 weeks and received a low dose, maximum 22 μg subcutaneously three times a week. In subsequent trials in multiple sclerosis, 44 μg three times weekly has been more effective on most parameters than 22 μg three times weekly (PRISMS 1998; PRISMS 2001). Radziwill et al. reported in an abstract that four of five patients improved on IFNb-1a 22 μg three times weekly or on alternate days (Radziwill 2001). In a non-randomised open study of intramuscular IFNb-1a 30 μg weekly, seven (35%) of 20 patients treated showed clinical improvement, 10 (50%) remained stable and three (15%) worsened (Vallat 2003).

These results led to the second randomised trial reported in this review which also failed to confirm benefit in the intention-to-treat analysis (Hughes 2010). In this trial, treatment lasted 32 weeks and the dose given ranged up to 60 μg intramuscularly twice weekly. The primary outcome was total IVIg dose (g/kg) administered from week 16 to week 32 in the placebo group compared with the IFNb-1a group. This was slightly lower in the combined IFNb-1a groups (1.20 g/kg; P = 0.75) compared with the placebo group (1.34 g/kg) but the difference was not statistically significant. However, in an exploratory analysis, patients who were more severely disabled or on higher doses of IVIg had a statistically significant response to IFNb-1a.

The evidence from the observational studies does not provide much support for the use of IFN-b1a and, while differences in design and outcomes prevented meta-analysis, neither of the randomised trials identified in this review showed significant benefit. The observation in an exploratory analysis of significant reduction of IVIg in the participants receiving high doses might be worth pursuing with further trials. However, the occurrence of worsening of CIDP following treatment of co-existent multiple sclerosis with IFNb-1a urges caution in using the drug outside a clinical trial (Matsuse 2005). This conclusion is supported by the frequent side effects and especially expense of IFNb. IFNb-1a often causes minor alterations of liver function and white cell counts and, with subcutaneous preparations, skin reactions but serious side effects are rare. The cost of being on 30 μg of IFNb-1a once a week for one year is about GBP 8502 (10481 euros) (BNF 2012).

Summary of observational studies of interferon beta-1a (IFNb-1a)

Series Dose Duration No of patients No. improved Notes
Choudhary 1995Six month course of IFNb-1a 22 μg thrice weekly for 3 weeks and then 44 μg thrice weekly for 8.5 to 10.3 monthsNot stated11 
Kuntzer 1999Not statedNot stated42There was no statistically significant benefit, two patients showed moderate improvement and one relapsed on treatment with IFNb-1a alone
Martina 1999Not statedNot stated11Pure motor (3 other patients with multifocal motor neuropathy also improved)
Radziwill 200122 μg three times weekly or on alternate daysNot stated54 
Vallat 200330 μg weeklyNot stated207Ten (50%) remained stable and three (15%) worsened)
Cocito 20116 million units (30 μg) weekly≥12 months30 
All studies  3415 

Interferon alfa

Interferon alfa (IFNa) is another naturally occurring cytokine which has complex, incompletely understood immunoregulatory actions. It is used to enhance immune reactions to combat hepatitis C. It up-regulates immune responses and has been reported to cause autoimmune diseases including CIDP (Marzo 1998; Meriggioli 2000). Despite this, IFNa has been used to treat CIDP. The largest study (Gorson 1997) treated 16 patients (of whom two had a paraprotein) with IFNa-2a three million international units (MIU) subcutaneously three times a week for six weeks. Of the 14 without a paraprotein, nine responded to IFNa-2a: five had a sustained improvement and one improved, received plasma exchange and then had sustained improvement, and three relapsed. Minor side effects consisting of fatigue, fever, malaise and myalgia and arthralgia were common. Pavesi et al. reported dramatic improvement in a single treatment resistant patient with IFNa. This patient had severe symmetric distal and proximal muscle weakness and made complete functional recovery six months after she was started on IFNa 3 MIU subcutaneously twice a week (Pavesi 2002). IFNa is also expensive. We share the view of the authors of this study and Saperstein and colleagues (Saperstein 2001) that randomised trials would be needed to establish whether IFNa is beneficial. The Italian retrospective study reported improvement in four of 11 patients treated with 800,000 to 3 million units every one to three weeks for at least a year (Cocito 2011).

Autologous and allogeneic peripheral blood stem cell transplantation

Autologous peripheral blood stem cell transplantation is an extreme form of immunosuppression in which the patient is treated with high dose cyclophosphamide and then granulocyte stimulating factor to allow harvesting of bone marrow stem cells from the blood. The patient is then treated with very high dose cyclophosphamide, anti-T cell antibodies and, in some regimes, whole body irradiation to ablate their immune system. Finally, the immune system is reconstituted with the stored stem cells. There are six reports of CIDP patients who had underwent PBSCT. Vermeulen et al. reported success in one patient with CIDP who had been dependent on frequent IVIg: the patient improved and became able to stop all immunotherapy afterwards (Vermeulen 2002) but relapsed after five years (Vermeulen 2007). Barreira and colleagues reported a 24 year old man with a 12 year history of CIDP who underwent PBSCT with only a transient response which lasted for a month (Barreira 2007). Oyama et al. reported a 32 year old woman who had had an inadequate response to standard treatments. She had clinical and electrophysiological improvement after her transplantation. Her Rankin function score improved from 4 to 1 and she came off corticosteroids, IVIg and plasma exchange (Oyama 2007). Axelson and colleagues reported a 56 year old man who underwent PBSCT. His strength and sensation returned to normal within three months of transplant. He relapsed two years later and underwent another transplant. His muscle strength became normal three weeks after transplantation and remained in remission at the time of publication three years later (Axelson 2008). A recent case series followed up two patients from an earlier publication (Mahdi-Rogers 2007) and one other: of the three patients two improved: one had a response which was transient (18 months) and the other was in remission after six months (Mahdi-Rogers 2009). A further prospective case series is being collected (NCT00278629). The use of allogeneic peripheral blood stem cell transplantation induced complete remission in one patient with CIDP who had had no relapse after 6.5 years after transplantation (Remenyi 2007).

Summary of studies of autologous and allogeneic peripheral blood stem cell transplantation

Series No. of patients No. improved Notes (autologous transplant unless noted)
Vermeulen 200211Relapse after 5 years
Barreira 200711Improvement lasted for 1 month
Oyama 200711No disease exacerbation 22 months after transplant. By six months after transplant her Rankin function score had improved from 4 to 1. Corticosteroids, IVIg and plasma exchange withdrawn
Axelson 200811Relapse and re-transplant with remission after 2 years
Mahdi-Rogers 200932One of the two who benefited relapsed after 18 months
Remenyi 200711Allogeneic transplant. No relapse after 6.5 years
Total87 

Alemtuzumab

Alemtuzumab is a monoclonal antibody against CD52 antigen. The first report of the use of alemtuzumab in CIDP was by Hirst et al. Their patient had 11 relapses within 18 months after the onset of her disease but went into remission for 16 months after receiving five daily infusions of alemtuzumab 30 mg/day (Hirst 2006). There has been a subsequent report of seven patients including the patient reported by Hirst and colleagues who were treated with alemtuzumab in five centres (Llewelyn 2009). These patients had been treated with oral prednisolone as well as conventional immunosuppressants without significant benefit. The patients received nine courses of alemtuzumab (dose range 60 to 150 mg). After treatment, mean monthly IVIg dose reduced by 26% (202 to 149 g) and frequency of IVIg infusion from 22 to 136 days. Two patients had prolonged remission, another two had a partial response and three had no clear benefit. Patients who responded had a younger age at disease onset and shorter disease duration than non-responders. Three of the seven patients developed an autoimmune condition. Two patients developed high levels of anti-thyroperoxidase antibodies. One of these patients also developed TSH-receptor antibodies and was diagnosed with Graves’ disease three years after first infusion with alemtuzumab. One patient developed autoimmune haemolytic anaemia at 18 months after treatment (Marsh 2010). Six of the patients in this publication had been previously reported in an abstract (Llewelyn 2009). There is an ongoing open-label multicentre trial of alemtuzumab in the treatment of CIDP (NCT01757574).

Nataluzimab

Natalizumab, a humanised monoclonal antibody against the T-cell adhesion molecule α4 integrin, has been approved for treatment of multiple sclerosis. Wolf 2010 gave a single intravenous infusion of 300 mg of natalizumab to a patient with CIDP who had failed to respond to corticosteroids, IVIg, plasma exchange, azathioprine, cyclophosphamide and mycophenolate mofetil (Wolf 2010). The patient got worse.

Future trials

New trials are needed to investigate the efficacy of immunosuppressive and immunomodulatory drugs in CIDP. Of those reported in this review, azathioprine, a higher dose of methotrexate, ciclosporin and rituximab are all candidates. Many other agents such as fingolimod and fumarate are used or being tested in other diseases and would be worth consideration in CIDP.

Future trials should preferably last longer than those undertaken so far and the 12 month duration recommended by a consensus group (ENMC 2005) selected for this review as the time for measuring the primary outcome seems appropriate.

Measuring disability is preferred to impairment or nerve conduction parameters as the primary outcome because it has greater relevance to the patient. A disability scale developed for and validated in CIDP, such as the ONLS (Graham 2006) would be preferable to a generic scale. Hitherto such scales have been ordinal scales. The R-ODS scale is a numerical scale which captures a wider range of disability than the ONLS and may be preferred if it can be shown to be at least as responsive (van Nes 2011).

An alternative outcome measure in patients who are receiving IVIg or corticosteroids is to introduce the agent being tested and look for worsening. This was done by measuring the percentage dose reduction of IVIg in the Hughes 2010 trial of IFNb, or the percentage of participants who could reduce the dose of IVIg or corticosteroids in the RMC 2009 trial. An alternative way of testing the same thing is to compare the times to relapse between the two groups as is being done in the ongoing trial of fingolimod (NCT01625182).

A high proportion of participants in the placebo groups, 14 of 32 in the RMC trial (RMC 2009) and 8 of 17 in the trial by IFNb-1a (Hughes 2010), were able to reduce their dose of IVIg or corticosteroids without deteriorating.This suggested that some participants had been on a higher dose at baseline than they required. This high proportion of responders in the placebo groups reduced the sensitivity of these trials to detect a significant difference in the reduction of IVIg or corticosteroids which made the assessment of the efficacy of methotrexate and IFNb-1a difficult. Future trials should allow for this in power calculations or include a run-in period during which the IVIg or corticosteroid dosage is reduced, after which only participants who had been observed to worsen and require the reintroduction of IVIg or corticosteroids would be randomised.

Authors' conclusions

Implications for practice

One randomised controlled trial of azathioprine, two of IFNb-1a and one of methotrexate have been performed in CIDP. None were adequate to support or refute mild or moderate benefit or harm. Small numbers of case reports and case series described the use of other immunosuppressant drugs, especially cyclophosphamide, ciclosporin and rituximab, but none consistently produced sufficient improvement to recommend their use without further research.

Implications for research

More research is needed to determine whether immunosuppressive drugs or IFNs are beneficial in CIDP. Future trials should measure outcomes including disability after at least one year. It is necessary to use scales for measuring disability and impairment that are more responsive and biometrically sound. If trials use change in dosage of corticosteroids or IVIg, or the need for rescue treatment when IVIg is stopped as an outcome measure, their design should include a run-in period during which the IVIg or corticosteroid dosage is reduced or stopped to determine whether that individual still needs the IVIg or corticosteroids which they had been receiving.

Acknowledgements

We thank the GBS/CIDP Foundation International for funding for MM-R.

We thank Dr Tony Swan, statistician, who co-authored earlier versions of this review.

Editorial support from the Cochrane Neuromuscular Disease Group is funded by the MRC Centre for Neuromuscular Diseases.

Data and analyses

Download statistical data

Comparison 1. Methotrexate versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Serious adverse events159Risk Ratio (M-H, Fixed, 95% CI)3.56 [0.39, 32.23]
Analysis 1.1.

Comparison 1 Methotrexate versus placebo, Outcome 1 Serious adverse events.

Comparison 2. IFNb-1a versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Serious adverse events167Risk Ratio (M-H, Fixed, 95% CI)4.5 [0.25, 80.05]
Analysis 2.1.

Comparison 2 IFNb-1a versus placebo, Outcome 1 Serious adverse events.

Appendices

Appendix 1. Overall Neuropathy Limitations Scale (ONLS) (Graham 2006)

Arm grade

0 = Normal

1= Minor symptoms in one or both arms but not affecting any of the functions:

washing and brushing their hair;

turning a key in a lock;

using a knife and fork together (or spoon, if knife and fork not used);

doing or undoing buttons or zips;

dressing the upper part of their body excluding buttons or zips

2= Disability in one or both arms affecting but not preventing any of the above functions

3= Disability in one or both arms preventing at least one but not all the above functions

4= Disability in both arms  preventing all the above functions but purposeful movement still possible

5= Disability in both arms preventing all purposeful movements

Leg grade

0= Walking/climbing stairs/running not affected

1= Walking/climbing stairs/running is affected, but gait does not look abnormal

2= Walks independently but gait looks abnormal

3= Requires unilateral support to walk 10 metres (stick, single crutch, one arm)

4= Requires bilateral support to walk 10 metres (sticks, crutches, crutch and arm, frame)

5= Requires wheelchair to travel 10 metres but able to stand and walk 1 metre with the help of one person

6= Restricted to wheelchair, unable to stand and walk 1 metre with the help of one person, but able to make

some purposeful leg movements

7= Restricted to wheelchair or bed most of the day, unable to make any purposeful movements of the legs

Overall grade = arm grade + leg grade (range: 0 (no disability) to 12 (maximum disability))

Appendix 2. Modified Rankin Scale

0: asymptomatic

1: non-disabling symptoms not interfering with lifestyle

2: minor disability symptoms leading to some restriction of lifestyle but not interfering with the patient's capacity to look after themselves

3: moderate disability symptoms significantly interfering with lifestyle or preventing fully independent existence

4: moderately severe disability symptoms preventing independent existence although patients do not need constant attention day and night

5: totally dependent, requiring constant attention day and night

Appendix 3. CENTRAL search strategy

#1 inflammatory demyelinating
#2 (polyradiculoneuropath* or polyneuropath*)
#3 MeSH descriptor Polyneuropathies explode all trees
#4 MeSH descriptor Polyradiculoneuropathy explode all trees
#5 (polyneuritis or polyradiculoneuritis)
#6 (#2 OR #3 OR #4 OR #5)
#7 MeSH descriptor Chronic Disease explode all trees
#8 Chronic disease
#9 (#7 OR #8)
#10 (#1 AND #6 AND #9)
#11 chronic inflammatory demyelinating polyradiculoneuropathy
#12 MeSH descriptor Polyradiculoneuropathy, Chronic Inflammatory Demyelinating explode all trees
#13 cidp
#14 (#10 OR #11 OR #12 OR #13)
#15 (#14)

Appendix 4. MEDLINE (OvidSP) search strategy

Database: Ovid MEDLINE(R) <1946 to June Week 4 2012>
Search Strategy:
--------------------------------------------------------------------------------
1 randomized controlled trial.pt. (331300)
2 controlled clinical trial.pt. (84583)
3 randomized.ab. (234775)
4 placebo.ab. (132675)
5 drug therapy.fs. (1548642)
6 randomly.ab. (169129)
7 trial.ti,ab. (291542)
8 groups.ab. (1110374)
9 or/1-8 (2892079)
10 exp animals/ not humans.sh. (3751397)
11 9 not 10 (2457501)
12 inflammatory demyelinating.tw. (2716)
13 (polyradiculoneuropath$3 or polyneuropath$3).tw. (10238)
14 Polyneuropathies/ or Polyradiculoneuropathy/ (7449)
15 (polyneuritis or polyradiculoneuritis).tw. (1641)
16 13 or 14 or 15 (15838)
17 12 and 16 and chronic.mp. (1458)
18 Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/ (778)
19 (chronic inflammatory demyelinating polyradiculoneuropathy or cidp).mp. (1116)
20 or/17-19 (1697)
21 exp immunologic factors/ (1056679)
22 exp adjuvants, immunologic/ (120095)
23 exp Immunosuppressive Agents/ (233247)
24 Peripheral Blood Stem Cell Transplantation/ (2541)
25 (immunologic or immunosuppress* or immunomodulat* or mycophenolate mofetil or etanercept or rituximab or alemtuzumab or autologous PBSCT or autologous peripheral blood stem cell transplantation).mp. (357505)
26 or/21-25 (1220127)
27 11 and 20 and 26 (347)
28 remove duplicates from 27 (345)

Appendix 5. EMBASE (OvidSP) earch strategy

Database: Embase <1980 to 2012 Week 27>
Search Strategy:
--------------------------------------------------------------------------------
1 crossover-procedure.sh. (34294)
2 double-blind procedure.sh. (109566)
3 single-blind procedure.sh. (16068)
4 randomized controlled trial.sh. (324607)
5 (random$ or crossover$ or cross over$ or placebo$ or (doubl$ adj blind$) or allocat$).tw,ot. (879217)
6 trial.ti. (132254)
7 or/1-6 (1006144)
8 (animal/ or nonhuman/ or animal experiment/) and human/ (1189440)
9 animal/ or nonanimal/ or animal experiment/ (3284152)
10 9 not 8 (2721241)
11 7 not 10 (922289)
12 limit 11 to embase (714898)
13 demyelination/ or demyelinating neuropathy/ or demyelinating disease/ (20817)
14 inflammatory demyelinating.tw. (3853)
15 13 or 14 (22862)
16 polyneuropathy/ or peripheral neuropathy/ or peripheral nervous system/ or polyradiculoneuropathy/ (91336)
17 (polyradiculoneur$ or polyneur$).mp. (22312)
18 16 or 17 (99316)
19 15 and 18 and chronic.mp. (2602)
20 (chronic inflammatory demyelinating neuropath$ or cidp).mp. (1580)
21 19 or 20 (2886)
22 exp immunomodulating agent/ (532254)
23 exp immunological adjuvant/ (23989)
24 (immunologic or immunosuppress$ or anti?inflammatory).mp. (396273)
25 exp interferon/ (289615)
26 exp antiinflammatory agent/ (1043012)
27 exp immunosuppressive agent/ (477420)
28 (azanthioprine or cyclophosphamide or methotrexate or ciclosporin or cyclosporin or mycophenolate mofetil or etanercept or rituximab or alemtuzumab or autologous PBSCT or autologous peripheral blood stem cell transplantation).mp. (333022)
29 or/22-28 (1678526)
30 12 and 21 and 29 (122)

Appendix 6. LILACS search strategy

(((Tw polyradiculoneuropath$ OR Tw polyneuropath$ OR Mh polyneuropathies OR Mh Polyradiculoneuropathy OR Tw polyneuritis OR Tw polyradiculoneuritis) AND (Tw chronic disease OR Mh Chronic Disease)) OR (Tw chronic inflammatory demyelinating polyradiculoneuropathy OR Tw cidp)) AND ((Pt randomized controlled trial OR Pt controlled clinical trial OR Mh randomized controlled trials OR Mh random allocation OR Mh double-blind method OR Mh single-blind method) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Pt clinical trial OR Ex E05.318.760.535$ OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR Tw experim$ OR Tw investiga$)) OR ((Tw singl$ OR Tw simple$ OR Tw doubl$ OR Tw doble$ OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR Tw cego$ OR Tw ciego$ OR Tw mask$ OR Tw mascar$)) OR Mh placebos OR Tw placebo$ OR (Tw random$ OR Tw randon$ OR Tw casual$ OR Tw acaso$ OR Tw azar OR Tw aleator$) OR Mh research design) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Ct comparative study OR Ex E05.337$ OR Mh follow-up studies OR Mh prospective studies OR Tw control$ OR Tw prospectiv$ OR Tw volunt$ OR Tw volunteer$) AND NOT (Ct animal AND NOT (Ct human and Ct animal)))

Appendix 7. CINAHL (EBSCOhost) search strategy

Monday, July 09, 2012 11:32:12 AM
S39 S32 and S38 43
S38 S33 or S34 or S35 or S36 or S37 85852
S37 autologous PBSCT or autologous peripheral blood stem cell transplantation 53
S36 etanercept or rituximab or alemtuzumab 2819
S35 immunologic or immunosuppress* or azathioprine or cyclophosphamide or methotrexate or ciclosporin or cyclosporin or mycophenolate mofetil 19821
S34 (MH "Immunologic Factors+") 70539
S33 (MH "Immunosuppressive Agents+") 9119
S32 S18 and S31 74
S31 S28 or S29 or S30 263
S30 chronic n3 inflammatory n3 demyelinating n3 polyradiculoneuropathy 97
S29 cidp 135
S28 S22 and S26 and S27 242
S27 chronic 120070
S26 S23 or S24 or S25 3286
S25 polyradiculoneuropath* or polyneuropath* or polyneuritis 1213
S24 (MH "Polyneuritis+") 326
S23 (MH "Polyradiculoneuritis+") or (MH "Polyradiculopathy") 2339
S22 S21 or (S19 and S20) 411
S21 inflammatory n3 demyelinating 359
S20 TI inflammatory or AB inflammatory 24536
S19 (MH "Demyelinating Diseases") 825
S18 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17 545944
S17 ABAB design* 77
S16 TI random* or AB random* 111052
S15 ( TI (cross?over or placebo* or control* or factorial or sham? or dummy) ) or ( AB (cross?over or placebo* or control* or factorial or sham? or dummy) ) 229447
S14 ( TI (clin* or intervention* or compar* or experiment* or preventive or therapeutic) or AB (clin* or intervention* or compar* or experiment* or preventive or therapeutic) ) and ( TI (trial*) or AB (trial*) ) 77463
S13 ( TI (meta?analys* or systematic review*) ) or ( AB (meta?analys* or systematic review*) ) 22592
S12 ( TI (single* or doubl* or tripl* or trebl*) or AB (single* or doubl* or tripl* or trebl*) ) and ( TI (blind* or mask*) or AB (blind* or mask*) ) 18118
S11 PT ("clinical trial" or "systematic review") 102736
S10 (MH "Factorial Design") 824
S9 (MH "Concurrent Prospective Studies") or (MH "Prospective Studies") 181072
S8 (MH "Meta Analysis") 14269
S7 (MH "Solomon Four-Group Design") or (MH "Static Group Comparison") 30
S6 (MH "Quasi-Experimental Studies") 5470
S5 (MH "Placebos") 7595
S4 (MH "Double-Blind Studies") or (MH "Triple-Blind Studies") 24480
S3 (MH "Clinical Trials+") 143934
S2 (MH "Crossover Design") 9381
S1 (MH "Random Assignment") or (MH "Random Sample") or (MH "Simple Random Sample") or (MH "Stratified Random Sample") or (MH "Systematic Random Sample") 57053

What's new

DateEventDescription
14 June 2013AmendedCorrection to author affiliation, acknowledgements and sources of support

History

DateEventDescription
6 February 2013New citation required but conclusions have not changedResults of new searches fully incorporated
9 July 2012New search has been performedNew search to 9 July 2012. No new completed trials. Three ongoing trials added. Text updated.
30 July 2008New citation required and conclusions have changed

Change of first author

Two new trials added

Change of title. This Cochrane review was previously published as Cytotoxic drugs and interferons for chronic inflammatory demyelinating polyradiculoneuropathy.

27 April 2008AmendedConverted to new review format.
21 March 2007New search has been performedThe searches were updated in March 2007. No new trials were identified.
1 January 2006New search has been performedWe updated the searches of the NMD Group Trials Register, MEDLINE and EMBASE (to September 2005). No new randomised trials were found. We included additional non-randomised studies in the Discussion section of the review.
1 July 2004New citation required and conclusions have changedSubstantive amendment

Contributions of authors

MM-R wrote the first draft of the 2010 and 2013 updates of this review. PAvD commented on all versions of this review. RACH wrote the first draft of previous versions and edited the 2010 and 2013 updates. All authors approved the final version of each update.

Declarations of interest

MM-R was an investigator and trial coordinator for the RMC 2009 trial (RMC 2009).

PAvD participated in the RMC 2009 trial (RMC 2009). He and his institution are in receipt of funding from Talecris and CSL Behring in relation to serving on the scientific board of the ICE trial in CIDP and scientific board on IVIg in chronic polyneuropathy. His institution is in receipt of a grant from Baxter to conduct a RCT comparing IVIg with IVIg and steroids in GBS, a grant from Sanquin to conduct a RCT investigating the effect of a second course of IVIg (SID-trial) in GBS patients with a poor prognosis and a grant from Talecris to conduct a prospective international study on the effect of a second course of IVIg in GBS patients with a poor prognosis.

RACH was the principal investigator of a company sponsored trial of beta interferon for CIDP, of an investigator-led trial of methotrexate for CIDP (Hadden 1999) and an investigator-led trial of interferon beta-1a (RMC 2009), all of which are included in this review. He is chair of the steering committee for the ongoing fingolimod trial (NCT01625182). RACH has consulted or is consulting for Baxter, CSL Behring, Grifols/Talecris, LFB and Octapharma which all manufacture human immunoglobulin, an alternative treatment for CIDP not considered in this review. RACH is a member of the Medical Advisory Board of GBS CIDP Foundation International and Medical Patron of GBS Support Group UK.

Sources of support

Internal sources

  • King's College London School of Medicine, UK.

  • University Hospital Rotterdam/Erasmus University Medical Center Rotterdam, Netherlands.

  • GBS/CIDP Foundation International, USA.

    Funding for MM-R

External sources

  • Donation from Mr and Mrs Chris Lazari, UK.

Differences between protocol and review

In the 2010 update, we accepted the EFNS/PNS 2005 criteria as adequate for diagnosis, the ONLS as the preferred disability scale (Graham 2006), and 24 week outcomes in the absence of the 12 month outcomes which we would have preferred. We added 'Risk of bias' and 'Summary of findings' tables.

Dr Tony Swan, an author of the protocol, withdrew from authorship of the review at this update. MM-R joined the review team for the 2010 update of the review.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Dyck 1985

MethodsOpen, parallel group, randomised trial
Participants30 adults with CIDP defined by criteria which approximate to the ad hoc 1991 criteria published later. 15 were randomised to azathioprine and prednisone but 1 was removed because of a changed diagnosis. 15 were randomised to prednisone only but 2 were removed because of a changed diagnosis. The median time from when participants were diagnosed with CIDP to when they were enrolled into the trial was 29 months (range 8 to 168) for those who received prednisone and 21 (range 6 to 84) for those who received azathioprine and placebo).
InterventionsAzathioprine 2 mg/kg for 9 months: prednisone was given to both groups starting at 120 mg every other day with subsequent tapering over 9 months.
OutcomesNeuropathy impairment score, maximal inspiratory pressure, maximal expiratory pressure, hand grip, finger pinch, and motor nerve conduction in one ulnar, median and peroneal nerve.
NotesFollow-up data were available on 13/14 azathioprine and prednisone and 10/13 prednisone only participants. No significant differences in any outcome between the groups. When both groups were combined and compared with the baseline values there was a significant improvement in the neuropathy impairment score of 20 points (P < 0.03).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDone by "restricted randomisation" according to age, sex and disease severity
Allocation concealment (selection bias)High riskNot attempted
Blinding (performance bias and detection bias)
All outcomes
High riskAssessors and participants were not blinded.
Incomplete outcome data (attrition bias)
All outcomes
High riskNot all participants returned for planned follow up. No reason was given for the 3 drop outs in the prednisone only group, and 1 in the azathioprine and prednisone group.
Selective reporting (reporting bias)Low riskAll the pre-specified clinical and electrophysiological outcome measurements were reported.
Other biasLow riskNone identified

Hadden 1999

MethodsDouble blind, cross-over trial
Participants20 adults with treatment resistant probable CIDP according to the ad hoc 1991 criteria. The median time from when participants were diagnosed with CIDP to when they were enrolled into the trial was 11 years (range 3-23).
InterventionsIFNb-1a 11 μg thrice weekly for 2 weeks then 22 μg thrice weekly for 10 weeks or placebo. Four week washout period. Then the opposite regime for 12 weeks.
OutcomesPrimary: number with clinically important improvement in at least 3 measurements of disability, impairment and quality of life (see Description of studies).
Secondary: changes in the same clinical measures and in median nerve compound muscle action potential amplitudes, distal motor latencies and motor conduction velocities after 12 weeks.
NotesOne participant deteriorated after 4 weeks during the first treatment period (IFNb) and was immediately switched to the alternative treatment (placebo). One participant showed clinically significant improvement during the IFNb treatment and two during placebo. In the secondary outcome measures the only statistically significant abnormality was a trivial improvement in the functional independence measure in favour of placebo treatment.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskCross-over design. Participants received either IFNb or placebo in the first arm and the opposite in the second arm. IFNb-1a and placebo injections were supplied in coded packages according to a sequence of random numbers.
Allocation concealment (selection bias)Low riskIFNb and placebo injections were supplied in coded packages according to a sequence of random numbers.
Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants were assessed by independently masked and treating neurologists at entry and at 2, 4, 8 and 12 weeks during each arm of the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low risk1 participant was on the first arm (IFNb-1a) for only 4 weeks because he deteriorated. The participant had no wash out and was transferred to the second arm.
Selective reporting (reporting bias)Low riskDetailed report of all clinical and electrophysiological outcomes.
Other biasLow riskNone identified

Hughes 2010

MethodsDouble blinded, placebo controlled, parallel group, dose ranging
Participants67 adults with CIDP between 18 and 75 years old requiring IVIg. The median time from when participants were diagnosed with CIDP to when they were enrolled into the trial was 2.9 years (range 0.6 to 29) for those who received placebo and 3.6 (range 0.4 to 23) for those who received IFNb-1a.
InterventionsIntramuscular IFNb-1a 30 μg once weekly, 60 μg once weekly, 30 μg twice weekly, or 60 μg twice weekly for 32 weeks or placebo
OutcomesTotal IVIg dose (g/kg) administered in the 16 weeks after 16 week visit (from weeks 16 to 32)
NotesFull trial data made available by the authors
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation took place across all investigational sites using a centralised interactive voice response system (IVRS) at randomisation.
Allocation concealment (selection bias)Low riskAt randomisation the IVRS assigned a unique 6 digit identification number to each participant.
Blinding (performance bias and detection bias)
All outcomes
Low riskTo maintain the double blind status of the study, all participants received 2 injections per week. Consequently, participants allocated to a once weekly active treatment also received placebo once weekly. All drugs were packaged identically.
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Overall, 34/45 (76%) IFNb-1a and 19/22 (86%) placebo participants completed the study.

In the combined intramuscular IFNb-1a groups, 31% of participants discontinued study drug but completed study evaluations compared with 14% in the placebo group. Overall, 24% of participants in the IFNb-1a groups and 14% of participants in the placebo group withdrew from the study. The main reasons for study drug discontinuation were adverse events (11%) and voluntary withdrawal (11%) in the combined IFN b-1a groups, and adverse events (5%), voluntary withdrawal (5%), and worsening of disease (5%) in the placebo group. The main reasons for withdrawal from the study were adverse events (9%) and voluntary withdrawal (7%) in the combined IFNb-1a groups, and adverse events (5%), voluntary withdrawal (5%), and worsening of disease (5%) in the placebo group. The majority of participants (80%) completed at least 28 weeks on study and 71% received at least 87.5% of their expected dose (56 of 64 injections of study drug). Four non-compliant participants (IFNb-1a, 2; placebo, 2) were excluded from efficacy analysis but included in safety analysis.

Selective reporting (reporting bias)Low riskAll pre-planned primary and secondary outcomes were reported.
Other biasLow riskNone identified

RMC 2009

  1. a

    1.IFNb: interferon beta

MethodsRandomised, double blind, placebo controlled
Participants60 adults with CIDP with or without paraprotein (but not anti-myelin-associated-glycoprotein antibodies), who were receiving corticosteroids or IVIg or both
InterventionsMethotrexate 7.5 mg weekly for 4 weeks, then 10 mg weekly for 4 weeks, then 15 mg weekly for 32 weeks, or placebo. Both groups received folic acid 5 mg twice weekly
Outcomes

Primary: percentage reduction in corticosteroids or IVIg in weeks 37 to 40 compared with weeks 1 to 4

Secondary: change in MRC sum score, Overall Neuropathy Limitation Score and Amsterdam Linear Disability Score from baseline to week 16 and to week 40

NotesIn the analysis of the primary outcome measure, the results were dichotomised into non-responders (reduction of corticosteroid or IVIg dose by 20% or less) and responders (reduction of corticosteroid or IVIg dose by more than 20%). There were 14 of 27 (52%) responders in the methotrexate group and 14 of 32 in the placebo group (44%), adjusted odds ratio 1.21 (95% CI 0.40 to 3.70).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial statistician prepared a computer-generated list of random assignments stratified by centre and in blocks in order to allocate participants to methotrexate or placebo in a balanced way within centres.
Allocation concealment (selection bias)Low riskEach trial pharmacy dispensed treatment packs according to the randomisation allocation sequence. Treatment packs were supplied in separate packs for each 4 week period in the trial labelled with a unique code for that participant.
Blinding (performance bias and detection bias)
All outcomes
Low riskDisability scales and impairment measures were collected by a blinded neurologist or other trained health professional at scheduled outpatient visits. This individual did not have access to the laboratory records and did not ask questions about possible side effects. The active medication and placebo were presented as tablets of identical colour and external markings. Treatment packs were supplied in separate packs for each 4 week period in the trial labelled with a unique code for that participant.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThere were no follow-up measurements for one participant
Selective reporting (reporting bias)Low riskAll the primary and secondary outcomes pre-specified in the study protocol were reported.
Other biasLow riskNone identified

Characteristics of studies awaiting assessment [ordered by study ID]

Hu 2009

MethodsRandomised study
Participants60
Interventionsgullong tongluo (Chinese herbal remedy)
OutcomesChanges before and after 3-months of treatment in terms of muscle force, functional and sensory disturbance of extremities, as well as scoring by Activity of Daily Living Scale (ADL) and electromyogram (EMG) for nerve conduction velocity
Notes 

Characteristics of ongoing studies [ordered by study ID]

NCT00278629

Trial name or titleHematopoetic stem cell transplantation in chronic inflammatory demyelinating polyneuropathy
MethodsNon randomised study
Participants50
InterventionsNon-myeloablative autologous hematopoetic stem cell transplant
OutcomesTime to worsening as the primary outcome
Starting dateJanuary 1996
Contact informationDr Spahovic: d-spahovic@northwestern.edu
NotesClinicaltrials.gov NCT00278629

NCT00962429

Trial name or titleLipoic acid to treat chronic inflammatory demyelinating polyneuropathy—a randomized, double-blind, placebo controlled pilot study
MethodsRandomized, double-blind, placebo controlled, parallel group, pilot study
ParticipantsPatients aged 18 to 80 with CIDP on a stable dose of immunotherapy for at least 3 months before enrolling in the study
InterventionsSingle daily dose of 600 mg of alpha lipoic acid or placebo for the first 4 weeks and then increased to 1200 mg for the remainder of the study
OutcomesPrimary outcome muscle strength for 16 weeks
Secondary outcomes
Hughes Functional Disability Scale
Forced vital capacity
Motor nerve conduction studies
Starting date2009
Contact informationJau-Shin Lou, Associate Professor, Oregon Health and Science University
NotesClinicaltrials.gov NCT00962429

NCT01625182

Trial name or titleEvaluate efficacy and safety of fingolimod 0.5 mg orally once daily versus placebo in chronic inflammatory demyelinating polyradiculoneuropathy patients
MethodsDouble-blind, randomized, multicentre, placebo-controlled, parallel-group study
Participants"Confirmed diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy and treated with IVIg, corticosteroids, or both therapies prior to study entry"
InterventionsOral fingolimod (0.5 mg/day) or matching placebo in a ratio of 1:1. The IVIg or corticosteroids are stopped or tailed off when the participant is randomised.
OutcomesThe primary outcome measure is time to first confirmed worsening on the adjusted INCAT Disability Scale by 1 point or more from the value at baseline, in patients being treated with IVIg and/or corticosteroids prior to the study start.
Starting dateNovember 2012
Contact informationNovartis Pharmaceuticals +1(862)778-8300
NotesClinicaltrials.gov NCT01625182

NCT01757574

Trial name or titleAlemtuzumab in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
MethodsOpen-label
Participants16
InterventionsParticipants will receive at least one cycle of alemtuzumab (5 days of drug infusion). Additional cycles of alemtuzumab (3 days of drug infusion) may be provided at the discretion of the participants' treating physician such as if clinical worsening occurs.
OutcomesPrimary outcome: change from baseline in disability at 36 months measured by GBS/CIDP Rasch-built Overall Disability Scale (GBS/CIDP-RODS). Time frame: every six months up to 36 months
Starting dateNovember 2012
Contact informationMichael Polydefkis, MD MHS mpolyde@jhmi.edu
NotesClinicaltrials.gov NCT01757574

Ancillary