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BPNS Discussion Forum: Steroids in CIDP
Liverpool
22 March 2013
Summary Minutes by Carolyn Gabriel
Dr Rob Hadden presented results of the email survey of BPNS members (11 respondents) and the same
questions were posed to those in attendance (20 members). The evidence for different regimes was then
presented.
This evidence seems to suggest that oral prednisolone versus intravenous dexamethasone is no different in
terms of outcome and there was discussion regarding the relative risk of side effects from these 2 regimes.
The IVMP versus IVIg data suggests that IVIg results in less early relapse but more longer term relapses. It
was noted that 50% given IVMP for 6 months were in remission at 1 year cf 33% given IVIg.
Most members use daily oral prednisolone. The PREDICT trial of this versus pulsed dexamethasone
suggested the pulsed regime was better in terms of both outcome and side effects. It was proposed that
this should be considered as a proposed change of practice point. It was noted by the membership that all
patients on daily steroid regimes become adrenal-insufficient.
Dr Charlotte Dougan presented data on side-effects of steroids. It was noted that side effects are
particularly prevalent after 3-4 months on therapy and that information sheets should be provided to
patients. It was noted by paediatric colleagues that children are tested for varicella immunity pre-steroids
and noted that adults should be questioned regarding previous chickenpox. If required, passive
immunisation with normal human Ig is required within 3 days of varicella infection in the
immunosuppressed.
Full presentations given by Dr Hadden (Therapeutic regimens and efficacy) and Dr Dougan (Adverse
effects and monitoring) now follow:
Dr Rob Hadden presentation
THERAPEUTIC REGIMENS AND EFFICACY OF STEROIDS
Email Survey of BPNS members: n=11 responses
 First line: IVIG 6, steroid 3, either 2
 Preferred type steroid: pred 8, dex 2, ivMP then pred 1
 Alternate days? Yes 5, no 6
 Ever used pulsed dex? No 8, yes 3
 Ever use steroids in predom motor CIDP? Yes 11
 Steroid sparing drug? Aza 9, mtx 1, none 1
 Steroid information sheet? No 8, yes 3
 Pre-steroid screen: TB/CXR 50%, glucose 50%, weight 80%, BP 90%, vaccinate 10% (paed), DEXA
60%, dietician 20%
EFNS/PNS CIDP guidelines 2010
 Treatment with corticosteroids or IVIg should be offered to patients with moderate or severe
disability.
 Contraindications to corticosteroids will influence the choice towards IVIg and vice versa.
 No evidence and no consensus about whether to use daily or alternate day prednisolone or
prednisone or intermittent high-dose monthly intravenous or oral regimens.
 For pure motor CIDP, IVIg first choice; if corticosteroids used, monitor closely for deterioration.
 Generally accepted dosage for Prednisolone is 60 mg/day (1–1.5 mg/kg in children) as induction.
Up to 12 weeks on starting dose before deciding whether there is no response. If there is a
response, tapering dose slowly to a low maintenance level over 1 or 2 years and eventual
withdrawal
Prednisolone v no treatment
Dyck et al Ann Neurol. 1982 ;11:136-41
 3 months prednisolone 120mg/0mg alt days then taper
 N=28 prednisolone, n=12 no treatment
 Prednisone gave small but significant improvement over no treatment in: neurological disability,
sensory detection threshold, graded muscle strength, and some NCS
 Cochrane reanalysis ITT: benefit not quite significant
 Improved neuropathy impairment scores after 3 months
 Prednisolone 12/19 (63%)
 no treatment 5/16 (31%)
 risk ratio (RR) for improvement 2.02 (95% CI 0.90 to 4.52).
Prednisolone v IVIG
Hughes INCAT et al. Ann Neurol. 2001;50:195-201
 randomized, double-blind, crossover trial n=32
 oral prednisolone 60 mg tapering to 10 mg over 6 week
 IVIg 2 g/kg over 1-2 days
 24 of the 32 patients completed both treatment periods.
 Both treatments produced significant improvements in primary outcome measure, change in an 11point disability scale two weeks after randomization.
 slightly, not significantly, more improvement after IVIg than prednisolone, mean difference in
change in disability grade 0.16 (95% CI -0.35 to 0.66).
 slightly, not significantly, greater improvements favoring IVIg in secondary outcomes: 10m walk
time at 2w, disability grade after six weeks.
 Prob biased against IVIg by 8 patients who did not complete the second arm of the trial.
 Very short term: primary outcome at 2w
Pulsed dexamethasone v daily prednisolone: PREDICT trial
van Schaik et al, Lancet Neurol. 2010; 9: 245-53.
 Newly diagnosed, untreated. n=40.
 Dexamethasone 40mg daily x 4d, monthly for 6m
 Prednisolone 60mg od x 5w then reduce over 8m
 Primary outcome remission at 12m.
 Dexamethasone 10/24 (42%)
 Prednisolone 6/16 (38%). NS
 Compare ICE trial 40% able to stop IVIG after 6m
 Median time to remission: dex 20w, pred 39w, p=0.06.
 % worsening: dex 7/24 (29%), pred 8/16 (50%), NS
 Adverse events:
 Significant: pred worse sleeplessness and Cushing’s face;
 NS trend: pred worse mood, weight gain, diabetes
 Of patients in remission at 1y, half had a relapse after median untreated interval of 18m (dex) or
11 m (pred).
IVIG v IVMP trial
Nobile-Orazio et al, Lancet Neurology 2012; 11: 493-502
 Placebo controlled RCT. New or treated CIDP. Randomised to one of the following, monthly for 6
months
 IVIG 0.5g/kg/d x 4d, or
 iv methylprednisolone 500mg/d x 4d
 Switch to other treatment: if not improved at 2m, or if worse or intolerant at any time
 Primary outcome: proportion stopping first treatment
Main therapeutic issues – CIDP
open for discussion
 IVIG or steroids first line?
 My view: steroids, because cheaper, except if severe or predom motor
 Which steroid regime?
 My view: pulsed dex as more convenient than ivMP
 If steroids fail, when to switch to IVIG?
 My view: if worse at any time, or if no better after 2m
Guidelines on monitoring Steroids
Dr Charlotte Dougan
Walton Centre
Adverse Effects
•
•
Mineralocorticoid (H20 retention, BP) or glucocorticoid
(diabetes, osteoporosis).
> 3/ 12 & frequent courses (3-4/year)
Adverse effects 1
• Cardiovascular: hypertension ; congestive cardiac failure.
• Central nervous system: psychosis, sleep disturbance
• Endocrine/metabolic: adrenal suppression , cushinoid
appearance, impotence, irregular menses, insulin resistance ,
diabetes, dysthyroid, hypokalaemia, metabolic acidosis
• Gastrointestinal: gastric effects (peptic ulceration , etc.), fatty
liver.
• Musculoskeletal: Myopathy, Osteoporosis, Avascular necrosis of
bone.
• Ophthalmic: cataracts, elevation of intraocular pressure ,
glaucoma
• Skin: acne, thinning & fragility, striae
Adverse effects 2: Immune
•
•
Suppression type IV hypersensitivity (interferes with Mantoux' test)
•
Suppression of primary antigen response (important with
vaccines)
Inhibitory effects (leukocytes, macrophages ,
cytokines)
Drug interactions
•
•
•
•
•
•
•
•
•
Anticoagulants- steroids may increase or reduce the anticoagulant effect. High-dose
corticosteroids increase the anticoagulant effect
Anticonvulsants - Therapeutic effects of prednisolone can be markedly reduced by carbamazepine,
phenytoin, and phenobarbital.
Antifungals - increase steroid effect so monitor
Bronchodilators- hypokalaemia, arrythmias
Digoxin - hypokalaemia increases the risk of digoxin toxicity
Diuretics - hypokalaemia
Ephedrine -increases the clearance of dexamethasone.
HIV protease inhibitors- Ritonavir may reduce the clearance of prednisolone.
•
•
•
•
•
- Dexamethasone may increase the levels of indinavir and saquinavir.
Macrolides - (especially clarithromycin and erythromycin) can reduce the clearance of
methylprednisolone, thereby increasing its therapeutic and adverse effects, consider dose
reduction.
Methotrexate- Dexamethasone may increase the acute hepatotoxicity of high-dose
methotrexate, monitor LFTs closely
NSAIDs - PPI required
Rifampicin -can significantly reduce the effects of oral corticosteroids, increase if
necessary.
Corticosteroids and infection
• Diagnosis of serious infection may be delayed/masked
(septicaemia, tuberculosis)
• Predispose to fungal infection in chronic lung disease
(aspergillosis).
• Patients on steroids should avoid exposure to measles; if
exposed, human normal immunoglobulin
Corticosteroids and VZV
• Patients on steroids or within 3/12 of use and are non-immune to
varicella infection, are at risk of severe infection (fulminant
pneumonia, hepatitis & DIC)
• Confirmed chickenpox in such patients warrants urgent
referral and treatment ; passive immunisation with VZ
immunoglobulin no later thanl0/7 after exposure
Live Vaccination
•
•
Live vaccines should not be given within 3/12 of:
An adult receiving 40 mg/day of prednisolone or
equivalent for more than a week .
Corticosteroids and surgery
•
For minor surgery under general anaesthesia either the
usual corticosteroid dose can be given orally, or 25-50
mg of hydrocortisone can be given intravenously (IV) at
induction.
•
For moderate/major surgery the usual oral dose on the day
of surgery with hydrocortisone at induction and the same IV
dose three times daily for between 24 and 72 hours after
surgery, depending on the extent of surgery. Followed by the usual
oral dose.
Osteoporosis-NICE guidelines for all
•
NICE guidelines recommend assessing fracture risk* in all
women
>
65 &:
• Women < 65 years & men < 75 who
have secondary causes of
osteoporosis (including immobility or
steroids)
*WHO FRAX tool to assess fracture
risk & identify those patients requiring
DXA scan regardless of their
neurological comorbidity
UK National Osteoporosis Guideline
Group
• All patients- not on steroids
• No consensus as to the magnitude of 5 or
10 year fracture risk at which to perform a
DXA scan
• Recommends an age-dependent intervention
threshold ranging from 7.5% to 30% 10-year
fracture risk
• Estimated fracture of risk 5-25%, depending on age
• Those patients who have sustained a fragility
fracture and are aged under 75 years should have
DXA scanning regardless of their calculated 10year fracture risk.
Rx of Osteoporosis
• Address Lifestyle factors
• Diet
• Smoking cessation
• ETOH reduction
• Daylight
• Exercise
NICE guidelines for the primary prevention of
osteoporotic fragility fractures- 2010
• Alendronate: Women aged >70 years with an independent
clinical risk factor for fracture* or an indicator of low bone
mineral density** & confirmed to have osteoporosis
• Women 65-69 years with an independent clinical risk factor for fracture
& confirmed to have osteoporosis
• Postmenopausal women younger than 65 years who have an
independent clinical risk factor for fracture, and at least one
additional indicator of low bone mineral density and who are
confirmed to have osteoporosis
• Risedronate, etidronate, strontium, for those intolerant to
Alendronate (see NICE guidelines)
*independent clinical risk factors for fracture are parental history of hip
fracture, ETOH > 4 units per day, and rheumatoid arthritis.
**Indicators of low bone mineral density are: low BMI (< 22 kg/m2),
medical conditions such as ankylosing spondylitis, Crohn's disease,
prolonged immobility and untreated menopause.
Glucocorticoid- induced osteoporosis
Who to treat? RCP, 2002
• Meta-analysis of seven cohort studies (n = 42,000) followed
up for 176,000 patient-years [Kanis et al, 2004].
• Offer bisphosphonates if > 3/12 steroids&:
- > 65 years of age
- < 65 years of age + a previous fragility fracture.
- < 65 years of age + T-score of -1.5 or less.
• If bisphosphonate Rx is not indicated because the Tscore is between 0 & -1.5, repeat DEXA scan in 1-3
years if corticosteroid use continues.
• DEXA scan is not necessary prior to starting steroids
• Refer premenopausal women and men who are
found to have osteoporosis to a specialist for
further investigation and management.
Bisphosphonates for treating steroid
induced osteoporosis, Cochrane 2010
• 13 trials, n= 842
• Bone mineral density of lumbar spine improved by 4.5%
• At the femoral neck, the bone mineral density improved
2.1%
• No difference in the number of spinal fractures
between the the two groups.
• Bisphosphonates effective at preventing and
treating corticosteroid-induced bone loss at the
lumbar spine and femoral neck.
• Not enough evidence to say whether
or not bisphosphonates prevent
fractures.
Calcium and vitamin D for treating steroid
induced osteoporosis
• Cochrane 2010, 5 trials, n= 742
• 2 yrs of Rx, bone mineral density
of the lumbar spine and forearm
improved
• No difference in the number of fractures
or laboratory measures of bone density
between the two groups.
• All patients should have Vit D level at baseline
& replacement if deficient
Rx of Vitamin D deficiency
• European guidelines 250m g/day (10 000 IU)
gave rise to no adverse effects, and recommend
a daily intake of 100m g/day (4000 IU).
• UK Department of Health guidance & the
National Osteoporosis Society- people> 65
years & those not exposed to much sunlight
should take a daily supplement containing 10
11 g (400 IU) of vitamin D
• *Vitamin D Rx can unmask undiagnosed
hyperparathyroidism; recent draft guidelines
recommend checking adjusted serum
calcium 1/12 after starting vitamin D.
• Likely to apply to many neuromuscular patients
Pregnancy & lactation, CSM 1997
• The importance of weighing risks v benefits & concluded:
• Vary in ability to cross the placenta. Prednisolone is mostly
{88%} inactivated as it crosses the placenta
{betamethasone and dexamethasone cross readily)
• Can cause abnormalities in fetal development in animals
but this has not been shown in humans
• Prolonged or repeat Rx increases the risk of intrauterine
growth restriction {IUGR}. Short-term treatment carries
no such risk.
• Prednisolone is excreted in small amounts in breast milk
and is unlikely to cause systemic effects in the infant
unless doses exceed 40 mg daily. Above this dose infants
should be monitored for adrenal suppression. No data are
available on other corticosteroids .
Initiation of Steroids CSM
advice
•
Every patient should be given a steroid card following
concern about severe chickenpox associated with
systemic steroids.
• Adrenal suppression can be
reduced by: Morning dosage.
Alternate day dosing.
Intermittent courses of
treatment. Steroid sparing
agent
STEROID TREATMENT CARD
I am a patient on Steroid treatment which must not be stopped suddenly.
Notes for Patients :
If you have been taking this medicine for more than 3 weeks, the
dose should be reduced gradually when you stop taking steroids
unless your doctor says otherwise.
Read the patient information leaflet given w ith the medicine.
Always carry this card with you and show it to anyone who treats
you . For one year after you stop treatment you must mention that
you have taken steroids.
If you become ill, or if you come in contact with anyone who has an
infectious disease, consult your doctor promptly. If you have never
had chickenpox, you should avoid close contact with people who
have chickenpox or shingles. If you do come into contact with
chickenpox, see your doctor urgently.
Make sure the information on the card is kept up to date.
Monitoring
• Baseline measures : BP, weight, optician, fasting
glucose, triglycerides , K+
• Regular monitoring:
BP, weight , Triglycerides and potassium 1/12, then every 6-12112
Diabetes- 1/12, then every 3/12. Dipstick urine at
each visit Monitor diabetics more closely
Osteoporosis
Growth suppression- record the height of children
and adolescents regularly
Adrenal suppression
*Document the history of VZV & advise about contact
Adverse effects -ask at each clinic visit
PREDICT study
Van schaik et al, Lancet Neurology 2012
• To compare remission rates in patients with CIDP Rx'd with
Pulsed high-dose dexamethasone versus standard
prednisolone in newly diagnosed CIDP
• 8 centres in the Netherlands, 1 in the UK
• Primary outcome: remission at 12/ 12, defined as
improvement of at least 3 points on the Rivermead mobility
index and improvement of at least 1 point on the INCAT
scale.
• n = 40 : 24 DXM V 16 prednisolone.
• At 12/12, 16/40 were in remission: 10/24 in the DXM group
& 6/16 in the prednisolone group (odds ratio [OR] 1.2, 95%
CI 0.3-4.4).
• Most adverse events were minor and did not differ
substantially between treatment groups; however,
sleeplessness and Cushing's face occurred more often in
the prednisolone group.
Withdrawal of Corticosteroids
• Insufficient evidence to support any particular
withdrawal regtmen
• As a general principle:
- Short courses of oral corticosteroids (< 3 weeks)
can be stopped abruptly.
- Gradual withdrawal if: > 40 mg prednisolone
daily or equivalent > 3/52 or repeated courses of
corticosteroids
- Other possible causes of adrenal suppression , excess
ETOH or stress (recent infection, trauma, or surgery)
- A Synacthen Test can be useful to assess potential
iatrogenic adrenal suppression prior to the
withdrawal of oral steroids.
Suggested regime for prednisolone withdrawal.
• Reduce by 2.5 mg every 3--4 days, down to 7.5
mg per day, then reduce more slowly, for
example by 2.5 mg every week, fortnight, or
month.
• If there is uncertainty about disease resolution
and/or therapy has been given for many weeksmonths. Reduce by 2.5 mg every 2-4/52 down
to 7.5 mg per day, then reduce by 1mg every
month.
• If Symptoms of the disease are likely to
recur on withdrawal, reduce by 1
mg/month.
• Aronson, 2006
References/resources
•
Cochrane Database
•
http://www.nice.org.uk/guidance/TA160
•
WHO FRAX tool http://www.shef.ac.uk/NOGG/downloads.html for guidance tables.
•
Osteoporosis - preventing steroid-induced, Prodigy (May 2009)
•
Current Problems In Pharmacovigilance: Focus on Corticosteroids. Volume 24, (Pages 5-10), Medicines and Healthcare products Regulatory
Agency (MHRA) - CSM (May 1998)
•
Osteoporosis - treatment (and prevention of fragility fractures), Clinical Knowledge Summaries (2007)
•
London and South East Medicines Information Service et al, 2008,
•
SIGN guidelines
•
British Thoracic Society, 2008b
•
British National Formulary [BNF 59, 2010].
•
www.immunosuppressionscreen.net.au
•
The recommendation on the withdrawal regimen is based on published expert opinion [Richter et al, 2002], the textbook Meyler's side
effects of drugs: the international encyclopedia of adverse drug reactions and interactions [Aronson, 2006b], and a drug reference database
[Sweetman, 2009].
•
www.patient.co.uk
•
Dobson R et al. Bone Health in chronic neurological diseases: a focus on MS & parkinsonian syndromes. Practical Neurology 2013; 13: 7079.