Guideline topic: Pharmacological management of asthma
Evidence table 4.13a: Immunosuppresive agents

Author

Adults

Alexander¹

1992

Double-blind, placebo-controlled
Cross-over 12 weeks treatment Oral CsA

+

33 adult patients aged 18-65 yrs. Oral steroids 5-20 mg (mean 8.5mg/day) and high dose inhaled corticosteroids. Mean FEV1 1.7L (60% pred.) 20% reversibility to b 2-agonist

1] am and pm PEFR
2] frequency of exacerbations

3] FEV1/FCV
4] Adverse effects

10-12% increase
48% reduction


17% increase FEC1

5.7% reduction GFR

p< 0.005

p < = 0.023


p< 0.001

p< 0.02

CsA caused a progressive increase in PEFR/ FEV1 over 12 weeks which had not plateaued and persisted for at least 11 weeks following drug withdrawal. Placebo group received more oral steroids for treatment of more frequent exacerbations of asthma.

Slight increase in BP, urea and creatinine with a reversible decrease in GFR seen in CsA group.

Bernstein²

1996

Double-blind placebo-controlled, parallel group 28 weeks treatment 12 week steroid reduction phase Oral gold

+

279 adult patients age 50 yrs 133 females and 146 males. Oral steroids >=10mg after 3 months pre-trial dose reduction. Mean FEV1 63.5% pred. 15% reversibility to b 2-agonist

1] % of patients achieving 50% reduction in steroid dose
2] FEV1/PEFR/ symptom scores/b2-agonist use
4] Adverse events

56% of patients on gold vs 32% of patients on placebo

nil
nil

Twice as many GI and dermatological adverse event on gold

p< 0.001

ns

p< 0.001

p=0.015

Large study show that 50% reduction in steroid dose was achieved in higher proportion of patients on gold than placebo, without a deterioration in lung function or asthma control. But gold was associated with a higher incidence of gastrointestinal and dermatological side effects.

The primary end-point(50% reduction in oral steroid dose) was poorly chosen and no measure of the actual total steroid reduction achieved was provided. 32ˆ % of patients in the placebo arm asspcoated with as deterioration in asthma control.

Kishiyama³

1999

Double-blind, placebo-controlled 7 months of monthly high or low doxe IVIG vs albumin

+

40 patients aged 7-66 yrs (mean age 40 yrs). Oral steroids 2.5 to 80 mg/day (mean 16.7 mg/day). Mean FEV1 2.21, ATS defined asthma.

1] reduction in oral steroid dose
2] FEV1/PEFR/ Symptom scores/days off school/work
3] Headaches

Nil


Nil





3 patients had asceptic meningitis on IVIG and other patients had severe headach

Ns


Ns





P-0.02

IVIG treatment provided no benefit in steroid requirement, lung function or exacerbation rate. However, IVIG was associated with an increase frequency of severe headache requiring opiate analgesia and a high rate of aseptic meningitis.

Lock⁴

1996

Double-blind, placebo-controlled, parallel group 36 233ks treatment Oral CsA

++

39 adult patients aged 26-67 yrs with asthma duration 2-56 yrs Oral steroids > 5mg/day (mean 12 mg/day] for > 1 yr Mean FEV1 < 65% pred. 20% reversibility to b 2-agonist

1] reduction in oral steroid dose on CsA
2] Mean PEFR am
3] FEV1
4] Symptom scores
5] Adverse effects

25% greater in CsA than placebo

10% increase PEFR

Nil
Nil

More mild adverse effects 10% reduction GFR compared to baseline

P=0.043



P=0.026

Ns
Ns
P=0.0013


P=0.04

For patients on long-term oral steroids CsA provided a steroid sparing effect during treatment, without deterioration in lung function or increase in exacerbation frequency, that did not persist once CsA withdrawn.

Minor infections, hypertrichosis, parasthesia and increase in BP all more common on CsA but well tolerated.

Deterioration in GFR seen on CsA treatment persistent at 4 weeks post treatment withdrawal.

Nierop⁵

1992

Double-blind placebo-controlled cross-over 26 weeks treatment Oral gold

+

32 adult patients aged 28-72 yrs Oral steroids > 2.5 mg (mean 7.9 mg/day) and 800 mg inhaled corticosteroids Mean FEV1 60% pred. 15% reversibility to b 2-agonist

1] reduction in daily oral steroid dose
2] reduction in high dose steroid courses
3] FEV1/PEFR
4] Adverse effects

4mg/day vs 0.3 mg/day on placebo

0.9 exac. On gold vs 2.1 axac on placebo

6% increase FEV1
2 severe & 2 mild eczema, 3 nausea

P= 0.056

P=0.02

p< 0.001

Treatment with gold reduced daily oral steroid requirement by almost half ( 5mg/day), associated with an increase in FEV1 of 6% and a reduction in asthma exacerbations. However, study flawed by the persistent reduction in steroid dose despite frequent exacerbations requiring high dose steroid courses. Small patient number.

Nizankowska⁶

1995

Double-blind, placebo-controlled, parallel group 34 weeks treatment (2 phases: 12 weeks efficacy and 22 weeks steroid reduction) Oral CsA

++

32 adult patients aged 25-57 yrs 27 females and 7 males
Oral steroids 5-345mg (mean 16 mg/day) after attempt at reduction
Mean FEV1 2.1L (64% pred.) 15% reversibility to b 2-agonist

1] PERF/FEV1/ FVC
2] b 2-agonist use
3] reduction in oral steroid dose
4]Symptom score
5] Adverse events

Nil

-0.7 puffs/day
-0.6 puffs/night

Nil

Nil

Approx 25% of patients had nausea, diarrhoea, paraesthesi ae and hypertrichosis.

Ns

-1.2 to –0.1
-0.8 to –0.5
ns
ns

During efficacy phase there was no benefit in lung function on CsA although there was an improvement in b 2-agonist use. CsA treatment allowed a reduction in oral steroid dosage which was not significantly greater than placebo. High number of aspirin sensitive asthmatics recruited due to center interest in aspirin sensitive asthma.

All adverse effects resolved following CsA withdrawal.