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JEADV ISSN 1468-3083

1386 © 2007 The Authors JEADV

2007, 21, 1386–1391 Journal compilation © 2007 European Academy of Dermatology and Venereology

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ORIGINAL ARTICLE

An alternate-day corticosteroid regimen for pemphigus vulgaris.A 13-year prospective studyG Ch Chaidemenos,*† O Mourellou,† T Koussidou,† F Tsatsou‡

†

Hospital for Skin and Venereal Diseases, State Department of Dematology and Venereology, Thessaloniki, Greece

‡ Department of Dermatology and Immunology, Dessau Medical Center, Dessau, Germany

Keywords

alternate-day, azathioprine,

immunosuppressants, Lever’s mini treatment,

pemphigus vulgaris, prednisone

*

Corresponding author, tel. +30 231 0 886392;

fax +30 231 0 864800;

E-mail: [email protected]/[email protected]

Received: 27 November 2006,

accepted 7 March 2007

DOI: 10.1111/j.1468-3083.2007.02286.x

Abstract

Background

Pemphigus vulgaris (PV) at the early, usually oral and relatively

stable stage, represents the majority of PV patients. Treatment modalities

usually do not differ compared to those for the fully established disease.

Objectives

To prospectively assess a standardized and effective therapeutic

approach that aims at less morbidity due to adverse reactions.

Methods

The following regimen, also known as Lever’s mini treatment (LMT),was used. Forty mg of oral prednisone on alternate days plus 100 mg azathioprine

every day were administered until the complete healing of all lesions. A gradual

monthly and later bimonthly decrease of prednisone was followed by the

tapering of a second immunosuppressive agent, in a one-year period.

Results

Seventy-four patients suffering from early-stage-PV, and representing

70% of all PV patients seen through the years 1991–2003, were eligible in the

study. Total follow-up period was 76 ± 37 (26–180) months. During the 53 ± 26

months of LMT, 6 (8%) patients dropped out of therapy, 9 (12%) required a

change to another treatment, two (3%) died and 57 (77%) achieved a lesion-

free condition. Forty-five (61%) patients were in complete remission for

27 ± 29 months. Significant morbidity was estimated 4/74 (5.2%). Disease

‘breakthroughs’ necessitating treatment adjustments occurred in 30 patients,usually throughout the last phase of therapy and post-treatment follow-up.

Conclusion

LMT may be a standardized therapeutic approach for the early

and relatively stable stage of PV, resulting in high efficacy, safety and quality of

life profile.

Introduction

Oral mucosa is the initial site of involvement in 50% to

70% of patients with pemphigus vulgaris (PV). Although

months to years may pass before extensive extraoral

lesions appear,

1

only a few authors propose a specific

therapeutic approach for this initial, mild, and relativelystable stage of the disease. Bystryn and Steinman suggest

20 mg of oral daily prednisone for 2 weeks and a rapid

dosage increase in case of no significant improvement.

2

Daily doses of 40 mg

3

or 45 to 60 mg

4

prednisone are pro-

posed in other articles. However, most clinical researchers

administrate the dose of 1 to 3 mg/kg per day,

5,6

which is

the treatment of choice for the fully established disease.

6

Lever and Schaumburg-Lever reported for the first time

in 1977 that the alternate-day 40-mg oral prednisone

regimen combined with 100 mg azathioprine daily was

effective and relatively safe.

7

Thereafter, the effectiveness

of this treatment modality was supported by a few scientific

articles.

8–10

The results of a preliminary survey that was conducted

at our Department during the years 1989 to 1990 (unpub-

lished data) disclosed that 40 mg every other day of pred-nisone monotherapy against oral PV was not adequately

effective. Only one of the five patients, who were treated

this way, experienced a lesion-free state after 6 months

of therapy. Azathioprine was given to one patient after

8 months, and three patients required a switch to high

oral daily prednisone dose in order to achieve disease

remission.

The favourable results of the combined regimen of

alternate-day corticosteroid plus daily azathioprine


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, 1386–1391 Journal compilation © 2007 European Academy of Dermatology and Venereology

that were observed and published at an earlier report

9

prompted us to undertake a prospectively designed study

to include all patients suffering from PV at its initial,

relatively stable stage during the years 1991 to 2003.

Methods and patients

Study population

A total of 74 patients, representing 70% (74 of 105) of all

PV patients admitted at the National Health Primary

through Tertiary-Care Department of Dermatology at

Thessaloniki, Greece during the years 1991 to 2003, were

initially enrolled in this prospective, single-centre, open

study. To be eligible, patients had to be suffering from PV

at its initial, relatively stable stage, usually manifesting

no or only a few skin lesions, along with the oral ones.

The inclusion criteria were as follows: clinical lesions

evocative of the disease; histopathologic presence of

supra-basilar epithelial splitting and acantholysis; IgG

intercellular immunostaining on perilesional tissue; in

case of inability to obtain proper mucosal tissue from

patients with exclusively oral disease, the healthy skin of

torso was examined for in vivo

bound ‘antipemphigus’

antibodies, as suggested in previous report.

11

Patients with

a history of previous everyday corticosteroid therapy were

excluded from the study. The 2-year period of follow-up

was arbitrarily chosen as a minimum time for treatment

evaluation.

Study definitions and end points

‘Early PV’ was the slowly progressing and usually oral

disease, manifesting no or only a few skin lesions, that is

a condition often present at the initial stage of PV. The

primary efficacy end-points were as follows: (i) ‘disease

control’, which was the lesion-free condition underLever’s mini treatment (LMT); (ii) ‘complete remission’

(CR), defined as the ‘lesion-free’ condition under 2.5 mg

prednisone twice weekly, because this dose is considered

a therapy end point at our department;

9

(iii) disease

progression, defined as a flare of many new lesions,

requiring a change in a more aggressive systemic therapy.

Disease progression was expressed either as a ‘relapse’ or

‘deterioration’, respectively, for patients experiencing

an initial control of the disease or not; (iv) disease ‘break-

through,’ defined as slow but steady manifestation of a

few, new, small, oral, and/or skin PV lesions after the

achievement of ‘disease control’; (v) significant morbidity,

expressed as the occurrence of serious treatment-related

adverse reactions that may lead to death, if inadequately

managed; (vi) fatality.

Study design

The treatment regimen, also called LMT, comprised three

consecutive phases (fig. 1). During the initial ‘control’

phase, oral prednisone (40 mg every other day) after

morning breakfast plus azathioprine (100 mg) in two

fig. 1 Treatment algorithm: ISA: immuno-

suppressive agent, namely azathioprine 100 mg

daily or, alternatively, cyclophosphamide 100 mg

daily or mycophenolate mofetil 1.500 mg daily


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divided daily doses were administered until the epithelia-

lization of all lesions. In the subsequent ‘consolidation’

phase, the prednisone dose was progressively decreased

at a rate of 5 mg per month until the level of 15 mg. There-

after, the decrease was slower at a rate of 5 mg every 2

months until the level of 5 mg. During the following

‘maintenance’ phase, the last prednisone dose remained

stable for at least 4 months. Thereafter, the dose dropped

to 2.5 mg per 2nd day for 4 months, 1.25 mg per 2nd day

for another 4 months, and finally 2.5 mg twice weekly,

which was administered indefinitely. Azathioprine was

progressively tapered until 0 in 1-year period. Due to ethical

reasons, the authors felt free to replace azathioprine

with mycophenolate mofetil or cyclophosphamide, or

vice versa, in the presence of the slightest sign(s) of side-effects attributable to these agents.

In case of disease deterioration or relapse, an aggressive

treatment regimen followed: either at least 100 mg

daily prednisone or pulse 10 to 15 mg/kg glycocorticoid

intravenous (i.v.) infusions

12

sometimes combined with

high-dose i.v. IgG.

13,14

Soon after the epithelialization of

all lesions, a 3-week course of intermediate prednisone

doses (i.e. 40–30–25 mg daily) was given to avoid pituitary

axis derangement, and then the LMT regimen was initi-

ated (Table 1).

In case of disease ‘breakthrough’, 40 mg prednisone on

alternate days supported by a 2nd immunosuppressiveagent, different from that administered during the initial

LMT regimen, was again instituted. Soon after the epithe-

lialization of all lesions, a rapid prednisone tapering at

biweekly intervals until the dose at ‘breakthrough’

followed. Thereafter, the guidelines of initial treatment

plan were used.

Patients were hospitalized for the initial diagnostic

work-up. Further follow-up was accomplished on an

outpatient basis.

P

-values were estimated according to chi-squared test

(

χ

2

) for the comparison of two proportions.

Results

Patient demographics

As of December 2005, the results were as follows: 68 of the

74 patients (92%) who were initially enrolled continued

the study because three patients were lost from follow-up,

and therapeutic protocol was violated in another three

cases. Female to male ratio was slightly higher than 2 : 1

(47/21). Patients’ mean age at diagnosis was 55 ± 12.5

years (range, 24–83 years). Women were younger than

men (mean, 54.8 vs. 58.6 years). Disease duration (i.e.duration of disease symptoms before diagnosis) was

3.6 ± 3 months (range, 0.5–18 months). Males asked for

medical advice later than women (4.2 vs. 3.5 months,

P

> 0.05). By definition, oral lesions of PV existed in all

68 (100%) patients. Genital and/or nasal lesions were

detected in 14 (21%) patients. Skin involvement was

present in 33 (49%) patients.

Duration of treatment phases

The total follow-up and treatment period were 76 ± 37

months (range, 26–172 months) and 53 ± 26 months(range, 26–156 months), respectively. The duration of each

treatment phase and post-treatment follow-up are shown

in fig. 1. A second immunosuppressive agent was admin-

istered for 41.5 ± 21.5 months (range, 2–103 months).

Clinical status and efficacy analysis

Nine patients (9 of 68, 13%) did not responded to LMT

and experienced a disease deterioration after 11 days to

Table 1 Demographics and treatment followed for the nine PV patients who were non-responsive to LMT

Gender/age,

years Involvement Duration of LMT Treatment followed

Duration

until CR Outcome

F/76 MM, S 2 mo 100 mg Pr + c, × 20 d, LMT 50 mo In CR for 57 mo

M/40 MM, S 7 mo 5 co of i.v. Pulse Glyc, LMT(c) 56 mo In CR for 51 mo

M/67 MM, S 11 d 5 co of i.v. Pulse Glyc + hdIvIgG, LMT (c) 32 mo In CR for 51 moF/40 MM, S 4 mo 7 co of i.v. Pulse Glyc, LMT(c) 32 mo In CR for 31 mo

F/39 MM 4 mo, 3 mo,

2 mo, 5 mo

5, 4, 3 and 7 co of i.v.

Pulse Glyc + hdIvIgG, LMT (m)

Occasional lesions at evaluation.

Follow-up: 69 mo

F/68 MM 2 mo 100 mg Pr × 20 d, LMT 39 mo In CR for 64 mo

F/54 MM 8 mo 80 mg Pr × 3 mo, LMT 101 mo In CR for 35 mo

F/46 MM, S 19 d 5 co of i.v. Pulse Glyc, LMT 30 mo In CR for 36 mo

M/66 MM, S 5 mo 100 mg Pr × 25 d, LMT (m) 34 mo In CR for 49 mo

Abbreviations : c, cyclophosphamide; CR, CR that is lesion-free under 2.5 mg prednisone twice weekly; d, days; F, female; Glyc, glycocorticoids;

m, mycophenolate mofetil; M, male; MM, mucous membrane; mo, months; Pr, prednisone, S, skin.


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8 months (110 ± 80 days) of therapy, requiring a change

to a more aggressive regimen (Table 1). The remaining 59

of the 68 (87%) patients, who continued the study,

achieved initially a ‘lesion-free’ condition. Their clinical

status at last evaluation is shown in Table 2.

Thirty (30 of 68, 44%) patients suffered 39 bouts of

‘disease-breakthrough’, half of them occurring during

‘maintenance’ phase and one fifth during the ‘consolidation’

phase. Nine patients (30%) suffered 11 ‘breakthroughs’while on post-treatment follow-up period for 20 ± 23

months (range, 4–82 months). Overall, only 24 (24 of 68,

35%) patients were able to achieve CR without ‘break-

throughs’. No difference in the initial presence or not of

skin lesions or the time required to induce a disease remis-

sion was noted between patients suffering or not of PV

breakthroughs. Eight of the 12 (67%) patients requiring

therapy at last evaluation were suffering at that time from

a disease ‘breakthrough’.

Because the results of any therapy for PV is also a

function of time, the number of patients in CR among all

59 subjects who continued on LMT was evaluated through-

out the 15 years of study period (fig. 2). The highest

percentage in CR, approaching 100% of patients under

follow-up on LMT, was noted from the 9th to 15th year of

the study period.

Safety

There were 2 (2 of 68, 3%) fatalities. An 80-year-old

patient died 3 years after treatment induction due to

disseminated colorectal cancer. Although the latter may be a

consequence of chronic steroid therapy, this probability

seems unexpected according to our previous experience

of steroid use. The patient had suffered a disease ‘break-

through’ during the ‘consolidation’ phase and finally

stopped all therapy 3 months before her death. A 71-year-

old man suffering from concomitant myelodysplastic

syndrome entered the ‘maintenance’ phase of LMT, but

repeated disease ‘breakthroughs’ disappointed him andled to abstention from regular treatment guidelines and

death of unknown reason 26 months following start of

therapy.

In all, four patients had a history of internal cancer

(lung, breast, colon, and breast). One died, one was

lesion-free under therapy, and two were in CR at the time

of last evaluation. No serious morbidity due to LMT was

observed in the seven patients who suffered from pre-

existing insulin-dependent diabetes mellitus. A tuberculosis

Table 2 Clinical status of patients (at last evaluation)

Patients lost from follow-up or abandoned therapy 6 (8%)

Patients with a disease progression

Deterioration 9 (12%)

Relapse 0

Fatalities 2 (3%)

Patients in a ‘lesion-free’ condition, under therapy 12 (16 %)

Patients in CR 45 (61 %)

Total number of patients 74 (100%)

fig. 2 Response to therapy as a function of time.


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reactivation was observed in another 71-year-old man

who was appropriately treated and achieved CR of the dis-

ease. Although longer treatment periods under azathio-

prine were not related to significant side-effects,

15

one of

our patients suffered from uneventful toxic hepatitis

because of this agent. The concomitant administration of

allopurinol and azathioprine

16

and the use of cyclophos-phamide were incriminated for the bone marrow depres-

sion that was observed in two patients who were

successfully managed with growth haemopoietic factor.

Overall, serious morbidity was estimated as 4 of 68 (6%)

patients. Minor disturbances of white blood cell counts or

hepatic enzyme values were the reason of substituting

azathioprine by cyclophosphamide in one case or myco-

phenolate mofetil in three cases.

Discussion

Oral corticosteroids have dramatically reduced mortality

from PV, once considered as almost invariably fatal.

7

Their

side-effects, however, continue to be the main cause of

significant morbidity and mortality, the latter still reaching

5% to 10%

14

of patients. Patients with exclusively oral PV

may also suffer from significant morbidity and mortality

because of the adverse effects of high and prolonged

corticosteroid therapy.

9

The resistance of mucosal lesions,

even to high doses of steroids, has been reported in several

occasions.

1,10

On the other hand, everyday prednisone

doses of 40 mg is neither harmless nor effective.

8

In a large

retrospective study, half of these patients were not con-

trolled and required high prednisone doses.

3

In another

British report, frequent disease relapses necessitatingcontinuous therapy were observed in 75% (21 of 28) of

patients, and a mortality rate of 7% (2 of 28) was recorded.

1

The alternate-day administration of corticosteroids

seems to provide a better safety profile in comparison with

its everyday use.

17

Infections, which are considered as the

main cause of death in PV,

1,4

are uncommon. Blood

pressure is not significantly deranged, and the likelihood

of mental irritability is low, provided that prednisone

doses do not exceed 20 mg daily. The risk of subcapsular

cataract is diminished, but the benefit of preventing

osteoporosis seems to be questionable.

17

The combination of alternate-day 40-mg prednisonedose with a second immunosuppressant agent, also known

as LMT,

10

seems to provide effective control of the disease.

Since its first description,

7

only 5 of 29 (17%) patients in

Lever’s reports

7,8

and 1 of 15 (7%) cases in our previous

article

9

did not respond and required other treatment

modalities. The percentage in the present study was 13%

(9 of 68), or 12% (9 of 74) on ‘intention-to-treat’ basis.

Overall, LMT was effective in conferring a ‘lesion-free’

condition in 76% (10 of 13),

8

93% (14 of 15),

9

and 82%

(18 of 22)

10

of patients. Our result of 77% (57 of 74) is

similar to that of Lever;

8

both of them estimated on an

‘intention-to-treat’ basis. The time required for the

epithelialization of the lesions was 7 ± 4.5 months, a little

longer than the mean 4.3 months of the study of Benois

et al

.

10

This may reflect more recalcitrant cases among our

patients.Conventionally, the term CR is used to describe patients

in remission and off all treatment. However, the goal of PV

therapy at our Department was and continues to be the

remission under the administration of 2.5 mg prednisone

twice weekly. In a recent article expressing the opinions of

experts, complete discontinuation of therapy was the goal

for only 37% of physicians, whereas others were satisfied

with doses from 2.5 to 10 mg prednisone daily.

6

The percentages of patients who achieved CR after

LMT were 54% (7 of 13),

8

55% (12 of 22),

10

and 61% (45

of 74) in the present study. These results outweigh the

benefits of conventional treatment of oral PV, where 76%

of patients suffer recalcitrant disease.

1

It is interesting to

mention that only one patient of the present study was in

CR after 2 years of LMT. One third of patients were in CR

after 3.5 to 4 years of therapy, and almost all of those

attended from the 9th to 15th year of the study. The 8.1%

(6 of 74) rate of drop-outs was not significant compared

with the value of 58% in other studies.

18

In accordance to previous series of patients,

8

the treat-

ment had no additive negative effect on the course of

the nine patients who did not responded and required

an aggressive regimen (Table 1). The relative absence

of hirsutism, buffalo hump, weight gain, and moon face

among our patients may be attributed to the every-other-day use of steroid.

17,19

In order to increase benefit to risk

ratio, expert authors prefer to change to every-second-

day administration from the level of 40 mg prednisolone

per day,

20

or to follow a rapid initial reduction, by 5 to

10 mg weekly, and more slowly below 20 mg pred-

nisolone per day.

21

The occurrence of disease breakthroughs, even 7 years

after CR, was also noted in other studies

8

and may suggest

that PV rests in a ‘dormant’ state until a stimulus, mostly

a stressful event,

22

reactivates the disease. No valid

explanation could be given for the relatively high number

of disease ‘breakthroughs’ seen among our patients (30 of68, 44%). The question on the responsibility of different

environmental factors for the disease initiation or exac-

erbation has been raised recently.

23

We were unable to

detect any significant difference in medication received

for blood pressure, such as angiotensin-converting

enzyme inhibitors, or for diabetes, such as sulphonylureas,

or antibiotics, such as rifampin, ampicillin, and cefadroxil,

between the group of patients who manifested a pem-

phigus breakthrough and those who did not. The only factor


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that was recalled by a few of our patients as probably

responsible for disease breakthrough was a highly stressful

event. No data were collected, however, regarding beha-

vioural, like smoking, or qualitative food frequency details.

In any case, a high relapse rate of 66% has been recorded

in PV patients who were followed-up for a long time.

15

In concluding, LMT seems to fulfill the need forimproved standardization of PV therapy. It is effective in

the management of the majority of patients with PV, at its

early, relatively stable stage. LMT is relatively safe, with

overall mortality 3% (2 of 74) and morbidity 5% (4 of 74);

it is effective achieving disease control in 57 of 74 (77%)

patients; requires no hospital admissions; and offers the

patients a high quality of life. Thus, LMT may be consid-

ered a valuable treatment regimen for patients suffering

from PV at its initial, relatively stable stage.

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