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 High-dose intravenous ‘pulse’
methylprednisolone in the treatment of
severe oropharyngeal pemphigus: a pilot
study

Michele Davide Mignogna1 Abstract

Lorenzo Lo Muzio2 Background: High-dose intravenous (i.v.) methylprednisolone
Elvira Ruoppo1 has been used therapeutically in severe blistering diseases to
Stefano Fedele1 avoid the complications and side-effects of long-term orally admi-
Lucio Lo Russo1 nistered glucocorticoid therapy. The aim of the study is to evaluate
Eduardo Bucci1 the capacity of methylprednisolone i.v. ‘pulse’ therapy to induce
1
remission in the treatment of severe oropharyngeal pemphigus.
Division of Oral Medicine, Department of
Methods: Twelve patients, all of whom had oropharyngeal severe
Odontostomatological and Maxillo-Facial
Sciences, School of Dentistry, University of pemphigus, were included in the analysis. There were eight
Naples, Federico II, Naples, Italy women and four men whose ages ranged from 22 to 78 years
2
Department of Odontostomatology and (mean age: 50.75 years) with a disease duration of 1–3 months
Surgery, University of Ancona, Italy (mean duration: 55 days). In order to obtain a rapid clinical remi-
ssion of extensive mucosal lesions, we performed ‘pulse’ ther-
apy with intravenous methylprednisolone (30 mg/kg body weight
to a maximum of 1 g per dose on each of 3–5 consecutive days)
evaluating the clinical response and the short-term side-effects.
Results: Our therapy was generally safe and well tolerated with a
very low rate of side-effects. All patients responded to i.v. methyl-
prednisolone with evidence of a decrease in signs and symptoms
within 1 week of commencing treatment and in all cases remis-
sion was observed after the second or the third cycle of ‘pulse’.
The most common adverse events during treatment were flushing
and hyperglycaemia; in a few cases we observed a metallic taste
in the mouth, pruritus, headaches ranging from mild to moderate,
palpitations, mood alterations, insomnia and fatigue.
Conclusions: High-dose ‘pulse’ administration of glucocorticoids
is a potentially effective therapy to be considered in the treatment
of patients with severe oropharyngeal pemphigus. Similar patients
treated with conventional oral administered doses of prednisone or
deflazacort had protracted courses requiring months of glucocorti-
coid therapy with no long-term remissions. However, further well-
designed, long-term comparative trials are required to confirm this.

Correspondance to: Key words: methylprednisolone; oral pemphigus; pulse therapy;

Michele D. Mignogna side-effects
Via Domenico Fontana 81, pal. 10,
80128, Naples, Italy J Oral Pathol Med 2002: 31: 339–44
Tel: þ39 0817 462 498
Fax: þ39 0817 462 197
e-mail: mdmig@tin.it

Systemic corticosteroids remain the mainstay of therapy for

Accepted for publication February 11, 2002
Copyright ß Blackwell Munksgaard 2002
J Oral Pathol Med . ISSN 0904-2512
Printed in Denmark . All rights reserved
pemphigus. Their use has transformed what was almost invari-
ably a fatal illness into one whose mortality is now below 10% (1).
Unfortunately, the high doses and prolonged administration of

339
Mignogna et al.
corticosteroids often result in numerous side-effects, many of
which are serious or even life-threatening. Patients with pemphi-
gus vulgaris are usually treated with high dosage oral adminis-
tration of steroids; occasionally, they may present highly active
widespread forms of the disease and may need prolonged con-
ventional oral steroid therapy with significant side-effects. In
these cases, pulse i.v. administration of steroids may be effective
(2).
Intravenous (i.v.) pulse steroid therapy consists of adminis-
tration of supraphysiological doses of glucocorticoids. It is useful
in conditions where rapid immunosuppression and anti-inflam-
matory effect is desired, as in systemic lupus erythematosus,
pemphigus, renal transplantation, steroid resistant nephrotic
syndrome, crescentic glomerulonephritis and other diseases
(2–8). This therapy may be associated with significant adverse
reactions including hypertension, arhythmias, hypokalaemia,
psychosis and infections and should, therefore, be used in
selected cases and under careful supervision. The drug most
widely used for this treatment is methylprednisolone (9).
In this non-comparative open-label pilot study, our purpose
was to assess the efficacy of i.v. pulse steroid therapy in 12 cases
of severe oropharyngeal pemphigus in order to evaluate the
rapidity of the clinical response, and the short-term side-effects
that are generally strictly connected to the total amount of
steroids needed to induce remission in the induction phase of
the therapy.
Patients and methods
Twelve patients, all of whom had oropharyngeal severe pemphi-
gus, were included in the analysis. All patients had a minimum of
6 months of follow-up. There were eight women and four men
whose ages ranged from 22 to 78 years (mean age: 50.75 years)
with a disease duration of 1–3 months (mean duration: 55 days).
All patients complained of symptoms such as severe oral pain,
dysphagia and odynophagia for the extensive mucosal erosions
(Table 1).
Diagnoses and clinical examination together with the assess-
ment of the extension of the disease were performed as reported
in our previous paper (10). Because of the severity of symptoms
in eight cases we performed i.v. feeding under the control of a
nutritionist. Medicinal intake was monitored for the 3 months
preceding diagnosis: no patient had received any medicines that
could be implicated in the development of pemphigus. In one
340 J Oral Pathol Med 31: 339–44
case, 4 weeks prior to the onset of the lesions, the patient had
received an influenza vaccination (11).
Treatment protocol for the initial/induction phase consisted of
i.v. pulse therapy with methylprednisolone 30 mg/kg body
weight to a maximum of 1 g per dose on each of 3–5 consecutive
days. Early in the morning, the patient received 40 mg of i.v.
omeprazole diluted in 100 ml of polysaline solution. After 2 h, 1 g
of methylprednisolone diluted in 250 ml of polysaline solution was
administered i.v. by an infusion set with bacteria air vent filter and
a dosi-flow to perform a controlled infusion of 4 ml/min. Infusion
was carried out under careful supervision monitoring the blood
pressure and cardiac activity. Blood glucose was monitored five
times a day (before breakfast, 30 min before and 1 h after meals).
This protocol was repeated for 3–5 days and, every day electro-
lytes and diuresis were monitored. Pulse therapy was repeated
after 21 days. Between the cycles we treated the patient with
40 mg of omeprazole and 60 mg of deflazacort daily. After the
second or third cycle, if clinical remission was obtained, the dose
of deflazacort was rapidly reduced in accordance with the
response to the disease. In addition, nine patients received
adjunctive systemic medication which included azathioprine
(100 mg daily) at the beginning of the therapy. Azathioprine
was gradually reduced when the deflazacort dosage was less
than 45 mg every other day without relapse.
Topical agents, including clobetasol 0.05% (Clobesol) oint-
ment mixed 1 : 1 with orabase and methylprednisolone as a mouth
rinse, were utilised in order to complete the clinical control of
signs and symptoms. Patients were monitored for signs of Can-
dida albicans by clinical appearance or culture. Throughout the
course of therapy patients received anti-fungal medication either
topically (Nystatin, Miconazole) or systemically (Fluconazole) as
initial therapy or as secondary prophylaxis. During this period,
calcium and Vitamin D were usually administered as dietary
supplements.
All patients were examined every day until remission and
every 2 weeks for 6 months after remission. After remission,
IIF was repeated periodically.
Results
Table 1 lists the clinical findings in the groups of PV patients at
admission. All patients showed severe involvement of the oro-
pharyngeal mucosa with extensive erosions, ulcerations and
pseudomembranous lesions. In seven cases, the lip involvement
 High-dose intravenous ‘pulse’ methylprednisolone in the treatment of severe oropharyngeal pemphigus

Table 1. Clinical and immunological findings in PV patients

Case Oral sites
no. Age (year) Sex (involvement degree) Other sites involved Symptoms IIF DIF
1 44 F Gengiva (þþþ) Oesophagus Severe 1 : 160 IgG (þþþ)
Tongue (þ)
Buccal mucosa (þ)
Oropharynx (þ)
2 74 F Palate (þ) Skin, vulva, oesophagus, Severe 1 : 320 IgG (þþ)
Oropharynx (þþ) nasal mucosa
Lips (þþ)
Tongue (þþþ)
Buccal mucosa (þþþ)
3 32 M Buccal mucosa (þþþ) Skin, glans, oesophagus, Severe 1 : 160 IgG (þþþ)
Palate (þþ) nasal mucosa C3 (þþ)
Oropharynx (þþ)
4 39 F Gingiva (þþþ) Skin, vulva, nasal mucosa Moderate 1 : 160 IgG (þþ)
Buccal mucosa (þþ)
Tongue (þþþ)
Oropharynx (þþ)
5 22 F Gengiva (þ) Skin, vulva, conjunctiva Moderate 1 : 80 IgG (þ)
Tongue (þþ) C3 (þ)
Buccal mucosa (þþþ)
Palate (þþþ)
Oropharynx (þþþ)
6 58 F Buccal mucosa (þþþ) Skin, vulva, nasal mucosa Severe 1 : 640 IgG (þþþ)
Palate (þþ) C3 (þþ)
Oropharynx (þþ)
Tongue (þþþ)
7 78 F Tongue (þþþ) Skin, vulva, nasal mucosa Severe 1 : 640 IgG (þþþ)
Buccal mucosa (þþþ) C3 (þ)
Lips (þþþ)
Oropharynx (þþ)
8 70 M Tongue (þþþ) Skin, glans, oesophagus, Moderate 1 : 160 IgG (þþ)
Buccal mucosa (þþþ) nasal mucosa
Palate (þ)
Lips (þ)
Oropharynx (þ)
9 67 M Tongue (þþ) Skin, nasal mucosa Moderate 1 : 640 IgG (þþþ)
Buccal mucosa (þþ) C3 (þþ)
Palate (þ)
Lips (þþ)
Oropharynx (þ)
10 43 F Tongue (þþþ) Skin, vulva, nasal mucosa Severe 1 : 40 IgG (þ)
Lips (þþþ) C3 (þ)
Buccal mucosa (þþþ)
11 30 M Tongue (þþþ) Skin, oesophagus, Severe 1 : 160 IgG (þþ)
Lips (þþþ) nasal mucosa
Buccal mucosa (þþþ)
12 52 F Tongue (þþþ) Skin, oesophagus, Severe 1 : 40 IgG (þþ)
Lips (þþþ) nasal mucosa, vulva C3 (þ)
Buccal mucosa (þþþ)

was very severe with blood-stained and crusted lips similar to
features of erythema multiforme.
All patients had extraoral manifestations: 10 had very mild and
one severe skin involvement, one had conjunctival monolateral
involvement, 10 had involvement of nasal mucosa predominantly
in the septal area, six women had vulvar, and one vulvar and
cervical involvement, and two men had glans involvement. Upper
gastrointestinal endoscopy (UGE) revealed oesophageal involve-
ment in six patients (three men and three women) with blisters or
erosions in the upper oesophagus. All patients presented oral
lesions first.
The endpoint of the initial high-dose treatment was considered
to have been reached when the patient was asymptomatic and
clinical signs were under control. Clinical remission was defined
as a state in which approximately 75% of the old lesions were
healed and no new lesions had developed.
Patients were instructed to avoid all proven medicines capable
of inducing or triggering the disease in genetically predisposed

J Oral Pathol Med 31: 339–44 341

Mignogna et al.

individuals, to have special caution in exposure to the sun and
other UV sources, and to eat a balanced diet and avoid foods with
proven acantholytic potential. Generally, we provided them with a
‘warning card’ reporting data on the steroidal and immunosup-
pressive therapy and a list of ‘behavioural suggestions’.
The most common adverse events during treatment were
flushing and hyperglycaemia. In a few cases, we observed a
metallic taste in the mouth, pruritus, headaches ranging from
mild to moderate, palpitations, mood alterations, insomnia and
fatigue (Table 2). In eight cases, we administered insulin (from 12
to 30 IU/day in relation to glycaemia levels). We consistently
observed a moderate increase of white blood cells. We observed
no azathioprine side-effects in our patients. In one case, we
observed a transient hypertransaminasaemia that was probably
due to the i.v. feeding.
Our ‘pulse’ therapy treatment protocol was generally safe and
well tolerated with a very low rate of side-effects. All patients
responded to i.v. methylprednisolone with evidence of a decrease
in signs and symptoms within 1 week of commencing treatment.
In all cases, remission was observed after the second or the third
cycle of ‘pulse’. UGE performed after ‘pulse’ cycles showed in all
patients with oesophageal involvement the disappearance of the
lesions and a healthy gastric mucosa.
In nine cases, we had one or more relapses during reduction or
maintenance-phase therapy: a relapse was defined as the appear-
ance of more than five new lesions within a period of 3 days;
smears, biopsy specimens, DIF and IIF investigations were
always performed after a relapse. These patients were treated
by doubling the steroid dose administered at the time.
Discussion

Oral corticosteroids may be effective in the treatment of severe

Table 2. Short time side-effects of the pulse therapy during the autoimmune diseases but the side-effects limit their use; patients
induction phase
treated with conventional orally administered doses of predni-
Total dosage of
sone, generally had protracted courses requiring months or years
Cycles of steroids at the end
pulse of initial phase to of glucocorticoid therapy with no long-term remissions (12). One
Case therapy Days per induce clinical
of the major disadvantages, in these cases, is the development of
no. (n) cycle remision Side-effects
1 2 3 MP: 6000 mg Headache, hypertricosis,
severe side-effects, e.g. obesity, moon-face, osteoporosis, lens
DZ: 1260 mg flushing, oral candidiasis opacities, and impaired adrenocorticotropic hormone reserve;
2 2 3 MP: 6000 mg Flushing, insomnia, mood potential side-effects of short- and long-term steroid therapy have
DZ: 1260 mg alterations, hyperglycaemia
been extensively reviewed (13–17). In order to decrease side-
3 3 3 MP: 9000 mg Flushing,
DZ: 2520 mg hypertransaminasemia, effects, pulsed administration of high-dose methylprednisolone
insomnia
has been used successfully in different autoimmune diseases: this
4 2 3 MP: 6000 mg Flushing, headache, mood
DZ: 1260 mg alterations, insomnia, oral form of therapy, although potentially dangerous in patients suf-
candidiasis, metallic taste
fering from cardiac or renal disease, has been found to be of low
5 3 3 MP: 9000 mg Headache, candidiasis,
DZ: 2520 mg insomnia, hypopotaxemia, risk in terms of significant adverse events if contraindications are
sialorrhoea, fatigue carefully observed (2, 9, 12). Pulse therapy with megadose
6 3 3 MP: 9000 mg Flushing, insomnia, mood
DZ: 2520 mg alterations,
corticosteroids is currently being used for severe pemphigus
hyperglycaemia, pruritus vulgaris (2, 9, 18) but there are several aspects that are actually
7 2 3 MP: 6000 mg Hypertension, palpitations,
DZ: 1260 mg candidiasis, mood not cleared enough. Firstly, as a single modality, pulse corticos-
alterations, hyperglycaemia, teroids usually seem to result only in a short-term respite from the
headache, fatigue
8 2 3 MP: 6000 mg Hyperglycaemia
disease and most likely require continued administration of oral
DZ: 1260 mg corticosteroids (9); secondly, whether this approach results in an
9 2 3 MP: 6000 mg Hyperglycaemia, insomnia. overall reduction in side-effects or mortality, or increases the
DZ: 1260 mg
10 2 4 MP: 8000 mg Hyperglycaemia, pruritus,
incidence of remissions, is unknown. Furthermore we need a
DZ: 1260 mg fatigue more objective approach to quantify the severity of the disease
11 2 3 MP: 6000 mg Hyperglycaemia, insomnia, before and during the course of therapy. Recent studies have
DZ: 1260 mg biliary stasis
12 2 3 MP: 6000 mg Hyperglycaemia,
outlined protocols to assess oral and systemic lesions in pemphi-
DZ: 1260 mg palpitations, metallic taste gus monitoring the specificity and titre of autoantibodies along
MP, methylprednisolone; DZ, deflazacort. with the clinical features (19, 20). Some of the neurologic and

342 J Oral Pathol Med 31: 339–44

 High-dose intravenous ‘pulse’ methylprednisolone in the treatment of severe oropharyngeal pemphigus
rheumatologic literature related to multiple sclerosis and lupus
nephritis suggests that i.v. methylprednisolone has therapeutic
effects that are different from those of conventional doses of oral
prednisone (2–8, 21, 22). There is still considerable debate about
this in the literature and extrapolation of the role of ‘pulse’ i.v.
methylprednisolone to blistering diseases, where trials are lack-
ing, is difficult. In pemphigus, the largest experience has been
made using i.v. megadoses of dexamethasone or methylpredni-
solone and cyclophosphamide; furthermore, in some patients, the
addition of an oral administered immunosuppressive agent, such
as azathioprine, cyclophosphamide or cyclosporine has been
used to reduce the overall steroid dose. Nevertheless, adjunctive
drugs have side-effects of their own which are additional to those
of corticosteroids with which they are usually given (26, 27).
Myelosuppression, haemorrhagic cystitis, infertility and bladder
cancers have been observed with azathioprine (14, 23) and
cyclophosphamide (18, 24, 26). In conclusion, the use of adjuvant
therapy with immunosuppressive drugs remains unclear, as there
are no objective data to support the purported corticosteroid-
sparing effects.
In view of these data, our pilot study evaluated the role of short-
term, high-dose i.v., methylprednisolone therapy in patients with
extensive oropharyngeal pemphigus. Based on the results of this
study, we conclude that high-dose i.v. glucocorticoid pulse ther-
apy may represent a therapeutic alternative in severe orophar-
yngeal pemphigus to induce remission. Our series demonstrates
that treatment with methylprednisolone ‘pulse’ therapy gives us a
very rapid clinical resolution of mucosal lesions with lower dosages
of steroids, in order to induce remission during the initial phase of
therapy, compared with conventional oral steroids administration.
Long-term follow-up has not been provided to examine the
influence of i.v. methylprednisolone on the clinical course of
disease, its efficacy as monotherapy and the benefit of using it
as maintenance therapy to keep the patient in prolonged clinical
remission. Clearly, long-term controlled studies are required and
it would be useful to compare the effects of i.v. methylpredniso-
lone with conventional oral steroid therapy in oral pemphigus
vulgaris.
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