364

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January 31, 2002

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The New Engl and Jour nal of Medi ci ne

a mean blood urea nitrogen level of 60 mg per dec-
iliter (21.4 mmol per liter). What would the outcome
have been if the delivered dose of dialysis had equaled
or exceeded the prescribed dose in each group? Thus,
undertreatment in the alternate-day group may have
been a more important factor in the outcome than
the frequency of the dialysis sessions. Perhaps a more
intensive regimen in the alternate-day group would
have reduced or eliminated the reported differences
between the two study groups.
If daily hemodialysis is better than alternate-day
hemodialysis, why is this so? One possible explanation
is that daily hemodialysis is associated with less dra-
matic changes in plasma components, a reduced need
for fluid removal, and hence less severe hemodynam-
ic instability. With less severe hemodynamic instabil-
ity, ischemia is less likely to recur at a time when the
normal autoregulatory safeguards against hypoten-
sion are impaired. As a result, there is a lower inci-
dence of progression to oliguria, as Schiffl et al. re-
ported, and recovery is more rapid. In addition, daily
exposure to the dialysis membrane may result in more
efficient filtration or the adsorption of blood com-
ponents that contribute to adverse systemic respons-
es, such as cytokines, although whether the removal of
inflammatory cytokines in this fashion can have sub-
stantial functional effects on systemic or local tissue
levels remains controversial.

7

Ronco and colleagues

4

have reported that contin-
uous venovenous hemofiltration at a dose that is high-
er than the standard dose, with higher ultrafiltration
volumes, increases survival among patients with acute
renal failure. Is this aggressive continuous approach
more effective than daily intermittent hemodialysis?
A number of other questions remain to be an-
swered. Which patients are likely to have a better out-
come with a continuous regimen, and which will be
better served by intermittent daily hemodialysis? When
should hemodialysis be initiated? What is the opti-
mal dose? Does an alternate-day regimen with an in-
creased dose of dialysis have results that are similar
to those of the daily regimen? The results of the study
by Schiffl and colleagues challenge physicians to con-
sider daily hemodialysis in patients with acute renal
failure and provide hope that better dialytic approach-
es may have a positive effect on the outcome in such
patients. The optimal treatment of critically ill pa-
tients with acute renal failure remains to be deter-
mined.

J

OSEPH

V. B

ONVENTRE

, M.D., P

H

.D.

Massachusetts General Hospital
Charlestown, MA 02129

REFERENCES

1.

Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J
Med 1996;334:1448-60.

2.

Liano F, Junco E, Pascual J, Madero R, Verde E. The spectrum of acute
renal failure in the intensive care unit compared with that seen in other set-
tings. Kidney Int Suppl 1998;66:S16-S24.

3.

Schiffl H, Lang SM, Fischer R. Daily hemodialysis and the outcome of
acute renal failure. N Engl J Med 2002;346:305-10.

4.

Ronco C, Bellomo R, Homel P, et al. Effects of different doses in con-
tinuous veno-venous haemofiltration on outcomes of acute renal failure:
a prospective randomised trial. Lancet 2000;356:26-30.

5.

Chertow GM. Wishing dont make it so why we need a random-
ized clinical trial of high-intensity hemodialysis. J Am Soc Nephrol 2001;
12:2850-3.

6.

Modi GK, Pereira BJ, Jaber BL. Hemodialysis in acute renal failure:
does the membrane matter? Semin Dial 2001;14:318-21.

7.

De Vriese AS, Colardyn FA, Philippe JJ, Vanholder RC, De Sutter JH,
Lameire NH. Cytokine removal during continuous hemofiltration in septic
patients. J Am Soc Nephrol 1999;10:846-53.
Copyright 2002 Massachusetts Medical Society.

B

ULLOUS

P

EMPHIGOID

T

HERAPY


T

HINK

G

LOBALLY

, A

CT

L

OCALLY

NTIL now, systemic immunosuppressive agents,
particularly oral corticosteroids, have been the
standard treatment for bullous pemphigoid, which
accounts for about 75 percent of cases of autoim-
mune blistering skin disease.

1-3

Nearly two thirds of
cases occur in persons 80 years of age or older.

2,3

In
France, whose population is one fifth that of the
United States, about 500 new cases of bullous pem-
phigoid occur each year.

2,3

Bullous pemphigoid can usually be distinguished
from other blistering skin diseases on the basis of at
least three of four criteria: the absence of atrophic
scars, the absence of mucosal involvement, the ab-
sence of involvement of the head and neck, and an
age of more than 70 years.

4

Bullous pemphigoid is
clinically and immunologically distinct from the pem-
phigus group of autoimmune intraepidermal diseases
whose symptoms are usually erosions of the skin and
mucous membranes rather than intact subepidermal
blisters.

5

The clinical and immunologic features of
bullous pemphigoid and other less common autoim-
mune blistering skin diseases (herpes gestationis, linear
IgA dermatosis, cicatricial pemphigoid, epidermolysis
bullosa acquisita, bullous systemic lupus erythemato-
sus, and chronis bullous disease of childhood) are
summarized in Table 1 and Figure 1.
Although clinical findings often lead to a correct
diagnosis, positive histopathological studies partic-
ularly direct immunofluorescence studies of perilesion-
al skin demonstrating deposition of complement (C3)
and immunoglobulins (IgG) in a linear pattern at the
epidermal basement membrane represent the usual
diagnostic standard.

6

Titers of circulating antibodies
are diagnostically helpful but do not correlate well
with disease activity; a therapeutic response occurs
more rapidly than any change in antibody titers.
U
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EDI TORI ALS

N Engl J Med, Vol. 346, No. 5

January 31, 2002

www.nejm.org

365

Loss of B-cell tolerance to bullous pemphigoid
antigen 2, a 180-kD transmembrane molecule and a
constituent of the hemidesmosome-anchoring fila-
ment complex, is probably the vital first step that in-
duces an autoimmune response (Fig. 1).

7

The binding
of the autoantibody to the antigen on the keratino-
cyte surface activates the classic complement pathway.
These events stimulate mast-cell degranulation and
induce keratinocytes to produce and secrete multiple
inflammatory cytokines.

8

The cytokines promote the
occurrence of a polymorphic infiltrate in the upper
dermis that includes many eosinophils. This infiltrate
releases enzymes that are most likely responsible for
cleavage at the dermalepidermal junction.
The much higher incidence of bullous pemphigoid
in the elderly distinguishes it from most other auto-
immune diseases. A number of immunologic mech-
anisms, such as loss of tolerance and autoreactivity
to additional antigens as a result of epitope spread-
ing, may account for the development of autoimmu-
nity so late in life. The importance of local factors in
the formation of blisters together with the high risk
associated with systemic immunosuppressive therapy
in the elderly argues for the use of local rather than
systemic therapy. High-potency topical corticoster-
oids have been used successfully for bullous pem-
phigoid that involves limited areas of the body. Top-
ical corticosteroids are particularly effective in
reducing cutaneous inflammation. Even when used
extensively, such local therapy is probably safer than
high-dose systemic corticosteroids.
Mortality rates are significantly higher among pa-
tients with bullous pemphigoid than among similar
persons without bullous pemphigoid,

9

but the clinical
course of the disease is highly variable. Although ul-
traviolet light may precipitate bullous pemphigoid,
other precipitating factors or strongly associated dis-
eases have not been determined. Spontaneous remis-
sions are infrequent, although remissions after ther-
apy do occur. Oral corticosteroid treatment, which
has been the standard treatment for widespread dis-
ease until now, is responsible for much of the excess
mortality and morbidity among patients with bullous
pemphigoid. The variable course of the disease makes
uncontrolled trials particularly unreliable in determin-
ing the efficacy of treatment. Previously, Guillaume
and colleagues demonstrated that a well-controlled
and reasonably powered study of bullous pemphig-
oid therapy was feasible.

10

Although their trial dem-
onstrated that neither azathioprine nor plasmapheresis
adds substantially to the effects of oral corticoster-
oids, the publication of its results has not greatly
changed either the recommendations of experts or
clinical practice.

10

On the basis of clinical experience

*BPAG1 denotes bullous pemphigoid antigen 1, and BPAG2 bullous pemphigoid antigen 2.
LAD-1 is a 97-kD protein located in the lamina lucida, but it is uncertain whether it is a distinct antigen or is part
of the extracellular portion of BPAG2.

T

ABLE

1.

C

LINICAL

F

EATURES



AND

A

NTIGENIC

T

ARGETS



OF AUTOIMMUNE BLISTERING SKIN DISEASES.*
BULLOUS DISEASE
PERCENTAGE
OF CASES
CHARACTERISTICS
OF PATIENTS CLINICAL FEATURES
PRINCIPAL TARGET
ANTIGENS
Bullous pemphigoid 74 Elderly (>60 yr old) Tense blisters, pruritic, involvement of
trunk and proximal extremities, in-
volvement of mucous membranes
(20%), absence of scarring
BPAG1, BPAG2
Cicatricial pemphigoid 12 Elderly (>60 yr old),
twice as common
in women
Involvement of mucous membranes
(especially oral cavity or conjuncti-
va) (95%), limited skin involvement,
scarring
BPAG2, integrin
b
4
, laminin-5
or 6, type VII
collagen
Herpes gestationis 4 Pregnant or post
partum
Papulovesicular, pruritic, involvement
of abdomen, self-limited
BPAG2
Linear IgA dermatosis 5 Adult Heterogeneous, pruritic, involvement
of extensor surface, involvement of
mucous membranes (70%)
BPAG2, type VII
collagen,
LAD-1
Chronic bullous dis-
ease of childhood
? Child (<5 yr old) Tense blisters, cluster of jewels ap-
pearance, perineal and perioral, in-
volvement of mucous membranes
(70%)
BPAG2, type VII
collagen,
LAD-1
Epidermolysis bullosa
acquisita
3 Adult, associated with
inflammatory bowel
disease
Tense blisters, noninflammatory, skin
fragility, acral distribution, scarring,
milia
Type VII collagen
Bullous systemic lupus
erythematosus
2 History of systemic lu-
pus erythematosus
Resembles epidermolysis bullosa
acquisita, systemic lupus erythema-
tosus
Type VII collagen
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366 N Engl J Med, Vol. 346, No. 5 January 31, 2002 www.nejm.org
The New Engl and Jour nal of Medi ci ne
alone, new systemic therapies, including very costly
ones such as intravenous immune globulin, continue
to be advocated.
11
In this issue of the Journal, Joly et al.
1
report that
large quantities of high-potency topical corticosteroids
(40 g per day initially) applied to the entire body sur-
face were safer and more effective in controlling exten-
sive bullous pemphigoid than oral corticosteroids.
Patients with extensive disease who were treated top-
ically had shorter hospitalizations, with more rapid
control of disease, fewer severe complications, and
lower mortality rates, than those who were treated
systemically with prednisone in a dose of 1 mg per
kilogram of body weight per day. The incidence of
severe adverse events that were probably related to
corticosteroid use was dramatically reduced. Among
those with less severe bullous pemphigoid, mortality
was similar regardless of whether they were treated
with oral corticosteroids (at a lower dose of 0.5 mg
per kilogram per day) or the same topical regimen
Figure 1. The Key Anchoring Elements at the DermalEpidermal Junction Associated with Autoimmune Blistering Diseases.
The dermalepidermal junction has three major components: the basal keratinocyte, which includes the hemidesmosome-anchor-
ing filament complex, the basement membrane, and the anchoring fibrils in the extracellular matrix of the papillary dermis. The
hemidesmosomal plaque is the intracellular component of the hemidesmosome-anchoring filament complex. The components of
the hemidesmosomal plaque include bullous pemphigoid antigen 1 (BPAG1), an intracellular member of the plectin family that links
the hemidesmosomal plaque to the keratin filaments of the cytoskeleton of the basal cell and the intraepidermal components of the
transmembrane proteins bullous pemphigoid antigen 2 (BPAG2) and a
6
b
4
integrin. The anchoring filaments are the extracellular
component of the hemidesmosome-anchoring filament complex. This complex includes the extracellular domain of BPAG2, a
6
b
4
integrin, laminin-5, and LAD-1 (a 97-kD protein located in the lamina lucida), which attach the epithelial cells to the underlying base-
ment membrane. The anchoring filaments together with the anchoring fibrils (type VII collagen) form adhesion complexes that link
the intracellular cytoskeleton to the anchoring plaques in the papillary dermis. When autoantibodies against one of the key con-
stituents of the dermalepidermal junction trigger an autoimmune reaction, loss of adhesion, skin fragility, and subepidermal blis-
ters result. In patients with bullous pemphigoid and herpes gestationis, an immunologically identical disease of pregnancy, the
antibodies recognize one of four major epitopes clustered within the noncollagenous region of BPAG2, just outside the basal-cell
membrane, termed NC16A. Antibodies directed against BPAG1 are often present in bullous pemphigoid. In patients with cicatricial
pemphigoid, the C terminal of the collagenous portion of the BPAG2 molecule, located in the lamina densa, is usually targeted. The
deeper location of the epitope in cicatricial pemphigoid is responsible for the more extensive scarring that occurs with this disorder
than with bullous pemphigoid. These disorders illustrate that antibodies against different epitopes of a single protein structure can
be associated with clinically different bullous diseases depending on the specific pemphigoid antigenic target. (Figure courtesy of
Dr. Tamar Nijsten.)
Cytoskeleton oskele oskele ooo eee
Hemidesmosomal plaque
Laminin
Plasma
membrane
Lamina lucida
Lamina densa
Extracellular
matrix
Type VII
collagen
6
b
4
integrin
LAD
NH
2
BPA
COOH
ermis
Basement B
membrane
p Epidermis
Basal sa aaasa sa sa
nocyte nn keratin nnnnnnnnnnnnnn
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EDI TORI ALS
N Engl J Med, Vol. 346, No. 5 January 31, 2002 www.nejm.org 367
those with more extensive disease received, but total
days of hospitalization and the number of severe ad-
verse events typically associated with corticosteroids
were lower in topically treated patients. However,
adverse events and death were more frequent than
would be expected in a comparable group of persons
without bullous pemphigoid, suggesting that the
elderly tolerate poorly even moderate doses of oral
corticosteroids as well as the large quantities of high-
potency topical corticosteroids used in this study.
Although they are not without risk, topical corti-
costeroids should now be the treatment of choice for
bullous pemphigoid. Particularly when the disease is
not extensive, smaller quantities of high-potency top-
ical corticosteroids than were used in this study might
control bullous pemphigoid and reduce treatment-
related morbidity.
A well-controlled clinical trial of bullous pemphi-
goid therapy is feasible.
1,10
Before other expensive,
complex, or potentially toxic treatments are adopted,
each should undergo a similarly robust evaluation.
Will this less expensive and safer approach to treat-
ment be widely adopted here in the United States?
Perhaps not. Our health care and social systems are
not supportive of therapies that require extensive
topical treatment. In Europe, inpatient care of skin
disease is still widely available. In the United States,
few hospitals provide specialized inpatient care for skin
disease. In this country, many patients with bullous
pemphigoid are not hospitalized, and those who are
hospitalized remain in the hospital less than half as
long as similar patients in France. In the United States,
access to and payment for long-term intensive nurs-
ing for skin diseases are limited. Medicare reimburse-
ment for the evaluation and management of complex
and chronic diseases is low. Without intensive nurs-
ing or family support, many elderly and frail patients
may be unable to adhere to a regimen that requires
topical therapy. Elderly patients, in whom bullous
pemphigoid is most likely to develop and who are
most likely to benefit from topical therapy, probably
lack the political and economic power to prompt
this logistically difficult change in medical practice.
In contrast to the situation in France, where this
study was conducted, the economics of clinical re-
search and medical care in the United States also
makes such clinical innovation difficult here. Since the
results of studies of this type are unlikely to provide
an economic benefit to the health care industry, it is
difficult to obtain funding for them. Pharmaceutical
companies lack incentives to compare two generic
drugs, and there are no obvious sources of support
for complex, multicenter studies that critically assess
old therapies for old persons. Joly et al. have pro-
vided important information that can improve the
outcome in elderly patients with bullous pemphig-
oid. The combined efforts of patients, their families,
and health care providers are needed to translate
these findings into routine clinical practice.
12

ROBERT S. STERN, M.D.
Beth Israel Deaconess Medical Center
Boston, MA 02215
REFERENCES
1. Joly P, Roujeau JC, Benichou J, et al. A comparison of oral and topical
corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002;
346:321-7.
2. Bernard P, Vaillant L, Labeille B, et al. Incidence and distribution of
subepidermal autoimmune bullous skin diseases in three French regions.
Arch Dermatol 1995;131:48-52.
3. Jung M, Kippes W, Messer G, Zillikens D, Rzany B. Increased risk of
bullous pemphigoid in male and very old patients: a population-based
study on incidence. J Am Acad Dermatol 1999;41:266-8.
4. Vaillant L, Bernard P, Joly P, et al. Evaluation of clinical criteria for di-
agnosis of bullous pemphigoid. Arch Dermatol 1998;134:1075-80.
5. Stanley JR. Pemphigus. In: Freedberg IM, Eisen AZ, Wolff K, et al.,
eds. Fitzpatricks dermatology in general medicine. 5th ed. Vol. 1. New
York: McGraw-Hill, 1999:654-66.
6. Jordon RE, Beutner EH, Witebsky E, Blumental G, Hale WL, Lever
WF. Basement zone antibodies in bullous pemphigoid. JAMA 1967;200:
751-8.
7. Xu L, Robinson N, Miller SD, Chan LS. Characterization of BALB/c
mice B lymphocyte autoimmune responses to skin basement membrane
component type XVII collagen, the target antigen of autoimmune skin dis-
ease bullous pemphigoid. Immunol Lett 2001;77:105-11.
8. Chen R, Ning G, Zhao M-L, et al. Mast cells play a key role in neutro-
phil recruitment in experimental bullous pemphigoid. J Clin Invest 2001;
108:1151-8.
9. Roujeau J-C, Lok C, Bastuji-Garin S, Mhalla S, Enginger V, Bernard P.
High risk of death in elderly patients with extensive bullous pemphigoid.
Arch Dermatol 1998;134:465-9.
10. Guillaume J-C, Vaillant L, Bernard P, et al. Controlled trial of azathi-
oprine and plasma exchange in addition to prednisolone in the treatment
of bullous pemphigoid. Arch Dermatol 1993;129:49-53.
11. Ahmed AR. Intravenous immunoglobulin therapy for patients with
bullous pemphigoid unresponsive to conventional immunosuppressive
treatment. J Am Acad Dermatol 2001;45:825-35.
12. Grol R. Improving the quality of medical care: building bridges
among professional pride, payer profit, and patient satisfaction. JAMA
2001;286:2578-85.
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