Drugs Aging 2010; 27 (1): 1-19

REVIEW ARTICLE 1170-229X/10/0001-0001/$49.95/0

ª 2010 Adis Data Information BV. All rights reserved.

Autoimmune Bullous Dermatoses

in the Elderly
An Update on Pathophysiology, Diagnosis and Management
Diya F. Mutasim
Department of Dermatology, University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1. Diagnosis and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2. Pharmacological Agents for the Treatment of Autoimmune Bullous Dermatoses . . . . . . . . . . . . . . . . . 4
2.1 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.2 Azathioprine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.3 Mycophenolate Mofetil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.4 Methotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.5 Cyclophosphamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.6 Ciclosporin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.7 Dapsone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.8 Tetracyclines and Niacinamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.9 High-Dose Intravenous Immunoglobulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.10 Rituximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.11 Plasmapheresis/Immunoapheresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.12 Extracorporeal Photochemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3. Pemphigoid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.1 Bullous Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.1.1 Diagnosis and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.1.2 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.2 Mucous Membrane Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.2.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.2.2 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
4. Epidermolysis Bullosa Acquisita . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4.2 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
5. Paraneoplastic Pemphigus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
5.1 Diagnosis and Prognosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
5.2 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
6. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Abstract Elderly individuals are susceptible to autoimmune bullous dermatoses

(ABDs), which may be associated with high morbidity and mortality. ABDs
result from an autoimmune response to components of the basement mem-
brane zone at the dermal-epidermal junction or desmosomes.
2 Mutasim

Bullous pemphigoid results from autoimmunity to hemidesmosomal

proteins present in the basement membrane of stratified squamous epithelia.
Patients present with tense blisters in flexural areas of the skin. Mild disease
may be treated with potent topical corticosteroids, while extensive disease
usually requires systemic corticosteroids or systemic immunosuppressive
agents such as azathioprine. Mucosal pemphigoid affects one or more mu-
cous membranes that are lined by stratified squamous epithelia. The two
most commonly involved sites are the eye and the oral cavity. Lesions fre-
quently result in scar formation that may cause blindness. Patients with
severe disease or ocular involvement require aggressive therapy with cortico-
steroids and cyclophosphamide.
Epidermolysis bullosa acquisita results from autoimmunity to type VII colla-
gen in the anchoring fibrils of the basement membrane. Lesions may either arise
on an inflammatory base or be non-inflammatory and result primarily from
trauma. Treatment options include corticosteroids, dapsone, ciclosporin,
methotrexate and plasmapheresis/immunoapheresis.
Paraneoplastic pemphigus results from autoimmunity to multiple desmo-
somal antigens. The disorder is associated with neoplasms, especially leu-
kaemia, lymphoma and thymoma. Patients present with stomatitis and
polymorphous skin eruption. The disease may respond to successful treat-
ment of the underlying neoplasm or may require immunosuppressive therapy.

Bullous diseases are a group of skin diseases in of autoantibody production and several auto-
which the primary lesion is a vesicle (0.1–1 cm immune diseases, including autoimmune bullous
diameter) or bulla (>1 cm diameter). Bullae that diseases (ABDs).[4]
are not infectious in aetiology may be divided
into four subgroups based on the pathogenesis of
Table I. Classification of non-infectious bullous diseases
blister formation: autoimmune, allergic, mecha- (reproduced from Mutasim,[1] with permission)
nical and metabolic (table I).[1] Although these
Autoimmune
diseases affect patients in all age groups, the
Pemphigus
elderly are particularly susceptible to the auto-
Pemphigoid
immune and metabolic bullous diseases. The high
Epidermolysis bullosa acquisita
incidence of bullous diseases in the elderly may be
Dermatitis herpetiformis
the result of several factors. Experimental induc-
Linear IgA disease
tion of blisters is easier in the elderly than in
Mechanical (epidermolysis bullosa)
younger individuals,[2] which is likely secondary
Epidermolysis bullosa simplex
to loss of structure and function of adhesion
Junctional epidermolysis bullosa
molecules that normally maintain the integrity of
Dystrophic epidermolysis bullosa
cell-cell and cell-matrix adhesion.[3] The normal
Metabolic
rete ridge pattern of the dermal-epidermal junc-
Porphyria
tion is gradually lost during aging. This results in
Diabetic bullae
a decrease in the surface area of attachment bet-
Bullous amyloidosis
ween the epidermis and dermis, resulting in
Allergic
gradual loss of strength of dermal-epidermal
Bullous erythema multiforme
adhesion, which results in easy blistering. In
Toxic epidermal necrolysis
addition, the incidence of immune dysregulation
Acute allergic contact dermatitis
increases with age, resulting in a higher incidence

ª 2010 Adis Data Information BV. All rights reserved. Drugs Aging 2010; 27 (1)
Autoimmune Bullous Dermatoses in the Elderly 3

Table II. Molecular classification of bullous diseases

Bullous disease Targeted molecule
BP BP180, BP230 (hemidesmosome and lamina lucida)
Mucous membrane pemphigoid BP180, laminin 5 (hemidesmosome and lamina lucida), a6b4 integrin
Epidermolysis bullosa acquisita Type VII collagen (anchoring fibrils)
Paraneoplastic pemphigus Desmoglein III, desmoplakin I, desmoplakin II, BP230, envoplakin, periplakin, 170 kDa protein, other
BP = bullous pemphigoid.

The ABDs (pemphigus, pemphigoid, epidermo- ideal specimen for DIF would include normal-
lysis bullosa acquisita [EBA] and linear IgA disease appearing skin immediately adjacent to a lesion
[LAD]) result from an immune response to pro- (commonly referred to as perilesional skin). If the
teins of desmosomes or the basement membrane patient does not have blisters and has ery-
zone (BMZ).[5] The various types of pemphigus are thematous or urticarial plaques, the specimen for
associated with antibodies to different desmosomal DIF should include normal-appearing skin ad-
proteins.[6-13] There is strong direct experimental jacent to such a lesion. For IIF, blood, serum or
evidence that antibodies in pemphigus vulgaris and blister fluid may be submitted. Immunofluore-
pemphigus foliaceus cause acantholysis and blister scence tests are usually performed in specialized
formation.[6,7,14] The subepidermal autoimmune immunopathology laboratories and are best inter-
bullous diseases result from antibodies against one preted by a dermatopathologist or immunoderma-
or more components of the BMZ.[15,16] Subepider- tologist with special expertise in the area of ABDs.
mal vesicles result from activation of complement, An accurate diagnosis is essential for predict-
resulting in a cellular inflammatory infiltrate that ing the course and prognosis of an ABD, and for
disrupts the BMZ.[17,18] Both complement and in- choosing therapy. The accuracy in making a diag-
flammatory cells are required for blister forma- nosis of an ABD increases as more tests are
tion.[19,20] There is evidence that lesions in mucous evaluated. For example, EBA may have clinical
membrane pemphigoid (MMP) may be induced by and histological overlap with bullous pemphigoid
antibodies without participation by complement or (BP) and LAD. However, the three diseases
inflammatory cells.[20,21] Table II shows the target are differentiated on the basis of IIF findings.
molecules for the ABDs discussed in this article. Similarly, PNP may have similar clinical and
This article addresses (i) the general diagnosis histological features to pemphigus vulgaris and
and prognosis of ABDs; (ii) the therapeutic basis other cutaneous diseases, especially erythema
of the pharmacological agents used; and (iii) the multiforme. Immunological studies help to dif-
diagnosis and management of ABDs (pemphi- ferentiate PNP from other diseases. An accurate
goid, EBA and paraneoplastic pemphigus [PNP]) diagnosis of PNP is essential for the appropriate
that are seen frequently in the elderly. workup and treatment.
The prognosis of bullous diseases in the elderly
1. Diagnosis and Prognosis is generally worse than in younger individuals.
Extensive blistering leads to extensive erosions that
The diagnosis of ABDs requires evaluation, heal slowly, especially in patients with nutri-
histopathology, direct immunofluorescence (DIF) tional deficiencies or systemic disease. Slow healing
and indirect immunofluorescence (IIF). The ideal of extensive erosions predisposes patients to con-
specimen for histological examination would in- siderable loss of fluids and electrolytes as well as
clude an early, intact vesicle with adjacent skin. secondary bacterial infection and sepsis. In addi-
Ruptured or old vesicles reveal secondary chan- tion, superficial erosions may progress to ulcers
ges of epithelial regeneration, secondary inflam- because of increased local pressure in immobile
mation or secondary infection. These changes may and bedridden patients. Finally, temperature
mask the primary diagnostic histopathology. The regulation may be compromised following loss of

ª 2010 Adis Data Information BV. All rights reserved. Drugs Aging 2010; 27 (1)
4 Mutasim

large areas of epidermis. Over the past several dryl compounds such as glutathione. This results
decades, mortality from bullous disease has de- in slow liberation of mercaptopurine in the
creased significantly. Presently, the common cau- tissue. Azathioprine has a superior immuno-
ses of death are complications secondary to the suppressive effect to mercaptopurine. The usual
therapeutic agents used. dosage of azathioprine is 1–4 mg/kg/day, which
may be taken in one or two divided doses. In low
2. Pharmacological Agents for the doses, azathioprine is usually well tolerated. In
Treatment of Autoimmune Bullous higher doses, bone marrow suppression may
Dermatoses occur, resulting in leukopenia (commonly),
thrombocytopenia (less commonly) and anaemia
This section covers the pharmacological basis (uncommonly). Severe bone marrow suppression
and toxicity of the agents commonly used in the may occur in patients taking azathioprine who
treatment of ABDs. For a more detailed discus- are homozygous for thiopurine methyltransfer-
sion, the reader is referred to major textbooks on ase deficiency. The immunosuppressive effects of
dermatological drug therapy.[22,23] Therapy of azathioprine may result in an increased suscept-
ABDs frequently includes drugs with immuno- ibility to infection. Other adverse effects include
suppressive properties, such as systemic cortico- hepatotoxicity, gastrointestinal toxicity and
steroids, mycophenolate mofetil, azathioprine pancreatitis. Long-term intake of azathioprine is
and cyclophosphamide. Elderly patients are par- associated with an increased risk of neoplasia,
ticularly susceptible to the adverse effects of these especially when taken in conjunction with other
drugs, and therefore, such patients should un- immunosuppressive drugs such as occurs in
dergo frequent clinical examination and labora- organ transplant patients. Use of azathioprine
tory evaluation while receiving therapy. in a patient with prior history of malignancy

2.1 Corticosteroids Table III. Complications of prolonged corticosteroid use (reproduced

from Mutasim,[1] with permission)
Corticosteroids have both anti-inflammatory
Complication Comment
and immunosuppressive effects that are tightly
Fluid and electrolyte Manifested by hypokalaemia, oedema
linked.[23] Immunosuppressive effects result from a balance and hypertension
decrease in the number of circulating lymphocytes Hyperglycaemia Does not necessitate treatment
(more pronounced in CD4 compared with CD8 discontinuation
cells), eosinophils, monocytes and basophils. Cir- Immunosuppression Results in an increased incidence of
culating neutrophils increase because of increased infections and potential reactivation of
tuberculosis. Corticosteroids should be
release from the bone marrow, decreased removal
used with extreme caution in patients
from the circulation and increased demargination with pre-existing, active infection
from vessel walls. The anti-inflammatory effects Osteoporosis/osteopenia Evaluated by DEXA scan and treated
result from suppression of the production of pro- Osteonecrosis Most commonly affected site is the
inflammatory cytokines by many cells, including femoral head, followed by the distal
macrophages, monocytes, endothelial cells, baso- femur and humoral head. Manifested by
pain and stiffness
phils, fibroblasts and lymphocytes.[23] Complica-
Proximal myopathy Usually manifested by pain and requires
tions from corticosteroid use are shown in table III. discontinuation of corticosteroids
Behavioural changes Include insomnia, nervousness, mood
2.2 Azathioprine changes, psychosis and suicide
ideation
Azathioprine is a purine analogue anti- Ophthalmological Cataracts may develop, depending on
metabolite and is the imidazolyl derivative of complications the dose and duration of treatment, and
6-mercaptopurine.[22] Azathioprine was developed may progress even after discontinuation
in order to decrease mercaptopurine inactivation. of therapy
DEXA = dual energy x-ray absorptiometry.
Once absorbed, azathioprine interacts with sulfhy-

ª 2010 Adis Data Information BV. All rights reserved. Drugs Aging 2010; 27 (1)
Autoimmune Bullous Dermatoses in the Elderly 5

should be discussed with the patient’s oncologist. spermatogenesis) and the liver.[22] Hepatic dys-
Allopurinol is contraindicated in patients receiv- function is manifested by transient and reversible
ing azathioprine because the former inhibits elevation of transaminases. Long-term use of me-
xanthine oxidase, which is involved in one of the thotrexate may rarely be associated with cirrhosis,
metabolic pathways of azathioprine. necessitating discontinuation of therapy. Hepato-
toxicity is more likely in patients with a history of
2.3 Mycophenolate Mofetil other predisposing factors, such as alcohol intake,
history of hepatitis and severe obesity. The exact
Mycophenolic acid is naturally made by
mechanism of hepatotoxicity from methotrexate is
Penicillium and was named in 1913.[22] Myco-
not known but may be secondary to accumulation
phenolate mofetil was developed later as a more
of drug metabolites in hepatocytes.
bioavailable precursor. Mycophenolate mofetil
was approved by the US FDA in 1995 for renal 2.5 Cyclophosphamide
transplant patients. Mycophenolic acid inhibits
inosine monophosphate dehydrogenase, which is Cyclophosphamide is an alkylating agent that
important for the conversion of inosine mono- binds DNA, resulting in cell cycle arrest, DNA
phosphate to xanthine monophosphate (a pre- repair and apoptosis.[23] Proliferating tissues with
cursor of guanine nucleotide). This results in high mitotic rate are most susceptible. The toxi-
inhibition of de novo purine synthesis. Mycopheno- city of cyclophosphamide is significantly higher
late mofetil suppresses lymphocyte proliferation than that of azathioprine and mycophenolate
in vivo and in vitro. This results in decreased mofetil. Acute myelosuppression is common with
antibody production. Most other cells have a a nadir at 6–10 days and recovery in 14–21
salvage pathway for purine synthesis that is cata- days.[23] Both cellular and humoral immunity are
lyzed by hypoxanthine-guanine phosphoribosyl suppressed. Cyclophosphamide is associated with
transferase. Adverse effects of mycophenolate mucosal ulcers, urotoxicity, haemorrhagic cysti-
mofetil include gastrointestinal, neurological, tis, cardiotoxicity, hepatotoxicity (venous occlu-
haematological and genitourinary effects. sive disease), interstitial lung fibrosis and toxicity
to reproductive systems, resulting in amenorr-
2.4 Methotrexate hoea and azoospermia that may be irreversible.
Cyclophosphamide is also mutagenic and carcino-
Methotrexate is an antimetabolite and a folic
genic. Its long-term use has been associated with
acid analogue.[22,23] Dihydrofolate reductase
acute non-lymphocytic leukaemia.
(DHFR) reduces folate into tetrahydrofolate.
The oxidization of tetrahydrofolate into dihy- 2.6 Ciclosporin
drofolate is associated with the synthesis of
thymidine monophosphate (from deoxyuridine Ciclosporin suppresses cellular immunity sig-
monophosphate). Dihydrofolate is then reduced nificantly and humoral immunity slightly.[22,23] It
by DHFR into tetrahydrofolate. Methotrexate preferentially inhibits antigen-triggered signal
inhibits DHFR, and methotrexate metabolites transduction in T lymphocytes, which results in
(glutamates) inhibit folate-dependent enzymes of decreased expression of several lymphokines,
de novo purine and thymidylate synthesis. This especially interleukin-2 (IL-2). After entering the
results in suppression of the synthesis of DNA target cells, ciclosporin forms complexes with the
and RNA, which causes decreased lymphocyte receptor protein cyclophilin. The drug-receptor
function and immune modulation. complex binds calcineurin and inhibits it. In
Methotrexate toxicity may affect multiple or- antigen-stimulated lymphocytes, calcineurin pro-
gans including bone marrow (suppression), intest- duces calcium-stimulated dephosphorylation of
inal epithelium (ulcers), hair follicles (alopecia), the cytosolic component of the nuclear factor of
lung (interstitial pneumonitis), kidney (nephrotoxi- activated T lymphocytes, which then moves to the
city), reproductive organs (defective oogenesis and nucleus to activate genes for IL-2 and other

ª 2010 Adis Data Information BV. All rights reserved. Drugs Aging 2010; 27 (1)
6 Mutasim

lymphokines. Inhibition of calcineurin results in inflammatory and immune-modulating properties.

failure of T-cells to respond to antigenic stimulation. The mechanism involved is not clear. Tetracyclines
Ciclosporin use may be associated with renal inhibit neutrophil and eosinophil chemotaxis[24-26]
dysfunction.[22,23] Short-term renal dysfunction is and likely modulate matrix metalloproteinases.
related to the blood concentration of ciclosporin Niacinamide is a vitamin whose mechanism of
and is usually reversible. It is usually manifested by action in ABDs and other cutaneous disorders is
elevation of the patient’s blood creatinine level. unknown.
Long-term renal dysfunction may be irreversible
and is usually manifested by an increase in the 2.9 High-Dose Intravenous Immunoglobulin
patient’s creatinine level and raised blood pressure.
Other adverse effects of ciclosporin include trem- High-dose intravenous immunoglobulin (IVIg)
ors, hirsutism, hyperlipidaemia, hypertension, is a purified human source of immunoglobulin
pancreatitis and gingival hyperplasia. Several from pooled plasma. Some preparations have a
drugs may interact with ciclosporin, and the list of trace of IgA. IVIg was originally used for con-
the patient’s medications should be monitored genital immune deficiency in small doses; for au-
closely. Agents that may increase ciclosporin blood toimmune diseases, high doses are used. The agent
concentrations include calcium channel antago- is usually given in a 2 g/kg/cycle divided over 5
nists (diltiazem, nicardipine, verapamil), antifungals consecutive days. It is given as a slow infusion over
(fluconazole, itraconazole, ketoconazole), anti- up to 8 hours.[27] If there is history of previous re-
bacterials (clarithromycin, erythromycin, quinupristin/ action, premedication with corticosteroids or an-
dalfopristin), corticosteroids (methylprednisolone), tihistamines is indicated. Treatment is repeated in
other drugs (allopurinol, bromocriptine, danazol, 3–4 weeks until remission, then tapered.
metoclopramide, colchicine, amiodarone) and grape- The mechanism of action of IVIg is un-
fruit juice. known.[27] It may produce immunomodulation
by supplying anti-idiotype antibodies. Alter-
2.7 Dapsone natively, it may increase the catabolism of the
patient’s pathogenic antibodies by saturating the
The mechanism of action of dapsone in in- major histocompatibility complex-like neonatal
flammatory conditions is not well understood.[22] fragment crystallizable (Fc) receptor.[28,29] IVIg
Dapsone is believed to inhibit the myeloperox- may also prevent complement-mediated tissue
idase-peroxide-halide-mediated cytotoxic system, damage. Adverse effects are rare and include
which likely plays a role in tissue destruction by fever, headache, myalgia, nausea, tachycardia,
neutrophils and eosinophils. It also inhibits neu- anaphylaxis in patients with IgA deficiency,
trophil chemotaxis. Dapsone has multiple poten- hepatitis C (prior to 1987), renal failure and
tial adverse effects. These include dose-related stroke. Baseline laboratory tests include complete
haemolysis. Methaemoglobulinaemia is common blood count, liver and renal function tests, IgA
and is severe in patients taking dapsone who are level, and hepatitis and HIV status.
deficient in nicotinamide adenine dinucleotide-
dependent methaemoglobin reductase. One of the 2.10 Rituximab
most serious adverse effects of dapsone is agranu-
locytosis. This is not dose-related but is an idio- Rituximab is a chimeric monoclonal antibody
syncratic reaction that occurs rarely in the first against CD20 that is a receptor on the surface of
3 months of therapy. pre-B, mature B and malignant B cells, and is not
expressed on stem, pro-B or plasma cells.[30] CD20
2.8 Tetracyclines and Niacinamide is involved in regulating early steps in B-cell acti-
vation and differentiation.[31] The chimeric mono-
Tetracyclines and niacinamide may be used clonal antibody against CD20 is a combination of
together or singly. Tetracyclines have anti- murine heavy- and light-chain variable regions

ª 2010 Adis Data Information BV. All rights reserved. Drugs Aging 2010; 27 (1)
Autoimmune Bullous Dermatoses in the Elderly 7

with human IgG1k constant regions.[30] B cells are immunosuppressive drugs in order to prevent the
depleted primarily by antibody-dependent cellular rebound of antibody production that happens
cytotoxicity and, to a lesser degree, complement- frequently.
dependent cytotoxicity or apoptosis. The antibody
depletes B lymphocytes for 3 months to 2 years. 2.12 Extracorporeal Photochemotherapy
The kinetics of depletion vary for different B-cell
compartments. For example, circulating B cells are Extracorporeal photochemotherapy (ECP)
rapidly depleted. However, depletion of spleen and was first approved by the FDA in 1988 for the
lymph node B cells is slower. Activated B cells and treatment of cutaneous T-cell lymphomas.[22]
lymph node germinal centre B cells are generally The patient ingests 8-methoxypsoralen 1.5 hours
more resistant.[32] Bone marrow stem cells and prior to the procedure, then blood is accessed in a
plasma cells lack CD20, and their population is peripheral vein, heparinized and collected by
accordingly not affected. Total serum immuno- the ECP unit. A small portion (<5%) of the peri-
globulin levels do not fall significantly, because of pheral lymphocyte pool is isolated and exposed
long-lived bone marrow plasma cells. Protective to UVA light. Treated lymphocytes are then re-
titres of antibodies against immunized pathogens infused into the patient along with the red cells
are usually preserved. Antibodies produced by and previously separated plasma. The procedure
short-lived plasma cells, such as autoantibodies, takes approximately 3 hours and is repeated the
decline.[33] The antibody is usually given in a do- following day to complete a 2-day cycle. The pa-
sage of 375 mg/m2/week for 4 weeks or 1000 mg tient receives a cycle every 4 weeks. The precise
infusion 2 weeks apart. Rituximab has been found mechanism of action of ECP is unknown. Pro-
to be of significant benefit in the treatment of re- posed mechanisms include stimulation of anti-
sistant ABD.[31] T-cell immune response (which may be the
Rituximab is generally safe.[31,33] Transfusion- primary mechanism of action in cases of cuta-
related reactions may occur and manifest as neous T-cell lymphomas), induction of apoptosis
fever, chills, hypotension, weakness, flushing and of activated T-cells, and induction of im-
shortness of breath. Transfusion reactions usually munoregulatory cytokine shifts. Adverse effects
respond to slowing the infusion rate, as well as to due to 8-methoxypsoralen include nausea, pho-
premedication with paracetamol (acetaminophen) tosensitivity, hypotension, congestive heart fail-
and antihistamines. Serious complications, includ- ure, flushing and tachycardia.
ing sepsis and death, have been reported.
3. Pemphigoid
2.11 Plasmapheresis/Immunoapheresis
The term pemphigoid refers to a group of
Plasmapheresis and immunoapheresis are diseases that share the clinical findings of vesicles
procedures that aim to physically remove patho- and bullae, the histological finding of a sub-
genic antibodies.[34] Plasmapheresis consists of epidermal blister with an eosinophil-rich inflam-
withdrawing the patient’s blood, filtering cellular matory infiltrate, and the additional presence
elements from the plasma, and returning the cel- of circulating as well as skin-bound IgG anti-
lular elements to the patient. Immunoapheresis bodies against two hemidesmosomal proteins,
consists of exposing the patient’s plasma to BP230 and BP180. There are three main types
immunoglobulin-binding matrix. This procedure of pemphigoid: (i) BP (primary cutaneous in-
allows processing of larger amounts of plasma, volvement); (ii) MMP (primary mucosal disease
limits loss of non-immunoglobulin proteins and also referred to as cicatricial pemphigoid);
avoids the need for substitution with foreign and (iii) pemphigoid (herpes) gestationis (pri-
proteins. Plasmapheresis and immunoapheresis mary cutaneous disease in pregnant women).
are usually used in patients who are resistant to The first two of these are discussed in the next
other therapies. The treatment is accompanied by sections.

ª 2010 Adis Data Information BV. All rights reserved. Drugs Aging 2010; 27 (1)
8 Mutasim

3.1 Bullous Pemphigoid of mucosal lesions varies from 8% to 39%.[43,45,47]

Mucosal lesions are mild and transient, and
3.1.1 Diagnosis and Prognosis
usually seen in patients with extensive cutaneous
BP primarily affects individuals aged >60 disease. The most commonly involved site is the
years,[35] and is rarely reported in children and oral mucosa.
infants.[36,37] It affects both sexes equally and has The course and prognosis of BP are variable.
no strong association with race or geographic Unlike pemphigus vulgaris, BP is a self-limited
location. There is no known HLA class II gene disease that usually resolves within 5 years. Ex-
that is associated with BP. The distribution of acerbations following remission are rare and are
lesions in BP tends to be generalized, with pre- usually mild.[38,47] The mortality from BP is
dilection for the inner thighs, groin, axillae, ab- low.[48,49] The risk of death increases with the age
domen, neck, and flexural aspects of the arms and of the patient at the onset of disease, the dose
legs[38] (figure 1). This predilection may reflect of corticosteroid and low serum albumin. Death
immunofluorescence observations that suggest most often occurs within the first 12 weeks of
that BP antigen is more abundant in these areas starting treatment.[50,51] Causes of death include
than in less commonly involved areas such as the the adverse effects of therapy, general debilita-
face and scalp.[39] BP may occasionally be loca- tion or underlying associated illness. In a recent
lized.[40,41] The disease is frequently associated study, the 1-year mortality rate for BP patients
with pruritus,[42,43] and an occasional patient may receiving prednisone 1 mg/kg/day was 41%.[52]
have only pruritus as the presenting feature of the Histological examination of a vesicle reveals a
disease.[44] Many patients present with a prodromal, subepidermal vesicle with an infiltrate rich in
prebullous eruption that consists of erythema- eosinophils.[53,54] DIF is positive in almost 100%
tous macules, urticarial papules and plaques or, of BP cases[55] and reveals linear deposition of
less frequently, eczematous lesions.[35,42,45,46] The IgG and complement 3 (C3) along the BMZ. IIF
vesicles and bullae tend to be widespread but reveals circulating antibodies against the BMZ of
occasionally may be grouped and occasionally normal human skin in approximately 70% of
form rosettes. The typical lesion is a tense, large patients.
bulla. The blister fluid is most commonly clear
but occasionally may be haemorrhagic. Blisters 3.1.2 Management
rupture, which leads to erosions that may become BP is a disease that results from an abnormal
crusted and occasionally invaded by bacterial immune response (autoantibodies) and has pro-
pathogens. Ruptured bullae most commonly heal minent inflammatory features (cellular infiltrate).
spontaneously without scarring. The frequency Therapies for BP should suppress inflammation
and/or the immune response. Before a choice of
therapy is made, variables that relate to the dis-
ease (extent of involvement and symptoms) and
to the patient (age, other illnesses such as diabetes
mellitus, hypertension or tuberculosis) need to be
considered. The goal of therapy is to heal the
existing lesions and prevent the appearance of
new lesions.
Potent topical corticosteroids should be
considered and favoured in the management of
patients with localized disease since this variant
of BP may respond well to such therapy. In a
recent study,[52] superpotent topical cortico-
Fig. 1. Bullous pemphigoid. Tense, clear blisters over the flexors of
steroid therapy was shown to be effective for both
the arm and forearm (reproduced from Mutasim,[1] with permission). moderate and severe BP and was superior to oral

ª 2010 Adis Data Information BV. All rights reserved. Drugs Aging 2010; 27 (1)
Autoimmune Bullous Dermatoses in the Elderly 9

corticosteroid therapy for extensive disease. The phamide (1–2 mg/kg/day),[61,62] methotrexate
primary endpoint in the study (which included (10–25 mg/week)[40] and ciclosporin (6 mg/kg/day
341 patients) was overall patient survival. In pa- in two equal doses).[63] The dose of these drugs is
tients with extensive BP, use of topical cortico- decreased a few months following remission and
steroids led to a 43% reduction in the 1-year the drug is ultimately discontinued. Dapsone or
mortality rate compared with patients receiving sulfapyridine has been used effectively in a few
prednisone 1 mg/kg/day. In the author’s experi- cases.[64] Dapsone is usually commenced at
ence, topical corticosteroid use is limited by its 25–50 mg/day and increased by 25 mg increments
atrophogenic effects and inability to prevent every week until a beneficial effect is obtained or the
new lesions. patient develops unacceptable adverse effects. In
Most patients with generalized BP require sys- the author’s experience, no additional benefit is
temic therapy. The most commonly used systemic obtained beyond a dosage of 250 mg/day. Plasma-
agents are corticosteroids.[56,57] Prednisone is the pheresis has been used in the management of
most commonly used corticosteroid and is suffi- BP.[65,66] It is used in severe cases in association
cient as the only therapy in the majority of cases. with immunosuppressive drugs. In 1984, Roujeau
The dosage is 0.25–0.5 mg/kg/day depending on et al.[66] reported on 41 patients with BP in whom
the severity of disease. Unlike in the treatment of plasmapheresis had a corticosteroid-sparing effect.
pemphigus vulgaris, higher doses of prednisone are In 1993, Guillaume et al.[67] failed to confirm the
very rarely needed. A clinical response is usually benefit of plasmapheresis in addition to cortico-
obtained within 1–2 weeks and is indicated by steroids compared with corticosteroids alone.
healing of existing lesions and cessation of new A rebound rise in the autoantibody titre occurs fre-
blister formation. The prednisone dose is then quently after plasmapheresis. Hence, plasmapher-
gradually decreased by relatively large amounts esis is used in conjunction with immunosuppressive/
(10 mg) initially and smaller portions (2.5–5 mg) cytotoxic therapy (e.g. cyclophosphamide). How-
subsequently. When the daily dose is 30–40 mg, ever, the procedure is costly, time consuming and
shifting to an every-other-day schedule is en- has only temporary benefit.
couraged in order to decrease the potential for High-dose IVIg is highly effective for selected
long-term corticosteroid adverse effects. This is cases.[68,69] It is given in cycles. Each cycle con-
usually accomplished by decreasing the second-day sists of 2 g/kg given in three to five equally divided
dose by 5–10 mg every 1–2 weeks. Once the second- daily doses. Patients usually receive two to four
day dose is nil, the first-day dose may be tapered cycles (once every 3–4 weeks) initially and one to
slowly. If the patient develops a disease flare during two cycles if their disease recurs. High-dose IVIg
the tapering phase, the dose may be increased by is usually well tolerated. Transfusion reactions
10–20 mg for 2–3 weeks and then tapered more are rare. This therapy is expensive and should be
slowly. In the majority of patients, prednisone can reserved for resistant cases.
be decreased to 5 mg every other day or completely Tetracycline or erythromycin with or without
discontinued after 3–6 months of therapy. Corti- niacinamide[24,70] have been used effectively for
costeroid pulse therapy with methylprednisolone BP. When the effectiveness of the combination of
intravenously 1 g/day for 3 consecutive days is tetracycline (500 mg four times daily) and niaci-
very rarely needed in the management of patients namide (500 mg three times daily) was compared
with BP. with that of prednisone in the treatment of
Other immunosuppressive drug therapy should several patients with generalized BP, the combi-
be considered for patients who require a high nation was found to be equally effective to pred-
maintenance dose of corticosteroids, patients who nisone.[71] In patients who developed adverse
develop corticosteroid adverse effects and patients effects from tetracycline, minocycline 100 mg or
whose disease does not respond completely to doxycycline 100 mg twice daily was substituted.
corticosteroid therapy. These drugs include Use of tetracycline and niacinamide may be in-
azathioprine (2–3 mg/kg/day),[58-60] cyclophos- dicated in two situations. In mild cases, the

ª 2010 Adis Data Information BV. All rights reserved. Drugs Aging 2010; 27 (1)
10 Mutasim

combination alone may lead to a clinical remis- ment of the oral and ocular mucosa occurs con-
sion without use of corticosteroids. In patients sistently. Oral involvement occurs in almost
with extensive disease, addition of this combina- 100% of patients in select series, and ocular in-
tion to prednisone may have a corticosteroid- volvement occurs in 61–80% of patients.[47,79-82]
sparing effect. Other mucous membranes that may be involved
The authors of a recent review of the litera- include the pharynx (43%), nasal mucosa (38%),
ture[72] that identified six randomized controlled larynx (30%), genital mucosa (20–35%), rectum
trials comprising 293 patients with BP could (11%) and oesophagus (7%). Skin involvement
not make strong recommendations based on the occurs in 10–43% of patients. The severity of
available evidence. However, an attempt at creat- involvement of one mucous membrane does
ing guidelines for the management of BP has been not correlate with the severity or presence of
made.[72,73] Systemic corticosteroids are the most involvement in other mucous membranes.
established treatment. Consideration should be Oral involvement may occur over the gingiva
given to potent topical corticosteroids for localized (65%), buccal mucosa (58%), palate (26%) [figure 2],
BP. A recent study suggests they may also be con- alveolar ridge (16%), tongue (15%) and lower lip
sidered for generalized BP.[52] For mild to moder- (7%).[81] The most common and characteristic
ate disease, tetracyclines and niacinamide should presentation is that of desquamative gingivitis.
be considered. Immunosuppressive agents should Early findings include gingival erythema and
not be routinely used and should be considered oedema followed by desquamation of gingival
only if the corticosteroid dose cannot be reduced to mucosa or frank blister formation following
an acceptable level. Of these agents, azathioprine is minor trauma, resulting in erosions. Lesions in
the most established agent, followed by metho- other sites in the oral cavity start as vesicles that
trexate. Rituximab has been reported to be effec- rupture and lead to erosions that are less pain-
tive in treatment-resistant cases of BP.[31,74,75] ful than those in pemphigus vulgaris. Lesions
invariably progress to scarring that presents as
3.2 Mucous Membrane Pemphigoid delicate white reticulated patches. Adhesions
may develop between the buccal mucosa and al-
MMP (also referred to as cicatricial pemphi- veolar process, as well as around the uvula and
goid) is a chronic blistering disease of the mucous tonsillar fossae.
membranes and occasionally the skin. The dis- Ocular involvement presents with intractable
order should be distinguished from localized cu- conjunctival inflammation that may be unilateral
taneous scarring pemphigoid, initially described or bilateral. Patients complain of burning, dryness
by Brunsting and Perry (also referred to as cica-
tricial pemphigoid of Brunsting-Perry or chronic
localized pemphigoid),[76-78] in which patients
develop recurrent blisters and scarring at one site,
usually the head or neck.

3.2.1 Diagnosis
The incidence and prevalence of MMP are
unknown, but it is diagnosed less frequently than
BP.[79,80] Most patients with MMP are middle-
aged or elderly, with a mean age of onset of
66 years.[81] There is a slight female predominance,
with a female to male ratio of 1.5 : 1.[81] There is
no apparent racial or geographic predilection.
MMP may involve any mucous membrane Fig. 2. Mucous membrane pemphigoid. Vesicles and erosions over
lined by stratified squamous epithelium. Involve- the buccal mucosa and soft palate.

ª 2010 Adis Data Information BV. All rights reserved. Drugs Aging 2010; 27 (1)
Autoimmune Bullous Dermatoses in the Elderly 11

bleeding and narrowing of the anal canal. Genito-

urinary involvement is associated with pain
on urination or with intercourse. After an early
phase of recurrent blistering and erosions, ure-
thral or vaginal stenosis may occur.
Skin involvement in patients with MMP is
variable. Some patients develop a transient
widespread bullous eruption similar to that of
generalized BP.[86] Others develop recurrent blis-
ters within a limited area of the skin in the head
and neck area similar to that of the Brunsting-
Perry type of pemphigoid.
Early specimens from skin or mucosal lesions
Fig. 3. Mucous membrane pemphigoid. Symblepharon formation
(reproduced from Mutasim,[1] with permission). reveal a subepithelial (or subepidermal) vesicle
with underlying mixed inflammatory infiltrate
consisting of lymphocytes, plasma cells, eosino-
or foreign body sensation. The normally deep and phils and neutrophils.[79,87,88] Electron micro-
redundant architecture of the inferior or superior scopic examination reveals a cleft in the lamina
fornix is lost in association with a faint violaceous lucida similar to BP.[89] DIF is positive in the
hue and gray superficial fine fibrosis. As the disease majority of patients with MMP.[90-92] The most
progresses, further scarring is manifested by white, common immune deposits in both mucosa
subepithelial, fibrotic striae or fibrous tracts that and skin basement membrane are IgG and C3
fuse the bulbar (scleral) and palpebral conjunctiva (figure 4).
(symblepharon)[83-85] (figure 3). Similar fibrosis
may lead to the fusion of the superior and inferior 3.2.2 Management
palpebral conjunctiva (ankyloblepharon). The Therapy of MMP varies with the disease extent
conjunctival contraction results in inversion of the and severity.[93,94] For limited oral involvement,
eyelid margins (entropion) and leads to inversion local therapy with topical anaesthetic agents and
of lashes onto the corneal surface (trichiasis). The corticosteroids in addition to oral hygiene may
combination of entropion and trichiasis leads suffice. The corticosteroid may be applied under
to further corneal injury that results in superficial occlusion with a prosthetic device, injected intra-
erosions and neovascularization with eventual lesionally or made into a solution for ‘swish and
blindness.
Involvement of the nasopharynx presents with
erosions of the nasal mucosa, crusting, discharge
and epistaxis. Pharyngeal involvement presents
with painful pharyngeal erosions. In severe cases,
progressive scar formation leads to stenosis and
eventual nasal obstruction.[79,80] Oesophageal
involvement is frequently overlooked. Patients
may complain of heartburn, dysphagia and phago-
dynia. The diagnosis may be suspected based on
findings seen on barium swallow and confirmed
by endoscopy and biopsies for histological and
immunofluorescence studies. Laryngeal and tra-
cheal involvement are rare but may be life threa- Fig. 4. Mucous membrane pemphigoid. Direct immunofluorescence
reveals deposition of complement 3 (C3) along the basement
tening. Involvement of the anorectal area is membrane zone of oral mucosa (reproduced from Mutasim,[1] with
associated with pain on defecation, intermittent permission).

ª 2010 Adis Data Information BV. All rights reserved. Drugs Aging 2010; 27 (1)
12 Mutasim

spit’ use. Patients with extensive oral involvement 4.1 Diagnosis

may require systemic therapy. Dapsone may be
effective in some patients.[95-98] The response of EBA affects middle-aged as well as elderly in-
oral lesions tends to be faster than that of ocular dividuals and does not appear to have any race or
lesions; the latter may not respond at all. The sex predilection. There may be an association
drug is commenced at a dosage of 25–50 mg/day with HLA-DR2. The clinical presentation of
and increased gradually as needed and as toler- EBA is variable. The ‘classical’ presentation is the
ated. Some reports[99-101] suggest that tetra- most recognized and has been known for several
cyclines, with or without niacinamide, may be decades. It is characterized by trauma-induced
effective. and rarely spontaneous blisters on the hands and
In severe cases, and those with ocular, pharyn- other trauma-prone sites. This presentation is si-
geal or laryngeal involvement, systemic corticoster- milar to that of porphyria cutanea tarda (PCT)
oids in combination with cyclophosphamide[94,102] and pseudo-PCT. Chronic lesions are associated
are indicated. Azathioprine[103] and mycophenolate with scarring and milia formation. The in-
mofetil are generally less effective but may be used if flammatory or BP-like presentation consists of
there are contraindications to cyclophosphamide vesicles and bullae with adjacent erythema over
use. Most patients have an excellent response with a the flexural areas of the trunk and extremities
prolonged remission after being treated with the (figures 5 and 6). EBA may be primarily or ex-
combination of prednisone (1 mg/kg/day) and clusively mucosal and thus clinically indis-
cyclophosphamide (1–2 mg/kg/day). Prednisone is tinguishable from MMP. EBA may also present
used for approximately 6 months, while cyclopho- with localized chronic recurrent blistering over
sphamide is used for 18–24 months. the head and neck area similar to that of localized
A group of investigators recently searched for scarring pemphigoid (Brunsting-Perry).
evidence regarding treatment of MMP.[104] To Histological examination reveals a subepider-
date, the literature contains two small trials mal vesicle with varying inflammatory infiltrate.
showing that severe ocular MMP responds best In the classical type of EBA, there is usually no or
to treatment with cyclophosphamide, while mild minimal (lymphocytic) infiltrate, which is similar
to moderate disease may be successfully treated to PCT and pseudo-PCT. The inflammatory type
with dapsone.[104] High-dose IVIg[105-110] has of EBA is associated with a usually dense infiltrate
been used successfully in patients who were re- of neutrophils. These findings may be indistinguish-
fractory to other therapies, resulting in induction able from dermatitis herpetiformis and LAD.
and maintenance of a sustained clinical and sero- DIF is positive in approximately 100% of cases.
logical remission. Rituximab has been reported
to be effective in treatment-resistant cases of
MMP.[74,75,111,112] Cases with severe ocular scar-
ring may benefit from cryotherapy ablation of
eyelashes. Ocular surgery is contraindicated
when the disease is active. Surgical intervention
may cause severe flares of the disease.

4. Epidermolysis Bullosa Acquisita

EBA was first described more than a century

ago. Its exact nosology and autoimmune nature
were defined in 1979. The disease is associated
with antibodies to type VII collagen, which is the
Fig. 5. Epidermolysis bullosa acquisita. Tense bullae and mild un-
major component of sublamina densa anchoring derlying inflammation over the knees (reproduced from Mutasim,[1]
fibrils.[113-117] with permission).

ª 2010 Adis Data Information BV. All rights reserved. Drugs Aging 2010; 27 (1)
Autoimmune Bullous Dermatoses in the Elderly 13

steroids, ciclosporin may be initiated and is often

associated with a rapid response. Ciclosporin[119]
is usually started at a dosage of 6 mg/kg/day in
two equally divided doses. For patients who res-
pond to corticosteroids or ciclosporin, the dose is
slowly decreased over several months. The drug
may be discontinued if there is no evidence of
disease activity.
The same agents that are used for the inflam-
matory form of EBA may be used for the classical
form. Patients who fail to respond may be treated
with azathioprine or cyclophosphamide in a man-
ner similar to treatment of BP or MMP. Patients
Fig. 6. Epidermolysis bullosa acquisita. Erosions on bullae with who are resistant to these agents may be treated
extreme skin fragility (reproduced from Mutasim,[1] with permission).
with high-dose IVIg alone[122] or in conjunction
There is continuous linear deposition of IgG and with plasmapheresis.[119] ECP has been reported to
C3 along the BMZ (figure 7). Immunoelectron be effective in four cases of patients with refractory
microscopy confirms deposition on anchoring EBA.[123,124] In one patient, improvement was seen
fibrils. There are cases in which the deposition is within a few days and a 2-year remission was
with IgA rather than IgG. These cases cannot be obtained after three cycles.[124] Three patients in
clinically distinguished from linear IgA bullous another report had significant improvement.[123]
dermatitis and IgG EBA.[118] Porphyria and Rituximab has been reported to be effective in
pseudoporphyria reveal deposition of immuno- treatment-resistant cases of EBA.[125]
globulins and C3 in blood vessel walls.
5. Paraneoplastic Pemphigus
4.2 Management
There have been several old reports of patients
Unlike BP and other subepidermal auto- with blistering and erosive mucosal and skin le-
immune bullous diseases, EBA is generally re- sions in association with neoplasms. Most of these
sistant to therapy.[104,119] The disease waxes and cases had high titres of ‘‘pemphigus-like’’ anti-
wanes with periods of remission and exacerba- bodies.[126-129] In 1990, Anhalt et al.[130] identified
tion. Because of the neutrophil predominance in
the inflammatory form, patients may respond to
dapsone. The drug is started at a dosage of
25–50 mg/day and increased by 25 mg/week until
clinical remission or intolerance. The dose is
maintained for several months. If the patient at-
tains prolonged complete remission, the dose
may be slowly decreased and ultimately dis-
continued. Colchicine 1–2 mg/day is generally
helpful,[120,121] but its use may be limited by its
gastrointestinal adverse effects.
Patients who do not tolerate or respond to
colchicine and dapsone may be treated with oral
corticosteroids such as prednisone at a dosage of
0.5–1 mg/kg/day in divided doses. If there is no Fig. 7. Epidermolysis bullosa acquisita. Direct immunofluore-
scence reveals deposition of IgG in a linear pattern along the
response to dapsone or colchicine, or the patient epidermal basement membrane (reproduced from Mutasim,[1] with
develops serious adverse effects of cortico- permission).

ª 2010 Adis Data Information BV. All rights reserved. Drugs Aging 2010; 27 (1)
14 Mutasim

five such patients with autoantibodies to a unique

complex of epidermal proteins that were different
from those in pemphigus vulgaris and pemphigus
foliaceus. The entity was named PNP.[131,132]

5.1 Diagnosis and Prognosis

Mucous membrane involvement is a prominent

feature that occurs in almost 100% of cases of PNP
(figure 8). Patients usually present with persistent,
painful blisters or erosions of the lips and of the
gingival, buccal and lingual mucosa. Erosions are
also seen in the nasopharynx, oropharynx, nasal
septum, epiglottis, hypopharynx, larynx, tracheo- Fig. 9. Paraneoplastic pemphigus. Discrete and confluent haemo-
rrhagic, eroded patches over the hands and forearms (reproduced
bronchial mucosa and oesophagus.[130-132] Ocular from Mutasim,[1] with permission).
and genital involvement as well as involvement of
the gastrointestinal tract and lungs may also occur. mately two-thirds of cases.[133] The neoplasm is
One patient developed dyspnoea secondary to ero- usually a lymphoma (non-Hodgkin’s type),
sion of the respiratory epithelium.[131] Post-mortem chronic lymphocytic lymphoma or Castleman’s
examination of the patient revealed involvement of disease. In a third of cases, PNP is a marker for
the mucosa of the oesophagus, trachea and lung. an occult neoplasm, including thymoma. Patients
The cutaneous lesions of the first five patients with have a mortality rate of approximately 93% when
PNP reported were polymorphous.[130] Lesions the disease is associated with a malignant neo-
mimic erythema multiforme, Stevens-Johnson plasm.[133] Death results from complications of
syndrome, toxic epidermal necrolysis and morbilli- immunosuppressive therapy, such as sepsis, or
form drug eruption (figure 9). Further presenta- progression of malignancy.
tions have been reported that mimic lichen planus, The histological findings are polymorphous.
BP and lichen planus pemphigoides. Most biopsy specimens reveal suprabasal acantho-
Both malignant and benign neoplasms have lysis similar to pemphigus vulgaris.[130,131,134] Ne-
been reported in association with PNP. Diagnosis crosis of epidermal keratinocytes as well as a
of the neoplasm has either preceded or shortly vacuolar degeneration of basal cells similar to that
followed the development of PNP. PNP is asso- seen in erythema multiforme are common. DIF re-
ciated with an existing neoplasm in approxi- veals deposition of IgG around epidermal cells and
deposition of C3 at the BMZ. The patient’s anti-
bodies recognize a large set of proteins (table II).

5.2 Management

The management of PNP includes treatment of

the underlying disorder as well as suppression of
the immune response to prevent production of the
pathogenic autoantibodies.[133,135,136] Surgical ex-
cision of benign tumours such as thymoma and
Castleman’s disease has been followed by clinical
and serological improvement. In patients with
malignant neoplasms, management of the under-
Fig. 8. Paraneoplastic pemphigus. Haemorrhagic erosions over the
lying neoplasm may not result in improvement in
lips (reproduced from Mutasim,[1] with permission). PNP. For such patients there is no definitively

ª 2010 Adis Data Information BV. All rights reserved. Drugs Aging 2010; 27 (1)
Autoimmune Bullous Dermatoses in the Elderly 15

effective therapy. Generally, skin lesions respond Improper or unsuccessful treatment leads to high
better than mucosal lesions. Most of the ther- morbidity and potential mortality.
apeutic agents used in the treatment of PNP are
those used in the treatment of other autoimmune
bullous diseases, especially pemphigus vulgaris. Acknowledgements
The usual dosage of prednisone is 1–2 mg/kg/day.
No sources of funding were used to assist in the prepara-
In general, this results in partial improvement tion of this review. The author has no conflicts of interest that
(especially of the skin lesions). In a patient with are directly relevant to the content of this review.
non-Hodgkin’s lymphoma (in remission), pred-
nisone 1 mg/kg/day cleared up PNP limited to the
skin and the patient remained disease free for 18
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