Pemphigus vulgaris and pemphigus foliaceus: an overview of the clinical presentation, investigations and management

Pemphigus vulgaris and pemphigus foliaceus: an overview of the clinical presentation, investigations and managementCPD
Pemphigus vulgaris and pemphigus foliaceus: an overview of the clinical presentation, investigations and management
V. Melchionda and K. E. Harman
Department of Dermatology, Leicester Royal Infirmary, Leicester, UK
doi:10.1111/ced.14041
Summary Pemphigus diseases are cutaneous and mucous membrane blistering diseases, related
to the key antigens of desmoglein 1 and 3. This article reviews the topic, including
diagnosis, and provides the physician with guidance on the treatment of these diffi-
cult to control disorders.
(PF) are immunobullous disorders that are clinically
significant because they can lead to high morbidity
and mortality if left untreated.1 Their diagnosis is
often delayed.2 Because their pathophysiology is dri-
ven by an autoimmune process, the autoantibodies
are the basis of diagnostic investigations and treat-
ment strategies. The key target antigens, desmoglein
(Dsg)1 and Dsg3, are important components of
desmosomes, which are the ‘rivets’ that hold ker-
atinocytes in epithelia together. When these desmo-
somes fail, the keratinocytes split from one another,
resulting in blistering.
It takes, on average, five doctors 10 months to make
a diagnosis of PV.3 Reasons for this delay include lack
of awareness with failure to recognize the clinical fea-
tures and failure to confirm the diagnosis. In the case
of PV, the initial presentation is usually with mucosal
ulceration and there is often a delay before the skin is
involved. At this stage, patients are likely to see special-
ists that deal with mucosal pathology such as dentists,
oral surgeons, gynaecologists, genitourinary medicine
physicians, and ear, nose and throat surgeons, who
may have limited awareness of immunobullous
diseases, owing to their rarity. In both PV and PF,
intact blisters may not be seen, which may mislead
even those who are familiar with these diseases.
Diagnostic clues
Pemphigus vulgaris
mucosal ulceration, especially in the mouth.4 These
ulcers are persistent; individual ulcers may come and
go but new lesions continue to appear. Many patients
will develop skin lesions over the following weeks or
months4 and, unlike bullous pemphigoid, these tend
not to be itchy. The age at presentation is wide, with
peak incidence over the third to the sixth decade of
life, hence age is not considered a diagnostic clue.
Physical examination reveals preferential involve-
ment of the upper torso in a shawl-like or seborrhoeic
distribution. Lesions are densest over the upper, cen-
tral chest and back in a ‘V’ shape (Fig. 1a). The
intraepidermal blisters of PV are flaccid and fragile,
frequently rupturing to leave raw erosions, which may
crust over. Thus, it is important to consider PV in any
patient with eroded skin, even if intact blisters are not
apparent (Fig. 1b). The face, including the eyelids, the
scalp, flexures and mucous membranes, can also be
involved. On hair-bearing scalp, it is more likely to see
lesions covered with fissured crusts (Fig. 1c), which
may be mistaken for psoriasis. PV can affect any site
in the oral mucosa with a predilection for gingival
papillary tips, in contrast to the diffuse gingival
*Correspondence: Dr Karen Harman, Department of Dermatology,
Leicester Royal Infirmary, Infirmary Square, Leicester, LE1 5WW, UK.
E-mail: [email protected]
Conflict of interest: The authors declare that they have no conflicts of
interest.
ª 2019 British Association of Dermatologists740 Clinical and Experimental Dermatology (2019) 44, pp740–746
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(Fig. 1d). It is common to see white patches of hyper-
keratosis of the mucosa as PV heals (Fig. 1e).
It is important to be aware that a small subset of
patients with PV may present with minimal or no
mucosal involvement. These patients typically have
relatively low levels of Dsg3 antibodies and higher
levels of Dsg1 antibodies. Patients with only mucosal
involvement will have absent or low levels of Dsg1
antibodies, while those with the most severe mucocu-
taneous disease will have high antibody titres to both
antigens5 (Fig. 2).
Pemphigus foliaceus
The level of blister formation in PF is high in the sub-
corneal region of the epidermis, so the blisters are
even more fragile than those in PV, and intact blisters
may not be seen at all. If the patient has seen blisters,
this will be an important clue, but otherwise, the his-
tory is unlikely to reveal the diagnosis. The distribu-
tion of skin lesions follows that of PV. However, due
to the absence of Dsg3 antibodies (PF is caused by
antibodies to Dsg1), the mucosal surfaces are unaf-
fected.
scaly or crusty, erythematous patches are also com-
mon. If very widespread, the presentation can be that
of an exfoliative dermatitis. In the scalp, as in PV, fis-
sured crusts rather than blisters or erosions are usu-
ally seen. The lack of blisters and mucosal
involvement means diagnostic delay is frequent, as PF
can be misdiagnosed as eczema, seborrhoeic dermati-
tis, actinic keratoses or psoriasis. On close inspection,
a very useful clue may be the presence of a peripheral
rim of scale or epidermal peeling representing the level
of split (Fig. 3). This sign is not exclusive to PF as it
can occur in any blistering disease, but it is particu-
larly useful when intact blisters are not present.
Investigations
immunofluorescence (DIF) relies heavily on a well-
(a)
(d)
(b)
(c)
(e)
chest in a V-shape, like a shawl. Indivi-
dual lesions are crusted. There were ero-
sions and flaccid blisters on the back. (b)
An eroded, crusted patch on the bald
scalp of a patient with PV. No intact blis-
ters were seen. An initial diagnosis of
erosive pustular dermatosis of the scalp
was suspected until a skin biopsy showed
suprabasal acantholysis, by which time
skin lesions had developed elsewhere. (c)
In both PV and pemphigus foliaceus, the
hair-bearing scalp is often covered in fis-
sured crusts. (d) Patchy erosion of the
anterior lower gingival segment in PV.
Note the poor oral hygiene, which is a
common problem in PV owing to pain
and bleeding on brushing. (e) Erosion of
the buccal mucosa with adjacent white
areas, a common appearance in PV.
Clinical and Experimental Dermatology (2019) 44, pp740–746 741ª 2019 British Association of Dermatologists
Pemphigus vulgaris and pemphigus foliaceus: an overview V. Melchionda and K. E. Harman
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give misleading results and can occur due to epithelial
fragility (with the epidermis tearing off during the pro-
cedure or transfer), lack of intact blisters clinically or
inappropriate biopsy technique.
edge is optimal, whether incisional in the case of large
blisters or excisional in the case of small blisters
(Fig. 4a,b). Ellipse incisional biopsies are preferred to
punch biopsies because round samples make it chal-
lenging for the pathologist to orientate the specimen
and ensure that sections are cut perpendicular to
the blister edge. The edge is where the level of split
is likely to be demonstrated, thus a sample taken
from the ulcer bed is not helpful. If there are no blis-
ters, the edge of an erosion is also acceptable. DIF
requires intact perilesional skin. If there is oral
involvement only and quick access to expertise in
taking intraoral biopsies is not available, a 4mm
punch biopsy of the buccal mucosa for DIF may suf-
fice, taken by reflecting out the cheek. The sensitiv-
ity of DIF on unaffected buccal mucosal has been
shown to be 100% in PV.6 Laboratory expertise will
maximize the chance of obtaining a true-positive
DIF result.
best diagnostic tool in combination with clinical find-
ings. Histology reveals acantholysis with suprabasal
blistering in PV and subcorneal blistering in PF. The
histology is often reported as nonspecific in PF because
the superficial blistering may mean that, if the thin
blister roof has detached, the remaining epidermis
looks relatively normal. In PV, if the blister roof is
missing, the basal keratinocytes may separate from
one another laterally, resembling a ‘row of tomb-
stones’, which provides an important diagnostic clue,
although this finding is not always seen. DIF reveals
intercellular IgG/C3 deposition in the epidermis, and
the fluorescence pattern resembles a chickenwire fence
or a honeycomb.
ELISA for Dsg1 and Dsg3 antibodies is complementary
to that of DIF. If there are technical issues that may
lead to a false-negative DIF result, such as missing epi-
dermis, or if a patient cannot have a biopsy taken, IIF
or ELISA can clinch the diagnosis. ELISA gives infor-
mation about the target antigen and can therefore dis-
tinguish PV from PF.
PV and PF can be managed in a similar manner,
although the latter tends to assume a less aggressive
course. Management can be considered in two main
phases: remission induction and remission mainte-
nance. Remission induction includes achieving disease
control (the point at which no new lesions form and
the existing ones heal) and the consolidation period
[the period from when the disease was controlled until
no new lesions have formed for at least 2 weeks and
there is established healing (> 80%) of existing
lesions].7 Remission maintenance involves keeping a
patient disease-free once remission has been induced.
Dsg1 Abs
Dsg3 Abs
(PV)
Figure 2 Pemphigus phenotype according to desmoglein (Dsg)
1 and Dsg3 antibody (Ab) levels: patients with Abs to Dsg1
only have skin disease and pemphigus foliaceus (PF); patients
with Abs to Dsg3 only have pemphigus vulgaris (PV) with
mucosal dominant disease and there may be additional skin
lesions but these are often minor; patients with Abs to Dsg3
and 1 have PV usually with both skin and mucosal involve-
ment and it is those patients with high Ab titres to both anti-
gens that have the most severe disease. Occasional patients
with PV have minimal or no mucosal involvement and these
patients tend to have Abs to both antigens but relatively low
titres to Dsg3.
Figure 3 Epidermal peeling around the edge of skin lesions can
be an important clue to a blistering disease. It is due to intraepi-
dermal separation and represents the edge of a blister roof. The
skin biopsy (inset) demonstrates this in cross-section.
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the approach to treatment (Fig. 5).
The management of PV has been reviewed in
recent British Association of Dermatologists (BAD)
guidelines and is summarized in Table 1.4 First-line
treatment includes corticosteroids, usually in the form
of oral prednisolone. The evidence base for the choice
of dose is poor; however, 1 mg/kg/day is commonly
used and 0.5–1 mg/kg/day is appropriate for milder
disease.4 If blistering continues, oral prednisolone can
be increased in 50–100% increments every 5–7 days.
Steroid dose tapering is generally commenced at the
end of the consolidation period, once healing is estab-
lished.7 The evidence base for how best to taper is
weak, and tapering schedules have varied widely in
publications. The BAD guidelines suggest reducing
prednisolone by 5–10 mg every 2 weeks until 20 mg
daily is achieved, then by 2.5 mg every 2–4 weeks
until 10 mg daily, then by 1 mg increments. Corti-
costeroids are fast-acting and traditionally favoured
for establishing disease control and remission induc-
tion compared with steroid-sparing agents, such as
azathioprine and mycophenolate mofetil, which have
a slower onset. However, steroid-sparing drugs play
an important role in remission maintenance when
the long-term effects of corticosteroids become a con-
cern, and they can be given in conjunction to corti-
costeroids from the outset if screening blood tests are
satisfactory, e.g. thiopurine methyltransferase testing
for azathioprine.
the skin and mucosal surfaces should be monitored. If
there is ongoing disease activity at any site, including
in the mouth, further dose reductions may result in
relapse. Use of an oral disease severity score sheet
(ODSS) provides a systematic approach to examining
the mouth.8 Second-line treatment is instigated if
treatment failure occurs, which is defined by interna-
tional consensus as the lack of disease control after
12 weeks of azathioprine 2.5 mg/kg/day, mycopheno-
late mofetil 1.5 g twice daily, cyclophosphamide
2 mg/kg/day or methotrexate 20 mg/week alongside
corticosteroids. Rituximab, a humanized chimeric anti-
CD20 monoclonal antibody, is currently approved as a
Histology DIF Histology DIF
(a) (b)
Figure 4 Taking a biopsy for histology and direct immunofluorescence (DIF) when an autoimmune blistering disease is suspected in the
case of (a) a small and (b) a large blister.
Induc on remission Remission maintenance
Role of steroids
Time
Figure 5 Relative role of treatments according to phase of disease.
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randomized controlled trial (RCT), 89% of patients
with pemphigus treated with rituximab and oral pred-
nisolone were disease-free and off all treatment after
24 months, compared with 34% on prednisolone
only.9 This 55% difference in efficacy was statistically
significant, and contrasts with RCTs using adjuvant
immunosuppressants, which so far have shown mar-
ginal benefits.9 In addition, the patients treated with
rituximab were exposed to much lower cumulative
doses of corticosteroids.
nisolone 500 mg for three consecutive days followed
by oral prednisolone 1 mg/kg/day. Our choice of adju-
vant drug in a treatment-naive patient would be a
pulse of intravenous cyclophosphamide 15 mg/kg
(maximum 1500 mg). In a patient who qualified
under NHS England policy, rituximab 1 g given on
two occasions, 2 weeks apart, would be given instead.
During the consolidation period, prednisolone 1 mg/kg
would be continued and cyclophosphamide pulses con-
tinued every 2–4 weeks. Remission would be main-
tained on tapering doses of prednisolone and the
cyclophosphamide switched at the earliest opportunity
to azathioprine, owing to concerns about the former’s
long-term toxicity.
earlier phases of the disease. It is likely that there
will be a shift to monoclonal antibody therapy, such
as rituximab, as a first-line treatment, minimizing
the adverse effects of high-dose systemic corticos-
teroids.
Acknowledgement
This review article is based on a presentation given at
the British Society for Medical Dermatology Blistering
Skin Diseases Meeting 2019.
Table 1 An overview of the management of pemphigus vulgaris.
Therapy
• Oral prednisolone: optimal dose not established but suggest start with prednisolone 1 mg/kg/day (or equivalent) in most
cases, 0.5–1 mg/kg in milder cases.
• Increase in 50–100% increments every 5–7 days if blistering continues (see ‘Treatment failure’ for guidance
on maximum dose†)
disease followed by 1 mg/kg/day oral prednisolone.
• Taper dose once remission induced and maintained, with absence of new blisters and healing of the majority of lesions
(skin and mucosal). Aim to reduce to 10 mg daily or less
Combine corticosteroids with an adjuvant immunosuppressant:
• Azathioprine 2–3 mg/kg/day (if TPMT normal)
• Mycophenolate mofetil 2–3 g/day
• Rituximab‡ (RA protocol, 1 g 9 2 infusions, 2 weeks apart)
Second-line Consider switching to alternate corticosteroid-sparing agent if treatment failure with first-line adjuvant drug† (azathioprine,
mycophenolate mofetil or rituximab) or mycophenolic acid 720–1080 mg twice daily if GI symptoms from
mycophenolate mofetil.
Third-line Consider choice of additional treatment options based on assessment of individual patient need.
Options include:
failure defined by international consensus7 as continued disease activity or failure to heal despite 3 weeks of prednisolone 1.5 mg/kg/
day, or equivalent, or any of the following, given for 12 weeks: azathioprine 2.5 mg/kg/day (assuming normal TPMT); mycophenolate
mofetil 1.5 g twice daily; cyclophosphamide 2 mg/kg/day; methotrexate 20 mg/week. a‡Rituximab is currently approved by NHS Eng-
land as a third-line treatment for pemphigus.
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conditions is essential.
sistent erosions of the oral mucosa with skin
lesions typically occurring weeks to months later.
• PV can rarely present with minimal mucosal
involvement, thus lack of mucosal involvement
does not always mean the diagnosis is PF.
• PF can present with scaly, erythematous
patches without overt blistering.
provides a diagnostic clue: both show a predilec-
tion for the upper, central torso, in a ‘shawl-like’
distribution, the scalp and face.
• Physicians should always consider an
immunobullous disease in any patient who pre-
sents with eroded skin or mucous membranes,
even if intact blisters cannot be seen.
• Care when taking a biopsy for histology and
DIF is essential to avoid diagnostic pitfalls.
References
1 Bystryn JC, Steinman NM. The adjuvant therapy of
pemphigus. An update. Arch Dermatol 1996; 132: 203–12. 2 Sirois DA, Fatahzadeh M, Roth R, et al. Diagnostic
patterns and delays in pemphigus vulgaris: experience
with 99 patients. Arch Dermatol 2000; 136: 1569–70. 3 International Pemphigus and Pemphigoid Foundation
(IPPF). Awareness program. Available at: http://www.pe
mphigus.org/awareness/about-the-awareness-campaign/
campaign-overview/
4 Harman KE, Brown D, Exton LS, et al. British Association
of Dermatologists’ guidelines for the management of
pemphigus vulgaris. Br J Dermatol 2017; 177: 1170– 1201.
5 Harman KE, Seed PT, Gratian MJ, et al. The severity of
cutaneous and oral pemphigus is related to desmoglein 1
and 3 antibody levels. Br J Dermatol 2001; 144:
775–80. 6 Carey B, Joshi S, Abdelghani A, et al. The optimal oral
biopsy site for diagnosis of mucous membrane pemphigoid
and pemphigus vulgaris. Br J Dermatol 2019. https://doi.
org/10.1111/bjd.18032
7 Murrell DF, Dick S, Ahmed AR, et al. Consensus statement
on definitions of disease, end points, and therapeutic
response for pemphigus. J Am Acad Dermatol 2008; 58:
1043–6. 8 Ormond M, McParland H, Donaldson ANA,et al. An oral
disease severity score validated for use in oral
pemphigus vulgaris. Br J Dermatol 2018; 179: 872–81. 9 Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al.
First-line rituximab combined with short-term prednisone
versus prednisone alone for the treatment of pemphigus
(Ritux 3): a prospective, multicentre, parallel-group,
open-label randomised trial. Lancet 2017; 389:
2031–40.
CPD questions
Learning objective
garis and pemphigus foliaceus, optimize investigations
in order to make a diagnosis and initiate a manage-
ment plan.
cal findings is not present in pemphigus vulgaris?
(a) Suprabasal blistering.
(c) Acantholysis.
(e) Interface changes.
distribution of skin lesions in pemphigus vulgaris and
pemphigus foliaceus?
(a) Photosensitive.
(b) Dermatomal.
(c) Seborrhoeic.
Question 3. What clinical features can be seen on the
hair-bearing scalp of patients with pemphigus vulgaris
and pemphigus foliaceus?
(a) Scarring alopecia.
Question 4. Which antigens are targeted in pemphigus
vulgaris and pemphigus foliaceus?
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(b) Dsg2…

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