Pemphogus

1. Adjuvant medications in Treatment of
Pemphigus Vulgaris
Surgical Pathology Of Oral Mucous
구강점막질환론 (852.800)
Seoul National University Dental Hospital
Mohammed Bakri
25/09/2017

2. Contents
•Introduction and definition
•Diagnostic features
•Management
•Prognosis

3. Introduction And Definition
 The term pemphigus is derived from
the Greek word ( pemphix) which
means blister or bubble. It has been
recognized as a disease for more than
two centuries and was originally
named by Wichman in 1791.
Introduction and definition (1)

4. Definition:
A group of potentially life-threatening
autoimmune diseases of the skin and
mucous membranes, characterized by
formation of blisters and erosions of the
skin and mucosa.
And histopathologically by
acantholysis.
Introduction and definition (2)

5. Acantholysis Is The Loss Of Intercellular Connections, Such
As Desmosomes, Resulting In Loss Of Cohesion
Between Keratinocytes.
 Kumar, Vinay; Fausto, Nelso; Abbas, Abul
(2004) Robbins & Cotran Pathologic Basis of
Disease (7th ed.). Saunders. Page 1230. ISBN 0-7216-
0187-1.

6. EPIDEMIOLOGY
 0.5 to 3.2 per 1,00,000 population
 Male: Female = 1:2
 Jews and people in Mediterranean origin.
 80-90% patients develop oral lesions, 60% develop oral
lesions as first symptom.
 Occasionally associated with other autoimmune disorders,
Herpes simplex infection, internal malignancies.
 The mean age of onset is approximately 50-60 years;
however, the range is broad, and disease onset in older
individuals and in children has been described
[Rai Arpita et al, 2015, ORAL PEMPHIGUS VULGARIS : A CASE REPORT ]
Diagnosis

7. Diagnosis
Diagnosis
Clinically, pemphigus vulgaris is characterized by extensive blisters and
mucocutaneous erosions. The severity of the skin disease, as well as the mucosal
lesions, is believed to be directly proportional to the levels of deattachement.
The disease arises most often in middle-aged or older people, usually starting with
a blister that ruptures easily. It can also start with blisters in the mouth. The lesions
can become quite extensive.
(loss of cohesion between keratinocytes in the epidermis)

8. Sign and Symptoms
 In juvenile pemphigus
vulgaris, stomatitis is the
presenting complaint in
more than 50% of cases.
 Other mucosal surfaces may
be involved, including the
conjunctiva, esophagus
(causes odynophagia and/or
dysphagia), labia, vagina,
cervix, vulva, penis, urethra,
nasal mucosa….
Diagnosis and clinical manifestation

9. MUCOUS MEMBRANES
 Mucous membranes of the oral
cavity are involved in almost all
patients with pemphigus
vulgaris.
 Patients may have irregularly
shaped, gingival, buccal, or
palatine erosions, which are
painful and slow to heal.
 Intact bullae are rare in the
mouth.
 Erosions may be seen on any part
of the oral cavity, and they may
spread to involve the larynx.
DiagnosisDiagnosis and clinical manifestation

10. Life-threatening Disease Skin lesion
it has a mortality rate of approximately 5-15%.
DiagnosisDiagnosis and clinical manifestation

11. SKIN
 Acute or chronic paronychia, subungual
hematomas, and nail dystrophies
affecting one or several fingers or toes
have been reported with pemphigus
vulgaris.
DiagnosisDiagnosis and clinical manifestation

12. PATHOPHYSIOLOGY AND HISTOPHTOLOGY
Histopathology : in pemphigus valgaris the basal keratinocytes are usually still
attached to the basement membrane.
Transudative fluid accumulates in between the keratinocytes and the basal layer
(suprabasal split), forming a blister and resulting in what is known as a
positive Nikolsky's sign.
This is a contrasting feature from bullous pemphigoid, which is thought to be due to
anti-hemidesmosome antibodies, and where the detachment occurs between
the epidermis and dermis (subepidermal bullae).
Diagnosis and clinical manifestation

13. NIKOLSKY SIGN
Diagnosis and clinical manifestation

14. Laboratory Studies Include The Following:
A. Histopathology: Demonstrates an intradermal blister; the earliest changes
consist of intercellular edema with loss of intercellular attachments in the
basal layer.
A. Direct immunofluorescence (DIF): On normal-appearing perilesional skin
demonstrates in vivo deposits of antibodies and other immunoreactants,
such as complements.
B. Indirect immunofluorescence (IDIF): If DIF results are positive; circulating
intercellular antibodies are detected using IDIF in 80-90% of patients with
pemphigus vulgaris.
DiagnosisDiagnosis and clinical manifestation

15. TREATMENT
 The treatment of pemphigus was unsatisfactory until the introduction of
corticosteroids in the 1950s. The majority of patients died, usually from
overwhelming sepsis, within one year of the onset of their disease.
 Systemic corticosteroids are still the most useful drugs in the treatment of
pemphigus. Their use decreased the disease mortality to less than 10%
and probably closer to 5%.
Management

16. Management’s Aims :
 The principle aim of treatment is to reduce inflammatory response and
autoantibody production, thereby achieving disease remission.
 A positive clinical response is associated with a decrease in the circulating
autoantibodies in the serum and absence of bound autoantibodies in the
skin. This is followed by a period of maintenance treatment using the
minimum drug doses required to achieve disease control and minimize
their side-effects
Management

17. Main Concern :
 Nowadays, the ultimate aim of management should be treatment
withdrawal.
 In approximately 50% of patients, all therapy can be discontinued and
patients will remain lesion free for months to years.
 A recent study reported remission rates of 38%, 50% and 75% achieved 3, 5
and 10 years from diagnosis.
Management

18. Corticosteroids Advantages:
 The major beneficial effect of corticosteroids in pemphigus relates to their
ability to decrease autoantibody levels.
 The oral route of administration is the one most preferred and
prednisone is the drug most frequently used.
 Clinical improvement may be seen within days of starting treatment but
new blisters stop to develop in 2-3 weeks and full healing may take 6-8
weeks
Management

19.  The optimum dosing schedule is not known and dosing schedules are
largely empirical. Previously it was routine to use regimens with high
doses of prednisone (100-200mg daily),which increased the potential for
life-threatening complications.
Management

20. One controlled trial has compared dosing schedules and found that there
was no significant difference in the duration to achieve remission and in
relapse rates at 5 years, between the group of patients treated with high-
dose (120-180mg daily) and those ones treated with low dose prednisolone
(45-60mg daily).
 Ratnam KV, Phay KL, Tan CK. Pemphigus therapy with oral prednisolone regimens. Int J Dermatol 1990;29:363-7
Management

21.  3 Topical and intralesional corticosteroids have been used in the
treatment of mild forms of the disease, but they are rarely effective.
 A single morning dose is safer for long-term use, but divided doses have
more anti-inflammatory effect. Most patients can be controlled with
prednisone 1.0-2.0 mg/kg/day
Management

22.  If prednisolone doses above 100mg daily are unresponsive, pulsed
intravenous therapy with 1gr of methylprednisolone or its equivalent in
150 ml of dextrose and water, administered over a period of 90 minutes
once daily, on 1-5 consecutive days, may be considered
Management

23. BUT
•Elevated pressure in the eyes (glaucoma)
•Fluid retention, causing swelling in your
lower legs
•High blood pressure
•Problems with mood, memory, behavior
and other psychological effects
•Weight gain, with fat deposits in your
abdomen, face and the back of your neck
When taking oral corticosteroids longer
term, you may experience:
•Clouding of the lens in one or both eyes
(cataracts)
•High blood sugar, which can trigger or
worsen diabetes
•Increased risk of infections
•Thinning bones (osteoporosis) and
fractures
•Suppressed adrenal gland hormone
production
•Thin skin, bruising and slower wound
healing

24. Why Adjuvant Drugs?
 To increase efficacy of
corticosteroids.
 Allow using reduced
corticosteroids doses.
 The disease still carries
significant morbidity
Management

25. But way not Adjuvant alone ?
Adjuvant drugs are slower in onset than corticosteroids, their effect may take
4-8 weeks to manifest and therefore are rarely used alone to induce
remission of the disease. Most often they are added to the treatment
schedule on time of the steroid tapering.
Management

26.  Common Adjuvant Therapy Includes:
 Immunosuppressive.
 A anti-inflammatory drugs.
 Alternative treatment modalities.
Management

27. 1- Immunosuppressive drugs
 The most commonly used are azathioprine(AZA)
and cyclophosphamide(CP).
 They are usually started when the prednisolone
tapering has begun and given in a dose of 1-2 or
3mg/kg/day.
 Cyclophosphamide appears to be the most
efficacious immunosuppressive drug for
pemphigus, but may be associated with various
side effects, like bone marrow suppression,
hemorrhagic cystitis, infertility and bladder or other
cancers
The use of pulse intravenous cyclophosphamide may
decrease adverse effects and risk of malignancy, while
maintaining or improving its efficacy
Management

28. METHOTREXATE
 Methotrexate was first reported to
be helpful by Lever and Goldberg
but there was a tendency to develop
life-threatening infections in patients
who were treated with high doses
(150 mg/week) and therefore it has
not been a commonly used adjuvant
drug for PV
Management - Immunosuppressive drugs

29. DAPSONE
 Dapsone may be useful in some patients with PV,
although there is greater support in the literature for
its efficacy in pemphigus foliaceous and therefore it
appears to be a preferred adjuvant for the treatment
of this form of pemphigus.
 There are only occasional reports that support its use
in the treatment of PV.
Management-antibiotic with anti imflamatory effect.

30. PLASMAPHERESIS
 Plasmapheresis has been used in refractory cases
in order to physically remove pathogenic
circulating antibodies. It is usually administered
three times weekly, removing about 2L of plasma.
Its effectiveness, however, is controversial.
 One controlled study in 1988 failed to
demonstrate any additional clinical benefit of
plasmapheresis in patients treated with oral
corticosteroids with or without additional
Plasmapheresis.
Management- Alternative treatment modalities.

31. Intravenous Immunoglobulin
 The administration of intravenous
immunoglobulin (IVIg) is being
increasingly used instead of
plasmapheresis in the treatment of
pemphigus.
Management

32. Treatment of pemphigus with gold.
Pandya AG1, dyke C.
 Although gold has been reported to be useful in treating pemphigus
vulgaris, its use has waned in recent years because of concerns
regarding efficacy and toxicity.
Objective: To review 26 patients with pemphigus who were treated with
intramuscular gold over a 10-year period.
Results: Gold was effective in 62% of patients as a primary treatment for
pemphigus or as a steroid-sparing agent. An average of 3 months of
therapy was required before the daily prednisone dosage could be
halved. Four patients were free of disease and stopped receiving all
therapy at the conclusion of the study. Toxic effects due to gold therapy
developed in 42% of patients and all adverse effects resolved with its
cessation.
Management

33. TREATMENT OF PEMPHIGUS WITH GOLD.
PANDYA AG1, DYKE C.
Management

34. New arrive !!
 Mycophenolate mofetil (MMF) is a
relatively new agent for the
treatment of PV
 The total daily dose most often
ranges from 2-2.5 g, divided in
two, together with prednisolone
Management - Immunosuppressive drugs

35.  A novel approach to control
pemphigus by suppressing the
production of pemphigus
antibodies is by the use of
rituximab
Management

36. Management

37. PROGNOSIS
 Left untreated, pemphigus is often fatal, usually because of dehydration
or infection.
 Mucosal lesions are recalcitrant, and they may persist even though skin
lesions are controlled, and topical corticosteroids may then help.
Management

38. CONCLUSION
 The use of adjuvant agents in treatment of PV is often limited by its
toxicity.
 The choice of the adjuvant therapies needs to be individualized.
 The past medical history, severity and course of the disease, possible
side effects of the therapy and availability of resources are all important
considerations.
Management

39. References
 Ioannides D, Lazaridou E, Rigopoulos D. Pemphigus. J Eur Acad Dermatol Venereol. 2008;22:1478–1496.
 Amagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell
adhesion. Cell. 1991;67:869–877.
 Hertl M, Jedlickova H, Karpati S, et al. Pemphigus. S2 guideline for diagnosis and treatment – guided by the European Dermatology
Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol.
2015;29: 405–414.
 Bystryn JC, Steinman NM. The adjuvant therapy of pemphigus. An update. Arch Dermatol. 1996;132:203–212.
 Martin LK, Werth VP, Villaneuva EV, Murrell DF. A systematic review of randomized controlled trials for pemphigus vulgaris and
pemphigus foliaceus. J Am Acad Dermatol. 2011;64:903–908.
 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;58:1043–1046.
 Pfűtze M, Niedermeier A, Hertl M, Eming R. Introducing a novel autoimmune bullous skin disorder intensity score (ABSIS) in
pemphigus. Eur J Dermatol. 2007;17:4–11.
 Rosenbach M, Murrell DF, Bystryn JC, et al. Reliability and convergent validity of two outcome instruments for pemphigus. J Invest
Dermatol. 2009;129:2404–2410.
 Rahbar Z, Daneshpazhooh M, Mirshams-Shahshahani M, et al. Pemphigus disease activity measurments pemphigus disease area
index, autoimmune bullous skin disorder intensity score, and pemphigus vulgaris activity score. J Am Acad Dermatol.
2014;150(3):266–272.

40. Thank you listening .
any question ?