RECENT ADVANCES IN PEMPHIGUS

PRATEEK PATHAK
Theories For Pathogenesis Of Pemphigus

1. The Desmoglein compensation theory

2. Multiple hits hypothesis
3. The Antibody-induced apoptosis theory
4. The Basal cell shrinkage hypothesis and the Apoptolysis
theory.
 DESMOSOME

 This architectural arrangement is essential for maintaining

cell integrity and its interaction with the adjacent cells.
CONVENTIONAL CONCEPT
1. STEARIC HINDRANCE:
IgG autoantibodies

Amino-terminal domain of desmogleins

Direct inhibition of desmosomal cadherin

Acantholysis.

 But pivotal role of Anti-Dsg Ab in under question

 Role of PERP & Ach R is proposed
2. PLASMINOGEN ACTIVATOR:
Ag-Ab complex

Induces production of Plasminogen activator

leads to the production of active Plasmin

causes cytoskeletal damage and cell dissociation

NEWER CONCEPTS IN ACANTHOLYSIS
1. P38 Signaling Mediated Acantholysis

 p38 MAPK inhibitors -potential therapeutic option

 Limitation - hepatotoxicity
2. Role Of Epidermal Growth Factor Receptor

 EGFR : a mediator of p38 MAPK pathway.

 Activated by binding of auto-antibodies to the keratinocytes.

 Inhibition of EGFR blocks antibody mediated acantholysis in

pemphigus.

 EFGR inhibitors - to inhibit this pathway of acantholysis.

 EGFR inhibitors like erlotinib and lapatinib
 Lapatinib
 Dual EGFR and ErbB2 inhibitor
 More effective control of skin as well as
mucosal blistering.
 3. Antibodies Against Keratinocyte Acetylcholine
Receptors
 Antibodies AchR - AchR a9 and Pemphaxin
 85% patients with Pemphigus.

 Binding of autoimmune Ab to AchRa 9

a)Blocks Ca ++ influx involved in desmosome assembly leading to
desmosomal dissociation.

b)Protein kinase C activation → phosphorylation of structural and

adhesion molecules → cytoskeletal collapse and weakening of
intercellular junctions

 AchR agonist : reduce blistering in pemphigus.

 4. Role Of B Reg Cells

 In pemphigus, CD4+T cells stimulate B cells for pathogenic IgG

production.

 B reg cells levels -- significantly higher but

A)Capability of IL-10 production is significantly impaired.
B)B reg cells are functionally impaired to down regulate IFN- a
production by CD4+ T cells.

 Thus B regs cells can be an important therapeutic target in the

management of pemphigus.
 5. Role Of The Cellular Immune System
 Cellular immunity – also provide protection against development
of pemphigus.

 CD28 is a co-stimulatory signal for T-cell activation & CD28-

deficient mice -- more sensitive to develop pemphigus

 CD 200 maintenance of pro-inflammatory reaction and immune

tolerance in the body, is also implicated in pathogenesis of
pemphigus,

 Therefore CD200 may also be a potentially important therapeutic

target.
 6. Desmoplakin Point Mutation Enhancing
Keratinocyte Adhesion
 A specific desmoplakin mutation S2849G -- serine residue is
replaced by glycine, results in increased anchorage of keratin
filaments.
 Mutated desmoplakin -- less prone to PK-C induced
phosphorylation, which occurs when pemphigus auto-antibodies
bind to keratinocytes.
 Keratinocytes expressing DP-S2849G-GFP were found to be less
susceptible to pathogenic effects of pemphigus autoantibodies.
 Therefore inhibition of PKC induced phosphorylation of
desmoplakin may be of therapeutic value.
The Desmoglein Compensation Theory
 Given by Mahoney M.G (1999) based on the differential
antigenic distribution and generation of autoantibodies.
 The presence of even a single type of desmoglein is enough
to maintain the continuity of the epithelium.
 There exists a difference in the expression patterns of
desmoglein 1 and 3 in the skin and mucous membranes.
 Multiple Hits Hypothesis
Multiple type of antibodies are involved:
 Desmosomal proteins :
 Desmogleins,
 Desmocollins,

 Plakins and

 Nondesmosomal proteins :
 Antimitochondrial Antibodies,
 Antibodies To Cell-membrane Receptor,
 Nicotinic Acetylcholine Receptor,
 Pemphaxin,
 Thyroperoxidase and some other Annexins.
 According to this theory, pemphigus is a complex disease,
initiated by at least three classes of auto-antibodies directed
against desmosomal, mitochondrial and other keratinocyte
autoantigens resulting in acantholysis.

 Clinically, the titer of antidesmoglein antibody directly

correlates with disease activity.
 Antibody-induced Apoptosis Theory
Auto-antibody

activation of signaling pathways, such as FasR pathway

• Increase levels of intracellular FasR, FasL, Bax and p53

Decrease in the levels of Bcl-2;
Enrichment of caspase-8; and
Activation of caspases 1 and 3

 Inhibitors of caspases 1 or 3 inhibit IgG-mediated apoptosis and

blocks acantholysis
The Basal-cell Shrinkage Hypothesis And
The Apoptolysis Theory

Auto-antibodies bind to the keratinocyte receptors

A series of signal-transduction pathways trigger the rupture of the

cytoskeleton

results in the collapse and shrinkage of the keratinocytes

known as Âpoptolysis
Treatment of Pemphigus
 DEFINITIONS
 Developed by the International Pemphigus Committee.
 Baseline : Therapy is started by a physician.
 Control of disease activity :
• New lesions cease to form
• Established lesions begin to heal.
 This marks the beginning of the consolidation phase.
 End of consolidation phase :
• No new lesions for a minimum of 2 weeks
• Approx 80% of established lesions have healed.
 Clinicians start to taper corticosteroids
 Complete remission on therapy : Absence of new or
established lesions for at least 2 months while the patient is
receiving minimal therapy.

 Minimal therapy : ≤10 mg/d prednisolone (or equivalent) and/or

minimal adjuvant therapy for at least 2 months.

 Minimal adjuvant therapy is defined as half of the dose

required to be defined as treatment failure.
 Complete remission off therapy : Absence of new and/or
established lesions for at least 2 months while the patient is off all
systemic therapy for at least 2 months.

 Relapse/flare : Appearance of ≥3 new lesions/month that do not

heal spontaneously within 1 week, or by the extension of
established lesions, in a patient who has achieved control of
disease activity
 Rituximab
 Anti-CD20 monoclonal humanized antibody with the potential to
reduce desmoglein autoantibodies and selectively deplete B cells.

 Indication :
(1) Recalcitrant disease
(2) Patients with multiple relapses
(3) Patients who remain dependent on >10 mg prednisolone
combined with an immunosuppressive adjuvant
 Schedule
1) RA : 2 doses 1,000 mg IV every 2 weeks
Variations in RA protocol are: High dose and Low dose protocol
2) Lymphoma : 375 mg/m² every week* 4 weeks.

 Remission in approximately 95% of the total patients.

 Few propose, Prophylactic infusion after complete remission

does not seem to provide any additional benefit
 FUTURE PROSPECT
▪ Rituximab for Maintenance Therapy:
o Infusion every 6 months to maintain clinical remission.

▪ Ultra Low dose Rituximab:

o 100 mg Rituximab to deplete B cell population.

▪ Other Anti CD 20 Ab:

o Ofatumumab
o Veltuzumab
o Obinutuzumab
Intravenous Immunoglobulins
 Used in refractory disease or in case of contraindications to
immunosuppressive adjuvants.

 Usual dose is 2 g/kg/cycle IV , over 2–5 consecutive days,

monthly.
 Mechanisms :
 Modulation of expression and function of Fc receptors,
 Interference with complement activation,
 Modulation of dendritic cell, T and B cells
 Immunomodulatory effects without suppressing the immune
system
 Treatment should be performed over several days to avoid
adverse effects

 ADRS :
 Headache

 Nausea.

 C/I : Complete IgA deficiency

 TNF- Alpha Antagonists
 TNF-α has been found to be strongly expressed by the
acantholytic cells in PV.

 Infliximab : dose of 5 mg/kg in weeks 0, 2, and 6, and then

every 8 weekly.

 Etanercept : double-blind phase II study as a steroid-sparing

drug.

 Adalimumab has also shown its efficacy

 Immunoadsorption
 Rapid removal of circulating autoantibodies against Dsg1 and
Dsg3 can be achieved by immunoadsorption.

 Indication : Patients with refractory PV when CSs combined with

azathioprine or MMF fail to control the disease.

 Recommended schedule :
➢ 4 treatments of immunoadsorption on 4 consecutive days,
repeated after 4 weeks, if needed
 Treatment could be undertaken in combination with
immunosuppressive agents such as rituximab and
cyclophosphamide.
 Contraindications :
1. Severe systemic infections,
2. Cardiovascular diseases
3. Hemorrhagic diathesis.

 It is far superior to plasmapheresis in terms of efficacy and

safety (high cost - major limiting factor)
 Therapeutic Plasma Exchange –
Plasmapheresis
 Plasmapheresis is an extracorporeal blood purification technique,

 The blood is continuously removed from the patient and separated

into cellular components and plasma

 The cellular compartments are returned to the patients along with

replacement fluid like albumin.

 Control disease activity by reducing serum levels of

autoantibodies.
 The double filtration plasmapheresis is a newer procedure that
currently prevails because of its safety advantage.

 In double filtration plasmapheresis, immunoglobulins are

selectively removed, while the loss of albumin is minimized.

 There is no standardized protocol for the number and frequency

of sessions; however, four or five plasma exchanges, each
exchange consisting of 1–1.5 plasma volumes, over a period of
7–10 days constitute an adequate short-term therapy to remove
90% of the total initial body immunoglobulin burden.
 ADRs
 Thrombocytopenia
 Anemia,
 Leucopenia

 Hypogammaglobulinemia,
 Fluid overload leading to hypertension and pulmonary
edema,
 Hypoproteinemia, Hypocalcemia.
 Extracorporeal Photochemotherapy
 It involves the collection of mononuclear cells with a cell
separator, their irradiation with UV-A light in the presence of 8-
methoxypsoralen, and reinfusion of the treated cells into the
patient.

Mechanism of action
 An amplifier of the immunogenicity of class I-associated peptides
that are present on the surface of the collected mono-nuclear cells.
 It has been approved by the US FDA (Food and Drug
Administration) for the treatment of cutaneous T-cell lymphoma,
 Also in the management of nonmalignant disorders of the
immune system such as
 PV
 Scleroderma,

 Systemic lupus erythematosus,

 Rheumatoid arthritis
 Autoimmune diabetes mellitus,
 Rejection of cardiac and renal allograft, and chronic graft
versus host disease.
 Cholinergic agonists
➢ Carbachol
➢ Pyridostigmine bromide
 Upregulation of adhesion molecules and reduce severity of
blistering in pemphigus.

Mizoribine
 Purine synthesis inhibitor
 Effective as an adjuvant for the treatment of PV
 Substantial reduction in the dose and side effects of the
corticosteroid therapy with mizoribine.
 Alemtuzumab
 Monoclonal antibody which inhibits CD52.

 It has shown to cause good improvement in case of paraneoplastic

pemphigus associated with chronic lymphocytic leukemia.

 Started at a low dose of 3 mg daily IV infusion reaction, the dose is

slowly increased over a period of one week to 30 mg, which is
given subcutaneously three times weekly for 12 weeks.

 Complications :
 Lymphopenia
 Secondary infections
DRUGS UNDER TRIAL

 Anti- BAFF antibodies.

 Monoclonal antibodies against CD 19 & 22.

 Chimeric Autoantibody Receptor (CAAR)T cell – B cell

depletor
 GUIDELINES
 1st line: Corticosteroids
Oral Prednisolone start with 0.5-1 mg/kg
Increase by 50-100 % every 5-7 days if blistering +
If dose goes > 1mg/kg consider Pulsed i.v. Steroids
Taper once remission induced & maintained

Combine steroids with adjuvants

Azathioprine 2-3mg/kg/d
MMF 2-3g/d
Rituximab
They are important for remission maintenance than induction
 2nd Line: Consider if treatment Failure.
• T/t failure is defined as Disease activity despite:
o 3 weeks of 1.5mg/kg/d Prednisolone
o Azathioprine 2.5 mg/kg/day
o MMF 1.5 g * BD
3 months
o Cyclophosphamide 2 mg/kg/d
o Methotrexate 20 mg/week
• Switch to alternate steroid sparing drug
 3rd line: Consider based on assessment
• Cyclophoshamide
• Immunoadsorption
• IvIg
• Plasmapheresis
• Methotrexate
 Step-by-step therapy after control
of the disease
 After the consolidation phase -- Start tapering steroids
 Taper prednisolone by 5-10 mg every 2 weeks till 20 mg
 At dose 20 mg – 2.5 mg reduction every 2-4 weeks till 10 mg
 At dose 10 mg – 1 mg
 If < 3 lesions reappear during tapering -- raise dose to the last
effective dose for the patient.
 If the patient presents with a relapse (>3 lesions), re-increase oral
CS therapy, going two steps back in the previous dose until control
of the lesions is achieved.
 Subsequently, restart tapering of systemic steroids.
 If cannot obtain disease control -- go back to the initial dose.

 If oral CSs are given as monotherapy, add an immunosuppressant.

 If oral CSs are already combined with an immunosuppressant, consider

replacing a first-line immunosuppressant by another or the use of a second-
line immunosuppressant

 Monitor the patient for adverse events, and remember that prolonged
immunosuppressive therapy increases the risk of side effects.

 Monitor titers of anti-DSg antibodies,

 Persistence of high levels of anti-Dsg1 : Skin relapses

 Persistence of anti-Dsg3 IgG does not necessarily indicate a mucosal

relapse.
 Pemphigus in Pregnancy:
▪ Safe are:
• Prednisolone
• Azathioprine
• IvIg
• Plasmapheresis
▪ Avoid:
• MMF
• Methotrexate
• Cyclophosphamide
• Rituximab
THANK YOU