Microsoft word - 10-pemphigus vulgaris - dr. s. m. b. ekanayake.doc

Pemphigus Vulgaris: Rituximab therapy – case series on three patients
S M B Ekanayake1, Senior Registrar in Dermatology, Teaching Hospital, Kandy
M Dissanayake2, Consultant Dermatologist, Teaching Hospital, Kandy

Abstract
Pemphigus vulgaris (PV) is an immunobullous disorder caused by pathogenic autoantibodies against
Desmogleins. Many therapies have been designed to reduce autoantibody production. Systemic
corticosteroids and immunosuppressive agents have greatly improved the prognosis of patients;
however these have limitations due to resistant disease states or side effects. Rituximab is a new
biologic agent that has been introduced to treat PV. It is a chimeric antiCD20 monoclonal antibody. It
destroys cells of B cell lineage thus inhibiting antidesmoglein antibody production. Three patients
with PV were treated with Rituximab once per week for four weeks. All patients showed favorable
response with minimal side effects.
Introduction
Systemic corticosteroids with or without immunosuppressive drugs remains the mainstay of treatment
of Pemphigus Vulgaris1, 2, 3. The introduction of these agents has greatly improved the prognosis of
PV; however, the morbidity and mortality is still significant. Numerous drugs and regimes are
available at present but controlled trials for these are few 1.
Rituximab, a chimeric monoclonal anti CD20 antibody which depletes B cells has shown promising
results even in treatment resistant patients3,4,5. It also has number of side effects but severe side effects
are rare. Patients should be closely monitored during therapy and should be followed up thereafter.
Method and results
Patients
All three were females (patients A,B, and C) and all of them had confirmed diagnosis with direct
immunofluoresence studies. Patient A was 31 year old and had PV since 2004. She was treated with
systemic steroids and immunosuppressants. She had residual localized disease which did not give
long standing remission even with second-line treatments (intravenous immunoglobulin and
plasmapheresis). Patient B was 63 year old with PV for 3 years. She responded well to conventional
treatment. While on oral steroids she developed haematemesis. Her steroid therapy was stopped by
the physicians. She developed severe relapse of disease two weeks later. Patient C was 39 year old
with PV for 1 ½ years. She responded partially to conventional therapy, but developed recurrences
whenever the dose of prednisolone was reduced. She had significant side effects with steroid therapy,
including hypertension, steroid induced diabetes mellitus, severe obesity, dyslipidaemia and
iatrogenic Cushing’s syndrome.
Treatment
All three patients received infusions of 500mg of Rituximab weekly for four weeks. Pre-medication
included 100mg of intravenous methylprednisolone, 10 mg of intravenous chlorpheniramine one hour
before infusion and two oral doses of 1g paracetamol twelve hours apart. Steroid dose was reduced to
maintenance dose of 12.5mg prednisolone daily and all other immunosuppressive drugs were
discontinued.
All three patients had full blood count, hepatitis B screening, ECG, liver and renal functions tests
performed before initiation of therapy. Patient B had to be kept in the ward throughout the treatment
duration due to the severity of the disease. Patients A and C were given Rituximab dose as in-patients
and were discharged from the ward after 24 hours observation. Patients were followed up in the clinic
monthly after treatment.
Response to treatment
Two months following Rituximab therapy patients A and C were disease free and the dose of
prednisolone was reduced further.(Figure-1).
Patient B who had severe disease achieved control of disease activity by the end of first month. She is
now in partial remission developing 1-2 small lesions per week. Her prednisolone dose remains
unchanged (Figure-2).
Figure 1: A resistant facial lesion of Patient A: a – before Rituximab therapy; b – two month after
completion of therapy
a 

Figure 2: Patient B: a, b – second week on Rituximab therapy; c – one month after completion of
therapy, d – two months after completion of therapy
a 
Adverse events
Patient A experienced transient hypotensive episodes during the second and third infusions. These
were managed with stopping the infusion and restarting along with normal saline infusion
simultaneously. Patient B developed a febrile reaction during third infusion which was treated
symptomatically. None of the patients developed severe infusion related reactions.
Patients A, B have now been followed for five months each and patient C for 3 months. Patient B had
developed widespread tinea corporis which was treated with oral Itraconazole. None of the patients
had severe bacterial or viral infections.
Discussion
Pemphigus vulgaris is an autoimmune bullous skin disease characterized by antibodies to the
desmosomal cadherin desmoglein-3 which have been shown to be directly pathogenic. However T
cells, other auto-antibodies and various cytokines are involved in the process of acantholytic blister
formation6.
Rituximab, is a Anti-CD20 chimeric monoclonal antibody which was initially approved for the
treatment of non-Hodgkin’s B cell lymphoma and later for resistant Rheumatoid arthritis. It has since
then been added to the treatment options of Pemphigus vulgaris2,3,4,5,7. CD20 molecule is expressed on
surface of cells of B cell lineage i.e. from pre-B to immature plasma cells and minority of mature
plasma cells2, 3, 7. Rituximab destroys CD20 positive cells of the B cell lineage. Mature plasma cells
continue to produce autoantibodies for few weeks . Therefore it takes few weeks to achieve remission.
Since it does not affect bone marrow stem cells there is no depletion of other bone marrow derived
cell lines2, 3, 7. Rituximab therapy is associated with prolonged B cell suppression. Since bone marrow
stem cells are spared B cell recovery occurs in about 6-9 months. However disease relapse was rare. It
was noted that B cell recovery is not associated with reappearance of pathogenic autoantbodies2, 3, 7.
In most of the reported cases of PV treated with Rituximab, steroids with or without
immunosuppressants have been used concomitantly. The probable reason for necessity of the other
drugs may be related to complex pathogenic mechanism of disease2, 3, 4, 5.
Rituximab has been used to treat PV when there is a failure of conventional therapy or in cases with
significant side effects or contraindications to conventional therapy2. Absolute contraindications are
allergy to drug or its components, pregnancy and breastfeeding. Hepatitis B carrier state, cardiac
arrythmias, angina pectoris, heart failure and active infection are relative contraindications2, 3, 7, 8.
Majority of side effects due to rituximab are mild transient and infusion related. These include chills
and fever, nausea, vomiting, diarrhea, heartburn, muscle or back pain, flushing, night sweats,
tiredness, burning or tingling in the hands or feet and runny nose8, 2, 3, 7.
Serious adverse effects include severe infusion-related reactions, arrhythmias, hypersensitivity, and
pulmonary toxicity. These are very rare and most frequently occur during the infusion of first dose of
the drug. These reactions are caused by release of massive amount of cytokines. These infusion
related adverse effects can be minimized by premedication with paracetamol, antihistamines and
corticosteroid8. Resuscitation facilities should be available at treatment setting for management of
reactions.
Hypotension during infusion is a common problem which can control by reducing the infusion rate
and the use of intravenous fluids. This problem can be minimized by withholding any
antihypertensive therapy 12 hours before infusion8.
Prolonged immunosuppression is associated with risk of viral infections like Hepatitis-B reactivation
and Progressive multifocal leukoencephalopathy (caused by JC virus).There are rare reports of severe
bacterial infections which can be fatal2, 4. Most of the reported severe infections occurred when
patients continued immunosuppressive drugs following Rituximab therapy. Thus maintenance therapy
with steroids only will be a safer option as suggested by Cianchini et al3.
The protocol being used to treat PV patients is most case reports was similar to that used to treat non-
Hodgkin’s lymphoma (375mg/m3 body surface area per dose) which may not be the ideal protocol in
the setting of immune mediated disease2. Ahmed et al have used combination treatment of Rituximab
and intravenous immunoglobulin successfully but cost for this regime is extremely high7.
Rarity of disease and high cost of the drug are obstacles to perform randomized controlled trials.
Recent literature review revealed 136 reported cases of Rituximab therapy for PV. 95% of those have
shown either complete or partial remission. However further studies are needed to establish an ideal
Rituximab regime5.
The dose of rituximab used for our patients was slightly lower than the required dose calculated
according to body surface area. This was unavoidable because Rituximab 100mg vials were not
available. Even with this slightly lower dosage regime all three patients showed good response.
In our patients there were transient milder infusion related events only. Patients are still being
followed up and there were no fatal or serious infections up to now. Antidesmoglein antibody titers
and B cell counts were not performed in our patients due to unavailability of facilities. These would
have been very valuable to assess the disease activity and response to therapy.
Rituximab was found to be an effective and relatively safe alternative treatment option in management
of these 3 difficult cases of PV even-though the cost was high.
References:
1. Herman KE, Albert S, Black MM. Guidelines for the management of pemphigus vulgaris. Br J
2. El Tal AK, Posner MR, Spigelman Z, Ahmed AR: Rituximab: a monoclonal antibody to CD20 used in the treatment of pemphigus vulgaris. J Am Acad Dermatol 2006; 55:449-459. 3. Cianchini G, Corona R, Frezzolini A, et al. Treatment of severe pemphigus with Rituximab: Report of 12 cases and a Review of the literature. Arch Dermatol 2007;143:1033-38. 4. Joly P, Mouquet H, Roujeau JC, et al. A single cycle of rituximab for the treatment of severe 5. Schmidt E, Goebeler M, Zillikens D. Rituximab in severe pemphigus. Ann N Y Acad Sci. 2009 6. Toto P, Feliciani C, Amerio P, et al. Immune Modulation in Pemphigus Vulgaris: Role of CD28 and IL-10. J Immunol 2000, 164: 522-529. 7. Ahmed AR, Spigelman Z, Cavacini LA, et al. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med2006; 355:1772-9. 8. Product monograph – Rituximab (Rituxan® ), Hofmann-La Roche Ltd. Ontario. 2010.

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