Laboratory Data

Pemphigus vulgaris

Pemphigus vulgaris is a potentially fatal autoimune blistering disease. He was admitted for inpatient treatment with IV fluids to correct his dehydration, IV antibiotics (cloxacillin and ceftriazone ) and oral prednisolone 40mg tid were administered. Azathiprine and oral dapsone was also re-introduced. Blood was drawn and punch biopsy taken. We are watching his progress closely and considering alternative adjuvant therapy.

The most commonly used adjuvants, the antimetabolites, azathioprine and mycophenolate mofetil are usually sufficient to induce remission in many patients. (1)

However, in severe refractory cases oral cyclophophamide would be an highly effective therapy for refractory PV. One serious adverse effect of oral cyclophosphamide therapy is the development of bladder carcinoma. (2)

A recent article suggested the use of monoclonal anti CD20 antibody therapy (rituximab) which could induce long term remission (forty weeks) This was administered with four infusions of anti CD20 antibody given intravenously once a week. (3)

The other issue involved is the compliance on the part of the patient. Why did he seek treatment from traditional healers and waited till the disease is so severe before he seek proper treatment? He did mention that he has fear of taking high dose corticosteroids.

Your comments would be highly appreciated.

1. Enk AH et al. Mycophenolate is effective in the treatment of pemphigus vulgaris. Arch Dermatol 1999;135:54-56 (view abstracts)
2. Cummins et al. Oral cyclophosphamide for the treatment of pemphigus vulgaris and foliceous. J Am Acad Dermatol 2003;49;276-280 (view abstracts)
3. Espana A et al. Long term complete remission of severe pemphigus vulgaris with monoclonal anti CD20 antibody therapy and immunophenotype correlation. J Am Acad Dermatol 2004;6;974-976

David Elpern MD, Williamstown, MA, USA on Nov 11, 2004

This case demonstrates how important the doctor-patient relationship is. The patient lives 120 km from you and needs to be seen regularly and to understand that without your meds he will die. Some of our older colleagues can remember pemphigus in the era before steroids. The dermatology wards were full of these patients just waiting for sepsis.
It will be interesting to hear the comments from some experts in bullous disease; but also keep in mind that your relationship with this patient will determine how he does. The treatment is more straightforward than forming a relationship with this man. I have confidence that you will forge a truly therapeutic partnership with him now that he knows what will happen if he is not compliant. I suspect you will need to see him every couple of weeks for a few months to make sure he understands the treatment and trusts you, not the traditional healers in his area.

Khalifa Shaquie MD, PhD, Professor of Dermatology, College of Medicine, University of Baghdad, Baghdad, Iraq on Nov 12, 2004

Pemphigus vulgaris is relatively a common social & medical problem in Iraq, often affecting young adult people. Most patients do not take their therapy in the right way & some of them default. All are afraid from the side effects of the drugs. So public education regarding the disease & therapy is strongly recommended. All patients should be told that the drug dose is initally high,then reduced gradually over time & might be stopped. This might minimise the trauma & make therapy more easy. I agree about diagnosis & management.

Abir Saraswat MD, Lucknow, India on Nov 12, 2004

This is a very common problem in India and we have faced it, alas all too often. In this case, the lure of a "permanent" cure without "toxic" allopathic medicines may have been too great for the patient to resist. We find that if too much emphasis is laid on acquainting the patient with adverse effects of steroids, they get scared, especially in pemphigus, where large doses are used for long (indefinite) periods.
As regards therapy, I would suggest monthly dexamethasone and cyclophosphamide pulse therapy (you can substitute methylpred for dexa), which works beautifully and with minimal side effects.
(Kanwar AJ, Kaur S, Thami GP. Long-term efficacy of dexamethasone-cyclophosphamide pulse therapy in pemphigus. Dermatology. 2002;204(3):228-31. )

Omid Zargari MD, Assistant Professor of Dermatology, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran on Nov 12, 2004

I'm working in an area that pemphigus is not uncommon (we have about 25 new cases each year). The first line therapy for pemphigus is systemic steroid, which reduces the responsible autoantibodies, but with regarding the relatively long half-life of these antibodies (about 3 weeks), response will occur slowly. Therefore, we should try to convince the patients about the importance of long-term therapy.
In the case of non compliance with long-term hospitalization, I have two suggestions; 1. Dexamethasone- Cyclophosphamide pulse therapy. It is effective, but needs closer monitoring. 2. IVIG. It is safe and usually works good in pemphigus (at least in early phases), but there is a major drawback: its cost!

Raafah Hayani, MD, Baghdad, Iraq on Nov 13, 2004

We've so many cases of severe pemphigus vulgaris in Iraq since most of the patients give up treatment after early good response. We manage these cases in isolated burn unit like room with iv fluids and under the cover of antibiotics with potassium permanganate bath 1:8000 with methylprednisolone pulse therapy iv in drip 1Gm daily for three days. All immunosuppressive therapy has delayed action to spare steroids and I agree with you that imuran is of little benefit in such cases and sometime we feel that steroid alone work in such cases. Cyclophosphamide is a good choice with the pulse therapy

Phung Huynh, MD, Department of Dermatology, NY Medical College, New York, NY, USA on Nov 13, 2004

Dr Ahmed at Harvard has written multiple studies regarding IVIG for possible cure of bullous disease refractory to other treatment or for the desired effect of reducing /stopping prednisolone therapy. He also discussed his method of treatment on one of the Dialogues in Dermatology. If you like more specific advice on this patient or the specifics on how to use IVIG I can get you in touch with Dr Ahmed's fellow.

Victoria P Werth, M.D., Professor of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA on Nov 13, 2004

Often when therapy is abruptly stopped for PV, the patient appears to become more steroid-resistant. Thus treatment is likely to be a challenge in this case. The dose of steroid seems appropriate. At times, pulse steroids (1 gm solumedrol/day for 5 days) can very rapidly halt a severe case of unresponsive PV. The choice of immunosuppressives are outlined well. Cytoxan does work better, but has more toxicity. If this case is refractory to improvement with steroids, then cytoxan would be a reasonable choice as adjunctive immunosuppressive therapy. Sometimes refractory cases respond with institution of either iVIG (2 gm/montly cycle, given over five consecutive days each month) or plasmapheresis 3 times a week for several cycles (every few weeks). Plasmapheresis should be undertaken only after immunosuppression with imuran, cellcept, or cytoxan has been on board for 3-4 weeks. Otherwise, there can be a rebound of disease activity after stopping plasmapheresis!
Another potential adjunctive therapy is rituximab, but experience is limited with this agent in pemphigus vulgaris and it can be very immunosuppressing and has been associated with atypical severe infections.
This patient is likely severely depessed, a combination of his severe disease and the prednisone therapy. This should be addressed in order to increase the likelihood of compliance to the current recommended therapies. It is not infrequent for patients to seek alternative therapies when they are frustrated with their disease or the side-effects of the therapies they are getting. The importance of compliance has to be repetitively stressed to the patient, but clearly there are patients who are unable to follow through with therapy. These patients do poorly long-term.

Richard Sontheimer M.D., Professor of Dermatology, University of Iowa Carver College of Medicine, Iowa City, IA, USA on November 14, 2004

I will play the devil's advocate with respect to diagnostic possibilities concerning the recrudescence of blistering disease.

Considering the very abrupt and aggressive pattern of blistering disease reoccurrence and other information given about this episode, I would first have several questions about the specific cause of the recurrent episode of blistering disease before accepting this is a case of recurrent pemphigus vulgaris mucocutaneous disease activity. Specifically, could there be a superimposed element of drug-induced (dapsone) hypersensitivity such as bullous erythema multiforme major (Stevens-Johnson syndrome)? In addition, could there be an element of staphylococcal scalded skin syndrome in this immunosuppressed adult?
Had the patient continued taking his prednisone, azathioprine, and dapsone after discharge from the hospital up until the time of recurrent skin disease activity? If so, had the doses of the drugs been significantly lowered immediately prior to re-expression of blistering disease activity?
The clinical photographs appear to have solitary skin lesions displaying a targetoid appearance. In addition, the hemorrhagic crusting of the lips that is present would also suggest a bullous erythema multiforme reaction although this would also be compatible with a recurrent episode of pemphigus vulgaris.
The photographs would suggest lip and oral mucosal involvement during the current episode of recurrent disease. Specifically, it would be important to know whether the ocular conjunctivae were also inflamed during the recurrent episode? If so, this would not be compatible with recurrent pemphigus vulgaris but would be expected to be a component of an erythema multiforme major reaction. If this man does have a component of Stevens-Johnson syndrome, is there any evidence that he might have HIV infection as a predisposing factor for the development of a Stevens-Johnson syndrome pattern of hypersensitivity?
Was the skin biopsy showing suprabasalar acantholysis taken from the original diagnostic skin biopsy or from skin lesions occurring during the period of recrudescent disease? If a skin biopsy taken during recrudescent skin disease activity showed a more superficial form of acantholysis, this would be supportive of a superimposed staphylococcal scalded skin syndrome. Was direct immunofluorescence microscopy examination carried out on the original and/or any follow-up skin biopsies?
Regarding management, if there is any evidence of drug- or infection- (herpes simplex, Mycoplasma pneumonia) induced erythema multiforme major, then withdrawal of suspected drugs and treatment of associated infections should be carried out. In addition to aggressive parenteral antibiotics covering staphylococcal infection (including the possibility of methicillin-resistant staphylococcus), high dose corticosteroids, cyclophosphamide, and anti-CD 20 monoclonal antibody, consideration might also be given to high dose intravenous immunoglobulin therapy as this could be of benefit in either recrudescent pemphigus vulgaris or the Stevens-Johnson syndrome.
Best on luck with this most challenging case.

Sunil Dogra MD, Dept. of Dermatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India on Nov 16, 2004

Pemphigus is a very common bullous disorder in India. At any point there are 4-5 patients admitted at our centre for management. There seems to be no doubt in diagnosis and clinical photographs are convincing. Regarding therapy we have very good experience with Dexamethasone - cyclophosphamide pulse (DCP) therapy as mentioned by Dr Abir Saraswat. However, septicemia compounded by DCP in such setting of widespread eroded skin is a potential practical problem. In such a critical situation tiding over the crisis with IVIg followed by DCP is a better option. However, because of cost consideration, most of patients are unable to afford IVIg in India.

Julian Manzur MD, Havana, Cuba on Nov 16, 2004

I have nothing to add. I agree completely with the thoughts and doubts of Professor Sontheimer

Nurul Amin MD, Dhaka, Bangladesh on Nov 17, 2004

Pulse therapy with cyclophosphamide & dexamethasone will be appropriate here. Since denuded areas are generalized then electrolyte estimation should be done frequently. Systemic antibiotic with topical antibiotic dressing is also required. More over close monitoring of the patient is essential.

Samer Ghosn MD, Department of Dermatology and Dermatopathology, Boston University School of Medicine, Boston, MA, USA on Dec 6, 2004

Whenever pemphigus vulgaris and erythema multiforme are part of a differential diagnosis, paraneoplastic pemphigus should be considered. I believe this patient should be investigated for a lymphoproliferative condition.