Case Series of Pemphigus Vulgaris and Pemphigus Vegetans

Introduction

Pemphigus is a set of rare, chronic, autoimmune illness characterized by flaccid blisters on mucous membranes and skin that ruptures to cause painful, large erosions which are difficult to heal and can be fatal by causing sepsis or metabolic disturbances. The annual incidence of pemphigus varies among different populations and is estimated to range between 0.75 and 5 new cases per million.^1,2 The European Dermatology Forum suggests that prednisolone should be reduced by 25 percent every two weeks after the consolidation process and by 5 mg every four weeks if the dose is reduced to <20 mg. If the patient relapses, options include increasing steroids back to the preceding dose, adding an immunosuppressant if steroid monotherapy is used, or modifying the first-line immunosuppressant via any other immunosuppressant if aggregate therapy is already used.³ Pemphigus vegetans is the most uncommon form of Pemphigus vulgaris, with vegetating lesions over the flexures. It accounts for less than 5% of pemphigus vulgaris cases, and it is more prevalent in intertriginous locations.⁴

Hallopeau pemphigus develops into vegetating plaque. Oral mucosa is normally not involved in this. The oral mucosa is involved in Neumann pemphigus, which evolves into hypertrophic granulating erosions.⁵ Treatment options for Pemphigus includes steroids, immunosuppressants, supportive and symptomatic medicines.⁶ Plasmapheresis, immunoadsorption, and haematopoietic stem cell transplant have all been found to be useful in some patients. Excision of the vegetative lesion is a surgical intervention.⁷

Case Report 1

A 65-year-old male patient, with no significant past medical history presented with complaints of raw areas in the oral cavity since six months, itchy fluid filled lesions over upper and lower limbs, trunk, genitals since three months, with aggravation of lesions since two weeks.

History revealed that patient first developed painful raw lesions over the oral cavity and around the mouth. The itchy flaccid fluid filled lesions gradually progressed to bilateral upper extremities, trunk, lower extremities, genitals and buttocks. Lesions ruptured on their own to form raw areas with little tendency to heal and they gradually increased in size and number. Patient also complained of swelling of bilateral feet since two weeks, difficulty in swallowing, itching prior to onset of lesions. Patient visited outpatient department (OPD) with symptoms of oral cavity- erosions, whitish discharge over oral buccal mucosa and lips and multiple hypopigmented scaly macules over the back. Accordingly differential diagnosis was derived which included Pemphigus vulgaris, behcet’s disease. After a week, based on biopsy and Direct immunofluorescence (DIF) reports along with cutaneous examination, patient was diagnosed with Pemphigus vulgaris and was admitted in the hospital for further treatment. Skin biopsy report and cutaneous examination showed features which were suspicious for Pemphigus vulgaris. DIF demonstrated deposition of both IgG and C3 along the intercellular spaces of the epidermis.

On examination, patient was afebrile with blood pressure of 120/80 mmHg, pulse rate- 88 beats per minute (bpm), respiratory rate- 20 cycles per minute (cpm). Patient was poorly built, nutrition was poor, considerable weight loss was noted. Bilateral pitting oedema was present and patient had disturbed sleep. Systemic examination was normal with no focal neurological deficits. Pain score was 6/10. Palms and soles were spared.

No history of (H/O) any drug ingestion and topical application prior to onset, no H/O trauma, and toxic exposure were noted. No similar complaints and history of any autoimmune disease in the family was given. Patient mentioned the history of taking treatment for the same with ayurvedic medications without any relief.

A complete blood count was done which revealed mild normocytic, normochromic anaemia with neutrophilic leucocytosis. Leucocyte count total (LCT) was 16600/cu mm, neutrophils were in higher percentage (72%), hemoglobin was 12.8 g/dL, Mean Corpuscular Haemoglobin Concentration (MCHC) was 32.5 g/dL and platelet count was 369000/cu.mm. His HIV status was negative. Serum sodium and serum chloride levels were slightly decreased to 128 mEq/L & 93.4 mEq/L respectively, concluding moderate hyponatremia & hypochloremia. Serum total protein was 5.22 g/dl and serum albumin level was decreased (2.07 g/dl) suggesting hypoalbuminemia. Skin biopsy section was studied which indicated skin with dermis and epidermis. Epidermis showed mild acanthosis and focal spongiosis. One focus showed acantholysis involving follicular epithelium. Superficial dermis showed mild perivascular lymphocytic infiltrate. Cutaneous examination was relevant with multiple crusted erosions, flaccid bullae containing pus noted over perioral region bilaterally (b/l), over upper and lower limb extremities, abdomen, back, b/l gluteal region. Nikolsky sign was positive.

Hypopigmented macules were observed on the chest. Crusted plaques were noted over nasal cavity on b/l sides.

In this case, patient was treated with the following medications: Topical fusidic acid & hydrocortisone were prescribed to be applied over the erosions along with an antibiotic Mupirocin ointment BD. Corticosteroids, Betamethasone injection OD for 12 days and oral Prednisolone 40 mg/day for initial 10 days followed by 50 mg/day for 3 days, immunosuppressant- Azathioprine tablet 50 mg OD for 7 days & BD for 5 days, antihistamine- Hydroxyzine hydrochloride tablet 10 mg TID for 10 days, multivitamin syrup and 2 egg whites per day were also advised. High protein diet was advised since the patient was malnourished. During his hospital stay, the patient’s condition improved and was discharged with prescription of Azathioprine tablet 50 mg and tablet Prednisolone 50 mg to be continued and was tapered during the next OPD visits.

Case Report 2

A 38-year-old female patient was hospitalized for painful raw areas in the oral cavity associated with difficulty in swallowing for past six months. Initially patient developed blisters in the mouth which increased in size and bursted open spontaneously, leaving raw areas which healed slowly. Patient then developed multiple fluid-filled lesions over the back of neck, right underarm, abdomen and genitalia. These lesions bursted on their own to form raw areas within four days. These lesions showed little tendency to heal and became hyperpigmented. The lesions were associated with itching. Patient also complained of weight loss (5 kgs in the past 6 months), redness of eyes for four months occasionally. No history of itching prior to the onset of the lesions was noted. No history of palm and sole involvement, new drug ingestion prior to onset of symptoms, photosensitivity, joint pain & insect bite was noted.

No history of similar complaints in the family was given. On her previous admission, she was treated initially with vitamin tablets, Fluconazole tablet 400 mg, Ornidazole tablet 500 mg, Cefixime tablet, triamcinolone oral paste and then with methotrexate tablet and a folic acid supplement and was diagnosed with Pemphigus vulgaris along with discharge medications including Tab prednisolone 10 mg BD for 10 days, Zinc tablet, white soft paraffin for application over lips. Biopsy reports showed intra-epithelial/suprabasal bullous lesion, double stranded DNA (Ds-DNA) was negative. Patient had experienced decrease in sleep and menstrual history revealed regular cycles with three days flow. On general examination, patient was conscious and well oriented to time, place and person. Blood pressure was 110/80 mmHg, pulse rate was 76 bpm, respiratory rate was 20 cpm and patient was afebrile. Systemic examination was normal with no focal neurological deficit.

Cutaneous examination revealed multiple crusted erosions over the lips along with few haemorrhagic crusts. Multiple erosions with white plaques were noted over buccal mucosa. Few pustules and papules were noted over the chin. Multiple vegetative hyperkeratotic plaques with erosion were noted over bilateral axilla, bilateral labia majora, mons pubis, inner aspect of bilateral thighs and abdomen. Single hyperkeratotic plaque with erosion and pus discharge was noted over posterior aspect of the lip. Nikolsky sign was positive. Bullae spread sign could not be elicited. In the scalp, single vesicle was noted. Palms and soles were normal. Mucosa showed conjunctival redness in bilateral eyes. Oral examination revealed cerebriform tongue, multiple erosions over buccal mucosa, crusted erosions over lips. Hair was normal and transverse ridges were noted over bilateral toe nails. In view of oral cavity manifestations and genital vegetative growth, a provisional diagnosis of Pemphigus vegetans and behcet’s syndrome were obtained.

Skin biopsy was done which showed revealing features suggestive of Pemphigus vegetans. Section studied showed the skin with epidermis and dermis. Epidermis exhibited acanthosis. Eosinophil predominant inflammatory infiltrate was seen in the epidermis and dermis producing spongiosis and abscess in the epidermis. Intra- epidermal abscess was composed predominantly of eosinophils with a few neutrophils, lymphocytes and degenerated cells. Suprabasal clefting containing eosinophils was noted focally. The dermis shows perivascular and periadnexal inflammatory infiltrate and melanin pigment incontinence. Direct immunofluorescence features were suggestive of Pemphigus vulgaris / Pemphigus vegetans. IgG and C3: Squamous intercellular junction showed lace like positivity while IgA & IgM were negative. The diagnosis of Pemphigus vegetans of Hallopeau was additionally confirmed by direct immunofluorescence of perilesional skin that exhibited intercellular deposits of IgG and C₃. Based on patient’s history, cutaneous examination, DIF and skin biopsy reports, final diagnosis of Pemphigus vegetans was made. She was treated with systemic steroids, IV antibiotics and topical antibiotics and other supportive management. Patient improved during the course of stay in the hospital and was discharged with stable vitals.

She was started with systemic corticosteroid Betamethasone 1 cc BD for initial five days and then tapered and switched on to oral corticosteroid Prednisolone 40 mg for three days. Patient reported to have significant regression of lesions. Patient was referred to ophthalmology in view of redness of both the eyes and was diagnosed with bilateral episcleritis secondary to systemic condition and was advised corticosteroid Loteprednol etabonate (0.5% w/v) and LUBREX (carboxymethylcellulose) eye drop.

Case Report 3

A 38-year-old male patient known case of Pemphigus vulgaris reported with the chief complaint of whitish lesion over the tongue & buccal mucosa and pain while swallowing since seven weeks, along with multiple fluid filled blisters over the trunk and pain & swelling around nails of both the hands since five weeks. History revealed that the patient first noticed lesions in the oral cavity along with whitish lesion over the tongue associated with dysphagia for solid food followed by multiple fluid filled blisters over the trunk which eventually bursted open to form raw areas over the trunk five weeks ago. The lesions then progressed involving the chest, extremities, back and genital areas. Initially lesions were fluid filled which bursted open to form raw areas, which showed little tendency to heal. Patient also complained of pain and swelling around finger nails of both the hands since five weeks. It was associated with redness of skin around the nails. Patient was admitted twice for the above complaints and was treated with two doses of Rituximab injection in 250 ml NS (Normal saline) & steroids, followed by persistence of lesions. The patient presently visited the hospital with the aggravation of oral lesions and with persistence of raw areas over the trunk and bilaterally over upper limbs. History of weight loss associated with loss of appetite and malaise was present. He was also diagnosed with oropharyngeal candidiasis and was treated with broad spectrum antifungals. A review of family history was non-contributory. He was an occasional alcohol consumer.

On general examination, the patient was moderately built and nourished. Multiple erosions with hemorrhagic crustings were noted over chest, abdomen, back, groin folds and face. Nikolsky’s sign showed a negative reaction. Oral examination revealed extensive whitish plaques along with multiple erythematous erosions over the tongue, buccal mucosa and palate. Erosions with hemorrhagic crustings were noted over lower lips and angle of mouth. Few erosions over bilateral groin folds were noted. Erythema, swelling and mild tenderness around finger nails of both the hands were present. Patient was found to have persistence and even exacerbation of lesions in the oral cavity and trunk. Medical oncology orders were followed and the patient was found to have raised Carcinoembryonic antigen (CEA). To evaluate the same, patient underwent Contrast enhanced computed tomography (CECT) chest and abdomen, gastroscopy and colonoscopy that showed a few ulcerations in the oral cavity, pharynx, vocal cords, colonic diverticulum, hemorrhoids and fissure-in-ano which were of minimal significance. The reports were normal, therefore paraneoplastic pemhigus was not considered as a likely diagnosis.

Azathioprine was started and was withheld in view of exacerbation of erosions in the oral cavity, reduced leucocyte count and deranged liver function tests. He was treated with 3^rd dose of Rituximab 500 mg in 500 ml NS, initiated at 20 ml/hr, increased every half hourly by 10 ml/hr up to a maximum of 80 ml/hr with vitals stable. No adverse reactions were noted during and post infusion. Fourth dose of Rituximab 500 mg in 250 ml NS infusion was started at 25 ml/hr, increased every half hour by 25 ml/hr up to a maximum of 125 ml/hr. The infusion was reduced to 80 ml/hr as bradycardia was noted. Vitals were stable following the same and no adverse events were noted during and post infusion. Immunosuppressant Mycophenolic acid 500 mg, steroid Prednisolone 50 mg/day were continued and tapered over subsequent follow-up visits.

  Discussion

Dermatological disorders associated with large bullae on the oral mucosa such as dermatitis herpetiformis, pemphigus erythematous, pemphigus folliaceus, pemphigus benignus familiaris chronicus should be screened during the differential diagnosis of Pemphigus vulgaris. Usually in Pemphigus vulgaris cases, 99% cutaneous lesions and 57% of oral lesions are detected within six months. Usually, the evolution of Pemphigus vulgaris begins with painful mucosal ulcerations, particularly inside the mouth. These ulcers are persistent, individual ulcers may come and go, but there are still fresh lesions. Pemphigus vulgaris will also need long- term therapy to hold it in remission.⁸ In most Pemphigus vegetans cases, oral mucosal and cutaneous lesions occur in the same person. Only mucosal appearance is observed very seldom.⁹ It is clinically characterized by vesicles; erosions result in thick hyperkeratotic masses particularlyy in the intertriginous regions with involvement of oral mucosa invariably.¹⁰ Cerebriform tongue which was seen in the present case has been regarded as an eponymous sign, a clinical sign or a clue for Pemphigus vegetans in cases of bullous dermatoses of flexures.¹¹ Pemphigus vegetans is a unique variant of pemphigus that is often under recognized and frequently misdiagnosed. Patients undergoing treatment for Pemphigus vegetans not only need to be educated about the adverse effects, but also require lifetime monitoring and treatment.

  Conclusion

Pemphigus is a life-threatening condition with a high fatality rate. As a result, diagnosis should be made as soon as possible, and treatment should begin at the earliest. Better understanding of the role of immune dysregulation in pemphigus pathogenesis will lead to the development of new targeted therapeutics.