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Case Note

Case Note: Painful Sores in the Mouth

History

A 59-year-old male with no significant past medical history presents for management of non-healing painful sores in the mouth.

Initial evaluation

  • Patient reports having the sores for the past 6 weeks
    • On examination, the sores are erythematous irregular erosions on the soft palate and gingiva
    • There has been no improvement despite emiric courses of azithromycin and acyclovir
  • Initial workup for herpetic stomatitis (viral direct fluorescent antibody [DFA] or culture or empiric acyclovir) is negative
  • As the oral ulcerations have been present for more than a month, they are evaluated via biopsy for both haematoxylin and eosin (H&E) and DIF (direct immunofluorescence)
  • The patient's medications are carefully reviewed to evaluate for any agents as causes of drug-induced pemphigus (including, but not limited to, thiol-containing drugs, penicillamine, enalapril, and captopril) so that any suspected culprits could be discontinued if possible
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Diagnosis

  • A diagnosis of pemphigus vulgaris is rendered

Initial Treatment

  • A positive H&E and DIF confirms diagnosis of pemphigus vulgaris
    • Baseline titers of circulating anti-epithelial cell surface immunoglobin G (IgG; via indirect immunofluorescence [IIF]) or anti-desmoglein 1 and 3 antibodies (enzyme-linked immunosorbent assay [ELISA]) were determined
      • All were elevated
  • Hepatitis serologies and Quantiferon Gold were checked and negative
  • Patient given vaccinations for zoster and influenza
  • Treatment initiated with 60 mg prednisone daily and 2 g mycophenolate mofetil daily

Follow-up evaluation strategy

Follow-up evaluation:

  • After 2 months, the patient was in clinical remission and able to gradually taper prednisone down to a dose of 5 mg per day
    • If remission is sustained, mycophenolate mofetil will be weaned at 6 months or later
  • The titers of the circulating anti-epithelial cell surface IgG (via IIF) or anti-desmoglein 1 and 3 antibodies (via ELISA) will be rechecked at approximately 6-month intervals while on treatment, as a marker of disease activity and likelihood of future relapse

 
Further recommendations:

  • In the case of persistent oral lesions, treat for candidiasis with oral fluconazole 150 mg once weekly
  • Evaluate for herpetic gingivostomatitis, which may be a complicating factor, and treat if positive
  • Dental trays filled with superpotent topical steroids and worn for 4-8 hours daily may be effective for refractory gingival disease

 
Subsequent treatment steps:

  • In patients responding to the above treatment, gradually taper the systemic steroids and immunosuppressives over many months
  • The titer of the circulating autoantibody (via IIF or ELISA, as described above) may be useful in determining response to treatment and the rate at which immunosuppressive therapy can be tapered
    • It should be monitored about every 6 months and should decrease with each measurement
  • In refractory pemphigus vulgaris, consider the following options:
    • Increasing the dose of mycophenolate mofetil to 3 g/day
    • Azathioprine 2-4 mg/day
    • Monthly pulse steroids of 1 g of methylprednisolone daily for one to several days intravenously (IV); or dexamethasone 100 mg oral daily for 3-5 days
    • Rituximab IV - either using the rheumatoid arthritis protocol (1 g IV on Days 1 and 14) or the lymphoma protocol (375 mg/m2) weekly for 4 weeks (studies have shown roughly equal efficacy in terms of initial and sustained remissions with both protocols)
      • Increasingly, rituximab is being considered as a first- or second-line treatment for early disease, given promising evidence of durable remissions and ability to maintain remission off medication
    • High-dose IV immunoglobulin 2 g/kg/month given over several days
    • Daily cyclophosphamide 1-3 mg/kg/day; or cyclophosphamide 50 mg per day in combination with monthly pulses of 0.5-1 mg/m2
    • Cyclophosphamide treatment (1-3 mg/kg/day) is combined with systemic steroid therapy and often pulse systemic steroid treatment in refractory cases

General discussion

Pemphigus vulgaris is an autoimmune-mediated intraepidermal blistering disorder caused by the production of IgG autoantibodies to epidermal cell-cell adhesion molecules (desmogleins 1 and 3, 160 kD and 130 kD, respectively), resulting in separation and rounding up of epithelial cells (acantholysis) and intraepidermal clefting leading to blister formation. The typical age of onset of pemphigus vulgaris is 40-60 years. Incidence is roughly equal in men and women. Pemphigus vulgaris is a rare disease, with an incidence of 1-10 people per million worldwide. Regional and ethnic variation in incidence is significant, with increased incidence in Ashkenazi Jews and in persons of Mediterranean and Asian descent.


The disease clinically manifests with superficial blisters that rapidly rupture, leaving moist and open erosions that are susceptible to superinfection. Affected areas include the cutaneous surface (often including the face) and mucosal surfaces of the mouth (palate, gingiva, buccal mucosa) and less commonly the pharynx and vocal folds and anogenital mucosa. The disease often begins in the oral mucosa, with only subsequent involvement of other skin areas that may appear weeks to months later. Disease may remain mucosal only (correlating with circulating anti-desmoglein 3 autoantibodies), cutaneous only (anti-desmoglein 1 antibody predominant), or manifest with mucocutaneous involvement (anti-desmoglein 1 and 3 antibodies). Mucosal lesions of pemphigus vulgaris tend to present as slow-healing, painful erosions that may make oral intake difficult. Given the rarity of this condition, the correct diagnosis may not be reached for a prolonged period, despite the patient presenting to multiple healthcare professionals.


Pemphigus vulgaris used to be almost uniformly fatal within several years prior to the availability of systemic corticosteroids, with patients typically dying from infection and other complications of epidermal barrier failure. The life-threatening nature of pemphigus vulgaris mandates aggressive therapy; however, in the era of corticosteroids, more morbidity has resulted from the treatment than from the disease itself.


While systemic steroids were previously the sole mainstay of treatment, availability of effective steroid-sparing agents, and more recently rituximab infusions, has greatly improved outcomes in this disease

Further reading

Ahmed AR, Shetty S. A comprehensive analysis of treatment outcomes in patients with pemphigus vulgaris treated with rituximab. Autoimmun Rev 2015;14:323-31.


Currimbhoy S, Zhu V, Dominguez AR, Pandya AG. Rituximab in the treatment of 38 patients with pemphigus with long-term follow-up. J Eur Acad Dermatol Venereol 2015. [Epub ahead of print]. doi: 10.1111/jdv.13103.


Gregoriou S, Efthymiou O, Stefanaki C, Rigopoulos D. Management of pemphigus vulgaris: challenges and solutions. Clin Cosmet Investig Dermatol 2015,8:521-7.


Leger S, Picard D, Ingen-Housz-Oro S, et al. Prognostic factors of paraneoplastic pemphigus. Arch Dermatol 2012;148:1165-72.


Olszewska M, Kolacinska-Strasz Z, Sulej J, et al. Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris. Am J Clin Dermatol 2007,8:85-92.


Sinistro A, Calabresi V, Lupi F, et al. The pathogenic activity of anti-desmoglein autoantibodies parallels disease severity in rituximab-treated patients with pemphigus vulgaris. Eur J Dermatol 2015. [Epub ahead of print].


Wang HH, Liu CW, Li YC, Huang YC. Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens. Acta Derm Venereol 2015;95:928-32.


Zhu X, Zhang B. Paraneoplastic pemphigus. J Dermatol 2007;34:503-11.

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