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 Table of Contents  
CASE REPORT
Year : 2019  |  Volume : 31  |  Issue : 4  |  Page : 386-390

Management of pemphigus vulgaris with rituximab: A case report and brief review on emerging treatment options


1 Department of Oral Medicine and Radiology, Ragas Dental College and Hospital, Uthandi, Chennai, Tamil Nadu, India
2 Department of Oral Medicine and Radiology, Sri Venkateshwara Dental College and Hospital, Off. Old Mahabalipuram Road, Near Navalur, Thalambur, Chennai, Tamil Nadu, India
3 Department of Dentistry, Sri Manakula Vinayagar Medical College and Hospital, Puducherry, India

Date of Submission12-Jul-2019
Date of Acceptance18-Nov-2019
Date of Web Publication03-Mar-2020

Correspondence Address:
Dr. Naga Leela Guntuku
Department of Oral Medicine and Radiology, Sri Venkateshwara Dental College and Hospital, Off. Old Mahabalipuram Road, Near Navalur, Thalambur, Chennai - 600 130, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaomr.jiaomr_132_19

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   Abstract 


Pemphigus vulgaris is the most common autoimmune vesiculobullous disorders. It presents with flaccid bullae on the skin and erosions on the mucosa. Severe cases can be life-threatening and hence prompt treatment can prevent untoward consequences. Earlier, steroids were the mainstay of treatment but it causes further medical problems. Nevertheless, new studies have emerged about the pathogenesis of the diseases and treatment protocols have been updated with newer drugs that had comparatively less adverse effects. We report a case of pemphigus vulgaris with extensive involvement of skin and oral mucosa treated with rituximab and adjuvant immunosuppressants and a brief update on various treatment protocols.

Keywords: Corticosteroids, pemphigus vulgaris, rituximab


How to cite this article:
Francis M, Guntuku NL, Leena D, Geetha R. Management of pemphigus vulgaris with rituximab: A case report and brief review on emerging treatment options. J Indian Acad Oral Med Radiol 2019;31:386-90

How to cite this URL:
Francis M, Guntuku NL, Leena D, Geetha R. Management of pemphigus vulgaris with rituximab: A case report and brief review on emerging treatment options. J Indian Acad Oral Med Radiol [serial online] 2019 [cited 2020 Jul 2];31:386-90. Available from: http://www.jiaomr.in/text.asp?2019/31/4/386/279847




   Introduction Top


Pemphigus is a group of autoimmune, blistering disease which is potentially fatal presenting as blisters and erosions involving the skin and mucosa. The origin of the name pemphigus is from the Greek word “Pemphix” meaning bubble or blister.[1] Pemphigus vulgaris is the most common type with incidence rate of 0.1–0.5/1000000 population/year.[2] This disease has a female predilection and shows a peak in the fifth and sixth decade of life. Oral lesions precede the occurrence of skin lesions in over 70% of cases and in cutaneous disease 90% of cases show concomitant oral lesions. The integrity of skin and mucosal keratinocytes is maintained by cell-cell adhesion molecules, namely desmosomes.[3] In pemphigus, IgG autoantibodies are directed against desmogleins causing breakdown of skin and mucosal barrier which is evident as an intraepithelial blister. This case report discusses a severe case of pemphigus vulgaris treated with a multidisciplinary approach by dentists and dermatologists using rituximab and adjuvant immunosuppressants as first line of treatment instead of conventional corticosteroid therapy.


   Case Report Top


A 55-year-old female patient reported with a complaint of ulcers in her mouth for the past 3 months. On further questioning, she revealed that she first developed bullae on her chest 5 months back which ruptured to form erosion and the lesion healed spontaneously leaving behind scab. Later she developed multiple ulcers in mouth which affected her normal oral functions. Her medical history was significant for epilepsy and she was under phenytoin for past 30 years.

Clinical examination revealed erythematous lesions with crustation of size 1 × 1.5 cm, irregular in shape which bleeds on touch on the lower lip as shown in [Figure 1]. Erosions were present on the chest and trunk of size 1 × 1 cm, oval, erythematous base, and surrounded by erythematous halo as shown in [Figure 2]. Intraoral examination revealed irregular ulcers in the lower labial mucosa below the vermilion border of size 1.5 × 2 cm, with erythematous base without surrounding erythematous halo, bleeds on touch. Ulcer involving the labial frenum of size 1 × 0.5 cm, covered with slough was present, Desquamation of upper and lower anterior gingiva was evident as shown in [Figure 3]. Ulcers of irregular shape were seen in the floor of mouth with hyperkeratinized border, erythematous base as shown in [Figure 4]. Ulcers were also seen in the buccal mucosa and palate. Mucosa over the lower lip and buccal mucosa peeled on lateral pressure with bleeding and showed a positive Nikolsky's sign. The various differential diagnosis as pemphigus, pemphigoid, erosive lichen planus, bullous lichen planus, and paraneoplastic pemphigus was observed.
Figure 1: Crustation on lower lip

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Figure 2: Erosions on the chest

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Figure 3: Ulcer of labial mucosa, labial frenum, and erosion of marginal gingiva

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Figure 4: Irregular ulcers on floor of the mouth

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A perilesional biopsy was attempted in the lower labial mucosa but extreme fragility of the mucosa was noted. Histological examination revealed a suprabasilar loss of epithelium. As histopathology was inconclusive, the ELISA test was done which has high specificity. ELISA test for anti-desmoglein 1 and 3 antibodies was done which revealed high levels of both anti-desmoglein antibodies 1 and 3, with predominant increase in anti-desmoglein antibody 3. Based on the examination and investigations, we came to a final diagnosis of pemphigus.

Baseline investigations including complete blood count, differential count, blood glucose level, urine analysis, serum electrolytes, liver function test, chest X-ray, and blood pressure were done. Recent advancements in the management of pemphigus advocate the use of biological therapies which has shown good results.[4] Management was based on an updated rheumatoid arthritis protocol with rituximab and immunosuppressants. Systemic corticosteroids 20 mg was started and oral prophylaxis was done. Routine oral hygiene instructions were given. Remission induction was done with rituximab, a monoclonal antibody given as 1 gm intravenously 2 infusions 15 days apart and systemic corticosteroids 20 mg once daily tapered by 5 mg every month, methotrexate 7.5 mg once a week along with vitamin B3, B6, B12 combination once daily throughout treatment. She was regularly under follow up. When the patient was observed 6 months later, there was complete regression of the lesion as seen in [Figure 5], [Figure 6], [Figure 7], [Figure 8].
Figure 5: 6 months post treatment healed lip

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Figure 6: 6 months post treatment healed labial mucosa and gingiva

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Figure 7: 6 months post treatment healed ulcer on floor of mouth

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Figure 8: 6 months post treatment healed erosions on chest

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   Discussion Top


Pemphigus is a potentially life-threatening, autoimmune, intraepithelial blistering disease of the skin and mucous membranes. It is due to autoantibodies directed against desmogleins which are cell-surface proteins. Among the various types as discussed above, pemphigus vulgaris is the most common form. It initially presents as oral ulceration in 70%–90% of cases and later the skin also becomes involved with blisters and erosions.[5] Pemphigus foliaceus is present in the endemic form and the blister occurs in the superficial granular cell layer, whereas in PV, the lesion is deeper, just above the basal cell layer. The foliaceous and erythematous forms of the disease do not involve the mucosa and are mostly drug-induced, namely D-penicillamine and captopril. IgA pemphigus is a rare form of pemphigus with deposition of IgA instead of IgG on surface epithelial cells.[6]

The epidermal cell-cell junction is contributed by intercellular adhesion proteins, desmosomes. They anchor the keratin intermediate filament to the cell membrane of epidermal cells. Desmosomal protein, desmoglein 1 (DSG 1) is the major component of epidermal desmosomes, whereas desmoglein 3(DSG 3) is the main cadherin or adhesion molecule in oral mucosa and also plays a role in skin adhesion. In pemphigus vulgaris, the desmosomes, DSG 1 and 3 act as autoantigens resulting in acantholysis.[7] Studies have shown the role of other nondesmosomal antigens, such as E-cadherins[8] and keratinocyte acetylcholine receptor which regulates intraepithelial expressions of desmogleins.[9] A type 2 hypersensitivity reaction occurs where antibodies are produced against the cell surface receptors. This leads to loss of integrity of keratinocytes present in the stratum spinosum. The cells are intact but are not attached to each other forming intraepidermal clefts, vesicles, and bullae.

Patients with certain HLA genotypes, particularly DR4 are predisposed to pemphigus. Environmental factors such as medicines, viruses, allergens, radiation, stress, and diet can trigger the immune system in susceptible individuals. Medicines such as penicillin, cephalosporin, captopril, aspirin, levodopa, heroin, viruses such as herpes virus and organophosphate exposure have been known to cause pemphigus.[10] In these patients, there is overactivation of T helper 2 (Th2) cells. This leads to increased production of interleukin (IL-4), which in turn activates primed B cells and isotype switching from IgG1 to IgG4 antibodies which are present during active stages of the disease. IL-4 also causes naive T cells to differentiate to Th2 cells. During remission, IL-10 production increases and T helper 1 response which causes antibody isotype switching from IgG4 to IgG1. Hence, pemphigus can be treated by the prevention of antibody production and prevention of isotype switching from IgG1 to IgG4.[11]

Treatment of pemphigus is aimed to control the disease progression and prevention of relapse. Conventional treatment is with systemic corticosteroids. The death occurred mostly in elderly patients or due to the adverse effects of corticosteroid treatment, due to bacterial septicemia, mostly from Staphylococcus aureus. Mortality rate reduced from 75% in the pre-corticosteroid era to 4.8% and 25.9%.[12] Corticosteroids downregulate the expression of pro-inflammatory proteins, resulting in suppression of B cell clone, thus reducing autoantibodies and suppression of cell-mediated immunity and further reduction T cell proliferation.[13] This results in the anti-inflammatory, antiproliferative, and immunosuppressive effects. The recommended dose of oral prednisolone is 0.5–1.5 mg/kg/day and to be increased to 2 mg/kg/day if control of disease does not occur after 2 weeks.[14] Once remission is achieved, prednisolone is tapered by 25% every 2 weeks after the consolidation phase and once the dose cell-mediated to 20 mg, it is tapered by 5 mg every 4 weeks.[15] When a higher dose of oral prednisolone of more than 100 mg is required, pulse therapy with 100 mg of dexamethasone intravenously is given for 3 days every 2–3 weeks.

Prolonged use of corticosteroid use of more than 4 months leads to various complication hence adjuvant immunosuppressants can be used. Once the patient enters remission, the dose of corticosteroids can be tapered slowly. When the steroids can be stopped and the patient kept in remission, the other immunosuppressant drugs can be tapered. According to European Dermatology Forum guidelines, commonly used first-line immunosuppressant adjuvant therapy are azathioprine in a dose of 1–3 mg/kg/day and mycophenolate mofetil at dose of 0.5–1.5 g twice daily. Azathioprine is an antimetabolite and causes myelosuppression. Hence, frequent blood check-ups and monitoring of kidney and liver function bi-weekly for the first 3 months and again periodically is required.[16] Gastrointestinal side effects are seen in mycophenolate but it has less glucocorticoid sparing effect when compared to azathioprine.[17] Recommended second-line adjuvant therapy is cyclophosphamide at dose of 500 mg IV infusion or as 2 mg/kg/day orally. Other steroid-sparing agents used are dapsone at dose of 100 mg/day and methotrexate at dose of 7.5 to 25 mg weekly.[18] Plasmapheresis can also be done in recalcitrant cases which nonspecifically removes high molecular weight substances from plasma. 4 to 5 sessions over a period of 7 to 10 days removes about 90% of immunoglobulins.[19] Immunoadsorption is also a type of extracorporeal blood purification method which specifically removes circulating antibodies.

New therapies with the introduction of intravenous immunoglobulins with immunomodulatory action that were safer, more targeted therapy rather than immunosuppressive actions of corticosteroids are the emerging treatment options for pemphigus. Intravenous immunoglobulins reduce IgG4 and IgG1 antibodies. Rituximab, a chimeric monoclonal antibody acting against CD 20 antigen present in B cells. It acts against autoreactive and mature B cells and against desmoglein three specific autoreactive T cells and spares plasma cells. Commonly used protocols in the treatment of pemphigus are lymphoma protocol and rheumatoid arthritis protocol. Rheumatoid arthritis protocol involves the administration of two doses of 1000 mg of rituximab given 2 weeks apart. Rituximab is given along with low dose corticosteroids and other adjuvant immunosuppressants. Though treatment guidelines[13] recommends rituximab as second or third line of treatment, study done by Joly et al.[20] used rituximab with low dose corticosteroids as first line of treatment with up to 85% of patients achieving clinical remission during 36 months follow up. Recent recommendations[21] have suggested use of rituximab as first line of management. Trials are being carried out with newer second-generation monoclonal antibodies with better and prolonged efficacy.[22],[23],[24] Other treatment options are T cell immunotherapy using anti-CD154 antibody, P38MAPK signaling pathway inhibition which inhibits p38 mitogen-activated protein kinase that causes remodeling of actin cytoskeleton and keratin filament retraction leading to loss of cell adhesion, inhibition of cAMP pathway, Bruton's tyrosine kinase inhibitors which cause modulation of B cell receptor-mediated B cell pathways.[25]

In this case report, pemphigus was treated with rituximab as the first line of treatment as per the rheumatoid arthritis protocol. About 1 gm rituximab was given intravenously with two infusions 15 days apart along with systemic corticosteroids 20 mg once daily tapered by 5 mg every month, methotrexate 7.5 mg once a week along with vitamin B3, B6, B12 combination once daily throughout treatment. Complete clinical remission was achieved with no adverse effects. The blood investigations are within normal levels and the patient is still under follow up. Thus targeted therapy provides a clinical remission with less side-effect profile than high dose corticosteroids and better patient compliance to treatment.


   Summary and Conclusion Top


Pemphigus vulgaris is an immune-mediated disorder. Management has evolved from high dose corticosteroid therapy with increased adverse effects to targeted therapy against antibodies. Future treatment strategies include targeting specific pathways of autoimmunity.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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[PUBMED]  [Full text]  
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]



 

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