Author Information
Pradhan M*, Vaidya A**, Gupta AS***.
(* Junior Resident, ** Senior Resident , *** Professor, Department of Obstetrics and Gynecology, Seth G S Medical College and K E M Hospital, Mumbai, India.)
Abstract
Pemphigus is an immune-mediated bullous disorder which leads to fragile blisters, extensive skin and mucosal lesions that can have life threatening consequences. The disease may be associated with unpropitious neonatal outcomes like prematurity and fetal death. Pemphigus is extremely rare in pregnancy as it is associated with infertility in its active phase and poses novel challenges to the patient, baby and the health care providers. We report a case who conceived during the remission phase of pemphigus, required corticosteroids and immunosuppressant therapy for disease control and delivered a term, appropriate for gestational age newborn.
Introduction
The term pemphigus comes from the Greek word “pemphix” which means blister or bubble. Pemphigus vulgaris is a rare autoimmune bullous dermatosis that affects all races and both the sexes in the middle age.[1] Predisposing factors include first degree relatives of patients affected by autoimmune disorders, Major Histocompatibility Complex (MHC) class 2 molecules especially HLA-DR4 allele and those affected by autoimmune disorders such as myasthenia gravis and lupus erythematosus.[2] Clinical presentation involves numerous skin vesicles which ulcerate without scarring with a predilection for scalp, face, axillae, groins and the pressure points along with mucosal involvement. Skin biopsy is the gold standard for the diagnosis of pemphigus vulgaris. Our present study reports a case of pregnant woman who conceived during the remission phase of pemphigus vulgaris, which was controlled with corticosteroids and immunosupressants and delivered a male child appropriate for gestational age by emergency cesarean section with a complicated neonatal course.
Case Report
A 22 year old second gravida with previous one medical termination of pregnancy presented to the dermatology outpatient department with widespread blistering dermatitis associated with burning and pruritus at 34 weeks of gestation. She was a known case of pemphigus vulgaris diagnosed in 2016. In 2017 she had conceived spontaneously but due to a flare up episode, she underwent medical termination of pregnancy at 10 weeks of gestation by suction and evacuation. In 2016 when she was first diagnosed with pemphigus vulgaris, she was given pulse therapy with dexamethasone-cyclophosphamide and started on oral Prednisone 30 mg once a day. This was followed with two more pulse therapy sessions with dexamethasone-cyclophosphamide. Prednisone was tapered to 20 mg/day and she was started on oral Azathioprine 50 mg once a day following which she conceived spontaneously during the remission and underwent medical termination of pregnancy due to the disease exacerbation. She was following up at a medical college hospital near her home town and was on oral prednisone 20 mg/day. She conceived spontaneously for the second time and presented to the dermatology department at 34 weeks of gestation with blisters and erosions largest measuring 2x2 cm, hemorrhagic crusts and erythema surrounding the erosions over the face, back, groins, buttocks, bilateral upper and lower limbs, soles, palm, scalp and buccal mucosa associated with nasal crusting. Genital mucosa was spared. She was started on oral prednisone 40 mg once a day that was then tapered and maintained at 35 mg/day, oral Azathioprine 50 mg, multivitamin supplements, potassium supplements, antacids and antihistaminics (chlorpheniramine) for symptomatic relief. She also had hemorrhoids which were managed conservatively with stool softening agents. She had complaints of galactorrhea (Azathioprine induced hyperprolactinemia is a known side-effect) which was treated with oral Cabergoline 0.5 mg. She was advised admission for elective cesarean section at 39 weeks of gestation for breech presentation but she did not get admitted. She came in labor with breech presentation at 40 weeks of gestation. After a dermatology consultation an emergency lower segment cesarean section for breech in early latent phase of labor was performed. An infraumblical midline vertical incision was taken sparing the area of the lesions. Hydrocortisone 100 mg was given by the intravenous route. Liquor was thick meconium stained, a male child of 2.580 kg was delivered. The baby had aspirated meconium and was given an Apgar score of 8/10, 9/10 and was shifted to neonatal intensive care unit for further management. The baby developed meconium aspiration syndrome followed by pulmonary artery hypertension and due to prolonged ventilatory support developed ventilation aquired pneumonia and is still on ionotropic support and higher antibiotics. Baby did not show presence of any skin lesions suggestive of neonatal pemphigous. She developed few new bullae near the finger webs in the postnatal period, dermatologist reviewed her and continued the same medications.
Pradhan M*, Vaidya A**, Gupta AS***.
(* Junior Resident, ** Senior Resident , *** Professor, Department of Obstetrics and Gynecology, Seth G S Medical College and K E M Hospital, Mumbai, India.)
Abstract
Pemphigus is an immune-mediated bullous disorder which leads to fragile blisters, extensive skin and mucosal lesions that can have life threatening consequences. The disease may be associated with unpropitious neonatal outcomes like prematurity and fetal death. Pemphigus is extremely rare in pregnancy as it is associated with infertility in its active phase and poses novel challenges to the patient, baby and the health care providers. We report a case who conceived during the remission phase of pemphigus, required corticosteroids and immunosuppressant therapy for disease control and delivered a term, appropriate for gestational age newborn.
Introduction
The term pemphigus comes from the Greek word “pemphix” which means blister or bubble. Pemphigus vulgaris is a rare autoimmune bullous dermatosis that affects all races and both the sexes in the middle age.[1] Predisposing factors include first degree relatives of patients affected by autoimmune disorders, Major Histocompatibility Complex (MHC) class 2 molecules especially HLA-DR4 allele and those affected by autoimmune disorders such as myasthenia gravis and lupus erythematosus.[2] Clinical presentation involves numerous skin vesicles which ulcerate without scarring with a predilection for scalp, face, axillae, groins and the pressure points along with mucosal involvement. Skin biopsy is the gold standard for the diagnosis of pemphigus vulgaris. Our present study reports a case of pregnant woman who conceived during the remission phase of pemphigus vulgaris, which was controlled with corticosteroids and immunosupressants and delivered a male child appropriate for gestational age by emergency cesarean section with a complicated neonatal course.
Case Report
A 22 year old second gravida with previous one medical termination of pregnancy presented to the dermatology outpatient department with widespread blistering dermatitis associated with burning and pruritus at 34 weeks of gestation. She was a known case of pemphigus vulgaris diagnosed in 2016. In 2017 she had conceived spontaneously but due to a flare up episode, she underwent medical termination of pregnancy at 10 weeks of gestation by suction and evacuation. In 2016 when she was first diagnosed with pemphigus vulgaris, she was given pulse therapy with dexamethasone-cyclophosphamide and started on oral Prednisone 30 mg once a day. This was followed with two more pulse therapy sessions with dexamethasone-cyclophosphamide. Prednisone was tapered to 20 mg/day and she was started on oral Azathioprine 50 mg once a day following which she conceived spontaneously during the remission and underwent medical termination of pregnancy due to the disease exacerbation. She was following up at a medical college hospital near her home town and was on oral prednisone 20 mg/day. She conceived spontaneously for the second time and presented to the dermatology department at 34 weeks of gestation with blisters and erosions largest measuring 2x2 cm, hemorrhagic crusts and erythema surrounding the erosions over the face, back, groins, buttocks, bilateral upper and lower limbs, soles, palm, scalp and buccal mucosa associated with nasal crusting. Genital mucosa was spared. She was started on oral prednisone 40 mg once a day that was then tapered and maintained at 35 mg/day, oral Azathioprine 50 mg, multivitamin supplements, potassium supplements, antacids and antihistaminics (chlorpheniramine) for symptomatic relief. She also had hemorrhoids which were managed conservatively with stool softening agents. She had complaints of galactorrhea (Azathioprine induced hyperprolactinemia is a known side-effect) which was treated with oral Cabergoline 0.5 mg. She was advised admission for elective cesarean section at 39 weeks of gestation for breech presentation but she did not get admitted. She came in labor with breech presentation at 40 weeks of gestation. After a dermatology consultation an emergency lower segment cesarean section for breech in early latent phase of labor was performed. An infraumblical midline vertical incision was taken sparing the area of the lesions. Hydrocortisone 100 mg was given by the intravenous route. Liquor was thick meconium stained, a male child of 2.580 kg was delivered. The baby had aspirated meconium and was given an Apgar score of 8/10, 9/10 and was shifted to neonatal intensive care unit for further management. The baby developed meconium aspiration syndrome followed by pulmonary artery hypertension and due to prolonged ventilatory support developed ventilation aquired pneumonia and is still on ionotropic support and higher antibiotics. Baby did not show presence of any skin lesions suggestive of neonatal pemphigous. She developed few new bullae near the finger webs in the postnatal period, dermatologist reviewed her and continued the same medications.
Figure 1. Old lesions on the chest.
Figure 2. Old lesions on the calf.
Figure 3. New lesions on the finger webs.
Figure 4. Relation of LSCS incision site with her lesions (arrow showing the incision site).
Discussion
The pathogenesis of Pemphigus vulgaris is linked to the presence of auto-antibodies against Desmoglein-3 that results in loss of cell-cell adhesion in the basal and suprabasal layers of the deeper epidermis that leads to epidermal blisters.[3] Skin biopsy is the gold standard for the diagnosis of Pemphigus vulgaris which shows the presence of acantholysis, suprabasal cleft formation and deposition of immunoglobulin IgG and complement in the intercellular spaces of the epidermis. Secondary infection, sepsis and electrolyte imbalance caused significant mortality in pemphigus until the advent of the corticosteroid therapy which has reduced the mortality from 70 % to 5-15 %.[4,5] There are 3 types of Pemphigus: Pemphigus vulgaris (PV), Pemphigus foliaceus (PF) and other variants of Pemphigus.[6] Pemphigus is characterized by the production of auto-antibodies directed against the transmembrane glycoproteins of desmosomes that inhibits the inter-molecular interactions of Desmogleins, and results in the formation of Dsg-1 deficient desmosomes in PF and Dsg-3 deficient desmosomes in PV.[7] The condition is more complex in pregnancy due to the change in mother’s hormone level and the effect of drug therapy on both the mother and her fetus. The mean age of onset of pemphigus is 20-42 years. The pemphigus course is characterized by exacerbation (61.9%), improvement (9.5%), and remaining stable (28.6%), during the pregnancy. The incidence of neonatal pemphigus is as high as 57.1 % (including 38.1 % of PV and 19 % of PF).[8] The disease is aggravated most likely during the first, second trimester and during the postpartum period and is relieved during the third trimester.[9] However, in our patient in her first pregnancy exacerbation occurred in the first trimester and in her second pregnancy it occurred in her third trimester. Pregnancy outcomes in pemphigus include live birth, stillbirth, spontaneous abortion and induced abortion.The rate of still birth in pregnancy is 1.4 – 27 % and are more related to the disease control and antibody level.[8] Except for obstetric indications, vaginal delivery is recommended though the trauma induced during vaginal delivery can lead to the wound deterioration.[10] Cesarean section complicates wound healing in pemphigus affected women with compromised immunity who are treated with corticosteroids.[10] Corticosteroid therapy in pregnant women affected with pemphigus is associated with a high rate of preterm premature rupture of membranes and preterm labor. Breast feeding is not contraindicated in women affected with pemphigus.[8] Neonatal pemphigus is characterized by transient flaccid blisters on skin, rarely involving the mucosa, self-healing within 2-3 weeks without any long term clinical sequelae. It mainly occurs due to transplacental transmission of antibodies especially IgG4 and a very small amount of IgG produced by the fetus.[11] The standard treatment for pemphigus irrespective of the pregnancy status is systemic glucocorticoids in combination with other immunosupressants and intravenous immunoglobulin or plasmapheresis.[8] If the disease exacerbates in the first trimester , medical termination of pregnancy can be offered.[8] Low dose prednisone (1.5 mg/kg/day) is considered safe in pregnancy as opposed to other less safer options like dexamethasone and betamethasone. Azathioprine (2.5 mg/kg/day) is the most widely used and efficacious steroid sparing agent for pemphigus but Cyclosporine though less effective is the safest drug in pregnancy.[12,13] However, there are no standardized guidelines for the treatment of pemphigus in pregnancy.
To conclude, pregnancy and pemphigus can both affect each other leading to exacerbation or remission of the disease, thereby challenging the physician with a holistic treatment plan. Current treatment of pemphigus involves the use of glucocorticoids as the first line agents along with immunosupressants and other less utilized options like intravenous immunoglobulin or plasmapheresis. The literature in this context is so far deficient to predict the change of conditions for an individual patient. Pemphigus and pregnancy is still an indistinct area that needs an integrated approach by obstetricians, dermatologists and neonatologists to establish a multidisciplinary treatment.
References
Figure 4. Relation of LSCS incision site with her lesions (arrow showing the incision site).
Discussion
The pathogenesis of Pemphigus vulgaris is linked to the presence of auto-antibodies against Desmoglein-3 that results in loss of cell-cell adhesion in the basal and suprabasal layers of the deeper epidermis that leads to epidermal blisters.[3] Skin biopsy is the gold standard for the diagnosis of Pemphigus vulgaris which shows the presence of acantholysis, suprabasal cleft formation and deposition of immunoglobulin IgG and complement in the intercellular spaces of the epidermis. Secondary infection, sepsis and electrolyte imbalance caused significant mortality in pemphigus until the advent of the corticosteroid therapy which has reduced the mortality from 70 % to 5-15 %.[4,5] There are 3 types of Pemphigus: Pemphigus vulgaris (PV), Pemphigus foliaceus (PF) and other variants of Pemphigus.[6] Pemphigus is characterized by the production of auto-antibodies directed against the transmembrane glycoproteins of desmosomes that inhibits the inter-molecular interactions of Desmogleins, and results in the formation of Dsg-1 deficient desmosomes in PF and Dsg-3 deficient desmosomes in PV.[7] The condition is more complex in pregnancy due to the change in mother’s hormone level and the effect of drug therapy on both the mother and her fetus. The mean age of onset of pemphigus is 20-42 years. The pemphigus course is characterized by exacerbation (61.9%), improvement (9.5%), and remaining stable (28.6%), during the pregnancy. The incidence of neonatal pemphigus is as high as 57.1 % (including 38.1 % of PV and 19 % of PF).[8] The disease is aggravated most likely during the first, second trimester and during the postpartum period and is relieved during the third trimester.[9] However, in our patient in her first pregnancy exacerbation occurred in the first trimester and in her second pregnancy it occurred in her third trimester. Pregnancy outcomes in pemphigus include live birth, stillbirth, spontaneous abortion and induced abortion.The rate of still birth in pregnancy is 1.4 – 27 % and are more related to the disease control and antibody level.[8] Except for obstetric indications, vaginal delivery is recommended though the trauma induced during vaginal delivery can lead to the wound deterioration.[10] Cesarean section complicates wound healing in pemphigus affected women with compromised immunity who are treated with corticosteroids.[10] Corticosteroid therapy in pregnant women affected with pemphigus is associated with a high rate of preterm premature rupture of membranes and preterm labor. Breast feeding is not contraindicated in women affected with pemphigus.[8] Neonatal pemphigus is characterized by transient flaccid blisters on skin, rarely involving the mucosa, self-healing within 2-3 weeks without any long term clinical sequelae. It mainly occurs due to transplacental transmission of antibodies especially IgG4 and a very small amount of IgG produced by the fetus.[11] The standard treatment for pemphigus irrespective of the pregnancy status is systemic glucocorticoids in combination with other immunosupressants and intravenous immunoglobulin or plasmapheresis.[8] If the disease exacerbates in the first trimester , medical termination of pregnancy can be offered.[8] Low dose prednisone (1.5 mg/kg/day) is considered safe in pregnancy as opposed to other less safer options like dexamethasone and betamethasone. Azathioprine (2.5 mg/kg/day) is the most widely used and efficacious steroid sparing agent for pemphigus but Cyclosporine though less effective is the safest drug in pregnancy.[12,13] However, there are no standardized guidelines for the treatment of pemphigus in pregnancy.
To conclude, pregnancy and pemphigus can both affect each other leading to exacerbation or remission of the disease, thereby challenging the physician with a holistic treatment plan. Current treatment of pemphigus involves the use of glucocorticoids as the first line agents along with immunosupressants and other less utilized options like intravenous immunoglobulin or plasmapheresis. The literature in this context is so far deficient to predict the change of conditions for an individual patient. Pemphigus and pregnancy is still an indistinct area that needs an integrated approach by obstetricians, dermatologists and neonatologists to establish a multidisciplinary treatment.
References
- Korman NJ. Pemphigus. Dermatol Clin. 1990;8(4):689-700.
- Fainaru O, Mashiach R, Kupferminc M, Shenhav M, Pauzner D, Lessing JB. Pemphigus vulgaris in pregnancy: a case report and review of literature. Hum Reprod. 2000;15(5):1195-7.
- Marren P, Wojnarowska F, Venning V, Wilson C, Nayar M. Vulvar involvement in autoimmune bullous diseases. The Journal of reproductive medicine 1993; 38(2):101-107.
- Ruach M, Ohel G, Rahav D, Samueloff A. Pemphigus vulgaris and pregnancy. Obstet Gynecol Surv. 1995;50(10):755-60.
- Carson PJ, Hameed A, Ahmed AR. Influence of treatment on the clinical course of pemphigus vulgaris. J Am Acad Dermatol. 1996;34(4):645-52.
- Kitajima Y, Aoyama Y. A perspective of pemphigus from bedside and laboratory-bench. Clin Rev Allergy Immunol. 2007;33(1-2):57-66.
- Joly P, Gilbert D, Thomine E, Zitouni M, Ghohestani R, Delpech A, et al. Identification of a new antibody population directed against a desmosomal plaque antigen in pemphigus vulgaris and pemphigus foliaceus. J Invest Dermatol. 1997;108(4):469-75.
- Lin L, Zeng X, Chen Q. Pemphigus and pregnancy. Analysis and summary of case reports over 49 years. Saudi Med J. 2015;36(9):1033-8.
- Schmutz JL. Dermatological diseases influenced by pregnancy. Presse Med. 2003;32(38):1809–1812.
- Goldberg NS, DeFeo C, Kirshenbaum N. Pemphigus vulgaris and pregnancy: risk factors and recommendations. J Am Acad Dermatol. 1993; 28(5 Pt 2):877–879.
- Campo-Voegeli A, Muñiz F, Mascaró JM, García F, Casals M, Arimany JL, et al. Neonatal pemphigus vulgaris with extensive mucocutaneous lesions from a mother with oral pemphigus vulgaris. Br J Dermatol. 2002; 147(4):801–805.
- Connell W, Miller A. Treating inflammatory bowel disease during pregnancy: risks and safety of drug therapy. Drug Saf. 1999; 21(4):311–323.
- Lehman JS, Mueller KK, Schraith DF. Do safe and effective treatment options exist for patients with active Pemphigus vulgaris who plan conception and pregnancy? Arch Dermatol. 2008; 144(6):783–785.
Citation
Pradhan M, Vaidya A, Gupta AS. Pemphigus Vulgaris In Pregnancy. JPGO 2019. Volume 6 No.3. Available from: https://www.jpgo.org/2019/03/pemphigus-vulgaris-in-pregnancy.html
Pradhan M, Vaidya A, Gupta AS. Pemphigus Vulgaris In Pregnancy. JPGO 2019. Volume 6 No.3. Available from: https://www.jpgo.org/2019/03/pemphigus-vulgaris-in-pregnancy.html