International Immunopharmacology 26 (2015) 1–3
Contents lists available at ScienceDirect
International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp
Short communication
Positive clinical outcome with IVIg as monotherapy in recurrent pemphigoid gestationis Tegan Nguyen a, Esraa Alraqum b, A. Razzaque Ahmed a,⁎ a b
Center for Blistering Diseases, 697 Cambridge St, Boston, MA, USA Asaad Alhamad Center for Dermatology, Kuwait City, Kuwait
a r t i c l e
i n f o
Article history: Received 26 January 2015 Received in revised form 25 February 2015 Accepted 27 February 2015 Available online 9 March 2015 Keywords: Pemphigoid gestationis Intravenous immunoglobulin Autoimmune disease
a b s t r a c t Pemphigoid gestationis (PG) is an autoimmune blistering disease associated with pregnancy. It is characterized by the presence of autoantibodies against bullous pemphigoid antigens in the basement membrane zone. A 32 year old female developed PG in the first pregnancy and had a stillbirth. PG recurred during the second trimester of her second pregnancy. Systemic corticosteroid therapy was cause for concern since patient developed gestational diabetes. Patient was unwilling to use insulin. Intravenous immunoglobulin (IVIg) was used as a treatment of last resort. The dose was 2 g/kg/cycle. It was given every two weeks antepartum and every three weeks for three months postpartum. PG improved within four weeks of IVIg therapy. Serum and tissue immunopathological studies were negative prior to delivery. A healthy neonate was born. No adverse events to IVIg were observed. No disease was observed ten months postpartum. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Pemphigoid gestationis (PG) is a rare autoimmune disease that occurs primarily in pregnancy [1,2]. Lesions may consist of eczematous papules and plaques and are predominantly located on the abdomen, trunk and extremities. Severe pruritus is common. Systemic corticosteroids (CS) have been the mainstay treatment [1,3]. Postpartum flare can last for several months and may require the use of immunosuppressive agents. We report a case of PG successfully treated with intravenous immunoglobulin (IVIg) as monotherapy.
2. Report A 32 year old female was evaluated three weeks after she had a stillbirth at 23 weeks of gestation. Three weeks prior to that delivery, she had intensely pruritic papules and vesicular eruptions initially on the abdomen and subsequently on the extremities and pelvic area. She had no mucosal involvement. Histology demonstrated a subepithelial vesicle with eosinophils. Direct immunofluorescence (DIF) revealed a smooth linear deposition of C3 at the basement membrane zone (BMZ). She was treated with prednisone 50 mg daily. The rash worsened after
⁎ Corresponding author at: 697 Cambridge Street, Suite 302, Boston, MA 02135, USA. Tel.: +1 617 562 1045; fax: +1 617 562 1047. E-mail address: [email protected] (A. Razzaque Ahmed).
http://dx.doi.org/10.1016/j.intimp.2015.02.038 1567-5769/© 2015 Elsevier B.V. All rights reserved.
delivery, but improved three months later and resolved six months after onset. The prednisone was gradually tapered and discontinued. The patient had a second pregnancy 14 months later. At 26 weeks of gestation, she developed a rash clinically similar to the earlier pregnancy, with pruritic blisters and papules on the abdomen and extremities. Immunopathological studies established the diagnosis of PG. PG did not respond to the initial dose of 20 mg daily of oral prednisone. It caused significant mood changes and behavioral issues in the patient. Severe gestational diabetes was diagnosed shortly thereafter. The dose of prednisone could not be increased. The patient refused insulin therapy. IVIg was therefore used as a treatment of last resort. The dose was 2 g/kg/cycle. The frequency of infusions was every two weeks antepartum and every three weeks postpartum for three months. PG clinically improved within four weeks and resolved completely within eight weeks. The patient was clinically and immunopathologically free of disease prior to delivery. The serum antibody titers on indirect immunofluorescence (IIF) at the time of diagnosis were 1:320. The anti-BPAg1 (BP230) on ELISA was 120 u/L and anti-BPAg2 (BP180) was 210 u/L. Prior to delivery, the titer on IIF was undetectable and the ELISA for BPAg1 and BPAg2 were negative. She had a spontaneous vaginal delivery at 38 weeks. The neonate had no skin lesions. The cord blood was negative for anti-BMZ antibodies, tested by IIF and ELISA. The DIF was negative after the last cycle of IVIg. Ten months postpartum, the patient remains disease free. No adverse events to the IVIg were reported. On a periodic basis, the patient was serologically tested for presence of anti-BMZ antibodies which continued to remain negative to date (Fig. 1).
2
T. Nguyen et al. / International Immunopharmacology 26 (2015) 1–3
IIF BPAg1
240 –
BPAg2
- 1:240
- 1:160 160 –
IIF Titer
ELISA Index Value
- 1:320
- 1:80 cessation of IVIg therapy
80 – IVIg initiation
- 1:40
40 –
- 1:20 0 – 0
biopsy diagnosis established
1
2
MONTH
3
4
biopsy negative at time of delivery
5
12
MONTH
Fig. 1. Levels of anti-basement membrane zone antibody titers as demonstrated by indirect immunofluorescence (IIF) on monkey esophagus and enzyme-linked immunosorbent assay (ELISA) of BPAg1 and BPAg2 prior to intravenous immunoglobulin (IVIg) therapy, at the time of the delivery, and throughout the postpartum period. ELISA for BPAg1 and BPAg2 were negative and the titer on IIF was undetectable prior to delivery. During the ten months follow-up, the IIF and ELISA remained negative.
3. Discussion A patient with PG who had a stillbirth during the first pregnancy is presented in this study. PG recurred during the second pregnancy. Simultaneously, she developed gestational diabetes. The patient was treated with IVIg monotherapy which resulted in the complete resolution of the disease prior to her delivery. The IVIg treatment continued postpartum. The patient did not develop postpartum exacerbation which is common in PG. The autoantibody titers that were high at the time of the disease onset became negative with the use of IVIg and continued to remain negative during a ten month follow-up period. The neonate was born without blisters and the cord blood was negative for autoantibodies. There are five published cases in the English literature in which IVIg was used to treat PG (Table 1) [1–5]. The age of onset ranged from 17 to 37 years (mean 30.6 years). PG initially developed during the second and third trimesters in four patients and two days postpartum in one patient. In two patients, PG recurred in subsequent pregnancies with an earlier onset [2,3]. Contrary to data in the literature, the onset of PG in the second pregnancy (26 weeks) of our patient was later than that in the previous pregnancy (20 weeks). Studies revealed that patients with PG have an increased risk in delivering small for gestational age or premature babies [6]. A patient reported in the literature had a stillbirth [4], as did our patient.
Postpartum flares were observed in all five patients. The duration varied from 2 to 16 months (mean 10 months). In all five patients from the literature, initial therapy consisted of varying doses of prednisolone (40–150 mg daily). Recurrence was observed when the dose was lowered to 10–25 mg daily. Systemic CS was used in all five patients to treat postpartum disease. Two patients received azathioprine (AZA) and one received cyclophosphamide as adjunct therapy to help lower the dose of systemic CS. The conventional treatment of severe PG consists of systemic CS [7]. The duration is often shorter and the dosage frequently lower than that used in treating other autoimmune blistering diseases, such as pemphigus vulgaris or bullous pemphigoid. Systemic CS used in pregnancy have been reported to cause intrauterine growth retardation, preeclampsia, and gestational diabetes amongst other side effects [7]. The patient described in this report developed gestational diabetes shortly after being diagnosed with PG in her second pregnancy. The use of systemic CS could have potentially worsened the diabetes and required insulin therapy. Therefore IVIg was used to avoid the use of insulin and other immunosuppressive agents that could cross the placenta and create potential problems in the neonate. The use of IVIg is considered safe in pregnancy [8]. It was given in all five reported cases with variable number of cycles (Table 2). The
Table 1 Clinical profiles of PG patients treated with IVIg in the literature. Authors [reference]
Onset Age
Pregnancy
Gestational age
Rodrigues [1]
31
1st
Day 2 Postpartum
Gan [2]
37
1st 2nd
28 weeks 9 weeks
Doiron [3]
34
Hern [4]
17
1st 2nd 3rd 1st
26 weeks 10 weeks 16 weeks 20 weeks
Kreuter [5]
34
1st
28 weeks
Disease distribution
Laboratory
Erythema, papules, vesicles & bullae on trunk & extremities Pruritic plaques, vesicles; paraumbilical, extremity involvement Pruritic vesicles; paraumbilical plaques; extremities, breasts & face involvement Large tense bullae on thighs, trunk & arms
Histo (+) DIF (+) Sera (+) Histo (+) DIF (+)
Paraumbilical papules, plaques & bullae; extremities & oral involvement
Histo (+) DIF (+) Histo (+) DIF (+) Sera (+) Histo (+) DIF (+) Sera (+)
Histo = histology; DIF = direct immunofluorescence; IVIg = intravenous immunoglobulin; PG = pemphigoid gestationis; sera = anti-hemidesmosome antibody results, indirect immunofluorescence analysis on monkey esophagus sections.
8.5 mos Active lesions Healthy P 150 mg QD for 10 days Kreuter [5]
Hern [4]
Doiron [3]
P 1 mg/kg QD for 2 weeks; 5 cycles IVIg 2 g/kg/cycle & P taper P 40 mg QD; 4 cycles IVIg 120 g/cycle P 80 mg QD Gan [2]
AZA = azathioprine; CR = complete remission; IVIg = intravenous immunoglobulin; mos = months; N/A = not applicable; P = prednisolone; PR = partial remission; QD = once daily.
CR
18 mos PR
Healthy
Vaginal delivery at 37.5 weeks Fetal death in-utero at 30 weeks Caesarean section at 30 weeks
Dead fetus
Healthy Vaginal delivery at 36 weeks
No clinical response to P therapy. Symptoms resolved post-IVIg. Resolution post-IVIg, P taper
N/A Rodrigues [1]
Active disease; Cushingoid; steroid myopathy; osteoporosis Disease progressed
N/A N/A N/A
Bullae with resolution of lesions after 2 weeks Paraumbilical vesicles
P taper; 2 cycles IVIg 2 g/kg/cycle; cyclosporine 100 mg QD for 6 mos AZA 100 mg QD; P 50 mg QD for 5 mos; 4 cycles IVIg 1 g/kg/cycle
7.5 mos
21 mos CR
CR
10 mos CR
P taper; AZA 100–150 mg QD; dapsone 100 mg QD; 6 cycles IVIg 2 g/kg/cycle P 8–15 mg QD for 12 mos; 3 cycles IVIg 2 g/kg/cycle; AZA 1 mg/kg QD for 14 mos P 25 mg QD; 3 cycles IVIg 2 g/kg/cycle Erythema, papules, vesicles & bullae on trunk & extremities Urticarial plaques & vesicles on trunk & extremities
Effect on neonate Mode of delivery Response Treatment
Antepartum
Authors [reference]
Table 2 Clinical course and treatment responses in patients with PG treated with IVIg from the literature.
Postpartum clinical picture
Postpartum
Treatment
Response
Time to achieve
T. Nguyen et al. / International Immunopharmacology 26 (2015) 1–3
3
dose was 2 g/kg/cycle in the majority of patients. It was given in combination with systemic CS in all five patients. The duration of postpartum treatments ranged from 2 to 16 months (mean 7 months). In all five cases, PG resolved within 2–3 cycles of IVIg. Three patients received immunosuppressive agent in addition to systemic CS and IVIg. Since systemic CS was ineffective, one patient was delivered via caesarean section at 30 weeks and immediately began AZA therapy [5]. AZA has been reported to cause fetal bone marrow suppression and immunosuppression [2]. Hence the caesarean section was performed in this patient to prevent possible fetal harm. The pathogenesis of PG remains unknown. PG has been associated with HLA-DR3 and HLA-DR4 [7]. Researchers postulate that the breakdown of the syncytiotrophoblast cell layer allows for the interaction between MHC class II molecules and the maternal immune system [7]. This results in an allogeneic reaction against the hemidesmosomal protein BP180 [7]. Similar to bullous pemphigoid, deposition of autoantibodies to BP180 to the BMZ may trigger a complement cascade that results in blister formation. Autoantibody serum levels of anti-BP180 reflect disease severity and may be used to monitor response to therapy in patients with PG [7]. It has been suggested that there are multiple mechanisms acting at different stages of PG that are influenced by IVIg and may account for its beneficial effect. In the initial stage of PG, IVIg acts as an antiinflammatory agent via IL-1 and IL-1 receptor antagonist pathways, amongst other cytokines and chemokines [9]. Subsequently it restores immune regulation via idiotypic anti-idiotypic networks, which may be capable of reducing or eliminating autoantibody production [9]. In our patient, the autoantibodies were present in high titers at the onset of the disease. They slowly reduced and eventually disappeared from the sera before the delivery. The decrease and elimination of the antibody was paralleled to the clinical resolution of the disease. This would suggest that IVIg may be one of the factors that helped in the reduction and elimination of the autoantibodies. Based on the literature review and the rarity of the disease, there is a lack of consensus on the treatment, especially the use of immunosuppressive agents and IVIg in PG patients refractory to therapy. The protocol used in our patient produced a positive outcome for the mother and child. If this protocol is used in an adequate number of patients, then its clinical utility will be established. It is possible that modifications or additions of other agents may be warranted in certain patients. Based on the results in patients treated by this protocol in the future, this protocol could become the standard of care. At the very least, this protocol may be particularly beneficial to women who have avoided subsequent pregnancy in fear of PG. References [1] Rodrigues C, Filipe P, Solana M, Soares L, Cirne J, Gomes M. Persistent herpes gestationis treated with high-dose intravenous immunoglobulin. Acta Derm Venereol 2007;87:184–6. [2] Gan DC, Welsh B, Webster M. Successful treatment of a severe persistent case of pemphigoid gestationis with antepartum and postpartum intravenous immunoglobulin followed by azathioprine. Australas J Dermatol 2012;53:66–9. [3] Doiron P, Pratt M. Antepartum intravenous immunoglobulin therapy in refractory pemphigoid gestationis: case report and literature review. J Cutan Med Surg 2010; 14:189–92. [4] Hern S, Harman K, Bhogal BS, Black MM. A severe persistent case of pemphigoid gestationis treated with intravenous immunoglobulins and cyclosporine. Clin Exp Dermatol 1998;23:185–8. [5] Kreuter A, Harati A, Breuckmann F, Appelhans C, Altmeyer P. Intravenous immunoglobulin in the treatment of persistent pemphigoid gestationis. J Am Acad Dermatol 2004;51:1027–8. [6] Intong LR, Murrell DF. Pemphigoid gestationis: pathogenesis and clinical features. Dermatol Clin 2011;29:447–52. [7] Huilaja L, Makikallio K, Tasanen K. Gestational pemphigoid. Orphanet J Rare Dis 2014; 9:136. [8] Ahmed AR, Gurcan HM. Use of intravenous immunoglobulin therapy during pregnancy in patients with pemphigus vulgaris. J Eur Acad Dermatol Venereol 2011;25:1073–9. [9] Mouthon L, Kaveri SV, Spalter SH, Lacroix-Desmazes S, Lefranc L, Desai R, et al. Mechanisms of action of intravenous immune globulin in immune-mediated diseases. Clin Exp Immunol 1996;104:3–9.
Contents lists available at ScienceDirect
International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp
Short communication
Positive clinical outcome with IVIg as monotherapy in recurrent pemphigoid gestationis Tegan Nguyen a, Esraa Alraqum b, A. Razzaque Ahmed a,⁎ a b
Center for Blistering Diseases, 697 Cambridge St, Boston, MA, USA Asaad Alhamad Center for Dermatology, Kuwait City, Kuwait
a r t i c l e
i n f o
Article history: Received 26 January 2015 Received in revised form 25 February 2015 Accepted 27 February 2015 Available online 9 March 2015 Keywords: Pemphigoid gestationis Intravenous immunoglobulin Autoimmune disease
a b s t r a c t Pemphigoid gestationis (PG) is an autoimmune blistering disease associated with pregnancy. It is characterized by the presence of autoantibodies against bullous pemphigoid antigens in the basement membrane zone. A 32 year old female developed PG in the first pregnancy and had a stillbirth. PG recurred during the second trimester of her second pregnancy. Systemic corticosteroid therapy was cause for concern since patient developed gestational diabetes. Patient was unwilling to use insulin. Intravenous immunoglobulin (IVIg) was used as a treatment of last resort. The dose was 2 g/kg/cycle. It was given every two weeks antepartum and every three weeks for three months postpartum. PG improved within four weeks of IVIg therapy. Serum and tissue immunopathological studies were negative prior to delivery. A healthy neonate was born. No adverse events to IVIg were observed. No disease was observed ten months postpartum. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Pemphigoid gestationis (PG) is a rare autoimmune disease that occurs primarily in pregnancy [1,2]. Lesions may consist of eczematous papules and plaques and are predominantly located on the abdomen, trunk and extremities. Severe pruritus is common. Systemic corticosteroids (CS) have been the mainstay treatment [1,3]. Postpartum flare can last for several months and may require the use of immunosuppressive agents. We report a case of PG successfully treated with intravenous immunoglobulin (IVIg) as monotherapy.
2. Report A 32 year old female was evaluated three weeks after she had a stillbirth at 23 weeks of gestation. Three weeks prior to that delivery, she had intensely pruritic papules and vesicular eruptions initially on the abdomen and subsequently on the extremities and pelvic area. She had no mucosal involvement. Histology demonstrated a subepithelial vesicle with eosinophils. Direct immunofluorescence (DIF) revealed a smooth linear deposition of C3 at the basement membrane zone (BMZ). She was treated with prednisone 50 mg daily. The rash worsened after
⁎ Corresponding author at: 697 Cambridge Street, Suite 302, Boston, MA 02135, USA. Tel.: +1 617 562 1045; fax: +1 617 562 1047. E-mail address: [email protected] (A. Razzaque Ahmed).
http://dx.doi.org/10.1016/j.intimp.2015.02.038 1567-5769/© 2015 Elsevier B.V. All rights reserved.
delivery, but improved three months later and resolved six months after onset. The prednisone was gradually tapered and discontinued. The patient had a second pregnancy 14 months later. At 26 weeks of gestation, she developed a rash clinically similar to the earlier pregnancy, with pruritic blisters and papules on the abdomen and extremities. Immunopathological studies established the diagnosis of PG. PG did not respond to the initial dose of 20 mg daily of oral prednisone. It caused significant mood changes and behavioral issues in the patient. Severe gestational diabetes was diagnosed shortly thereafter. The dose of prednisone could not be increased. The patient refused insulin therapy. IVIg was therefore used as a treatment of last resort. The dose was 2 g/kg/cycle. The frequency of infusions was every two weeks antepartum and every three weeks postpartum for three months. PG clinically improved within four weeks and resolved completely within eight weeks. The patient was clinically and immunopathologically free of disease prior to delivery. The serum antibody titers on indirect immunofluorescence (IIF) at the time of diagnosis were 1:320. The anti-BPAg1 (BP230) on ELISA was 120 u/L and anti-BPAg2 (BP180) was 210 u/L. Prior to delivery, the titer on IIF was undetectable and the ELISA for BPAg1 and BPAg2 were negative. She had a spontaneous vaginal delivery at 38 weeks. The neonate had no skin lesions. The cord blood was negative for anti-BMZ antibodies, tested by IIF and ELISA. The DIF was negative after the last cycle of IVIg. Ten months postpartum, the patient remains disease free. No adverse events to the IVIg were reported. On a periodic basis, the patient was serologically tested for presence of anti-BMZ antibodies which continued to remain negative to date (Fig. 1).
2
T. Nguyen et al. / International Immunopharmacology 26 (2015) 1–3
IIF BPAg1
240 –
BPAg2
- 1:240
- 1:160 160 –
IIF Titer
ELISA Index Value
- 1:320
- 1:80 cessation of IVIg therapy
80 – IVIg initiation
- 1:40
40 –
- 1:20 0 – 0
biopsy diagnosis established
1
2
MONTH
3
4
biopsy negative at time of delivery
5
12
MONTH
Fig. 1. Levels of anti-basement membrane zone antibody titers as demonstrated by indirect immunofluorescence (IIF) on monkey esophagus and enzyme-linked immunosorbent assay (ELISA) of BPAg1 and BPAg2 prior to intravenous immunoglobulin (IVIg) therapy, at the time of the delivery, and throughout the postpartum period. ELISA for BPAg1 and BPAg2 were negative and the titer on IIF was undetectable prior to delivery. During the ten months follow-up, the IIF and ELISA remained negative.
3. Discussion A patient with PG who had a stillbirth during the first pregnancy is presented in this study. PG recurred during the second pregnancy. Simultaneously, she developed gestational diabetes. The patient was treated with IVIg monotherapy which resulted in the complete resolution of the disease prior to her delivery. The IVIg treatment continued postpartum. The patient did not develop postpartum exacerbation which is common in PG. The autoantibody titers that were high at the time of the disease onset became negative with the use of IVIg and continued to remain negative during a ten month follow-up period. The neonate was born without blisters and the cord blood was negative for autoantibodies. There are five published cases in the English literature in which IVIg was used to treat PG (Table 1) [1–5]. The age of onset ranged from 17 to 37 years (mean 30.6 years). PG initially developed during the second and third trimesters in four patients and two days postpartum in one patient. In two patients, PG recurred in subsequent pregnancies with an earlier onset [2,3]. Contrary to data in the literature, the onset of PG in the second pregnancy (26 weeks) of our patient was later than that in the previous pregnancy (20 weeks). Studies revealed that patients with PG have an increased risk in delivering small for gestational age or premature babies [6]. A patient reported in the literature had a stillbirth [4], as did our patient.
Postpartum flares were observed in all five patients. The duration varied from 2 to 16 months (mean 10 months). In all five patients from the literature, initial therapy consisted of varying doses of prednisolone (40–150 mg daily). Recurrence was observed when the dose was lowered to 10–25 mg daily. Systemic CS was used in all five patients to treat postpartum disease. Two patients received azathioprine (AZA) and one received cyclophosphamide as adjunct therapy to help lower the dose of systemic CS. The conventional treatment of severe PG consists of systemic CS [7]. The duration is often shorter and the dosage frequently lower than that used in treating other autoimmune blistering diseases, such as pemphigus vulgaris or bullous pemphigoid. Systemic CS used in pregnancy have been reported to cause intrauterine growth retardation, preeclampsia, and gestational diabetes amongst other side effects [7]. The patient described in this report developed gestational diabetes shortly after being diagnosed with PG in her second pregnancy. The use of systemic CS could have potentially worsened the diabetes and required insulin therapy. Therefore IVIg was used to avoid the use of insulin and other immunosuppressive agents that could cross the placenta and create potential problems in the neonate. The use of IVIg is considered safe in pregnancy [8]. It was given in all five reported cases with variable number of cycles (Table 2). The
Table 1 Clinical profiles of PG patients treated with IVIg in the literature. Authors [reference]
Onset Age
Pregnancy
Gestational age
Rodrigues [1]
31
1st
Day 2 Postpartum
Gan [2]
37
1st 2nd
28 weeks 9 weeks
Doiron [3]
34
Hern [4]
17
1st 2nd 3rd 1st
26 weeks 10 weeks 16 weeks 20 weeks
Kreuter [5]
34
1st
28 weeks
Disease distribution
Laboratory
Erythema, papules, vesicles & bullae on trunk & extremities Pruritic plaques, vesicles; paraumbilical, extremity involvement Pruritic vesicles; paraumbilical plaques; extremities, breasts & face involvement Large tense bullae on thighs, trunk & arms
Histo (+) DIF (+) Sera (+) Histo (+) DIF (+)
Paraumbilical papules, plaques & bullae; extremities & oral involvement
Histo (+) DIF (+) Histo (+) DIF (+) Sera (+) Histo (+) DIF (+) Sera (+)
Histo = histology; DIF = direct immunofluorescence; IVIg = intravenous immunoglobulin; PG = pemphigoid gestationis; sera = anti-hemidesmosome antibody results, indirect immunofluorescence analysis on monkey esophagus sections.
8.5 mos Active lesions Healthy P 150 mg QD for 10 days Kreuter [5]
Hern [4]
Doiron [3]
P 1 mg/kg QD for 2 weeks; 5 cycles IVIg 2 g/kg/cycle & P taper P 40 mg QD; 4 cycles IVIg 120 g/cycle P 80 mg QD Gan [2]
AZA = azathioprine; CR = complete remission; IVIg = intravenous immunoglobulin; mos = months; N/A = not applicable; P = prednisolone; PR = partial remission; QD = once daily.
CR
18 mos PR
Healthy
Vaginal delivery at 37.5 weeks Fetal death in-utero at 30 weeks Caesarean section at 30 weeks
Dead fetus
Healthy Vaginal delivery at 36 weeks
No clinical response to P therapy. Symptoms resolved post-IVIg. Resolution post-IVIg, P taper
N/A Rodrigues [1]
Active disease; Cushingoid; steroid myopathy; osteoporosis Disease progressed
N/A N/A N/A
Bullae with resolution of lesions after 2 weeks Paraumbilical vesicles
P taper; 2 cycles IVIg 2 g/kg/cycle; cyclosporine 100 mg QD for 6 mos AZA 100 mg QD; P 50 mg QD for 5 mos; 4 cycles IVIg 1 g/kg/cycle
7.5 mos
21 mos CR
CR
10 mos CR
P taper; AZA 100–150 mg QD; dapsone 100 mg QD; 6 cycles IVIg 2 g/kg/cycle P 8–15 mg QD for 12 mos; 3 cycles IVIg 2 g/kg/cycle; AZA 1 mg/kg QD for 14 mos P 25 mg QD; 3 cycles IVIg 2 g/kg/cycle Erythema, papules, vesicles & bullae on trunk & extremities Urticarial plaques & vesicles on trunk & extremities
Effect on neonate Mode of delivery Response Treatment
Antepartum
Authors [reference]
Table 2 Clinical course and treatment responses in patients with PG treated with IVIg from the literature.
Postpartum clinical picture
Postpartum
Treatment
Response
Time to achieve
T. Nguyen et al. / International Immunopharmacology 26 (2015) 1–3
3
dose was 2 g/kg/cycle in the majority of patients. It was given in combination with systemic CS in all five patients. The duration of postpartum treatments ranged from 2 to 16 months (mean 7 months). In all five cases, PG resolved within 2–3 cycles of IVIg. Three patients received immunosuppressive agent in addition to systemic CS and IVIg. Since systemic CS was ineffective, one patient was delivered via caesarean section at 30 weeks and immediately began AZA therapy [5]. AZA has been reported to cause fetal bone marrow suppression and immunosuppression [2]. Hence the caesarean section was performed in this patient to prevent possible fetal harm. The pathogenesis of PG remains unknown. PG has been associated with HLA-DR3 and HLA-DR4 [7]. Researchers postulate that the breakdown of the syncytiotrophoblast cell layer allows for the interaction between MHC class II molecules and the maternal immune system [7]. This results in an allogeneic reaction against the hemidesmosomal protein BP180 [7]. Similar to bullous pemphigoid, deposition of autoantibodies to BP180 to the BMZ may trigger a complement cascade that results in blister formation. Autoantibody serum levels of anti-BP180 reflect disease severity and may be used to monitor response to therapy in patients with PG [7]. It has been suggested that there are multiple mechanisms acting at different stages of PG that are influenced by IVIg and may account for its beneficial effect. In the initial stage of PG, IVIg acts as an antiinflammatory agent via IL-1 and IL-1 receptor antagonist pathways, amongst other cytokines and chemokines [9]. Subsequently it restores immune regulation via idiotypic anti-idiotypic networks, which may be capable of reducing or eliminating autoantibody production [9]. In our patient, the autoantibodies were present in high titers at the onset of the disease. They slowly reduced and eventually disappeared from the sera before the delivery. The decrease and elimination of the antibody was paralleled to the clinical resolution of the disease. This would suggest that IVIg may be one of the factors that helped in the reduction and elimination of the autoantibodies. Based on the literature review and the rarity of the disease, there is a lack of consensus on the treatment, especially the use of immunosuppressive agents and IVIg in PG patients refractory to therapy. The protocol used in our patient produced a positive outcome for the mother and child. If this protocol is used in an adequate number of patients, then its clinical utility will be established. It is possible that modifications or additions of other agents may be warranted in certain patients. Based on the results in patients treated by this protocol in the future, this protocol could become the standard of care. At the very least, this protocol may be particularly beneficial to women who have avoided subsequent pregnancy in fear of PG. References [1] Rodrigues C, Filipe P, Solana M, Soares L, Cirne J, Gomes M. Persistent herpes gestationis treated with high-dose intravenous immunoglobulin. Acta Derm Venereol 2007;87:184–6. [2] Gan DC, Welsh B, Webster M. Successful treatment of a severe persistent case of pemphigoid gestationis with antepartum and postpartum intravenous immunoglobulin followed by azathioprine. Australas J Dermatol 2012;53:66–9. [3] Doiron P, Pratt M. Antepartum intravenous immunoglobulin therapy in refractory pemphigoid gestationis: case report and literature review. J Cutan Med Surg 2010; 14:189–92. [4] Hern S, Harman K, Bhogal BS, Black MM. A severe persistent case of pemphigoid gestationis treated with intravenous immunoglobulins and cyclosporine. Clin Exp Dermatol 1998;23:185–8. [5] Kreuter A, Harati A, Breuckmann F, Appelhans C, Altmeyer P. Intravenous immunoglobulin in the treatment of persistent pemphigoid gestationis. J Am Acad Dermatol 2004;51:1027–8. [6] Intong LR, Murrell DF. Pemphigoid gestationis: pathogenesis and clinical features. Dermatol Clin 2011;29:447–52. [7] Huilaja L, Makikallio K, Tasanen K. Gestational pemphigoid. Orphanet J Rare Dis 2014; 9:136. [8] Ahmed AR, Gurcan HM. Use of intravenous immunoglobulin therapy during pregnancy in patients with pemphigus vulgaris. J Eur Acad Dermatol Venereol 2011;25:1073–9. [9] Mouthon L, Kaveri SV, Spalter SH, Lacroix-Desmazes S, Lefranc L, Desai R, et al. Mechanisms of action of intravenous immune globulin in immune-mediated diseases. Clin Exp Immunol 1996;104:3–9.
