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In New Zealand, vildagliptin became fully subsidised by PHARMAC on 1 October 2018. Bullous pemphigoid is an autoimmune blistering disorder that typically affects the elderly. Dipeptidyl peptidase-four inhibitors (DPP4is, or gliptins) are a cause of drug-induced bullous pemphigoid.

Case presentation

A 69-year-old Caucasian man with type two diabetes mellitus (T2DM) and no known dermatological conditions presented with a one-month-old, widespread pruritic blistering rash. This rash developed nine months after the addition of vildagliptin to his diabetic medication regimen. The Naranjo algorithm score of causality was five, indicating a ‘probable’ adverse drug reaction.

There were widespread crusted erosions with scattered tense bullae over the scalp, trunk and limbs, and mucosal erosion on the lower lip (Figures 1 and 2). The diagnosis of bullous pemphigoid was confirmed by histology, which showed a subepidermal split with increased numbers of dermal eosinophils and positive anti-basement membrane antibody of 1:1280 titre. Direct immunofluorescence staining was not possible. Vildagliptin was ceased and oral doxycycline (200mg daily) initiated.[[1]] Re-epithelialisation on doxycycline monotherapy progressed slowly, therefore oral prednisone (40mg daily) was added, resulting in rapid re-epithelialisation. Blood glucose levels were monitored closely and managed with metformin and correctional scale insulin while the patient was taking prednisone.

Figure 1: Bullous pemphigoid on the back, consisting of vesicles, erosions from ruptured bullae and an erythematous urticated rash.

Figure 2: Mucosal involvement.

Discussion

Bullous pemphigoid is an autoimmune condition. Autoantibodies target hemidesmosomes in basal keratinocytes, causing loss of adhesion between the epidermis and dermis.[[2]] It is characterised by localised or generalised bullae with preceding and/or accompanying pruritus. Bullous pemphigoid is most commonly observed in the seventh to ninth decade of life and is associated with neurological diseases, including cerebrovascular accidents.[[3]] The mainstay of treatment is steroid therapy. However, high-dose systemic corticosteroid treatment (prednisolone equivalent >40mg daily) is associated with significantly higher mortality during the first year.[[4]] A randomised controlled trial comparing the efficacy and safety profile of doxycycline and oral prednisolone concluded non-inferiority of high-dose doxycycline (200mg oral daily) as a first-line treatment for bullous pemphigoid.[[1]]

DPP4is have become a popular second-line treatment in T2DM as they do not cause weight gain and have a lower adverse effect profile than sulphonylureas. However, in the last decade an increasing number of case reports and epidemiological studies have been published suggesting there is a relationship between bullous pemphigoid and DPP4is.[[5-7]] The latency time between the initiation of DPP4is and onset of bullous pemphigoid ranges from 1 to 37 months in case reports.[[5,6]] The association between bullous pemphigoid and DPP4is was first described in 2011.[[8]] There are several hypotheses about the pathogenesis of DPP4i-induced bullous pemphigoid, but the exact mechanism remains unknown.[[3]] Five cases of bullous pemphigoid in patients who had been on dual metformin and DPP4i therapy for 2 to 13 months prior to disease onset were described, and two cases were resistant to immunosuppressive therapy but later achieved stable remission upon cessation of DPP4is.[[8]] A  meta-analysis of case-control studies further supported this association and found that vildagliptin had a higher degree of association with bullous pemphigoid compared to sitagliptin and linagliptin.[[9]] The other available oral hypoglycaemic agents available in New Zealand do not cause blistering as a common adverse effect.

In New Zealand, vildagliptin became fully subsidised by PHARMAC on 1 October 2018. Before then, no cases of DPP4i-associated bullous pemphigoid had been reported to the Centre for Adverse Reactions Monitoring (CARM). Eight cases were reported between October 2018 and September 2020.[[10]] There were six females, and the average age was 75 years (standard deviation ± 10 years). The Australian Database of Adverse Event Notifications has recorded three cases of suspected vildagliptin-related pemphigoid. This increased incidence reflects the wider use of vildagliptin in the community since subsidisation. Bullous pemphigoid should be suspected in a patient on vildagliptin who develops an inflammatory rash with blisters.

Summary

Abstract

In New Zealand, vildagliptin became fully subsidised by PHARMAC on 1 October 2018. Bullous pemphigoid is an autoimmune blistering disorder that typically affects the elderly. Dipeptidyl peptidase-four inhibitors (DPP4is, or gliptins) are a cause of drug-induced bullous pemphigoid.

Aim

Method

Results

Conclusion

Author Information

Annabelle Yi Zhang, Medical Student: Faculty of Medical and Health Sciences, University of Auckland, New Zealand. Paul Jarrett, Dermatologist: Department of Dermatology, Middlemore Hospital, Counties Manukau District Health Board, Auckland, New Zealand; Department of Medicine, The University of Auckland, Auckland, New Zealand.

Acknowledgements

Dr Natalie Poppito, Consultant Histopathologist, Middlemore Hospital. New Zealand Pharmacovigilance Centre, University of Otago.

Correspondence

Dr Paul Jarrett, Module 7, Manukau SuperClinic, PO Box 98743, Manukau 2241, Auckland, New Zealand, +64 9 276 0000 (phone), +64 9 276 0282 (fax)

Correspondence Email

Paul.Jarrett@middlemore.co.nz

Competing Interests

Nil.

1. Williams H, Wojnarowska F, Kirtschig G, Mason J, Godec T, Schmidt E et al. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial. The Lancet. 2017;389(10079):1630-8.

2. Nishie W. Update on the pathogenesis of bullous pemphigoid: An autoantibody-mediated blistering disease targeting collagen XVII. Journal of Dermatological Science. 2014;73(3):179-86.

3. Tasanen K, Varpuluoma O, Nishie W. Dipeptidyl Peptidase-4 Inhibitor-Associated Bullous Pemphigoid. Frontiers in Immunology. 2019;10.

4. Rzany B, Partscht K, Jung M, Kippes W, Mecking D, Baima B et al. Risk Factors for Lethal Outcome in Patients With Bullous Pemphigoid. Archives of Dermatology. 2002;138(7).

5. Béné J, Jacobsoone A, Coupe P, Auffret M, Babai S, Hillaire-Buys D et al. Bullous pemphigoid induced by vildagliptin: a report of three cases. Fundamental & Clinical Pharmacology. 2014;29(1):112-4.

6. Yoshiji S, Murakami T, Harashima S, Ko R, Kashima R, Yabe D et al. Bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors: A report of five cases. Journal of Diabetes Investigation. 2017;9(2):445-7.

7. Plaquevent M, Tétart F, Fardet L, Ingen-Housz-Oro S, Valeyrie-Allanore L, Bernard P et al. Higher Frequency of Dipeptidyl Peptidase-4 Inhibitor Intake in Bullous Pemphigoid Patients than in the French General Population. Journal of Investigative Dermatology. 2019;139(4):835-41.

8. Skandalis K, Spirova M, Gaitanis G, Tsartsarakis A, Bassukas I. Drug-induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase-IV inhibitors plus metformin. Journal of the European Academy of Dermatology and Venereology. 2011;26(2):249-53.

9. Phan K, Charlton O, Smith S. Dipeptidyl peptidase‐4 inhibitors and bullous pemphigoid: A systematic review and adjusted meta‐analysis. Australasian Journal of Dermatology. 2019;61(1).

10. New Zealand Pharmacovigilance Centre. Vildagliptin Review. October 2020.

For the PDF of this article,
contact nzmj@nzma.org.nz

View Article PDF

In New Zealand, vildagliptin became fully subsidised by PHARMAC on 1 October 2018. Bullous pemphigoid is an autoimmune blistering disorder that typically affects the elderly. Dipeptidyl peptidase-four inhibitors (DPP4is, or gliptins) are a cause of drug-induced bullous pemphigoid.

Case presentation

A 69-year-old Caucasian man with type two diabetes mellitus (T2DM) and no known dermatological conditions presented with a one-month-old, widespread pruritic blistering rash. This rash developed nine months after the addition of vildagliptin to his diabetic medication regimen. The Naranjo algorithm score of causality was five, indicating a ‘probable’ adverse drug reaction.

There were widespread crusted erosions with scattered tense bullae over the scalp, trunk and limbs, and mucosal erosion on the lower lip (Figures 1 and 2). The diagnosis of bullous pemphigoid was confirmed by histology, which showed a subepidermal split with increased numbers of dermal eosinophils and positive anti-basement membrane antibody of 1:1280 titre. Direct immunofluorescence staining was not possible. Vildagliptin was ceased and oral doxycycline (200mg daily) initiated.[[1]] Re-epithelialisation on doxycycline monotherapy progressed slowly, therefore oral prednisone (40mg daily) was added, resulting in rapid re-epithelialisation. Blood glucose levels were monitored closely and managed with metformin and correctional scale insulin while the patient was taking prednisone.

Figure 1: Bullous pemphigoid on the back, consisting of vesicles, erosions from ruptured bullae and an erythematous urticated rash.

Figure 2: Mucosal involvement.

Discussion

Bullous pemphigoid is an autoimmune condition. Autoantibodies target hemidesmosomes in basal keratinocytes, causing loss of adhesion between the epidermis and dermis.[[2]] It is characterised by localised or generalised bullae with preceding and/or accompanying pruritus. Bullous pemphigoid is most commonly observed in the seventh to ninth decade of life and is associated with neurological diseases, including cerebrovascular accidents.[[3]] The mainstay of treatment is steroid therapy. However, high-dose systemic corticosteroid treatment (prednisolone equivalent >40mg daily) is associated with significantly higher mortality during the first year.[[4]] A randomised controlled trial comparing the efficacy and safety profile of doxycycline and oral prednisolone concluded non-inferiority of high-dose doxycycline (200mg oral daily) as a first-line treatment for bullous pemphigoid.[[1]]

DPP4is have become a popular second-line treatment in T2DM as they do not cause weight gain and have a lower adverse effect profile than sulphonylureas. However, in the last decade an increasing number of case reports and epidemiological studies have been published suggesting there is a relationship between bullous pemphigoid and DPP4is.[[5-7]] The latency time between the initiation of DPP4is and onset of bullous pemphigoid ranges from 1 to 37 months in case reports.[[5,6]] The association between bullous pemphigoid and DPP4is was first described in 2011.[[8]] There are several hypotheses about the pathogenesis of DPP4i-induced bullous pemphigoid, but the exact mechanism remains unknown.[[3]] Five cases of bullous pemphigoid in patients who had been on dual metformin and DPP4i therapy for 2 to 13 months prior to disease onset were described, and two cases were resistant to immunosuppressive therapy but later achieved stable remission upon cessation of DPP4is.[[8]] A  meta-analysis of case-control studies further supported this association and found that vildagliptin had a higher degree of association with bullous pemphigoid compared to sitagliptin and linagliptin.[[9]] The other available oral hypoglycaemic agents available in New Zealand do not cause blistering as a common adverse effect.

In New Zealand, vildagliptin became fully subsidised by PHARMAC on 1 October 2018. Before then, no cases of DPP4i-associated bullous pemphigoid had been reported to the Centre for Adverse Reactions Monitoring (CARM). Eight cases were reported between October 2018 and September 2020.[[10]] There were six females, and the average age was 75 years (standard deviation ± 10 years). The Australian Database of Adverse Event Notifications has recorded three cases of suspected vildagliptin-related pemphigoid. This increased incidence reflects the wider use of vildagliptin in the community since subsidisation. Bullous pemphigoid should be suspected in a patient on vildagliptin who develops an inflammatory rash with blisters.

Summary

Abstract

In New Zealand, vildagliptin became fully subsidised by PHARMAC on 1 October 2018. Bullous pemphigoid is an autoimmune blistering disorder that typically affects the elderly. Dipeptidyl peptidase-four inhibitors (DPP4is, or gliptins) are a cause of drug-induced bullous pemphigoid.

Aim

Method

Results

Conclusion

Author Information

Annabelle Yi Zhang, Medical Student: Faculty of Medical and Health Sciences, University of Auckland, New Zealand. Paul Jarrett, Dermatologist: Department of Dermatology, Middlemore Hospital, Counties Manukau District Health Board, Auckland, New Zealand; Department of Medicine, The University of Auckland, Auckland, New Zealand.

Acknowledgements

Dr Natalie Poppito, Consultant Histopathologist, Middlemore Hospital. New Zealand Pharmacovigilance Centre, University of Otago.

Correspondence

Dr Paul Jarrett, Module 7, Manukau SuperClinic, PO Box 98743, Manukau 2241, Auckland, New Zealand, +64 9 276 0000 (phone), +64 9 276 0282 (fax)

Correspondence Email

Paul.Jarrett@middlemore.co.nz

Competing Interests

Nil.

1. Williams H, Wojnarowska F, Kirtschig G, Mason J, Godec T, Schmidt E et al. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial. The Lancet. 2017;389(10079):1630-8.

2. Nishie W. Update on the pathogenesis of bullous pemphigoid: An autoantibody-mediated blistering disease targeting collagen XVII. Journal of Dermatological Science. 2014;73(3):179-86.

3. Tasanen K, Varpuluoma O, Nishie W. Dipeptidyl Peptidase-4 Inhibitor-Associated Bullous Pemphigoid. Frontiers in Immunology. 2019;10.

4. Rzany B, Partscht K, Jung M, Kippes W, Mecking D, Baima B et al. Risk Factors for Lethal Outcome in Patients With Bullous Pemphigoid. Archives of Dermatology. 2002;138(7).

5. Béné J, Jacobsoone A, Coupe P, Auffret M, Babai S, Hillaire-Buys D et al. Bullous pemphigoid induced by vildagliptin: a report of three cases. Fundamental & Clinical Pharmacology. 2014;29(1):112-4.

6. Yoshiji S, Murakami T, Harashima S, Ko R, Kashima R, Yabe D et al. Bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors: A report of five cases. Journal of Diabetes Investigation. 2017;9(2):445-7.

7. Plaquevent M, Tétart F, Fardet L, Ingen-Housz-Oro S, Valeyrie-Allanore L, Bernard P et al. Higher Frequency of Dipeptidyl Peptidase-4 Inhibitor Intake in Bullous Pemphigoid Patients than in the French General Population. Journal of Investigative Dermatology. 2019;139(4):835-41.

8. Skandalis K, Spirova M, Gaitanis G, Tsartsarakis A, Bassukas I. Drug-induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase-IV inhibitors plus metformin. Journal of the European Academy of Dermatology and Venereology. 2011;26(2):249-53.

9. Phan K, Charlton O, Smith S. Dipeptidyl peptidase‐4 inhibitors and bullous pemphigoid: A systematic review and adjusted meta‐analysis. Australasian Journal of Dermatology. 2019;61(1).

10. New Zealand Pharmacovigilance Centre. Vildagliptin Review. October 2020.

For the PDF of this article,
contact nzmj@nzma.org.nz

View Article PDF

In New Zealand, vildagliptin became fully subsidised by PHARMAC on 1 October 2018. Bullous pemphigoid is an autoimmune blistering disorder that typically affects the elderly. Dipeptidyl peptidase-four inhibitors (DPP4is, or gliptins) are a cause of drug-induced bullous pemphigoid.

Case presentation

A 69-year-old Caucasian man with type two diabetes mellitus (T2DM) and no known dermatological conditions presented with a one-month-old, widespread pruritic blistering rash. This rash developed nine months after the addition of vildagliptin to his diabetic medication regimen. The Naranjo algorithm score of causality was five, indicating a ‘probable’ adverse drug reaction.

There were widespread crusted erosions with scattered tense bullae over the scalp, trunk and limbs, and mucosal erosion on the lower lip (Figures 1 and 2). The diagnosis of bullous pemphigoid was confirmed by histology, which showed a subepidermal split with increased numbers of dermal eosinophils and positive anti-basement membrane antibody of 1:1280 titre. Direct immunofluorescence staining was not possible. Vildagliptin was ceased and oral doxycycline (200mg daily) initiated.[[1]] Re-epithelialisation on doxycycline monotherapy progressed slowly, therefore oral prednisone (40mg daily) was added, resulting in rapid re-epithelialisation. Blood glucose levels were monitored closely and managed with metformin and correctional scale insulin while the patient was taking prednisone.

Figure 1: Bullous pemphigoid on the back, consisting of vesicles, erosions from ruptured bullae and an erythematous urticated rash.

Figure 2: Mucosal involvement.

Discussion

Bullous pemphigoid is an autoimmune condition. Autoantibodies target hemidesmosomes in basal keratinocytes, causing loss of adhesion between the epidermis and dermis.[[2]] It is characterised by localised or generalised bullae with preceding and/or accompanying pruritus. Bullous pemphigoid is most commonly observed in the seventh to ninth decade of life and is associated with neurological diseases, including cerebrovascular accidents.[[3]] The mainstay of treatment is steroid therapy. However, high-dose systemic corticosteroid treatment (prednisolone equivalent >40mg daily) is associated with significantly higher mortality during the first year.[[4]] A randomised controlled trial comparing the efficacy and safety profile of doxycycline and oral prednisolone concluded non-inferiority of high-dose doxycycline (200mg oral daily) as a first-line treatment for bullous pemphigoid.[[1]]

DPP4is have become a popular second-line treatment in T2DM as they do not cause weight gain and have a lower adverse effect profile than sulphonylureas. However, in the last decade an increasing number of case reports and epidemiological studies have been published suggesting there is a relationship between bullous pemphigoid and DPP4is.[[5-7]] The latency time between the initiation of DPP4is and onset of bullous pemphigoid ranges from 1 to 37 months in case reports.[[5,6]] The association between bullous pemphigoid and DPP4is was first described in 2011.[[8]] There are several hypotheses about the pathogenesis of DPP4i-induced bullous pemphigoid, but the exact mechanism remains unknown.[[3]] Five cases of bullous pemphigoid in patients who had been on dual metformin and DPP4i therapy for 2 to 13 months prior to disease onset were described, and two cases were resistant to immunosuppressive therapy but later achieved stable remission upon cessation of DPP4is.[[8]] A  meta-analysis of case-control studies further supported this association and found that vildagliptin had a higher degree of association with bullous pemphigoid compared to sitagliptin and linagliptin.[[9]] The other available oral hypoglycaemic agents available in New Zealand do not cause blistering as a common adverse effect.

In New Zealand, vildagliptin became fully subsidised by PHARMAC on 1 October 2018. Before then, no cases of DPP4i-associated bullous pemphigoid had been reported to the Centre for Adverse Reactions Monitoring (CARM). Eight cases were reported between October 2018 and September 2020.[[10]] There were six females, and the average age was 75 years (standard deviation ± 10 years). The Australian Database of Adverse Event Notifications has recorded three cases of suspected vildagliptin-related pemphigoid. This increased incidence reflects the wider use of vildagliptin in the community since subsidisation. Bullous pemphigoid should be suspected in a patient on vildagliptin who develops an inflammatory rash with blisters.

Summary

Abstract

In New Zealand, vildagliptin became fully subsidised by PHARMAC on 1 October 2018. Bullous pemphigoid is an autoimmune blistering disorder that typically affects the elderly. Dipeptidyl peptidase-four inhibitors (DPP4is, or gliptins) are a cause of drug-induced bullous pemphigoid.

Aim

Method

Results

Conclusion

Author Information

Annabelle Yi Zhang, Medical Student: Faculty of Medical and Health Sciences, University of Auckland, New Zealand. Paul Jarrett, Dermatologist: Department of Dermatology, Middlemore Hospital, Counties Manukau District Health Board, Auckland, New Zealand; Department of Medicine, The University of Auckland, Auckland, New Zealand.

Acknowledgements

Dr Natalie Poppito, Consultant Histopathologist, Middlemore Hospital. New Zealand Pharmacovigilance Centre, University of Otago.

Correspondence

Dr Paul Jarrett, Module 7, Manukau SuperClinic, PO Box 98743, Manukau 2241, Auckland, New Zealand, +64 9 276 0000 (phone), +64 9 276 0282 (fax)

Correspondence Email

Paul.Jarrett@middlemore.co.nz

Competing Interests

Nil.

1. Williams H, Wojnarowska F, Kirtschig G, Mason J, Godec T, Schmidt E et al. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial. The Lancet. 2017;389(10079):1630-8.

2. Nishie W. Update on the pathogenesis of bullous pemphigoid: An autoantibody-mediated blistering disease targeting collagen XVII. Journal of Dermatological Science. 2014;73(3):179-86.

3. Tasanen K, Varpuluoma O, Nishie W. Dipeptidyl Peptidase-4 Inhibitor-Associated Bullous Pemphigoid. Frontiers in Immunology. 2019;10.

4. Rzany B, Partscht K, Jung M, Kippes W, Mecking D, Baima B et al. Risk Factors for Lethal Outcome in Patients With Bullous Pemphigoid. Archives of Dermatology. 2002;138(7).

5. Béné J, Jacobsoone A, Coupe P, Auffret M, Babai S, Hillaire-Buys D et al. Bullous pemphigoid induced by vildagliptin: a report of three cases. Fundamental & Clinical Pharmacology. 2014;29(1):112-4.

6. Yoshiji S, Murakami T, Harashima S, Ko R, Kashima R, Yabe D et al. Bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors: A report of five cases. Journal of Diabetes Investigation. 2017;9(2):445-7.

7. Plaquevent M, Tétart F, Fardet L, Ingen-Housz-Oro S, Valeyrie-Allanore L, Bernard P et al. Higher Frequency of Dipeptidyl Peptidase-4 Inhibitor Intake in Bullous Pemphigoid Patients than in the French General Population. Journal of Investigative Dermatology. 2019;139(4):835-41.

8. Skandalis K, Spirova M, Gaitanis G, Tsartsarakis A, Bassukas I. Drug-induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase-IV inhibitors plus metformin. Journal of the European Academy of Dermatology and Venereology. 2011;26(2):249-53.

9. Phan K, Charlton O, Smith S. Dipeptidyl peptidase‐4 inhibitors and bullous pemphigoid: A systematic review and adjusted meta‐analysis. Australasian Journal of Dermatology. 2019;61(1).

10. New Zealand Pharmacovigilance Centre. Vildagliptin Review. October 2020.

Contact diana@nzma.org.nz
for the PDF of this article

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