Correspondence Clinical Letter
Clinical Letter Successful treatment of lichen planus pemphigoides using acitretin as monotherapy
DOI: 10.1111/ddg.12380
Dear Editors, Lichen planus pemphigoides (LPP) is a bullous autoimmune disease with overlapping features of both bullous pemphigoid and lichen planus. Due to its low incidence, there is no evidence-based therapy. In most cases, treatment with systemic corticosteroids, if necessary combined with immunosuppressive agents, results in a resolution of lesions. The use of acitretin as effective supplementary agent to systemic steroids in previously recalcitrant LPP has been described in rare cases [1, 2]. An obese 21-year-old man initially developed severely pruritic erythematous papules on the arms, which later became generalized. He subsequently also experienced blister formation on arms and legs. The patient was referred to us after topical treatment with clobetasol propionate cream over the course of four weeks had failed to result in sufficient clinical improvement. The entire integument showed multiple flat polygonal erythematous papules. In addition, the distal extremities revealed tense blisters measuring up to 2.5 cm in diameter (Figure 1a, b). There was marked palmoplantar hyperkeratosis and reticular white lines on the buccal mucosa bilaterally. Histopathology from a violaceous papulovesicle showed hyperkeratosis, focal hypergranulosis, subepidermal blister formation as well as a band-like lymphohistiocytic infiltrate in the adjacent dermis (Figure 1c). Direct immunofluorescence of a perilesional biopsy revealed linear C3 and fibrinogen deposits along the dermoepidermal basement membrane (Figure 1d) as well as IgM and IgA reactive cytoid bodies. Routine lab workup, including cholesterol and glucose, was unremarkable. Indirect immunofluorescence on salt-split skin showed circulating IgG antibodies on the epidermal side. Serum ELISA displayed IgG antibodies against BP180 (> 200 U/ml, normal range < 20 U/ml), but no antibodies directed against BP230, desmoglein 1 and 3. Based on the clinical presentation, histologic and serologic findings, we made the diagnosis of LPP and supplemented the topical therapy with clobetasol propionate with the systemic administration of acitretin (0.5 mg/kg body weight QD). This led to complete resolution of blisters and marked improvement of lichenoid papules within 14 days. After four months, only postinflammatory erythema had remained (Figure 1e, f) and serum BP180 antibodies had dropped to
818
74 U/ml. Subsequently, while the acitretin dose was reduced, topical therapy was completely discontinued. Ten months after the diagnosis, acitretin was finally also discontinued. Currently, the patient is still free of disease. LPP usually starts with pruritic polygonal papules with Wickham striae, especially on the distal extremities, but sometimes also generalized [3]. A few weeks later, tense blisters develop on these lichenoid lesions but also on previously healthy skin. The diagnosis is made by detection of IgG antibody or complement deposits in direct immunofluorescence along the basement membrane and by serologic detection of circulating antibodies through indirect immunofluorescence or ELISA. Here, the hemidesmosomal protein BP180/collagen XVII constitutes the major autoantigen. In LPP, autoantibodies primarily react with C-terminal epitopes within the NC16A domain of BP180 (NC16A MCW4), whereas in bullous pemphigoid, N-terminal areas of the NC16A domain represent the autoantibodies’ target structure [4]. LPP is an extremely rare disease, predominantly affecting younger adults between 30 and 50 years of age but sometimes also children [5]. While the disorder is generally idiopathic, some cases have been reported in which drugs, infections, phototherapy, or neoplasms were implicated as possible triggering factors [6]. It is crucial to differentiate LPP from other bullous autoimmune diseases, particularly bullous pemphigoid and the mechanobullous variant of epidermolysis bullosa acquisita which also frequently involves the distal extremities [7]. Another differential diagnosis is bullous lichen planus. Here, however, blisters develop on preexisting lichenoid lesions and, unlike LPP, direct immunofluorescence is negative and there are no circulating antibodies against basement membrane proteins. The classification of LPP as separate entity has been subject to controversy. Some authors posit this condition solely represents a chance concurrence of lichen planus and bullous pemphigoid. However, the fact that LPP predominantly affects younger patients and lichenoid papules characteristically precede blisters in LPP argues against this hypothesis. Degeneration of basal keratinocytes in the context of chronic lichenoid inflammation most likely contributes to the presentation of immunogenic epitopes of basement membrane proteins and thus to the activation of autoreactive lymphocytes with subsequent blister formation [8]. Consequently, treatment of the lichenoid component of LPP, e.g. with antiproliferative agents such as retinoids, is essential for any therapeutic success. In contrast, in moderate bullous pemphigoid sole topical therapy with clobetasol propionate conforms with current guidelines [9] but did not yield any improvement in our patient. We therefore initiated systemic monotherapy with acitretin while simultaneously continuing the aforementioned topical treatment, leading to swift and
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209
Correspondence Clinical Letter
Figure 1 Initial presentation with coalescing violaceous polygonal papules. There are also some tense blisters on the dorsum of the hand and plantar hyperkeratosis (a, b). Hematoxylin-eosin staining of lesional skin with hypergranulosis, subepidermal blister formation and a band-like lymphohistiocytic infiltrate (c). Direct immunofluorescence of perilesional skin showing linear C3 deposits along the basement membrane zone (d). Four months after initiation of acitretin therapy, there is a good clinical response with only postinflammatory erythema (e, f).
complete resolution of lesions. This case shows for the first time that systemic therapy with acitretin alone may be effective in LPP and should be considered, especially if there are contraindications with respect to systemic steroid therapy.
References 1
2
Conflict of interest None.
3
Katri Hackländer, Percy Lehmann, Silke C. Hofmann
4
Center for Dermatology, Allergology, and Dermatosurgery, University Witten/Herdecke, HELIOS Hospital Wuppertal, Wuppertal, Germany
5
Correspondence to Priv.-Doz. Dr. med. Silke Hofmann Zentrum für Dermatologie, Allergologie und Dermatochirurgie HELIOS Klinikum Wuppertal Universität Witten/Herdecke Heusnerstraße 40, 42283 Wuppertal Germany E-mail: [email protected]
6 7 8
9
Yoon KH, Kim SC, Kang DS, Lee IJ. Lichen planus pemphigoides with circulating autoantibodies against 200 and 180 kDa epidermal antigens. Eur J Dermatol 2000; 10: 212–4. Kolb-Maurer A, Sitaru C, Rose C et al. Therapie des Lichen planus pemphigoides durch Acitretin und pulsweise verabreichtes Kortikosteroid. Hautarzt 2003; 54: 268–73. Zaraa I, Mahfoudh A, Sellami MK et al. Lichen planus pemphigoides: four new cases and a review of the literature. Int J Dermatol 2013; 52: 406–12. Zillikens D, Caux F, Mascaro JM et al. Autoantibodies in lichen planus pemphigoides react with a novel epitope within the C-terminal NC16A domain of BP180. J Invest Dermatol 1999; 113: 117–21. Goldscheider I, Herzinger T, Varga R et al. Childhood lichen llanus lemphigoides: Report of two cases treated successfully with systemic glucocorticoids and dapsone. Pediatr Dermatol 2013 Oct 21. doi: 10.1111/pde.12214. [Epub ahead of print]. Zhu YI, Fitzpatrick JE, Kornfeld BW. Lichen planus pemphigoides associated with ramipril. Int J Dermatol 2006; 45: 1453–5. Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 1: Clinical manifestations. J Dtsch Dermatol Ges 2011; 9: 844–56; quiz 57. Mignogna MD, Fortuna G, Leuci S et al. Lichen planus pemphigoides, a possible example of epitope spreading. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109: 837–43. Venning VA, Taghipour K, Mohd Mustapa MF et al. British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012. Br J Dermatol 2012; 167: 1200–14.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209
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Clinical Letter Successful treatment of lichen planus pemphigoides using acitretin as monotherapy
DOI: 10.1111/ddg.12380
Dear Editors, Lichen planus pemphigoides (LPP) is a bullous autoimmune disease with overlapping features of both bullous pemphigoid and lichen planus. Due to its low incidence, there is no evidence-based therapy. In most cases, treatment with systemic corticosteroids, if necessary combined with immunosuppressive agents, results in a resolution of lesions. The use of acitretin as effective supplementary agent to systemic steroids in previously recalcitrant LPP has been described in rare cases [1, 2]. An obese 21-year-old man initially developed severely pruritic erythematous papules on the arms, which later became generalized. He subsequently also experienced blister formation on arms and legs. The patient was referred to us after topical treatment with clobetasol propionate cream over the course of four weeks had failed to result in sufficient clinical improvement. The entire integument showed multiple flat polygonal erythematous papules. In addition, the distal extremities revealed tense blisters measuring up to 2.5 cm in diameter (Figure 1a, b). There was marked palmoplantar hyperkeratosis and reticular white lines on the buccal mucosa bilaterally. Histopathology from a violaceous papulovesicle showed hyperkeratosis, focal hypergranulosis, subepidermal blister formation as well as a band-like lymphohistiocytic infiltrate in the adjacent dermis (Figure 1c). Direct immunofluorescence of a perilesional biopsy revealed linear C3 and fibrinogen deposits along the dermoepidermal basement membrane (Figure 1d) as well as IgM and IgA reactive cytoid bodies. Routine lab workup, including cholesterol and glucose, was unremarkable. Indirect immunofluorescence on salt-split skin showed circulating IgG antibodies on the epidermal side. Serum ELISA displayed IgG antibodies against BP180 (> 200 U/ml, normal range < 20 U/ml), but no antibodies directed against BP230, desmoglein 1 and 3. Based on the clinical presentation, histologic and serologic findings, we made the diagnosis of LPP and supplemented the topical therapy with clobetasol propionate with the systemic administration of acitretin (0.5 mg/kg body weight QD). This led to complete resolution of blisters and marked improvement of lichenoid papules within 14 days. After four months, only postinflammatory erythema had remained (Figure 1e, f) and serum BP180 antibodies had dropped to
818
74 U/ml. Subsequently, while the acitretin dose was reduced, topical therapy was completely discontinued. Ten months after the diagnosis, acitretin was finally also discontinued. Currently, the patient is still free of disease. LPP usually starts with pruritic polygonal papules with Wickham striae, especially on the distal extremities, but sometimes also generalized [3]. A few weeks later, tense blisters develop on these lichenoid lesions but also on previously healthy skin. The diagnosis is made by detection of IgG antibody or complement deposits in direct immunofluorescence along the basement membrane and by serologic detection of circulating antibodies through indirect immunofluorescence or ELISA. Here, the hemidesmosomal protein BP180/collagen XVII constitutes the major autoantigen. In LPP, autoantibodies primarily react with C-terminal epitopes within the NC16A domain of BP180 (NC16A MCW4), whereas in bullous pemphigoid, N-terminal areas of the NC16A domain represent the autoantibodies’ target structure [4]. LPP is an extremely rare disease, predominantly affecting younger adults between 30 and 50 years of age but sometimes also children [5]. While the disorder is generally idiopathic, some cases have been reported in which drugs, infections, phototherapy, or neoplasms were implicated as possible triggering factors [6]. It is crucial to differentiate LPP from other bullous autoimmune diseases, particularly bullous pemphigoid and the mechanobullous variant of epidermolysis bullosa acquisita which also frequently involves the distal extremities [7]. Another differential diagnosis is bullous lichen planus. Here, however, blisters develop on preexisting lichenoid lesions and, unlike LPP, direct immunofluorescence is negative and there are no circulating antibodies against basement membrane proteins. The classification of LPP as separate entity has been subject to controversy. Some authors posit this condition solely represents a chance concurrence of lichen planus and bullous pemphigoid. However, the fact that LPP predominantly affects younger patients and lichenoid papules characteristically precede blisters in LPP argues against this hypothesis. Degeneration of basal keratinocytes in the context of chronic lichenoid inflammation most likely contributes to the presentation of immunogenic epitopes of basement membrane proteins and thus to the activation of autoreactive lymphocytes with subsequent blister formation [8]. Consequently, treatment of the lichenoid component of LPP, e.g. with antiproliferative agents such as retinoids, is essential for any therapeutic success. In contrast, in moderate bullous pemphigoid sole topical therapy with clobetasol propionate conforms with current guidelines [9] but did not yield any improvement in our patient. We therefore initiated systemic monotherapy with acitretin while simultaneously continuing the aforementioned topical treatment, leading to swift and
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209
Correspondence Clinical Letter
Figure 1 Initial presentation with coalescing violaceous polygonal papules. There are also some tense blisters on the dorsum of the hand and plantar hyperkeratosis (a, b). Hematoxylin-eosin staining of lesional skin with hypergranulosis, subepidermal blister formation and a band-like lymphohistiocytic infiltrate (c). Direct immunofluorescence of perilesional skin showing linear C3 deposits along the basement membrane zone (d). Four months after initiation of acitretin therapy, there is a good clinical response with only postinflammatory erythema (e, f).
complete resolution of lesions. This case shows for the first time that systemic therapy with acitretin alone may be effective in LPP and should be considered, especially if there are contraindications with respect to systemic steroid therapy.
References 1
2
Conflict of interest None.
3
Katri Hackländer, Percy Lehmann, Silke C. Hofmann
4
Center for Dermatology, Allergology, and Dermatosurgery, University Witten/Herdecke, HELIOS Hospital Wuppertal, Wuppertal, Germany
5
Correspondence to Priv.-Doz. Dr. med. Silke Hofmann Zentrum für Dermatologie, Allergologie und Dermatochirurgie HELIOS Klinikum Wuppertal Universität Witten/Herdecke Heusnerstraße 40, 42283 Wuppertal Germany E-mail: [email protected]
6 7 8
9
Yoon KH, Kim SC, Kang DS, Lee IJ. Lichen planus pemphigoides with circulating autoantibodies against 200 and 180 kDa epidermal antigens. Eur J Dermatol 2000; 10: 212–4. Kolb-Maurer A, Sitaru C, Rose C et al. Therapie des Lichen planus pemphigoides durch Acitretin und pulsweise verabreichtes Kortikosteroid. Hautarzt 2003; 54: 268–73. Zaraa I, Mahfoudh A, Sellami MK et al. Lichen planus pemphigoides: four new cases and a review of the literature. Int J Dermatol 2013; 52: 406–12. Zillikens D, Caux F, Mascaro JM et al. Autoantibodies in lichen planus pemphigoides react with a novel epitope within the C-terminal NC16A domain of BP180. J Invest Dermatol 1999; 113: 117–21. Goldscheider I, Herzinger T, Varga R et al. Childhood lichen llanus lemphigoides: Report of two cases treated successfully with systemic glucocorticoids and dapsone. Pediatr Dermatol 2013 Oct 21. doi: 10.1111/pde.12214. [Epub ahead of print]. Zhu YI, Fitzpatrick JE, Kornfeld BW. Lichen planus pemphigoides associated with ramipril. Int J Dermatol 2006; 45: 1453–5. Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 1: Clinical manifestations. J Dtsch Dermatol Ges 2011; 9: 844–56; quiz 57. Mignogna MD, Fortuna G, Leuci S et al. Lichen planus pemphigoides, a possible example of epitope spreading. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109: 837–43. Venning VA, Taghipour K, Mohd Mustapa MF et al. British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012. Br J Dermatol 2012; 167: 1200–14.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209
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