JEADV
LETTERS TO THE EDITOR
Refractory antilaminin c1 pemphigoid successfully treated with intravenous immunoglobulin and mycophenolate mofetil Editor Antilaminin c1 pemphigoid, formally known as anti-p200 pemphigoid, is a rare subepidermal bullous disease that is commonly treated with mild to moderate immunosupression.1–3 Cases of refractory disease require a multifaceted therapeutic approach. Herein, we present a patient with refractory antilaminin c1 pemphigoid successfully treated with intravenous immunoglobulin (IVIg) and mycophenolate mofetil.
An 83-year-old man presented to the hospital with multiple erythematous plaques studded with shallow erosions on his trunk, acral surfaces and oral mucosa (Fig. 1). His chest, back, palms, soles and genitals had urticarial plaques, tense vesicles and bullae, some with a strikingly arcuate configuration, several lakes of pus and large erosions. Laboratory studies were within normal limits. Skin biopsies revealed a subepidermal bulla with a neutrophilic infiltrate and linear C3 and IgG deposition at the basement membrane zone, suggestive of bullous pemphigoid (Fig. 2). Given the atypical nature of his presentation, along with the neutrophilic predominance on histology, indirect immunofluorescence was performed. This demonstrated a linear pattern of IgG bound to the dermal aspect of salt-split skin. The presence of the antilaminin c1 antigen was subsequently confirmed via immunoblot assay.
(a)
(b)
(c)
(d)
Figure 1 Antilaminin c1 pemphigoid: (a) Multiple erythematous plaques with shallow erosions on the chest and (b) back. (c) Tense haemorrhagic vesicobullae and urticarial erythematous plaques in arcuate and annular arrangement on the palm. (d) Large, coalescent urticarial bullae, with some in an annular configuration, on the sole.
JEADV 2014, 28, 1401–1406
© 2014 European Academy of Dermatology and Venereology
Letters to the Editor
1402
(a)
(c)
(d)
(b)
Figure 2 Antilaminin c1 pemphigoid: Histologic section with haematoxylin and eosin stain demonstrates a subepidermal blister containing numerous neutrophils (original magnification 9200) (a). On direct immunofluorescence examination, there is IgG deposition at the basement membrane zone (b) and on salt-split skin indirect immunofluorescence examination, the patient’s IgG reacts on dermal side of the blister (c). Immunoblotting studies demonstrated a weak 200 kDa band, laminin gamma-1, 1 : 20 (lane 4) and 1 : 10 (lane 5) dilution of patient’s serum, corresponding to antilaminin gamma 1 monoclonal antibody (purchased from Santa Cruz Biotechnology, Heidelberg, Germany) in lane 2 and p200 control in lane 3. There was no reaction observed for epidermolysis bullosa acquisita antigen (290 kDa type VII collagen) in lane 1. Although not shown, there were no reactions observed for bullous pemphigoid antigens (BP230 and BP180), paraneoplastic pemphigus antigens (210 kDa envoplakin and 190 kDa periplakin), pemphigus vulgaris antigen (130 kDa desmoglein 3) and pemphigus foliaceus antigen (160 kDa desmoglein 1). Therefore, all the biochemical results were supportive of the diagnosis of antilaminin c1 (p200) pemphigoid (d).
The patient was started on prednisone 80 mg daily and azathioprine 150 mg daily with rapid improvement enabling discharge. Upon tapering the prednisone to 60 mg daily, his lesions recurred requiring readmission and up-titration of his prednisone. Ten days into this second hospitalization, dapsone 100 mg daily was added in an effort to better taper his prednisone. Shortly thereafter, he developed leucopenia and acute renal failure requiring haemodialysis–necessitating discontinuation of both azathioprine and dapsone. Given the refractory nature of his disease, IVIg 1 g/kg dosing was initiated biweekly, resulting in significant improvement. Mycophenolate mofetil 1 g twice daily was added, and together with IVIg, allowed prednisone to be tapered over the subsequent 6 weeks of hospitalization with no further disease flares.
JEADV 2014, 28, 1401–1406
Two months later, the patient was clear on mycophenolate mofetil, IVIg and prednisone 10 mg daily. Over the next 6 months, his prednisone and IVIg were discontinued and mycophenolate mofetil was tapered to 500 mg daily and subsequently stopped. He remains clear off all medications for over 1 year. Antilaminin c1 pemphigoid is a rare autoimmune bullous disease that may clinically and histologically mimic bullous pemphigoid or linear IgA bullous dermatosis. Since the first reports in the 1990s, approximately 70 cases have been described.1–6 Treatment algorithms for this condition follow guidelines similar to that of other subepidermal autoimmune bullous diseases–employing topical and systemic steroids as well as steroid-sparing agents.2,4–6 Unfortunately, the issue of refractory
© 2014 European Academy of Dermatology and Venereology
Letters to the Editor
disease has not been well addressed. Two other reports illustrate the inability to achieve disease control with conventional therapy, with one case ultimately requiring plasmapheresis.7,8 Intravenous immunoglobulin has demonstrated significant efficacy in the treatment of autoimmune bullous dermatoses.2,6,9,10 Two other reports have employed the use of IVIg in patients with antilaminin c1 pemphigoid.6,10 However, unlike our case, these reports employed a single cycle of IVIg to achieve control and both patients also demonstrated a unique disease phenotype, with antibodies to EBA-associated antigens.6,10 Given the morbidity associated with autoimmune bullous diseases, IVIg represents an attractive therapeutic option to rapidly quell disease activity and maintain long-term disease remission. In addition, IVIg may provide a temporizing window in which a steroid-sparing immunosuppressive agent, such as mycophenolate mofetil, can be titrated to enable discontinuation of highdose systemic steroids. Although quite costly, the usage of IVIg may be cost-effective overall by decreasing readmission rates and minimizing adverse events. Continued research is needed to better understand the pathogenesis of this complex disease and help develop strategies for the management of refractory cases. A. Alloo,1 L. Strazzula,2 B. Rothschild,1 E. Hawryluk,1 D. Levine,1 M.P. Hoang,3 H. Koga,4 T. Hashimoto,4 D. Kroshinsky1,* 1
Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 2Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA, 3Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 4Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan *Correspondence: D. Kroshinsky. E-mail: [email protected]
References 1 Zillikens D, Kawahara Y, Ishiko A et al. A novel subepidermal blistering disease with autoantibodies to a 200-kDa antigen of the basement membrane zone. J Invest Dermatol 1996; 106: 465–470. 2 Dilling A, Rose C, Hashimoto T et al. Anti-p200 pemphigoid: a novel autoimmune subepidermal blistering disease. J Dermatol 2007; 34: 1–8. 3 Dainichi T, Kurono S, Ohyama B et al. Anti-laminin gamma-1 pemphigoid. Proc Natl Acad Sci U S A 2009; 106: 2800–2805. 4 Iwata H, Hiramitsu Y, Aoyama Y, Kitajima Y. A case of anti-p200 pemphigoid: evidence for a different pathway in neutrophil recruitment compared with bullous pemphigoid. Br J Dermatol 2009; 160: 462–464. 5 Yamane N, Sawamura D, Nishie W et al. Anti-p200 pemphigoid in a 17-year-old girl successfully treated with systemic corticosteroid and dapsone. Br J Dermatol 2007; 156: 1075–1078. 6 Pastar Z, Rados J, Lipozencic J et al. Case of concurrent epidermolysis bullosa acquisita and anti-p200 pemphigoid – how to treat it? Int J Dermatol 2007; 46: 295–298. 7 Egan CA, Yee C, Zillikens D, Yancey KB. Anti-p200 pemphigoid: diagnosis and treatment of a case presenting as an inflammatory subepidermal blistering disease. J Am Acad Dermatol 2002; 46: 786–789. 8 Watanabe M, Tsunoda T, Tagami H. A subepidermal blistering dermatosis associated with coexistent IgG and IgA anti-dermal basement membrane zone anti-bodies; demonstration of IgG antibodies reactive against a 200-kDa dermal antigen. Eur J Dermatol 2002; 12: 603–606.
JEADV 2014, 28, 1401–1406
1403
9 Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immunoglobulin. N Engl J Med 2001; 345: 747–755. 10 Morris SD, Mallipeddi R, Oyama N et al. Psoriasis bullosa acquisita. Clin Exp Dermatol 2002; 27: 665–669. DOI: 10.1111/jdv.12352
Actinic lichen nitidus in a Caucasian European patient Editor Actinic lichen nitidus (ALN) is a photoinduced lichenoid eruption that displays histologic features of classic lichen nitidus with some clinical similarities. It appears only on photo-distributed areas. Up to date, it has been reported in deeply pigmented patients (Fitzpatrick skin types V and VI), in African American, Middle Eastern and Indian descent population.1 To our knowledge, it has not been yet described in Caucasian patients. We report a 12-year-old Spanish Caucasian male, Fitzpatrick skin phototype III, who presented with pruritic non-scaly papules just on sun-exposed areas. For 6 years, he had outbreaks of moderately itchy lesions that appeared after 1–2 days of sun exposure when he remained more than an hour under the sunlight. The lesions lasted for weeks and vanished slowly during late summer, once sun exposure was avoided. He had never presented such lesions in covered areas. He achieved a partial control of the outbreaks with deflazacort and topical steroids, but the lesions recurred days after leaving them. Physical examination showed numerous 1–2 mm whitish, mildly pruritic papules limited to sun-exposed areas: back of both hands (Fig. 1), forearms, legs, thighs and over the ‘V’ area of the neck. The lesions spared areas covered by the clothes. There was no involvement of the scalp, nails or oral mucosa. A biopsy of a papule from the dorsum of the hand showed circumscribed lichenoid granulomatous infiltrates composed of lymphocytes and histiocytes. Thin rete ridge epidermal elongations were seen at the lateral borders of the circumscribed infiltrates with an image of a ‘claw clutching a ball’. There was an absence of the granular layer over the infiltrate (Fig 2). Laboratory tests showed only an increase percentage of eosinophils (7.2%) and an IgE of 436 UI/mL. Broad-band UVB phototesting (five spots, up to 122 mJ/cm2 with Gigatest, Medisun, France, 2006) showed an adjusted to erythema MED of 33 mJ/cm2, that is normal for his skin phototype. UVA phototesting (five spots, up to 9 mJ/cm2 with Gigatest, Mediun, France, 2006) showed no abnormal reaction to UVA. Broad-band UVA provocation using lamp banks for
© 2014 European Academy of Dermatology and Venereology
LETTERS TO THE EDITOR
Refractory antilaminin c1 pemphigoid successfully treated with intravenous immunoglobulin and mycophenolate mofetil Editor Antilaminin c1 pemphigoid, formally known as anti-p200 pemphigoid, is a rare subepidermal bullous disease that is commonly treated with mild to moderate immunosupression.1–3 Cases of refractory disease require a multifaceted therapeutic approach. Herein, we present a patient with refractory antilaminin c1 pemphigoid successfully treated with intravenous immunoglobulin (IVIg) and mycophenolate mofetil.
An 83-year-old man presented to the hospital with multiple erythematous plaques studded with shallow erosions on his trunk, acral surfaces and oral mucosa (Fig. 1). His chest, back, palms, soles and genitals had urticarial plaques, tense vesicles and bullae, some with a strikingly arcuate configuration, several lakes of pus and large erosions. Laboratory studies were within normal limits. Skin biopsies revealed a subepidermal bulla with a neutrophilic infiltrate and linear C3 and IgG deposition at the basement membrane zone, suggestive of bullous pemphigoid (Fig. 2). Given the atypical nature of his presentation, along with the neutrophilic predominance on histology, indirect immunofluorescence was performed. This demonstrated a linear pattern of IgG bound to the dermal aspect of salt-split skin. The presence of the antilaminin c1 antigen was subsequently confirmed via immunoblot assay.
(a)
(b)
(c)
(d)
Figure 1 Antilaminin c1 pemphigoid: (a) Multiple erythematous plaques with shallow erosions on the chest and (b) back. (c) Tense haemorrhagic vesicobullae and urticarial erythematous plaques in arcuate and annular arrangement on the palm. (d) Large, coalescent urticarial bullae, with some in an annular configuration, on the sole.
JEADV 2014, 28, 1401–1406
© 2014 European Academy of Dermatology and Venereology
Letters to the Editor
1402
(a)
(c)
(d)
(b)
Figure 2 Antilaminin c1 pemphigoid: Histologic section with haematoxylin and eosin stain demonstrates a subepidermal blister containing numerous neutrophils (original magnification 9200) (a). On direct immunofluorescence examination, there is IgG deposition at the basement membrane zone (b) and on salt-split skin indirect immunofluorescence examination, the patient’s IgG reacts on dermal side of the blister (c). Immunoblotting studies demonstrated a weak 200 kDa band, laminin gamma-1, 1 : 20 (lane 4) and 1 : 10 (lane 5) dilution of patient’s serum, corresponding to antilaminin gamma 1 monoclonal antibody (purchased from Santa Cruz Biotechnology, Heidelberg, Germany) in lane 2 and p200 control in lane 3. There was no reaction observed for epidermolysis bullosa acquisita antigen (290 kDa type VII collagen) in lane 1. Although not shown, there were no reactions observed for bullous pemphigoid antigens (BP230 and BP180), paraneoplastic pemphigus antigens (210 kDa envoplakin and 190 kDa periplakin), pemphigus vulgaris antigen (130 kDa desmoglein 3) and pemphigus foliaceus antigen (160 kDa desmoglein 1). Therefore, all the biochemical results were supportive of the diagnosis of antilaminin c1 (p200) pemphigoid (d).
The patient was started on prednisone 80 mg daily and azathioprine 150 mg daily with rapid improvement enabling discharge. Upon tapering the prednisone to 60 mg daily, his lesions recurred requiring readmission and up-titration of his prednisone. Ten days into this second hospitalization, dapsone 100 mg daily was added in an effort to better taper his prednisone. Shortly thereafter, he developed leucopenia and acute renal failure requiring haemodialysis–necessitating discontinuation of both azathioprine and dapsone. Given the refractory nature of his disease, IVIg 1 g/kg dosing was initiated biweekly, resulting in significant improvement. Mycophenolate mofetil 1 g twice daily was added, and together with IVIg, allowed prednisone to be tapered over the subsequent 6 weeks of hospitalization with no further disease flares.
JEADV 2014, 28, 1401–1406
Two months later, the patient was clear on mycophenolate mofetil, IVIg and prednisone 10 mg daily. Over the next 6 months, his prednisone and IVIg were discontinued and mycophenolate mofetil was tapered to 500 mg daily and subsequently stopped. He remains clear off all medications for over 1 year. Antilaminin c1 pemphigoid is a rare autoimmune bullous disease that may clinically and histologically mimic bullous pemphigoid or linear IgA bullous dermatosis. Since the first reports in the 1990s, approximately 70 cases have been described.1–6 Treatment algorithms for this condition follow guidelines similar to that of other subepidermal autoimmune bullous diseases–employing topical and systemic steroids as well as steroid-sparing agents.2,4–6 Unfortunately, the issue of refractory
© 2014 European Academy of Dermatology and Venereology
Letters to the Editor
disease has not been well addressed. Two other reports illustrate the inability to achieve disease control with conventional therapy, with one case ultimately requiring plasmapheresis.7,8 Intravenous immunoglobulin has demonstrated significant efficacy in the treatment of autoimmune bullous dermatoses.2,6,9,10 Two other reports have employed the use of IVIg in patients with antilaminin c1 pemphigoid.6,10 However, unlike our case, these reports employed a single cycle of IVIg to achieve control and both patients also demonstrated a unique disease phenotype, with antibodies to EBA-associated antigens.6,10 Given the morbidity associated with autoimmune bullous diseases, IVIg represents an attractive therapeutic option to rapidly quell disease activity and maintain long-term disease remission. In addition, IVIg may provide a temporizing window in which a steroid-sparing immunosuppressive agent, such as mycophenolate mofetil, can be titrated to enable discontinuation of highdose systemic steroids. Although quite costly, the usage of IVIg may be cost-effective overall by decreasing readmission rates and minimizing adverse events. Continued research is needed to better understand the pathogenesis of this complex disease and help develop strategies for the management of refractory cases. A. Alloo,1 L. Strazzula,2 B. Rothschild,1 E. Hawryluk,1 D. Levine,1 M.P. Hoang,3 H. Koga,4 T. Hashimoto,4 D. Kroshinsky1,* 1
Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 2Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA, 3Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 4Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan *Correspondence: D. Kroshinsky. E-mail: [email protected]
References 1 Zillikens D, Kawahara Y, Ishiko A et al. A novel subepidermal blistering disease with autoantibodies to a 200-kDa antigen of the basement membrane zone. J Invest Dermatol 1996; 106: 465–470. 2 Dilling A, Rose C, Hashimoto T et al. Anti-p200 pemphigoid: a novel autoimmune subepidermal blistering disease. J Dermatol 2007; 34: 1–8. 3 Dainichi T, Kurono S, Ohyama B et al. Anti-laminin gamma-1 pemphigoid. Proc Natl Acad Sci U S A 2009; 106: 2800–2805. 4 Iwata H, Hiramitsu Y, Aoyama Y, Kitajima Y. A case of anti-p200 pemphigoid: evidence for a different pathway in neutrophil recruitment compared with bullous pemphigoid. Br J Dermatol 2009; 160: 462–464. 5 Yamane N, Sawamura D, Nishie W et al. Anti-p200 pemphigoid in a 17-year-old girl successfully treated with systemic corticosteroid and dapsone. Br J Dermatol 2007; 156: 1075–1078. 6 Pastar Z, Rados J, Lipozencic J et al. Case of concurrent epidermolysis bullosa acquisita and anti-p200 pemphigoid – how to treat it? Int J Dermatol 2007; 46: 295–298. 7 Egan CA, Yee C, Zillikens D, Yancey KB. Anti-p200 pemphigoid: diagnosis and treatment of a case presenting as an inflammatory subepidermal blistering disease. J Am Acad Dermatol 2002; 46: 786–789. 8 Watanabe M, Tsunoda T, Tagami H. A subepidermal blistering dermatosis associated with coexistent IgG and IgA anti-dermal basement membrane zone anti-bodies; demonstration of IgG antibodies reactive against a 200-kDa dermal antigen. Eur J Dermatol 2002; 12: 603–606.
JEADV 2014, 28, 1401–1406
1403
9 Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immunoglobulin. N Engl J Med 2001; 345: 747–755. 10 Morris SD, Mallipeddi R, Oyama N et al. Psoriasis bullosa acquisita. Clin Exp Dermatol 2002; 27: 665–669. DOI: 10.1111/jdv.12352
Actinic lichen nitidus in a Caucasian European patient Editor Actinic lichen nitidus (ALN) is a photoinduced lichenoid eruption that displays histologic features of classic lichen nitidus with some clinical similarities. It appears only on photo-distributed areas. Up to date, it has been reported in deeply pigmented patients (Fitzpatrick skin types V and VI), in African American, Middle Eastern and Indian descent population.1 To our knowledge, it has not been yet described in Caucasian patients. We report a 12-year-old Spanish Caucasian male, Fitzpatrick skin phototype III, who presented with pruritic non-scaly papules just on sun-exposed areas. For 6 years, he had outbreaks of moderately itchy lesions that appeared after 1–2 days of sun exposure when he remained more than an hour under the sunlight. The lesions lasted for weeks and vanished slowly during late summer, once sun exposure was avoided. He had never presented such lesions in covered areas. He achieved a partial control of the outbreaks with deflazacort and topical steroids, but the lesions recurred days after leaving them. Physical examination showed numerous 1–2 mm whitish, mildly pruritic papules limited to sun-exposed areas: back of both hands (Fig. 1), forearms, legs, thighs and over the ‘V’ area of the neck. The lesions spared areas covered by the clothes. There was no involvement of the scalp, nails or oral mucosa. A biopsy of a papule from the dorsum of the hand showed circumscribed lichenoid granulomatous infiltrates composed of lymphocytes and histiocytes. Thin rete ridge epidermal elongations were seen at the lateral borders of the circumscribed infiltrates with an image of a ‘claw clutching a ball’. There was an absence of the granular layer over the infiltrate (Fig 2). Laboratory tests showed only an increase percentage of eosinophils (7.2%) and an IgE of 436 UI/mL. Broad-band UVB phototesting (five spots, up to 122 mJ/cm2 with Gigatest, Medisun, France, 2006) showed an adjusted to erythema MED of 33 mJ/cm2, that is normal for his skin phototype. UVA phototesting (five spots, up to 9 mJ/cm2 with Gigatest, Mediun, France, 2006) showed no abnormal reaction to UVA. Broad-band UVA provocation using lamp banks for
© 2014 European Academy of Dermatology and Venereology
