Letters to the Editor
(a)
455
(b)
Figure 2 (a) Levels of IL-31 before and after 6 months therapy with omalizumab. All 15 chronic spontaneous urticaria patients included in this figure had a complete response to omalizumab. (b) Levels of IL-31 before and after 6 months therapy with placebo. Statistical significance of difference was calculated using Wilcoxon’s ranked sum test.
that induced only inconsistent, mild and delayed itch sensations when pricked into human skin.8 In conclusion, our results would be consistent with the production of IL-31 by mast cells9 and the down regulation of mast cell activation in CSU by omalizumab.10 However, the functional relationship of IL-31 to the pathogenesis and symptom severity of CSU remains unclear.
Acknowledgements We thank the investigators of the X-CUISITE study centres who provided the sera analysed in this project. This work was supported by the Deutsche Forschungsgemeinschaft Grant BA 1803/ 7-1 to J.B. and B.L. €nel,2,3 K. Czaja,2 S. Altrichter,1 T. Hawro,1 K. Ha 3 1 €scher, M. Maurer, M.K. Church,1,* J.M. Baron2 B. Lu 1 Department of Dermatology and Allergology, Charit e– €tsmedizin Berlin, Berlin, Germany, 2Department of Dermatology Universita and Allergology, Medical School RWTH Aachen University, Aachen, Germany, 3Medical School RWTH Aachen University, Institute of Biochemistry and Molecular Biology, Aachen, Germany *Correspondence: M. Church. E-mail: [email protected]
References 1 Cornelissen C, Luscher-Firzlaff J, Baron JM, Luscher B. Signaling by IL-31 and functional consequences. Eur J Cell Biol 2012; 91: 552– 566. 2 Cevikbas F, Wang X, Akiyama T et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1. J Allergy Clin Immunol 2014; 133: 448–460.
JEADV 2016, 30, 446–556
3 Raap U, Wichmann K, Bruder M et al. Correlation of IL-31 serum levels with severity of atopic dermatitis. J Allergy Clin Immunol 2008; 122: 421– 423. 4 Raap U, Weissmantel S, Gehring M, Eisenberg AM, Kapp A, Folster-Holst R. IL-31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis. Pediatr Allergy Immunol 2012; 23: 285–288. 5 Raap U, Wieczorek D, Gehring M et al. Increased levels of serum IL-31 in chronic spontaneous urticaria. Exp Dermatol 2010; 19: 464–466. 6 Zuberbier T, Asero R, Bindslev-Jensen C et al. EAACI/GA(2)LEN/EDF/ WAO guideline: definition, classification and diagnosis of urticaria. Allergy 2009; 64: 1417–1426. 7 Maurer M, Altrichter S, Bieber T et al. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase. J Allergy Clin Immunol 2011; 128: 202–209. e5. 8 Hawro T, Saluja R, Weller K, Altrichter S, Metz M, Maurer M. Interleukin-31 does not induce immediate itch in atopic dermatitis patients and healthy controls after skin challenge. Allergy 2014; 69: 113–117. 9 Niyonsaba F, Ushio H, Hara M et al. Antimicrobial peptides human beta-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cells. J Immunol 2010; 184: 3526–3534. 10 Chang TW, Chen C, Lin CJ, Metz M, Church MK, Maurer M. The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria. J Allergy Clin Immunol 2014; in press. DOI: 10.1111/jdv.12831
Rapid transition from pemphigus vulgaris to pemphigus foliaceus Editor In March 2013, a 57-year-old Japanese man presented with a 1-month history of oral ulcerations and cutaneous erosions. Physical examination revealed small erosions on the oral mucosa and erosive, crusted, scaly erythematous plaques with a few bullae on the trunk (Fig. 1a). Histological findings were characterized by suprabasilar acantholytic bullae (Fig. 1b), IgG deposits on the keratinocyte cell surface in all layers of the epidermis as shown by direct immunofluorescence examination, and high titers of anti-Dsg1 and anti-Dsg3 autoantibodies as determined by antigen-specific enzyme-linked immunosorbent assay (ELISA) (ELISA index 125 and 57, respectively). This led to a diagnosis of mucocutaneous pemphigus vulgaris (PV). Oral prednisolone at 1 mg/kg/day was moderately effective. Additional treatment with a combination of intravenous immunoglobulin (IVIG) and methyl prednisolone pulse therapy (1000 mg/day for 3 days) was effective in resolving the mucosal lesions. At one and a half months from the initial visit, the disease flared up, and flaccid blisters became apparent on the extremities but without the relapse of any mucosal lesions (Fig. 1c). Histological examination of a vesicle on the right arm showed subcorneal acantholytic bullae (Fig. 1d), and direct immunofluorescence examination showed
© 2014 European Academy of Dermatology and Venereology
Letters to the Editor
456
(a)
(b)
(c)
(d)
Figure 1 (a) Erosions of mucocutaneous pemphigus vulgaris (PV) on the upper chest area (mucocutaneous PV phase). (b) Histological examination shows suprabasilar acantholysis in the PV stage (hematoxylin and eosin, original magnification 9200). (c) Multiple flaccid bullae on the right arm one and a half months later [pemphigus foliaceus (PF) stage]. (d) Histological examination shows subcorneal acantholysis in the PF phase (hematoxylin and eosin, original magnification 9200).
Figure 2 Anti-desmoglein 1/3 enzymelinked immunosorbent assay (ELISA) index of mucocutaneous pemphigus vulgaris and pemphigus foliaceus. Longitudinal data of anti-Dsg1/3 ELISA index: Note the rapid drop in anti-Dsg3 index while the anti-Dsg1 index increased drastically.
IgG deposits on the keratinocyte cell surface of the upper layer of the epidermis. The titre of anti-Dsg1 autoantibodies was quite high (index 1818), but anti-Dsg3 autoantibodies were undetectable (Fig. 2). These findings suggested that the transition from PV to pemphigus foliaceus (PF) was completed quite rapidly. Adjuvant therapy with IVIG and azathioprine failed to improve his condition. Finally, plasmapheresis was effective and the lesions gradually re-epithelialized. The patient is being treated with oral corticosteroid and azathioprine, and no new lesions have been observed.
JEADV 2016, 30, 446–556
Pemphigus is an autoimmune blistering disease that presents clinically with flaccid intraepithelial blisters, erosions and mucous membranes. It is caused by circulating IgG autoantibodies against Dsg, which are molecules that promote the cell–cell adhesion of keratinocytes.1,2 It can be divided into two major subtypes: PV and PF. Dsg3 and Dsg1 have been identified as targets of mucosal PV and mucocutaneous PV/PF.3 The anti-Dsg autoantibody profile determines the clinical phenotype of pemphigus.4 Sera from patients with mucocutaneous PV have both anti-Dsg1 and anti-Dsg3 autoantibodies, whereas sera from
© 2014 European Academy of Dermatology and Venereology
Letters to the Editor
patients with PF have anti-Dsg1 autoantibodies only.4 Several cases of the disease transitioning from PV to PF or vice versa have been reported.5 In most of these cases, the transition was expressed by striking changes in the anti-Dsg1 and anti-Dsg3 autoantibodies levels.6,7 To date, fifteen cases showed transition from PV to PF5 and all of them took at least 6 months to accomplish the process. The mechanism of subtype transition in pemphigus that occurs with a shift in autoantibodies profile remains elusive. With regard to the shift from PF to PV, the pathogenesis could be explained by the ‘epitope spreading’ hypothesis.8 However, Chan et al. and Ohyama et al., respectively, demonstrated that epitope spreading is rarely seen in PF and PV.9,10 With regard to the shift from PV to PF, fifteen cases have been reported, including the present case. This transition means the antigenicity loss of Dsg3. The ‘epitope spreading’ hypothesis cannot be applied to these cases, and the pathomechanism remains controversial. To our knowledge, this is the first report of a pemphigus case that showed rapid subtype transition in one and a half months confirmed by clinical manifestations as well as by antigen-specific ELISA. T. Ito,* R. Moriuchi, K. Kikuchi, S. Shimizu Department of Dermatology, Sapporo City General Hospital, Sapporo, Japan *Correspondence: T. Ito. E-mail: [email protected]
References 1 Beutner EH, Jordon RE, Chorzelski TP. The immunopathology of pemphigus and bullous pemphigoid. J Invest Dermatol 1968; 51: 63– 80. 2 Amagai M. Adhesion molecules. I. Keratinocyte-keratinocyte interactions; cadherins and pemphigus. J Invest Dermatol 1995; 104: 146–152. 3 Amagai M, Tsunoda K, Zillikens D et al. The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J Am Acad Dermatol 1999; 40: 167–170. 4 Amagai M, Komai A, Hashimoto T et al. Usefulness of enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus. Br J Dermatol 1999; 140: 351–357. 5 Park SG, Chang JY, Cho YH et al. Transition from pemphigus foliaceus to pemphigus vulgaris: case report with literature review. Yonsei Med J 2006; 47: 278–281. 6 Komai A, Amagai M, Ishii K et al. The clinical transition between pemphigus foliaceus and pemphigus vulgaris correlates well with the changes in autoantibody profile assessed by an enzyme-linked immunosorbent assay. Br J Dermatol 2001; 144: 1177–1182. 7 Harman KE, Gratian MJ, Shirlaw PJ et al. The transition of pemphigus vulgaris into pemphigus foliaceus: a reflection of changing desmoglein 1 and 3 autoantibody levels in pemphigus vulgaris. Br J Dermatol 2002; 146: 684–687. 8 Salato VK, Hacker-Foegen MK, Lazarova Z et al. Role of intramolecular epitope spreading in pemphigus vulgaris. Clin Immunol 2005; 116: 54–64. 9 Ohyama B, Nishifuji K, Chan PT et al. Epitope spreading is rarely found in pemphigus vulgaris by large-scale longitudinal study using desmoglein 2-based swapped molecules. J Invest Dermatol 2012; 132: 1158– 1168. 10 Chan PT, Ohyama B, Nishifuji K et al. Immune response towards the amino-terminus of desmoglein 1 prevails across different activity
JEADV 2016, 30, 446–556
457
stages in nonendemic pemphigus foliaceus. Br J Dermatol 2010; 162: 1242–1250. DOI: 10.1111/jdv.12832
Patient compliance: the main drawback in the dermoscopic follow-up of melanocytic lesions Editor We conducted a retrospective study in the Department of Dermatology of Cluj-Napoca, between January 2009 and June 2014, to assess patient dermoscopic follow-up compliance, defined as spontaneous return to the clinic within the time interval suggested, without receiving a reminder call or letter, and the factors that influence compliance. In patients with lesion excision indication we determined compliance with excision. The study included 365 patients. Only 157 (43.01%) patients complied with the first check-up visit. In the case of the patients with 3-month-dermoscopic follow-up, 64.28% returned for the check-up visit, whereas compliance for those due to return within 6–12 months was 56.8% and 24.11% respectively. Table 1 shows the demographic and clinical characteristics of patients according to the first follow-up compliance. The univariate analysis shows statistically significant differences in compliance related to patient age, personal history of melanoma and time-interval to the first visit. Seventy of the patients included in the study had a personal history of melanoma, and their compliance with the first follow-up visit was 72.85%. One hundred and six of the 157 patients who returned for the first follow-up visit were to return for a second follow-up. Eighty-three people (78.3%) were compliant with the second follow-up. Table 2 shows the demographic and clinical characteristics of the patients who returned for the second follow-up visit. All the 83 patients who returned for the second follow-up visit also returned for the following visits. Thirty-eight (10.4%) patients included in the study were indicated excision of a lesion. Compliance with excision was 92.10%. The dermoscopic follow-up of melanocytic lesions allows early diagnosis of cutaneous melanoma.1 However, non-compliance with dermoscopic follow-up is a serious challenge for the evaluator.2 As in previous studies,3,4 we also noticed that compliance decreases with increased time interval to the check-up visit, which can be seen in the case of both the first and the second follow-up visits. To improve compliance, the patient should be scheduled for a first follow-up visit shortly after the initial examination. This strategy, however, is time
© 2014 European Academy of Dermatology and Venereology
(a)
455
(b)
Figure 2 (a) Levels of IL-31 before and after 6 months therapy with omalizumab. All 15 chronic spontaneous urticaria patients included in this figure had a complete response to omalizumab. (b) Levels of IL-31 before and after 6 months therapy with placebo. Statistical significance of difference was calculated using Wilcoxon’s ranked sum test.
that induced only inconsistent, mild and delayed itch sensations when pricked into human skin.8 In conclusion, our results would be consistent with the production of IL-31 by mast cells9 and the down regulation of mast cell activation in CSU by omalizumab.10 However, the functional relationship of IL-31 to the pathogenesis and symptom severity of CSU remains unclear.
Acknowledgements We thank the investigators of the X-CUISITE study centres who provided the sera analysed in this project. This work was supported by the Deutsche Forschungsgemeinschaft Grant BA 1803/ 7-1 to J.B. and B.L. €nel,2,3 K. Czaja,2 S. Altrichter,1 T. Hawro,1 K. Ha 3 1 €scher, M. Maurer, M.K. Church,1,* J.M. Baron2 B. Lu 1 Department of Dermatology and Allergology, Charit e– €tsmedizin Berlin, Berlin, Germany, 2Department of Dermatology Universita and Allergology, Medical School RWTH Aachen University, Aachen, Germany, 3Medical School RWTH Aachen University, Institute of Biochemistry and Molecular Biology, Aachen, Germany *Correspondence: M. Church. E-mail: [email protected]
References 1 Cornelissen C, Luscher-Firzlaff J, Baron JM, Luscher B. Signaling by IL-31 and functional consequences. Eur J Cell Biol 2012; 91: 552– 566. 2 Cevikbas F, Wang X, Akiyama T et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1. J Allergy Clin Immunol 2014; 133: 448–460.
JEADV 2016, 30, 446–556
3 Raap U, Wichmann K, Bruder M et al. Correlation of IL-31 serum levels with severity of atopic dermatitis. J Allergy Clin Immunol 2008; 122: 421– 423. 4 Raap U, Weissmantel S, Gehring M, Eisenberg AM, Kapp A, Folster-Holst R. IL-31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis. Pediatr Allergy Immunol 2012; 23: 285–288. 5 Raap U, Wieczorek D, Gehring M et al. Increased levels of serum IL-31 in chronic spontaneous urticaria. Exp Dermatol 2010; 19: 464–466. 6 Zuberbier T, Asero R, Bindslev-Jensen C et al. EAACI/GA(2)LEN/EDF/ WAO guideline: definition, classification and diagnosis of urticaria. Allergy 2009; 64: 1417–1426. 7 Maurer M, Altrichter S, Bieber T et al. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase. J Allergy Clin Immunol 2011; 128: 202–209. e5. 8 Hawro T, Saluja R, Weller K, Altrichter S, Metz M, Maurer M. Interleukin-31 does not induce immediate itch in atopic dermatitis patients and healthy controls after skin challenge. Allergy 2014; 69: 113–117. 9 Niyonsaba F, Ushio H, Hara M et al. Antimicrobial peptides human beta-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cells. J Immunol 2010; 184: 3526–3534. 10 Chang TW, Chen C, Lin CJ, Metz M, Church MK, Maurer M. The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria. J Allergy Clin Immunol 2014; in press. DOI: 10.1111/jdv.12831
Rapid transition from pemphigus vulgaris to pemphigus foliaceus Editor In March 2013, a 57-year-old Japanese man presented with a 1-month history of oral ulcerations and cutaneous erosions. Physical examination revealed small erosions on the oral mucosa and erosive, crusted, scaly erythematous plaques with a few bullae on the trunk (Fig. 1a). Histological findings were characterized by suprabasilar acantholytic bullae (Fig. 1b), IgG deposits on the keratinocyte cell surface in all layers of the epidermis as shown by direct immunofluorescence examination, and high titers of anti-Dsg1 and anti-Dsg3 autoantibodies as determined by antigen-specific enzyme-linked immunosorbent assay (ELISA) (ELISA index 125 and 57, respectively). This led to a diagnosis of mucocutaneous pemphigus vulgaris (PV). Oral prednisolone at 1 mg/kg/day was moderately effective. Additional treatment with a combination of intravenous immunoglobulin (IVIG) and methyl prednisolone pulse therapy (1000 mg/day for 3 days) was effective in resolving the mucosal lesions. At one and a half months from the initial visit, the disease flared up, and flaccid blisters became apparent on the extremities but without the relapse of any mucosal lesions (Fig. 1c). Histological examination of a vesicle on the right arm showed subcorneal acantholytic bullae (Fig. 1d), and direct immunofluorescence examination showed
© 2014 European Academy of Dermatology and Venereology
Letters to the Editor
456
(a)
(b)
(c)
(d)
Figure 1 (a) Erosions of mucocutaneous pemphigus vulgaris (PV) on the upper chest area (mucocutaneous PV phase). (b) Histological examination shows suprabasilar acantholysis in the PV stage (hematoxylin and eosin, original magnification 9200). (c) Multiple flaccid bullae on the right arm one and a half months later [pemphigus foliaceus (PF) stage]. (d) Histological examination shows subcorneal acantholysis in the PF phase (hematoxylin and eosin, original magnification 9200).
Figure 2 Anti-desmoglein 1/3 enzymelinked immunosorbent assay (ELISA) index of mucocutaneous pemphigus vulgaris and pemphigus foliaceus. Longitudinal data of anti-Dsg1/3 ELISA index: Note the rapid drop in anti-Dsg3 index while the anti-Dsg1 index increased drastically.
IgG deposits on the keratinocyte cell surface of the upper layer of the epidermis. The titre of anti-Dsg1 autoantibodies was quite high (index 1818), but anti-Dsg3 autoantibodies were undetectable (Fig. 2). These findings suggested that the transition from PV to pemphigus foliaceus (PF) was completed quite rapidly. Adjuvant therapy with IVIG and azathioprine failed to improve his condition. Finally, plasmapheresis was effective and the lesions gradually re-epithelialized. The patient is being treated with oral corticosteroid and azathioprine, and no new lesions have been observed.
JEADV 2016, 30, 446–556
Pemphigus is an autoimmune blistering disease that presents clinically with flaccid intraepithelial blisters, erosions and mucous membranes. It is caused by circulating IgG autoantibodies against Dsg, which are molecules that promote the cell–cell adhesion of keratinocytes.1,2 It can be divided into two major subtypes: PV and PF. Dsg3 and Dsg1 have been identified as targets of mucosal PV and mucocutaneous PV/PF.3 The anti-Dsg autoantibody profile determines the clinical phenotype of pemphigus.4 Sera from patients with mucocutaneous PV have both anti-Dsg1 and anti-Dsg3 autoantibodies, whereas sera from
© 2014 European Academy of Dermatology and Venereology
Letters to the Editor
patients with PF have anti-Dsg1 autoantibodies only.4 Several cases of the disease transitioning from PV to PF or vice versa have been reported.5 In most of these cases, the transition was expressed by striking changes in the anti-Dsg1 and anti-Dsg3 autoantibodies levels.6,7 To date, fifteen cases showed transition from PV to PF5 and all of them took at least 6 months to accomplish the process. The mechanism of subtype transition in pemphigus that occurs with a shift in autoantibodies profile remains elusive. With regard to the shift from PF to PV, the pathogenesis could be explained by the ‘epitope spreading’ hypothesis.8 However, Chan et al. and Ohyama et al., respectively, demonstrated that epitope spreading is rarely seen in PF and PV.9,10 With regard to the shift from PV to PF, fifteen cases have been reported, including the present case. This transition means the antigenicity loss of Dsg3. The ‘epitope spreading’ hypothesis cannot be applied to these cases, and the pathomechanism remains controversial. To our knowledge, this is the first report of a pemphigus case that showed rapid subtype transition in one and a half months confirmed by clinical manifestations as well as by antigen-specific ELISA. T. Ito,* R. Moriuchi, K. Kikuchi, S. Shimizu Department of Dermatology, Sapporo City General Hospital, Sapporo, Japan *Correspondence: T. Ito. E-mail: [email protected]
References 1 Beutner EH, Jordon RE, Chorzelski TP. The immunopathology of pemphigus and bullous pemphigoid. J Invest Dermatol 1968; 51: 63– 80. 2 Amagai M. Adhesion molecules. I. Keratinocyte-keratinocyte interactions; cadherins and pemphigus. J Invest Dermatol 1995; 104: 146–152. 3 Amagai M, Tsunoda K, Zillikens D et al. The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J Am Acad Dermatol 1999; 40: 167–170. 4 Amagai M, Komai A, Hashimoto T et al. Usefulness of enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus. Br J Dermatol 1999; 140: 351–357. 5 Park SG, Chang JY, Cho YH et al. Transition from pemphigus foliaceus to pemphigus vulgaris: case report with literature review. Yonsei Med J 2006; 47: 278–281. 6 Komai A, Amagai M, Ishii K et al. The clinical transition between pemphigus foliaceus and pemphigus vulgaris correlates well with the changes in autoantibody profile assessed by an enzyme-linked immunosorbent assay. Br J Dermatol 2001; 144: 1177–1182. 7 Harman KE, Gratian MJ, Shirlaw PJ et al. The transition of pemphigus vulgaris into pemphigus foliaceus: a reflection of changing desmoglein 1 and 3 autoantibody levels in pemphigus vulgaris. Br J Dermatol 2002; 146: 684–687. 8 Salato VK, Hacker-Foegen MK, Lazarova Z et al. Role of intramolecular epitope spreading in pemphigus vulgaris. Clin Immunol 2005; 116: 54–64. 9 Ohyama B, Nishifuji K, Chan PT et al. Epitope spreading is rarely found in pemphigus vulgaris by large-scale longitudinal study using desmoglein 2-based swapped molecules. J Invest Dermatol 2012; 132: 1158– 1168. 10 Chan PT, Ohyama B, Nishifuji K et al. Immune response towards the amino-terminus of desmoglein 1 prevails across different activity
JEADV 2016, 30, 446–556
457
stages in nonendemic pemphigus foliaceus. Br J Dermatol 2010; 162: 1242–1250. DOI: 10.1111/jdv.12832
Patient compliance: the main drawback in the dermoscopic follow-up of melanocytic lesions Editor We conducted a retrospective study in the Department of Dermatology of Cluj-Napoca, between January 2009 and June 2014, to assess patient dermoscopic follow-up compliance, defined as spontaneous return to the clinic within the time interval suggested, without receiving a reminder call or letter, and the factors that influence compliance. In patients with lesion excision indication we determined compliance with excision. The study included 365 patients. Only 157 (43.01%) patients complied with the first check-up visit. In the case of the patients with 3-month-dermoscopic follow-up, 64.28% returned for the check-up visit, whereas compliance for those due to return within 6–12 months was 56.8% and 24.11% respectively. Table 1 shows the demographic and clinical characteristics of patients according to the first follow-up compliance. The univariate analysis shows statistically significant differences in compliance related to patient age, personal history of melanoma and time-interval to the first visit. Seventy of the patients included in the study had a personal history of melanoma, and their compliance with the first follow-up visit was 72.85%. One hundred and six of the 157 patients who returned for the first follow-up visit were to return for a second follow-up. Eighty-three people (78.3%) were compliant with the second follow-up. Table 2 shows the demographic and clinical characteristics of the patients who returned for the second follow-up visit. All the 83 patients who returned for the second follow-up visit also returned for the following visits. Thirty-eight (10.4%) patients included in the study were indicated excision of a lesion. Compliance with excision was 92.10%. The dermoscopic follow-up of melanocytic lesions allows early diagnosis of cutaneous melanoma.1 However, non-compliance with dermoscopic follow-up is a serious challenge for the evaluator.2 As in previous studies,3,4 we also noticed that compliance decreases with increased time interval to the check-up visit, which can be seen in the case of both the first and the second follow-up visits. To improve compliance, the patient should be scheduled for a first follow-up visit shortly after the initial examination. This strategy, however, is time
© 2014 European Academy of Dermatology and Venereology
![[Transition from pemphigus vulgaris to pemphigus foliaceus: a case report].](/assets/img/hold.png)
