Journal of Dermatology 2014; 41: 536–538
doi: 10.1111/1346-8138.12503
CONCISE COMMUNICATION
Blepharochalasis: Possibly associated with matrix metalloproteinases Sei-ichiro MOTEGI, Akihiko UCHIYAMA, Kazuya YAMADA, Sachiko OGINO, Yuko TAKEUCHI, Osamu ISHIKAWA Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
ABSTRACT Blepharochalasis is a rare disorder characterized by recurrent episodic swelling of eyelids, eventually leading to atrophy of skin. Although immunological mechanisms may be involved in the degradation of elastic fibers, the pathogenesis is not well characterized. We report a 10-year-old Japanese boy with an 11-month history of the swelling of bilateral upper eyelids with atrophic skin. Attacks of non-painful swelling in eyelids with erythema have recurred several times a month and lasted for 2–3 days. Histological examination revealed perivascular and interstitial infiltration of lymphocytes in the dermis. Elastica Van Gieson staining showed a marked decrease of elastic fibers throughout the dermis. Results of direct and indirect immunofluorescence analyses were negative. Staining of matrix metalloproteinase (MMP)-3 and MMP-9 was observed in and around infiltrating cells in the dermis, suggesting that MMP-3 and MMP-9 may play, in part, roles in the development of blepharochalasis, and that inhibitor of MMP may have a possibility of therapeutic application.
Key words:
blepharochalasis, elastic fiber, matrix metalloproteinase.
INTRODUCTION Blepharochalasis, a variant of acquired cutis laxa, is a rare disorder. In the early stage, recurrent episodic swelling of upper and/or lower eyelids occurs several times over several months, resulting in the degradation of elastic fibers in the eyelids and atrophy of the skin. It has been suggested that immunoglobulin (Ig)A autoantibody-mediated immunological mechanisms may play a role in the degradation of elastic fibers.1,2 However, the pathogenesis is not well characterized. We herein report an 11-year-old boy with blepharochalasis and the results of immunohistochemical analysis on matrix metalloproteinases (MMP) expression.
CASE REPORT A 10-year-old Japanese boy visited our hospital in August 2013 with swelling of bilateral upper eyelids. He noticed the swelling of upper eyelids in November 2011. Attacks of nonpainful swelling in bilateral upper eyelids with pale-reddish erythema had recurred several times a month (Fig. 1a,b) and lasted for 2–3 days. The frequency of attacks gradually decreased and attacks disappeared in October 2012. However, the swelling of eyelids without erythema remained. He consulted another hospital and treatment with oral prednisolone 25 mg/day was started from June 2013. Because the skin lesions did not improve, treatment with prednisolone was
stopped in October 2013. The patient’s family and past history were unremarkable. Physical examination revealed swelling of the bilateral upper eyelids with atrophic skin and telangiectasia (Fig. 1c,d). The lips were not affected. Vision and ocular movement were normal. The results of routine laboratory tests including blood cell counts, eosinophil count and serum IgG, IgA, IgE and C-reactive protein were within normal ranges. C3, C4 and C1-esterase inhibitor levels were normal. Function of the thyroid gland was normal. Antinuclear antibody was negative. Histological examination of the upper eyelids revealed edema of the upper dermis and perivascular and interstitial infiltration of lymphocytes in the dermis (Fig. 2a,b). Elastica Van Gieson staining showed a marked decrease of elastic fibers throughout the dermis (Fig. 2c). Based on the clinicopathological findings, the diagnosis of blepharochalasis was established. There has been no recurrence of attacks and exacerbation of lesions without treatment during a 7-month follow-up period. He is scheduled for blepharoplasty in the future. To examine the immunological pathogenesis, direct immunofluorescence analysis was performed. There was no deposition of IgA, IgG and IgM in the dermis (data not shown). An indirect immunofluorescence test using the patient’s serum and normal skin sections did not detect circulating autoantibodies (data not shown). Next, we immunohistochemically investigated the expression of MMP-2, MMP-3 and MMP-9 in the lesional skin using anti-MMP-2 antibody (1/100, AB19167; Chemicon, Billerica, MA, USA), anti-MMP-3 antibody (1/100,
Correspondence: Sei-ichiro Motegi, M.D., Ph.D., Department of Dermatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. Email: [email protected] Received 9 March 2014; accepted 29 March 2014.
536
© 2014 Japanese Dermatological Association
Blepharochalasis and MMP
Figure 1. Physical examination of bilateral upper eyelids. (a,b) Attacks of non-painful swelling in bilateral upper eyelids with pale-reddish erythema. (c,d) Swelling of bilateral upper eyelids with atrophic skin and telangiectasia remained.
Figure 2. Histological examination of skin lesions in upper eyelids. (a,b) Edema of upper dermis and perivascular and interstitial infiltration of lymphocytes in the dermis (hematoxylin–eosin; original magnifications: [a] 940; [b] 9200). (c) Marked decrease of elastic fibers throughout the dermis (elastica Van Gieson staining, 9400). SL-1 IID4; Millipore, Bedford, MA, USA) and anti-MMP-9 antibody (1/50, ab2167; Abcam, Cambridge, MA, USA). The staining of MMP-3 and MMP-9 was observed in and around infiltrating cells in the dermis (Fig. 3c,d). In contrast, the staining of MMP-2 was not observed (Fig. 3b). Control IgG staining was negative (Fig. 3a). These results suggest that MMP-3 and MMP-9 may be responsible for the degradation of elastic fibers in our patients.
DISCUSSION Koursh et al.3 summarized 67 cases of blepharochalasis reported in English from 1977 to 2006. Twenty-two cases were male and 45 cases were female. The average age of onset was 11 years old (0–27 years old). Twenty-seven cases were unilateral and 40 cases were bilateral. The duration of an
© 2014 Japanese Dermatological Association
Figure 3. Immunohistochemically investigation of the expression of matrix metalloproteinases (MMP) in the dermis of skin lesions. (a) Control immunoglobulin G staining was negative. (b) No staining of MMP-2 in the dermis. (c) Staining of MMP-3 and (d) MMP-9 in and around infiltrating cells in the dermis. attack ranged from a few hours to days, with an average of 2 days. These episodes of attack become less frequent and eventually most cases entered a quiescent stage within 2–3 months. The differential diagnosis was mainly recurrent angioedema, heredity angioedema, contact dermatitis and Ascher’s syndrome. We could exclude heredity angioedema by no familial history, normal C1-esterase inhibitor and serum complement levels in our patient. Ascher’s syndrome is characterized by swelling of the lips (double upper lip) and eyelids, and thyroid enlargement, however, lip and thyroid gland were not affected in our case. The loss of elastic fibers in the dermis leading to the reduced elasticity is considered to be a cause of blepharochalasis. Kaneoya et al.4 reported that elastin mRNA expression in the patient’s cultured fibroblasts was not decreased compared with that in control fibroblasts, suggesting that environmental factors or other matrix components of elastic fibers may be involved in the loss of elastic fibers. It has been reported that immunofluorescence and immunoelectron microscopy studies showed abundant IgA deposits around the remaining elastic fibers, suggesting that immunopathogenetic mechanisms may contribute to the elastolytic process.1,2 Therefore, we investigated the expression of IgA depositions in the patient’s lesional skin. However, IgA deposition was not detected in our patient. The degradation of elastic fibers is mediated by elastases, including MMP. MMP consist of more than 25 well-characterized members of secreted or transmembrane proteins that degrade the extracellular matrix and basement membrane macromolecules.5,6 Four groups of the MMP family of proteinases are known to be capable of degrading elastic fibers: the gelatinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B), matrilysin MMP-7, and the macrophage metalloelastase MMP12.5,6 The greater elastolytic potential of MMP-9 as compared with MMP-2 in human skin tissue sections was demonstrated
537
S.-i. Motegi et al.
by a previous study, which also showed that MMP-9, in contrast to MMP-2, did not promote any collagen-degrading activity.7 In many previous studies, the loose skin diseases with the loss of elastic fibers, including cutis laxa, anetoderma and middermal elastolysis, were associated with altered expression of MMP.8–12 We identified that immunohistochemical staining was positive for MMP-3 and MMP-9 and negative for MMP-2 in the foci of inflammatory cells in the patient’s skin lesion. These results were consistent with previous studies performed on elastolytic diseases, such as mid-dermal elastolysis, anetoderma, floppy eyelid syndrome and cutis laxa.9,10,12,13 These studies showed the degradation of elastic fibers and the overexpression of MMP-3 and MMP-9 in inflammatory infiltrates such as leukocytes and macrophages. These findings suggesting that MMP-3 and MMP-9 may play, in part, roles in the development of blepharochalasis, and that inhibitor of MMP may have a possibility of therapeutic application. Interestingly, Karaconji et al.14 reported two cases of blepharochalasis which have remained symptom-free for 18 and 8 months, respectively, after treatment with doxycycline. Doxycycline inhibits MMP activity in vitro, independent of its antimicrobial activity.15 Surgical treatment is primarily chosen for blepharochalasis. Patients who received surgical treatment were often complicated with overcorrection, therefore, surgical treatment should be performed when the disease activity is in a quiescent phase.3 However, certain cases with functional vision problems or severe cosmetic disturbance need early treatment. Currently, our patient does not have functional and severe cosmetic problems without treatments, and blepharoplasty will be taken into consideration in the future. Blepharochalasis is rare and sometimes misdiagnosed. Awareness of the clinical and histological characteristics of the disease is important for dermatologists, ophthalmologists and pediatricians to establish an early diagnosis and an appropriate treatment can be initiated.
CONFLICT OF INTEREST:
The authors declare that there
REFERENCES 1 Grassegger A, Romani N, Fritsch P, Smolle J, Hintner H. Immunoglobulin A (IgA) deposits in lesional skin of a patient with blepharochalasis. Br J Dermatol 1996; 135: 791–795. zsa A, Ka rolyi ZS, Degrell P. Bilateral blepharochalasis. J Eur 2 Do Acad Dermatol Venereol 2005; 19: 725–728. 3 Koursh DM, Modjtahedi SP, Selva D, Leibovitch I. The blepharochalasis syndrome. Surv Ophthalmol 2009; 54: 235–244. 4 Kaneoya K, Momota Y, Hatamochi A et al. Elastin gene expression in blepharochalasis. J Dermatol 2005; 32: 26–29. 5 Somerville RP, Oblander SA, Apte SS. Matrix metalloproteinases: old dogs with new tricks. Genome Biol 2003; 4: 216.1–216.11. 6 Birkedal-Hansen H, Moore WG, Bodden MK et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 1993; 4: 197– 250. 7 Berton A, Godeau G, Emonard H et al. Analysis of the ex vivo specificity of human gelatinases A and B towards skin collagen and elastic fibers by computerized morphometry. Matrix Biol 2000; 19: 139–148. 8 Venencie PY, Winkelmann RK. Histopathologic findings in anetoderma. Arch Dermatol 1984; 120: 1040–1044. 9 Ghomrasseni S, Dridi M, Gogly B et al. Anetoderma: an altered balance between metalloproteinases and tissue inhibitors of metalloproteinases. Am J Dermatopathol 2002; 24: 118–129. 10 Patroi I, Annessi G, Girolomoni G. Mid-dermal elastolysis: a clinical, histologic, and immunohistochemical study of 11 patients. J Am Acad Dermatol 2003; 48: 846–851. 11 Suda T, Hara H, Yoshitake M, Ohbayashi T, Nakamura T, Terui T. Immunohistochemical investigation of mid-dermal elastolysis with a history of erythema. Am J Dermatopathol 2008; 30: 477–480. 12 Gu W, Liu W, Yang X et al. Cutis laxa: analysis of metalloproteinases and extracellular matrix expression by immunohistochemistry and histochemistry. Eur J Dermatol 2011; 21: 717–721. € tzer-Schrehardt U, Stojkovic M, Hofmann-Rummelt C, 13 Schlo Cursiefen C, Kruse FE, Holbach LM. The Pathogenesis of floppy eyelid syndrome: involvement of matrix metalloproteinases in elastic fiber degradation. Ophthalmology 2005; 112: 694–704. 14 Karaconji T, Skippen B, Di Girolamo N, Taylor SF, Francis IC, Coroneo MT. Doxycycline for treatment of blepharochalasis via inhibition of matrix metalloproteinases. Ophthal Plast Reconstr Surg 2012; 28: e76–e78. 15 Iovieno A, Lambiase A, Micera A, Stampachiacchiere B, Sgrulletta R, Bonini S. In vivo characterization of doxycycline effects on tear metalloproteinases in patients with chronic blepharitis. Eur J Ophthalmol 2009; 19: 708–716.
are no conflicts of interest.
538
© 2014 Japanese Dermatological Association
doi: 10.1111/1346-8138.12503
CONCISE COMMUNICATION
Blepharochalasis: Possibly associated with matrix metalloproteinases Sei-ichiro MOTEGI, Akihiko UCHIYAMA, Kazuya YAMADA, Sachiko OGINO, Yuko TAKEUCHI, Osamu ISHIKAWA Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
ABSTRACT Blepharochalasis is a rare disorder characterized by recurrent episodic swelling of eyelids, eventually leading to atrophy of skin. Although immunological mechanisms may be involved in the degradation of elastic fibers, the pathogenesis is not well characterized. We report a 10-year-old Japanese boy with an 11-month history of the swelling of bilateral upper eyelids with atrophic skin. Attacks of non-painful swelling in eyelids with erythema have recurred several times a month and lasted for 2–3 days. Histological examination revealed perivascular and interstitial infiltration of lymphocytes in the dermis. Elastica Van Gieson staining showed a marked decrease of elastic fibers throughout the dermis. Results of direct and indirect immunofluorescence analyses were negative. Staining of matrix metalloproteinase (MMP)-3 and MMP-9 was observed in and around infiltrating cells in the dermis, suggesting that MMP-3 and MMP-9 may play, in part, roles in the development of blepharochalasis, and that inhibitor of MMP may have a possibility of therapeutic application.
Key words:
blepharochalasis, elastic fiber, matrix metalloproteinase.
INTRODUCTION Blepharochalasis, a variant of acquired cutis laxa, is a rare disorder. In the early stage, recurrent episodic swelling of upper and/or lower eyelids occurs several times over several months, resulting in the degradation of elastic fibers in the eyelids and atrophy of the skin. It has been suggested that immunoglobulin (Ig)A autoantibody-mediated immunological mechanisms may play a role in the degradation of elastic fibers.1,2 However, the pathogenesis is not well characterized. We herein report an 11-year-old boy with blepharochalasis and the results of immunohistochemical analysis on matrix metalloproteinases (MMP) expression.
CASE REPORT A 10-year-old Japanese boy visited our hospital in August 2013 with swelling of bilateral upper eyelids. He noticed the swelling of upper eyelids in November 2011. Attacks of nonpainful swelling in bilateral upper eyelids with pale-reddish erythema had recurred several times a month (Fig. 1a,b) and lasted for 2–3 days. The frequency of attacks gradually decreased and attacks disappeared in October 2012. However, the swelling of eyelids without erythema remained. He consulted another hospital and treatment with oral prednisolone 25 mg/day was started from June 2013. Because the skin lesions did not improve, treatment with prednisolone was
stopped in October 2013. The patient’s family and past history were unremarkable. Physical examination revealed swelling of the bilateral upper eyelids with atrophic skin and telangiectasia (Fig. 1c,d). The lips were not affected. Vision and ocular movement were normal. The results of routine laboratory tests including blood cell counts, eosinophil count and serum IgG, IgA, IgE and C-reactive protein were within normal ranges. C3, C4 and C1-esterase inhibitor levels were normal. Function of the thyroid gland was normal. Antinuclear antibody was negative. Histological examination of the upper eyelids revealed edema of the upper dermis and perivascular and interstitial infiltration of lymphocytes in the dermis (Fig. 2a,b). Elastica Van Gieson staining showed a marked decrease of elastic fibers throughout the dermis (Fig. 2c). Based on the clinicopathological findings, the diagnosis of blepharochalasis was established. There has been no recurrence of attacks and exacerbation of lesions without treatment during a 7-month follow-up period. He is scheduled for blepharoplasty in the future. To examine the immunological pathogenesis, direct immunofluorescence analysis was performed. There was no deposition of IgA, IgG and IgM in the dermis (data not shown). An indirect immunofluorescence test using the patient’s serum and normal skin sections did not detect circulating autoantibodies (data not shown). Next, we immunohistochemically investigated the expression of MMP-2, MMP-3 and MMP-9 in the lesional skin using anti-MMP-2 antibody (1/100, AB19167; Chemicon, Billerica, MA, USA), anti-MMP-3 antibody (1/100,
Correspondence: Sei-ichiro Motegi, M.D., Ph.D., Department of Dermatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. Email: [email protected] Received 9 March 2014; accepted 29 March 2014.
536
© 2014 Japanese Dermatological Association
Blepharochalasis and MMP
Figure 1. Physical examination of bilateral upper eyelids. (a,b) Attacks of non-painful swelling in bilateral upper eyelids with pale-reddish erythema. (c,d) Swelling of bilateral upper eyelids with atrophic skin and telangiectasia remained.
Figure 2. Histological examination of skin lesions in upper eyelids. (a,b) Edema of upper dermis and perivascular and interstitial infiltration of lymphocytes in the dermis (hematoxylin–eosin; original magnifications: [a] 940; [b] 9200). (c) Marked decrease of elastic fibers throughout the dermis (elastica Van Gieson staining, 9400). SL-1 IID4; Millipore, Bedford, MA, USA) and anti-MMP-9 antibody (1/50, ab2167; Abcam, Cambridge, MA, USA). The staining of MMP-3 and MMP-9 was observed in and around infiltrating cells in the dermis (Fig. 3c,d). In contrast, the staining of MMP-2 was not observed (Fig. 3b). Control IgG staining was negative (Fig. 3a). These results suggest that MMP-3 and MMP-9 may be responsible for the degradation of elastic fibers in our patients.
DISCUSSION Koursh et al.3 summarized 67 cases of blepharochalasis reported in English from 1977 to 2006. Twenty-two cases were male and 45 cases were female. The average age of onset was 11 years old (0–27 years old). Twenty-seven cases were unilateral and 40 cases were bilateral. The duration of an
© 2014 Japanese Dermatological Association
Figure 3. Immunohistochemically investigation of the expression of matrix metalloproteinases (MMP) in the dermis of skin lesions. (a) Control immunoglobulin G staining was negative. (b) No staining of MMP-2 in the dermis. (c) Staining of MMP-3 and (d) MMP-9 in and around infiltrating cells in the dermis. attack ranged from a few hours to days, with an average of 2 days. These episodes of attack become less frequent and eventually most cases entered a quiescent stage within 2–3 months. The differential diagnosis was mainly recurrent angioedema, heredity angioedema, contact dermatitis and Ascher’s syndrome. We could exclude heredity angioedema by no familial history, normal C1-esterase inhibitor and serum complement levels in our patient. Ascher’s syndrome is characterized by swelling of the lips (double upper lip) and eyelids, and thyroid enlargement, however, lip and thyroid gland were not affected in our case. The loss of elastic fibers in the dermis leading to the reduced elasticity is considered to be a cause of blepharochalasis. Kaneoya et al.4 reported that elastin mRNA expression in the patient’s cultured fibroblasts was not decreased compared with that in control fibroblasts, suggesting that environmental factors or other matrix components of elastic fibers may be involved in the loss of elastic fibers. It has been reported that immunofluorescence and immunoelectron microscopy studies showed abundant IgA deposits around the remaining elastic fibers, suggesting that immunopathogenetic mechanisms may contribute to the elastolytic process.1,2 Therefore, we investigated the expression of IgA depositions in the patient’s lesional skin. However, IgA deposition was not detected in our patient. The degradation of elastic fibers is mediated by elastases, including MMP. MMP consist of more than 25 well-characterized members of secreted or transmembrane proteins that degrade the extracellular matrix and basement membrane macromolecules.5,6 Four groups of the MMP family of proteinases are known to be capable of degrading elastic fibers: the gelatinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B), matrilysin MMP-7, and the macrophage metalloelastase MMP12.5,6 The greater elastolytic potential of MMP-9 as compared with MMP-2 in human skin tissue sections was demonstrated
537
S.-i. Motegi et al.
by a previous study, which also showed that MMP-9, in contrast to MMP-2, did not promote any collagen-degrading activity.7 In many previous studies, the loose skin diseases with the loss of elastic fibers, including cutis laxa, anetoderma and middermal elastolysis, were associated with altered expression of MMP.8–12 We identified that immunohistochemical staining was positive for MMP-3 and MMP-9 and negative for MMP-2 in the foci of inflammatory cells in the patient’s skin lesion. These results were consistent with previous studies performed on elastolytic diseases, such as mid-dermal elastolysis, anetoderma, floppy eyelid syndrome and cutis laxa.9,10,12,13 These studies showed the degradation of elastic fibers and the overexpression of MMP-3 and MMP-9 in inflammatory infiltrates such as leukocytes and macrophages. These findings suggesting that MMP-3 and MMP-9 may play, in part, roles in the development of blepharochalasis, and that inhibitor of MMP may have a possibility of therapeutic application. Interestingly, Karaconji et al.14 reported two cases of blepharochalasis which have remained symptom-free for 18 and 8 months, respectively, after treatment with doxycycline. Doxycycline inhibits MMP activity in vitro, independent of its antimicrobial activity.15 Surgical treatment is primarily chosen for blepharochalasis. Patients who received surgical treatment were often complicated with overcorrection, therefore, surgical treatment should be performed when the disease activity is in a quiescent phase.3 However, certain cases with functional vision problems or severe cosmetic disturbance need early treatment. Currently, our patient does not have functional and severe cosmetic problems without treatments, and blepharoplasty will be taken into consideration in the future. Blepharochalasis is rare and sometimes misdiagnosed. Awareness of the clinical and histological characteristics of the disease is important for dermatologists, ophthalmologists and pediatricians to establish an early diagnosis and an appropriate treatment can be initiated.
CONFLICT OF INTEREST:
The authors declare that there
REFERENCES 1 Grassegger A, Romani N, Fritsch P, Smolle J, Hintner H. Immunoglobulin A (IgA) deposits in lesional skin of a patient with blepharochalasis. Br J Dermatol 1996; 135: 791–795. zsa A, Ka rolyi ZS, Degrell P. Bilateral blepharochalasis. J Eur 2 Do Acad Dermatol Venereol 2005; 19: 725–728. 3 Koursh DM, Modjtahedi SP, Selva D, Leibovitch I. The blepharochalasis syndrome. Surv Ophthalmol 2009; 54: 235–244. 4 Kaneoya K, Momota Y, Hatamochi A et al. Elastin gene expression in blepharochalasis. J Dermatol 2005; 32: 26–29. 5 Somerville RP, Oblander SA, Apte SS. Matrix metalloproteinases: old dogs with new tricks. Genome Biol 2003; 4: 216.1–216.11. 6 Birkedal-Hansen H, Moore WG, Bodden MK et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 1993; 4: 197– 250. 7 Berton A, Godeau G, Emonard H et al. Analysis of the ex vivo specificity of human gelatinases A and B towards skin collagen and elastic fibers by computerized morphometry. Matrix Biol 2000; 19: 139–148. 8 Venencie PY, Winkelmann RK. Histopathologic findings in anetoderma. Arch Dermatol 1984; 120: 1040–1044. 9 Ghomrasseni S, Dridi M, Gogly B et al. Anetoderma: an altered balance between metalloproteinases and tissue inhibitors of metalloproteinases. Am J Dermatopathol 2002; 24: 118–129. 10 Patroi I, Annessi G, Girolomoni G. Mid-dermal elastolysis: a clinical, histologic, and immunohistochemical study of 11 patients. J Am Acad Dermatol 2003; 48: 846–851. 11 Suda T, Hara H, Yoshitake M, Ohbayashi T, Nakamura T, Terui T. Immunohistochemical investigation of mid-dermal elastolysis with a history of erythema. Am J Dermatopathol 2008; 30: 477–480. 12 Gu W, Liu W, Yang X et al. Cutis laxa: analysis of metalloproteinases and extracellular matrix expression by immunohistochemistry and histochemistry. Eur J Dermatol 2011; 21: 717–721. € tzer-Schrehardt U, Stojkovic M, Hofmann-Rummelt C, 13 Schlo Cursiefen C, Kruse FE, Holbach LM. The Pathogenesis of floppy eyelid syndrome: involvement of matrix metalloproteinases in elastic fiber degradation. Ophthalmology 2005; 112: 694–704. 14 Karaconji T, Skippen B, Di Girolamo N, Taylor SF, Francis IC, Coroneo MT. Doxycycline for treatment of blepharochalasis via inhibition of matrix metalloproteinases. Ophthal Plast Reconstr Surg 2012; 28: e76–e78. 15 Iovieno A, Lambiase A, Micera A, Stampachiacchiere B, Sgrulletta R, Bonini S. In vivo characterization of doxycycline effects on tear metalloproteinases in patients with chronic blepharitis. Eur J Ophthalmol 2009; 19: 708–716.
are no conflicts of interest.
538
© 2014 Japanese Dermatological Association
