More recently, intralesional hyaluronidase (150IU/mL) weekly for 18 weeks was used on the left foot of two pretibial myxedema patients.31 One patient had substantial plaque regression, while a second patient treated with the same regimen had marked flattening of their plaque and a decrease in pain.31
Paver reported the successful treatment of pretibial myxedema and cutaneous myxoid cysts following treatment with hyaluronidase (1500IU) and TAC (1mg) combination (n=4).32
Localized myxedema (distinct from pretibial) can also occur in Grave’s disease.33 A case report33 presented a patient with scalp myxedema treated with repeated hyaluronidase injections with a reduction in the scalp thickness confirmed by ultrasound.33
Scleroderma
Scleroderma is an autoimmune disorder that can result in sclerosis and cutaneous inflammation leading to impairment of function and quality of life.34 Excessive fibrosis with increased collagen deposition is the hallmark with increased HA in the ECM.34 The first report of hyaluronidase used in localized scleroderma (off-label) dates back to 1953.35 Further uses in scleroderma were in microstomia and radiation-induced morphea all demonstrating a symptomatic improvement and a low side-effect profile.36-39
Abbas and colleagues 40 demonstrated the efficacy of hyaluronidase (four injections, 150IU) in improving sclerosis.40 Their patient suffered from microstomia of the mouth resulting in tongue atrophy and decreased mouth-opening.40 The patient’s sclerotic bands resolved almost completely and the patient could open her mouth more widely.40
Scleredema
Scleredema is a rare disorder of connective tissue, characterized by mucin deposition with skin induration.41 It has been reported to occur after streptococcal infection42 and in diabetic patients (scleredema diabeticorum).43-44 Dermal thickening is associated with an increase in glycosaminoglycans and can be recalcitrant and challenging to treat.41
Injections of hyaluronidase solution (80U,1% lidocaine) were given over 12-weeks to a diabetic scleredema patient (total of 18 injections) with no reported adverse effects.44 Reduced dermal thickening and reduced thickness of subcutaneous tissue was observed upon T2-weighted magnetic resonance imaging. Other lesions progressively flattened and became softer and this was maintained at two years follow–up.44 The authors did not comment upon control of diabetes during this time.44
Cutis verticis gyrata
Cutis verticis gyrata (CVG) is a cutaneous fibrotic scalp condition characterized clinically by scalp folds and furrows, which may be malodorous, pruritic, and cause a burning sensation.45 A biopsy-confirmed case of CVG was successfully treated with 150IU of hyaluronidase injections every six-weeks for a total of six treatments,46 with less noticeable furrows and some hair regrowth with no reported adverse effects. The authors postulate that hyaluronidase decreased HA in scalp areas with excessive dermal thickening, resulting in decreased skin elasticity and hence, improved cosmetic appearance.46
Surgical Uses
Neoadjuvant for dermatofibroscarcoma protuberans
Dermatofibrosarcoma protuberans (DFSP) is a cutaneous malignancy arising in the dermis that shows increased HA.47 Adjunctive hyaluronidase prior to surgical excision of DFSP was used in two studies.47-48 Intralesional hyaluronidase was injected at doses of 300–450 IU, followed by Mohs surgery 2–10 days later.47 Greater polarizable collagen was seen further from the biopsy scar of hyaluronidase-treated tumors and these cells had decreased CD34 expression. Inflammatory reactions further from the biopsy site were greater in hyaluronidase pretreated cells.47 The transmembrane glycoprotein CD34 was used to confirm tumor-free margins, since CD34 is commonly used to identify residual DFSP.49 The decreased CD34 and increased polarized collagen, not usually found in DFSPs, could support hyaluronidase’s role in increasing cell differentiation in spindle cells.47 Decreased margins following hyaluronidase treatment might be due to increased cellular differentiation, possibly accelerating apoptotic progression.49
Larger RCTs and long-term recurrence data are required to assess hyaluronidase’s use in adjuvant DFSP treatment.47 Hyaluronidase poses little risk, and could have significant surgical and cosmetic benefits in DFSP treatment.47
Periorbital edema
Chronic periorbital edema is a non-specific sign manifesting as swelling beneath the eyelid skin with possible immunological, dermatological, endocrinological, cardiological, and gastroenterological causes.50
Acquired lymphedema is a common post-surgical cancer treatment side-effect shown in several animal studies.51-52 Animal studies revealed that post-operatively, mice had higher HA accumulation following lymph-node removal.51 This lymphedema was reduced following hyaluronidase treatment in animal studies and immunohistochemical analysis demonstrated that hyaluronidase could augment lymphangiogenesis in lymphedematous limbs.51 In a separate study, mice with post-surgical lymphedema were injected with human hyaluronidase sustained-release gel pre and postsurgery.52 Statistically significant enzyme degradation of HA was found, highlighting that hyaluronidase activity can support dispersal of accumulated post-surgical edema.52
Paver reported the successful treatment of pretibial myxedema and cutaneous myxoid cysts following treatment with hyaluronidase (1500IU) and TAC (1mg) combination (n=4).32
Localized myxedema (distinct from pretibial) can also occur in Grave’s disease.33 A case report33 presented a patient with scalp myxedema treated with repeated hyaluronidase injections with a reduction in the scalp thickness confirmed by ultrasound.33
Scleroderma
Scleroderma is an autoimmune disorder that can result in sclerosis and cutaneous inflammation leading to impairment of function and quality of life.34 Excessive fibrosis with increased collagen deposition is the hallmark with increased HA in the ECM.34 The first report of hyaluronidase used in localized scleroderma (off-label) dates back to 1953.35 Further uses in scleroderma were in microstomia and radiation-induced morphea all demonstrating a symptomatic improvement and a low side-effect profile.36-39
Abbas and colleagues 40 demonstrated the efficacy of hyaluronidase (four injections, 150IU) in improving sclerosis.40 Their patient suffered from microstomia of the mouth resulting in tongue atrophy and decreased mouth-opening.40 The patient’s sclerotic bands resolved almost completely and the patient could open her mouth more widely.40
Scleredema
Scleredema is a rare disorder of connective tissue, characterized by mucin deposition with skin induration.41 It has been reported to occur after streptococcal infection42 and in diabetic patients (scleredema diabeticorum).43-44 Dermal thickening is associated with an increase in glycosaminoglycans and can be recalcitrant and challenging to treat.41
Injections of hyaluronidase solution (80U,1% lidocaine) were given over 12-weeks to a diabetic scleredema patient (total of 18 injections) with no reported adverse effects.44 Reduced dermal thickening and reduced thickness of subcutaneous tissue was observed upon T2-weighted magnetic resonance imaging. Other lesions progressively flattened and became softer and this was maintained at two years follow–up.44 The authors did not comment upon control of diabetes during this time.44
Cutis verticis gyrata
Cutis verticis gyrata (CVG) is a cutaneous fibrotic scalp condition characterized clinically by scalp folds and furrows, which may be malodorous, pruritic, and cause a burning sensation.45 A biopsy-confirmed case of CVG was successfully treated with 150IU of hyaluronidase injections every six-weeks for a total of six treatments,46 with less noticeable furrows and some hair regrowth with no reported adverse effects. The authors postulate that hyaluronidase decreased HA in scalp areas with excessive dermal thickening, resulting in decreased skin elasticity and hence, improved cosmetic appearance.46
Surgical Uses
Neoadjuvant for dermatofibroscarcoma protuberans
Dermatofibrosarcoma protuberans (DFSP) is a cutaneous malignancy arising in the dermis that shows increased HA.47 Adjunctive hyaluronidase prior to surgical excision of DFSP was used in two studies.47-48 Intralesional hyaluronidase was injected at doses of 300–450 IU, followed by Mohs surgery 2–10 days later.47 Greater polarizable collagen was seen further from the biopsy scar of hyaluronidase-treated tumors and these cells had decreased CD34 expression. Inflammatory reactions further from the biopsy site were greater in hyaluronidase pretreated cells.47 The transmembrane glycoprotein CD34 was used to confirm tumor-free margins, since CD34 is commonly used to identify residual DFSP.49 The decreased CD34 and increased polarized collagen, not usually found in DFSPs, could support hyaluronidase’s role in increasing cell differentiation in spindle cells.47 Decreased margins following hyaluronidase treatment might be due to increased cellular differentiation, possibly accelerating apoptotic progression.49
Larger RCTs and long-term recurrence data are required to assess hyaluronidase’s use in adjuvant DFSP treatment.47 Hyaluronidase poses little risk, and could have significant surgical and cosmetic benefits in DFSP treatment.47
Periorbital edema
Chronic periorbital edema is a non-specific sign manifesting as swelling beneath the eyelid skin with possible immunological, dermatological, endocrinological, cardiological, and gastroenterological causes.50
Acquired lymphedema is a common post-surgical cancer treatment side-effect shown in several animal studies.51-52 Animal studies revealed that post-operatively, mice had higher HA accumulation following lymph-node removal.51 This lymphedema was reduced following hyaluronidase treatment in animal studies and immunohistochemical analysis demonstrated that hyaluronidase could augment lymphangiogenesis in lymphedematous limbs.51 In a separate study, mice with post-surgical lymphedema were injected with human hyaluronidase sustained-release gel pre and postsurgery.52 Statistically significant enzyme degradation of HA was found, highlighting that hyaluronidase activity can support dispersal of accumulated post-surgical edema.52
