PracticalDermatology

Systemic sclerosis (SS) is an autoimmune connective tissue disease characterized by widespread fibroproliferative vasculopathy and immune-mediated collagen deposition that presents with both systemic and cutaneous manifestations.1 Although SS can affect any organ system, skin involvement is a hallmark of disease and is often used to guide staging and categorization of clinical phenotypes.2 Clinical care is primarily dictated by managing organ-specific manifestations of disease including, but not limited to, telangiectasias, hypo- and hyper-pigmentary changes, and calcinosis cutis for patients with skin involvement.2

An additional cutaneous manifestation of SS with cosmetic and functional significance is microstomia, defined by the reduction of the total oral aperture to an interincisal distance (IID) of less than 50mm.3 This narrowing can result in difficulty speaking, chewing, and maintaining proper dental hygiene as well as significant reductions in health outcomes and quality of life.3 For patients with microstomia secondary to SS, there have been a few recent reports of treatment with intradermal hyaluronidase leading to successful widening of the oral aperture, improved mouth closure, and subjective functional and dental health benefits.2

One of these studies used a progressive, step-up series of injections of Vitrase, a prescription formulation of hyaluronidase, during four different treatment sessions.4 The first two treatments were single injections done at the corners of the top lip to establish the safety, tolerance, and efficacy of intradermal hyaluronidase (20 units undiluted into the right side and 50 units undiluted into the left side for injections one and two respectively).4 These appointments were spaced 2 months apart and tolerated without complication. Visits three and four were full dose treatments (200 units diluted in 6ml of saline and 200 units diluted in 10ml of saline respectively) spaced 1 month apart. At each of these final visits, the authors used a total of 16 evenly spaced injections sites (8 over the top lip and 8 over the bottom lip) that alternated locations between appointments.4

Using the injection placement pattern described in this recent report, we were able to demonstrate that Hylenex, an alternative lower-cost prescription formulation of hyaluronidase, can achieve excellent improvement in functionality in patients with microstomia. Our study further supports the use of hyaluronidase as an effective therapy for microstomia associated with systemic sclerosis but offers unique insight into the use of Hylenex as a more affordable formulation that is potentially equivalent in efficacy to Vitrase.

Case Report

Our patient was a 35-year-old female who was diagnosed with limited cutaneous systemic sclerosis (CREST syndrome) 2 years prior to presentation at our clinic. Within the first year of diagnosis, she developed diffuse skin inflammation, redness, and tightening throughout the chest, shoulders, back, arms, and face. Despite the use of several topical medications, she reported continued progression of skin tightness, particularly in the perioral region. She noticed narrowing of the mouth opening, loss of wrinkles on her face, difficulty swallowing, and shortness of breath. Approximately 1 year after her initial diagnosis, she required hospitalization for GJ tube placement after she lost 50 pounds due to an inability to swallow both solids and liquids, which was exacerbated by her microstomia. Her disease continued to progress despite being trialed on prednisone, mycophenolate mofetil, and sildenafil.

Given her significant functional impairment and recent reports of successful treatment with hyaluronidase therapy for systemic sclerosis patients with microstomia, we offered to treat her with intradermal hyaluronidase.3,4 After a thorough discussion of the risks (including urticaria and angioedema) and benefits, she elected to proceed.

At her initial visit, she received a single injection of 30 units of Vitrase without complication. At her next treatment 5 months later, she received 60 units of Hylenex. At her third appointment a month later, she received 150 units of Hylenex at 16 different injection sites. A month later at her fourth and final treatment, she was given an additional 150 units of Hylenex using the same number of injections (Table 1). We elected to use a different number of units per session than previously described. Our modified dose escalation scale was due to differences in units per ml between formulations (150 units/ml and 200 units/ml for Hylenex and Vitrase respectively). Perioral injection locations were determined using the placement documented by Melvin et al (2019).

With each subsequent visit, she reported significant improvement in speech and oral functionality. Increased oral patency was documented via photos at each treatment and the patient endorsed satisfaction with her results (Figure 1). At all four appointments, she denied any adverse effects or consequences related to treatment. Unfortunately, despite patient-reported and provider-documented improvement in symptoms and oral function, she has yet to receive insurance approval for hyaluronidase injection for microstomia.

The use of Hylenex injection for microstomia in this report led to documented increases in oral aperture as well as improvements in the patient’s oral patency, function, and satisfaction. Our results mirror and support the potential opportunity for cosmetic dermatologists to improve both cosmesis and physiological function using intradermal hyaluronidase as an adjunct to systemic medication for patients with microstomia secondary to CREST syndrome.3,4

Conclusion and Discussion

The role of intradermal hyaluronidase in treating microstomia has yet to be well studied. Hyaluronic acid, hyaluronan, is a hydrophilic molecule in the extracellular matrix (ECM) that is key to viscoelastic properties of the dermis and is broken down by the enzyme hyaluronidase.3 The stiff, sclerotic dermal tissue seen in patients with scleroderma is due to an overabundance of hyaluronan and collagen (types I, III, VII) from type 2 helper T lymphocyte-activated fibroblasts.4 Injecting hyaluronidase into sclerotic tissues may help patients with scleroderma by hydrolyzing excess glycosidic and glucosaminidic bonds within the ECM of affected tissues.4 Further research is needed to elucidate the exact mechanism by which hyaluronidase relieves tension in sclerotic areas.

Although several reports exist showing that this traditionally cosmetic treatment is capable of providing significant functional benefits, including increased oral aperture, better oral hygiene, and improved Mouth Handicap in Systemic Sclerosis (MHISS) score, getting prior authorization for these treatments from insurance remains a challenge.3,4,5 Given that intradermal hyaluronidase treatment for microstomia largely remains an out-of-pocket cost to patients, it is important that cosmetic dermatologists investigate the most cost-effective methods of providing this option to patients. A unique, beneficial aspect of this report is the observation that Hylenex may be equivalent in efficacy to Vitrase but at a lower cost per unit. Thus, our study potentially expands the accessibility of treatment with hyaluronidase injections for SS patients with microstomia. Additional head-to-head prospective studies are needed to determine if the cheaper 150-unit Hylenex is as effective as the more expensive 200-unit Vitrase.

The use of Hylenex hyaluronidase was a successful and more cost-effective treatment option for the management of microstomia secondary to scleroderma in a patient who had significant functional defects due to disease. Use of this lower cost formulation could allow more patients interested in pursuing hyaluronidase therapy the ability to cover the out-of-pocket costs. Further studies regarding best cosmetic practices, treatment options, and potential benefits of using intradermal hyaluronidase for patients suffering with SS are needed.

Contents of this paper were presented in part at the Cosmetic Surgery Forum (Cosmetic SurgeryForum.com) in Nashville, in December 2022. This presentation was recognized as a top resident presentation at CSF 2022.

Financial Support: None. Conflicts of Interest: All authors declare that they have no conflicting relationships to disclose.

1. Odonwodo A, Badri T, Hariz A. Scleroderma. In: StatPearls. StatPearls Publishing; 2022. Accessed January 23, 2023. http://www.ncbi.nlm.nih.gov/books/NBK537335/

2. Zhu JL, Black SM, Chen HW, Jacobe HT. Emerging treatments for scleroderma/systemic sclerosis. Fac Rev. 2021;10:43. doi:10.12703/r/10-43

3. Chopra D, Brehm JE, Morrison B. Hyaluronidase as a successful treatment modality for scleroderma-induced microstomia. Epub 2022 Jul 13. Accessed January 9, 2023. Dermatol Surg. https://journals.lww.com/dermatologicsurgery/Fulltext/2022/09000/Hyaluronidase_as_a_Successful_Treatment_Modality.27.aspx

4. Melvin OG, Hunt KM, Jacobson ES.Hyaluronidase treatment of scleroderma-induced microstomia. JAMA Dermatol. JAMA Network. Accessed January 9, 2023. https://jamanetwork.com/journals/jamadermatology/fullarticle/2734012

5. Abbas LF, Coias J, Jacobe HT, Nijhawan RI. Hyaluronidase injections for treatment of symptomatic pansclerotic morphea-induced microstomia. JAAD Case Rep. 2019;5(10):871-873. doi:10.1016/j.jdcr.2019.08.004