Hyaluronidase Injections for Oral Microstomia (2024)

Research Letter

Michelle S.Min,MD, MS1,2; NathanielGoldman,MD1; Daniel R.Mazori,MD1,3; et al Lisa N.Guo,MD1; Ruth AnnVleugels,MD, MPH, MBA1; Avery H.LaChance,MD, MPH1

Author Affiliations Article Information

Systemic sclerosis (SSc) is an autoimmune, inflammatory, sclerosing disease of the skin and internal organs.¹ Disease negatively affects quality of life, particularly when facial disfigurement occurs.^1,2 Perioral changes, such as mouth furrowing and small oral aperture, are leading causes of concern to individuals with SSc.² Unfortunately, perioral involvement is challenging to treat, with few therapeutic options.¹ Case reports have described treating oral microstomia with hyaluronidase injections for various autoimmune sclerosing conditions, such as scleroderma and scleromyxedema.^3,4 Since varying hyaluronidase doses and treatment intervals have been reported, we evaluated hyaluronidase for oral microstomia in a cohort of patients with autoimmune sclerosing disease.

This study took place from June 2020 to December 2022 and was approved by the Mass General Brigham Institutional Review Board. All patients provided written informed consent. We included adults with autoimmune sclerosing conditions that resulted in oral microstomia, as confirmed by a connective tissue disease specialist (M.S.M., D.R.M., R.A.V., A.H.L.). Patients with change to immunosuppressive therapy within 3 months or during treatment were excluded. Primary outcomes included improvements in mouth opening capacity (MOC), measured vertically in centimeters from upper to lower vermillion border, and Mouth Handicap in Systemic Sclerosis (MHISS) score.⁵ The MHISS is a validated tool that assesses oral disability due to systemic sclerosis, comprising 12 items with 5 levels of answers (0 [never] to 4 [always]) for a maximum of 48 points. Secondary outcomes of this study were time to initial improvement, time to improvement plateau, and adverse events.

After obtaining consent, we photographed patients and measured MOC and MHISS at each visit. Local anesthesia was administered with topical and/or perioral nerve blocks with lidocaine. The highest dose of hyaluronidase reported was 200 mg at the time of study initiation.³ Therefore, 200 units were diluted in 6 mL of normal saline and injected subcutaneously in aliquots approximately 1 cm apart in 2 rows surrounding mucosal lips. Patients returned monthly for treatment and assessment.

Four patients with autoimmune sclerosing conditions (2 with limited SSc, 1 with diffuse SSc, and 1 with mixed connective tissue disease with sclerodermoid features) were included. All patients were women, aged 43 to 61 years (mean age, 52.3 years), with clinically significant oral microstomia, baseline MOC of 4.4 to 5.2 cm (mean, 4.8 cm), and MHISS score of 24 to 37 (mean, 31). Two patients were taking mycophenolate mofetil; 1 taking rituximab, low-dose methylprednisolone, and hydroxychloroquine; and 1 was no longer taking systemic immunosuppression.

All 4 patients perceived improvement after initial treatment. All improved in MOC and MHISS, with change stabilizing between 3 and 5 treatments (Figure 1). Patients gained an average of 0.9 cm (range, 0.5-1.6 cm) or 19.1% (range, 11.1%-36.3%) in MOC (Figure 1A), and MHISS score decreased by 19.3 (range, 17-24) points or 61.9% (range, 48.4%-70.8%) (Figure 1B). Perioral skin softened in all patients, as seen in Figure 2A and B. Interestingly, patient 4 delayed her third treatment by a month due to COVID-19 infection and noted a slight setback in MOC, which recovered after reinitiating treatment (Figure 2C and D). Benefits were otherwise maintained at least 6 months after final treatment based on patient report and MOC measurements. All patients experienced self-resolving bruising and pain with injections. No serious adverse events were noted.

Prior research has demonstrated that hyaluronidase activity is decreased in late-stage SSc.⁶ This affects hyaluronic acid degeneration, ultimately leading to the formation of fibrotic tissue. It is therefore hypothesized that hyaluronidase can help patients with SSc. Indeed, this case series highlights that hyaluronidase injections are a localized therapeutic option for oral microstomia caused by SSc and other autoimmune sclerosing disease. All 4 patients included noted rapid improvement in mouth opening, requiring 3 to 5 monthly injection sections of 200 hyaluronidase units before effects plateaued.

Limitations of this study include the small sample size and measurements dependent on patient cooperation and recall. Further studies are warranted to better investigate optimal dosage and longevity of treatment response. However, overall we conclude that hyaluronidase injections can serve as a valuable therapy for problematic oral microstomia in patients with cutaneous sclerosis.

Accepted for Publication: August 20, 2023.

Published Online: October 18, 2023. doi:10.1001/jamadermatol.2023.3893

Corresponding Authors: Michelle S. Min, MD, MS, Department of Dermatology, University of California, Irvine School of Medicine, 118 Med Surg I, Irvine, CA 92697 (michellesmin@gmail.com); Avery H. LaChance, MD, MPH, Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02215 (alachance@bwh.harvard.edu).

Author Contributions: Dr LaChance had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Min, Vleugels, LaChance.

Acquisition, analysis, or interpretation of data: Min, Goldman, Mazori, Guo, LaChance.

Drafting of the manuscript: Min, Goldman.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Min.

Administrative, technical, or material support: Goldman, Mazori.

Supervision: Min, Vleugels, LaChance.

Conflict of Interest Disclosures: Dr Min reported personal fees from Horizon Pharmaceuticals outside the submitted work. Dr LaChance reported grants from Pfizer outside the submitted work. No other disclosures were reported.

Data Sharing Statement: See the Supplement.

Additional Contributions: We thank the patients in Figure 2 for granting permission to publish images of them.