Laser Therapy for Lichen Sclerosus

Lichen sclerosus (LS) is an atrophic, noncontagious, chronic skin disease (lichen sclerosus et atrophicus (LSA)) that occurs in episodes. The disease can occur in both sexes, even in early adolescence, but is most common in women, usually after menopause (female menopause). The condition is often unrecognized and unsuccessfully treated repeatedly as a genital infection (vaginal infection), usually mycosis (fungal infection), or genital herpes. However, it is the most common non-infectious, burning, itching, painful skin disease of the external genitalia. The condition is often accompanied by fungal colonization, which can mask the underlying disease. Typical of the disease is,

• That it is a taboo subject and those affected do not talk about it.
• That the disease is often only recognized after 3-4 years.
• That doctor hopping is typical because of the ineffectiveness of therapies made.
• That four to five different gynecologists are visited before the diagnosis is made.
• That gynecologists are sometimes insufficiently aware of the clinical picture and therefore do not think about it, especially when it comes to young women whose external genitals “look normal”.

A comprehensive, very valuable information platform about this disease is provided by the association Lichen sclerosus, originally founded in Switzerland, but now active throughout Europe.For more information, see the European S3 treatment guideline: European Dermatology Forum: Guideline on Lichen sclerosus [see guidelines below]. This paper presents an overview of the current state of therapeutic options when first-line therapy (first-line therapy), i.e., the preferred treatment of a disease according to evidence-based medicine, with topical preparations (drugs applied topically), especially highly potent corticosteroids, is not or not sufficiently effective and alternatives have to be sought. Emphasis is placed on innovative fractionated laser therapy.

Definition

Lichen sclerosus is a chronic inflammatory skin disease that occurs preferentially in the external genital area. The cause is probably an immune disorder (a familial cluster of up to 10% is known).

Pathophysiology (disease development)

The pathogenesis of lichen sclerosus is largely unknown. What is known is that immunocompetent cells destroy the elastic connective tissue of the subcutis of the external genitalia, accompanied by inflammation of the vessels of the corium. Histology (fine tissue examination)

The histologic expression of the changes can be highly variable, depending on the stage of the disease:

• Epithelium:
  • Atrophy (flattened epidermis (loss of the rete ridges/protrusions of the epidermis (cuticle) that extend into the underlying dermis (corium)).
  • At the same time often and typically hyperkeratosis (excessive keratinization of the skin).
  • Basal cell layer disordered
  • Absence of melanosomes and melanocytes (cells that produce melanin) in keratinocytes (cells that form horns)
  • Corium (dermis):
    • Upper area
      • Edematous degenerative collagen
      • Absence or reduction of elastic fibers
    • Below
      • Lymphocytic infiltration
      • Reduction of capillaries

The lack of pigment and edema of collagen (clarification of collagen) lead to the external whitish to porcelain appearance.

Typical symptoms [guidelines 1, 2, 3, 4]

• Occurrence in episodes
  • Pruritus (itching; severe)
  • Burning
  • Pain (similar to cystitis) in the area of the external genitalia
• Skin discoloration (various):
  • Erythema (redness of the skin), possibly with petechial hemorrhages (flea-like bleeding).
  • Brown-red discoloration as in eczema.
  • Whitish areas and nodules (hyperkeratosis and sclerosis/diseased hardening of the tissue), which can form plaques (areal or plate-like substance proliferation of the skin)
  • White, porcelain-like spots
• Dyspareunia (pain during sexual intercourse)/apareunia (inability to have coitus).
• Painful urination (dysuria).
• Vulnerable skin (frequent tearing, spontaneous, bes.For intercourse) with a tendency to superinfection.
• In the late stage, different degrees of severity of atrophy.
  • Parchment-like skin (cigarette paper).
  • Disappearance
    • Of the small and later the large labia (labia majora) of the clitoris (clitoris).
  • Shrinkage
    • Of the vulva (external genitals) with sclerosis of the subcutaneous adipose tissue.
    • Synechiae of the greater and lesser labiae.
    • Stenosis (narrowing)
      • Of the introitus vaginae (vaginal entrance).
      • Of the anus (anus)
      • Of the urethral outlet

Diagnosis

The diagnosis is often made according to the clinical picture based on the skin changes in combination with the symptoms. Histologic (fine tissue) evidence is not currently required. On the other hand, [Guidelines 1, 2, 3, 4] especially in young women, the disease may be completely inconspicuous visually, but histologic diagnosis reveals lichen sclerosus.

Course and prognosis

Lichen sclerosus is a chronic inflammatory connective tissue disease with a relapsing course that may last for decades. In female infants, the disease can destroy the hymen (hymen). In women, the genitoanal area (sex and anal area) is affected in about 90% of cases. The disease shows different degrees of severity of atrophy of the vulva in the late stage. In infantile lichen sclerosus, there is a chance of cure. Comorbidities: There is a frequent comorbidity with autoimmune diseases such as diabetes mellitus type 1, Hashimoto thyroiditis and vitiligo (white spot disease). Furthermore, inflammatory bowel disease, alopecia areata, pernicious anemia, rheumatoid arthritis, and psoriasis are common.

Consequences for those affected

Lichen sclerosus disease means a lifelong reduction in quality of life for those affected:

• Psychological (taboo subject, shame, loss of femininity).
• Physical (recurrent (recurring) complaints, pain).
• Social (occasional inability to work during acute episodes, isolation).
• Sexual and partner (pain, risk of injury, impossibility of intercourse because of shrinkage).
• Risk of degeneration of about 4-5% (squamous cell carcinoma, not HPV-associated) (consistent therapy can reduce the risk as much as possible)

If the diagnosis is made early and treated efficiently, it is possible in most cases to maintain the quality of life for the affected woman through

• A largely pain-free life
• A psychological, physical, social, sexual and partnership relief.
• A delay in the progression of the disease
• Reduction of the risk of degeneration

The Association Lichen sclerosus provides comprehensive information material on all these topics and makes broad public relations.

Therapy options

The gold standard (currently generally accepted action regarding a disease) is therapy with the potent glucocorticoids (immunomodulators) clobetasol or mometasone [guidelines 1, 2, 3, 4]. The success rate is about 70-80%. Both glucocorticoids are superior to topical therapy with tacrolimus according to randomized controlled trials. These antagonize (counteract) inflammation but simultaneously inhibit collagen synthesis with the risk of inducing skin atrophy (tissue loss (atrophy) of the skin). Second-line therapy (therapy used when there is no therapeutic success after completion of the first treatment (first-line therapy)) is topical (“local”) therapy with calcineurin inhibitors (immunosuppressants): tacrolimus (ointment), pimecrolimus (ointment) (off label therapy) [1, guideline 1, 2, 3, 4]. The success rate is approximately 40-80%. Calcineurin inhibitors block the release of inflammatory cytokines from T-lymphocytes, so they only have an anti-inflammatory effect without influencing collagen synthesis, i.e. without the risk of skin atrophy. In therapy-resistant cases, systemic therapy with retinoids (substances related to retinol (vitamin A) in their chemical structure or biological activity) can be attempted for 3-4 months (caveat: risk of teratogenicity/fertilization damage), possibly also ciclosporin or low-dose methotrexate [1, guideline 1, 2, 3, 4].According to the recommendations of the guidelines, local testosterone therapy is now considered obsolete (no longer in use). Therapy with estrogens (the most important female sex hormones from the class of steroid hormones) is not recommended because its efficacy has not been proven. Non-drug therapy options

Recommended:

• Little soaps when washing in the genital area.
• No intimate sprays
• The application of emollients (especially fatty ointments) and / or oils several times a day, e.g. almond oil, olive oil.
• Silk underwear instead of cotton underwear
• Avoidance of mechanical irritation, e.g. rough paper towels, damp toilet paper, hard towels, tight-fitting clothing, cycling, horseback riding
• Apply ointments containing grease before bathing in chlorinated water.

Alternative therapy methods

Many women shy away from permanent cortisone therapy because they fear atrophic changes in the skin (tissue atrophy of the skin). Although this is usually unfounded and avoidable if the dosage guidelines are applied appropriately in interval form [Guidelines: 1, 2, 3, 4], it is deeply rooted in the subconscious despite education. Occasionally, the above therapeutic measures are not effective or insufficiently effective. Platelet-rich plasma (PRP): injection of PRP promotes healing processes preferentially by stimulating growth factors that modulate proliferation of mesenchymal cells and extracellular matrix synthesis. At the same time, anti-inflammatory cytokines (proteins that regulate cell growth and differentiation) reduce the healing process. There have been few studies on this method, mostly case reports. However, a randomized placebo-controlled double-blind study of 30 patients in 2019 found no statistically significant efficacy over the control group using a validated questionnaire that assessed the severity of LS based on patients’ plagued symptoms. Energy-based therapies

• Photodynamic therapy (PDT): photodynamic therapy is a widely used form of therapy in dermatology, e.g., for actinic keratosis (chronic damage to the keratinized epidermis caused by long-term intensive exposure to sunlight), but also for malignant (malignant) skin diseases. The principle is that the damaged skin is treated with a special cream (photosensitizer), the active ingredient of which is irradiated with light of a special wavelength after penetration into the skin. Free oxygen radicals are activated in the diseased cells, leading to their cell death. The surrounding healthy cells remain largely undamaged. In a review of 11 studies showed good efficacy of symptoms, but with very different histological results.
• High-intensity focused ultrasound (HIFU): high-intensity focused ultrasound (HIFU) therapy is currently preferred for the treatment of prostate carcinoma (prostate cancer). Gynecologic indications include treatment of fibroids (benign muscular growths of the uterus) and therapy of adenomyosis uteri (hyperplasia of the myometrium stimulated by endometriosis). The use in non-malignant (malignant) diseases of the skin, especially genital atrophy (thinning of genital tissue) and lichen sclerosus, has been carried out for many years, mostly in small studies. Whereas in myoma and prostate therapy the tissue is heated and subsequently vaporized by targeted bundling of high intensity sound waves, the focus in benign skin lesions is shifted more toward absorption of heat energy due to relatively low energy. The effect is a stimulation of cell proliferation, protein synthesis and revascularization whereby tissue regeneration is initiated. This therapy is probably more widespread, preferably in China. At present, it is too early for a general assessment. Of interest is a comparative study to topical (topical) corticosteroids, in which histological controls were more effective in the HIFU group than in the corticosteroid group. Side effects such as blistering and pain should be considered in the indication for therapy compared with other therapeutic options.
• Radiofrequency therapy: in radiofrequency therapy, energy is delivered to the tissue with focused electromagnetic waves.This leads to a heat effect of the subepithelial connective tissue, which leads to a contraction of collagen and the formation of new elastic fibers. Currently, it is mainly used in dermatology for skin tightening. Occasionally, there is also experience with good results in vulvovaginal atrophy (tissue atrophy of the external genitalia and vagina) [review: 11]. About the therapy in lichen sclerosus can be found on the Internet individual references but so far no published studies.
• Fractionated laser therapy: fractionated laser therapy with the CO2 or ER-YAG laser has been a proven option for many years for the therapy of the genitourinary syndrome of menopause both in relation to vulvovaginal atrophy and stress and urge incontinence.

Fractionated laser therapy is so new that it has yet to be mentioned in guidelines [Guidelines 1, 2, 3, 4] or at a recent review. A 2019 update mentions only the ablative form of laser therapy (techniques used to destroy tissue by heat or cold). However, an increasing number of publications show high efficacy, especially in cases of failure of established therapies.Particularly noteworthy are the excellent results in therapy, most of which eliminate the need for cortisone therapy (see below).

Contraindications

• Acute inflammation
• Premalignant (tissue changes that histopathologically show signs of malignant (malignant) degeneration)/malignant (malignant) disease

Before treatment

Before the start of treatment should be an educational and counseling discussion between the doctor and the patient. The content of the conversation should be the goals, expectations and the possibilities of treatment, as well as side effects and risks. Above all, there must be a detailed discussion of other therapeutic options, including previously performed therapies. Before the treatment, a local anesthetic is applied to the external area, as a slight burning sensation and/or needle-prick-like slightly painful sensations may occur here. The anesthetic ointment reduces the relatively strong sensitivity of the external genital area, so that the laser therapy can be performed largely pain-free. It is important to coordinate with the therapist, who can reduce the dosage in case of painful sensations.

The procedure

The application is performed with a microscanner, which is also used for skin lesions outside the genital area. The mode of action of lasers (erbium YAG laser, CO2 laser) used for urogynecologic indications is based on hyperthermia (overheating) and coagulation. Hyperthermia leads to tissue tightening and regeneration of epidermal and subepidermal structures by heating the tissue to 45-60 °C or by coagulation and ablation at 60-90 °C via activation of heat shock proteins and denaturation of collagen fibers through

• Stimulation of the extracellular matrix (intercellular substance) in terms of nutrient uptake and fluid retention.
• New formation of
  • Elastic and collagen fibers
  • Capillaries

Depending on the energy setting, the focus is on the effect of hyperthermia or coagulation and ablation. Combined settings are possible. The wavelength of the CO2 laser is 10.6 µm, the Er: Yag laser 2940 nm. Both are absorbed by the tissue water. That of the Erbium YAG laser is about 15 times higher than that of the CO2 laser. Fractional laser therapy

In contrast to the ablative forms of laser therapy, in which the epidermis is removed over a wide area, resulting in a wound area that depends on the size of the ablated area, fractionated therapy, which is used today in urogynecology, creates tiny needle-like micro-wounds with healthy areas of skin between them. Since only about 20-40% of the treated skin area is lasered, leaving the rest intact, there are few side effects and healing is rapid. The laser energy penetrates the epithelium and reaches the subepithelial tissue layer. The underlying fibromuscular skin layers are not reached, i.e. they are spared. Depending on the laser energy, the maximum penetration depth is about 200-700 µm (0.2-0.7 mm). This ensures that surrounding tissue is not damaged.The targeted injury stimulates skin regeneration via the release of heat shock proteins and various growth factors (e.g. TGF-Beta). The result is the restoration of a healthy epithelium and the underlying subepithelial layer with normal function. Through these actions, fluid, water-binding glycoproteins and hyaluronic acid are deposited, and the formation of collagen and elastic fibers is stimulated. Especially important is the formation of new capillaries, which guarantees a long-term supply of oxygen and nutrients.

Results

Overall, there are very few, mostly case reports with one or a few female patients. This is certainly due to the rarity of the disease and the gold standard therapy with corticosteroids (preferably clobetasol, mometasone). Therefore, laser therapy is practically only used when the therapeutic success with highly potent corticosteroids and other topical therapies was insufficient. Ablative laser therapies

Ablative CO2 laser therapies have been described since 1991. 7 patients were ablated with good success and were symptom-free for a long time. In 2009, Fillmer reported 184 patients treated ablatively between the year 2000-2009 with good success. In the discussion of the paper, the three other published papers from 1997 (Kartamaa M), 2000 (Hackenjos K), 2004 (Peterson CM) are discussed. Fractional laser therapies

After the year 2010, after fractionated laser therapy had become established in dermatology, there are a total of seven studies to date. Common to all of them is a preceding more or less unproductive, unsuccessful therapy with highly potent corticosteroids and other tropical therapy options. This has ultimately led to the use of an alternative solution in the form of laser therapy. Occasionally, it is also the fear of atrophic changes due to high insufficiently effective use of corticosteroids. Criteria for the assessment of lichen sclerosus disease

Assessment criteria are usually severity of disease, symptoms, quality of life (general, sexual), and treatment success. Unfortunately, there are no generally accepted bases for these criteria that allow comparability. This is true for all studies conducted so far, especially not for topical therapies. Initial attempts to do this were made in a Delphi consensus exercise by a selected panel of experienced therapists on the basis of 338 publications, which were assessed according to certain criteria, from the point of view of practicability. Therefore, the comparability of laser therapies with each other and also with topical preparations will also be difficult in the future. Results of the laser studies

The laser studies are small, the majority of them concern case reports and have different criteria of evaluation. The results are characterized by good success with respect to

• Symptoms: Burning, itching, pain.
• Of the clinical appearance
  • By examiner assessment, e.g., ecchymosis (small-area bleeding of the skin or mucosa), excoriations (substance defect of the skin), fissures (fissure), hypopigmentation (depigmentation), inflammation, ulceration (ulceration), hyperkeratosis/excessive keratinization of the skin
  • By image documentation
• Of histology before and after therapy
• Of quality of life and sexual quality measured with different scores in the studies.
• Low side effects over a relatively short period of a few days.
• Symptom freedom/improvement: > 6 months, > 6 months to 4 years, > 1 year.

Of particular note is a controlled pilot study by Ogrinc et al comparing corticosteroid therapy with clobetasol (N=20) with laser therapy three times (N=20) under histologic control before and after therapy. The results show not only superiority of laser therapy in clinical symptoms and quality of life, but also in histology in the form of marked tissue regeneration.

After treatment

The following is our own unpublished experience from treatment cycles of more than 40 patients:

• No special therapeutic measures are necessary after treatment. Recommended are care products, especially fatty ointments or oils (olive oil, almond oil, etc.).
• Many patients feel safer if they initially continue corticosteroid therapy for a few weeks after starting therapy, and then gradually reduce it and attempt discontinuation.
• If possible, refrain from mechanical stress for a few days, such as cycling, horseback riding, sexual intercourse.

Possible complications

• Swelling (rare)
• Feeling of soreness
• Pruritus (itching)
• Burning

The above complaints are most pronounced 2-3 hours after laser applications. In rare cases, they can exist decreasing up to 3-4 days. Caring substances such as fatty ointments, oils (olive oil, almond oil), occasional cooling elements for a short period may be recommended. Painkillers (paracetamol, ibuprofen) are useful if the condition is particularly severe.

Benefits of laser therapy

• Virtually painless therapy due to local application of anesthetic.
• Without pretreatment
• Without more severe side effects (swelling and feeling of soreness may persist for about 3-4 days see above).
• Without anesthesia
• Without necessary aftercare (local measures to reduce side effects are possible, but often not necessary).
• Cortisone-free
• Can be performed on an outpatient basis in a few minutes
• Often already 1-2 weeks after the first therapy session
  • Pronounced symptom improvement
  • Visually well visible improvements in the appearance of the skin

Résumé

Gold standard of therapy remains, recommended worldwide, the highly potent corticosteroids clobetasol and mometasone, although the comparability of previous studies has problems. In case of therapy failure, also of other topical therapies, or due to fear of late effects of permanent and high-dose corticosteroid therapy, there have been requests for alternative therapies for many years. Fractionated laser therapy offers itself as an effective, easy-to-perform, outpatient alternative with few side effects:

• In therapy-resistant previous treatment attempts.
• To reduce the need for corticosteroids.
• For fear of atrophic side effects during continuous therapy of corticosteroids.

To date, there are few studies and experience, as with other non-drug therapies (see above). It is certainly useful to plan this form of therapy in larger, controlled studies against topical preparations, other alternatives (see above) and the different settings of fractional laser therapy. The low side effect rate and lack of complications is impressive. Currently, the following controlled trials are in planning NCT02573883, NCT02573883. From practice for practice

Experience from therapy cycles of >40 patients and the experience from the above-mentioned studies can be confirmed throughout; in particular

• The improvement in quality of life and freedom from pain often already one week after the first therapy session.
• Particularly impressive is the optical improvement of the affected skin already after one week
• The cortisone therapy can usually be largely reduced, is often discontinued
• Care with fatty ointments or oils (eg, almond oil, olive oil, etc.) is important
• In the rare case of insufficient efficacy, the combination with topical preparations is promising
• The symptom freedom is individually very different 6 months to 1 ½ years (on average about a year), then a single so to speak booster therapy is sufficient