Balanitis Xerotica Obliterans 

Updated: Nov 11, 2019
Author: Amira M Elbendary, MBBCh, MSc; Chief Editor: William D James, MD 

Overview

Background

Lichen sclerosus is a chronic, progressive, sclerosing inflammatory dermatosis of unclear etiology. Most reported lichen sclerosus cases (83%) involve the genitalia. In men, this genital involvement has traditionally been known as balanitis xerotica obliterans (BXO). A more accurate term is male genital or penile lichen sclerosus. The image below shows the condition.

BXO was first described by Stühmer in 1928 as a postcircumcision phenomenon.[1] It may affect the foreskin, glans, frenulum, and meatus or urethra and is responsible for most cases (80-90%) of acquired phimosis.[2]

Balanitis xerotica obliterans (lichen sclerosus). Balanitis xerotica obliterans (lichen sclerosus). Courtesy of Wilford Hall Medical Center Slide collection.

Yardley et al[3] believe that the prevalence of BXO is greater than previous series have shown and that it may manifest in children at an earlier age than previous series have shown. This belief is based on a study of 422 boys at a median age of 6 years 2 months (range, 3 mo to 16 y), of whom 186 (44.1%) received treatment involving surgery (148 circumcision, 33 preputial adhesiolysis, 5 frenuloplasty). Of the 186 boys, 110 had histological tissue examination; 84.8% of skin samples were pathologic. Specifically, tissue showed chronic inflammation (n = 69; 46.6%), BXO (n = 51; 34.5%), and fibrosis (n = 4; 2.7%).

Related Medscape Drugs & Diseases articles include Lichen Sclerosus et Atrophicus, Balanitis Circumscripta Plasmacellularis, and Balanitis in Emergency Medicine.

Pathophysiology

The etiology of male genital lichen sclerosus is unknown, but it is thought to be multifactorial. Balanitis xerotica obliterans (BXO) has occurred in monozygotic twins, which suggests a genetic basis for the disease in some cases. Human papillomavirus type 6 or type 16 has not been detected in patients with BXO, which strongly suggests that genital papillomaviruses do not have a strong association with BXO. Increased levels of tumor necrosis factor, interferon-gamma, and interleukin 1 have been demonstrated.[4]

Etiology

The etiology of male genital lichen sclerosus (balanitis xerotica obliterans [BXO]) is unknown but is thought to be multifactorial. Several contributing factors are possible, as described below.

Circumcision after age 13 years/uncircumcised state

This may very well be due to the effect known as the isomorphic, or Koebner, phenomenon. The large majority of inflammatory dermatoses of the male genitalia, including lichen sclerosus, occur in uncircumcised or late-circumcised men.

The presence of a foreskin may promote chronic irritation or serve to maintain a friendly environment for an as-yet unidentified infectious agent. Such chronic irritation and subsequent inflammation may initiate the changes noted in lichen sclerosus.

Uncircumcised men have higher incidence of urine pooling between the prepuce and glans penis, whereupon occlusion precipitates a Koebner phenomenon and subsequent inflammation.[5]

Postmicturition dribbling or microincontinence

It has been proposed that postmicturation drippling could be a a contributing factor in the pathogenesis of BXO. In a 2018 study, it was found that 91% of men diagnosed with BXO reported microincontinence, compared with 14% in the control group.[6] It is was also proposed that with the tendency of BXO to spare the anogenital region, the distribution of BXO mirrors the areas subject to urine under occlusion and sparing areas that are shielded from urine by the scrotum.

Hormonal factors

Hormonal influences in the development of lichen sclerosus have long been postulated, mainly in female vulvar lichen sclerosus.

Most studies have concentrated on the role of testosterone in the pathogenesis of vulvar lichen sclerosus. Childhood vulvar lichen sclerosus frequently resolves with the onset of menarche and the related pubertal increase in testosterone production in genital skin; additionally, adults with lichen sclerosus have been found to have decreased serum levels of free testosterone, androstenedione, and dihydrotestosterone compared with control subjects.

The underlying defect may be a problem with the function of the enzyme 5-alpha reductase.

Autoimmune disease

Various autoantibodies (including antinuclear, thyroid antimicrosomal, antigastric parietal cell, anti-adrenal cortex, antismooth muscle, and antimitochondrial antibodies) have been detected in patients with lichen sclerosus.

Vitiligo, thyroid disease, diabetes, and alopecia areata have also been commonly reported in association with lichen sclerosus.

In a study by Farrell et al,[4] IgG autoantibodies to extracellular matrix proteins were found in 80% of lichen sclerosus patients. An association between BXO and the major histocompatibility complex class II antigen HLA-DQ7 has also been found.[7] This region is known to confer increased risk of autoimmune disease such as rheumatoid disease, type 1 diabetes mellitus, and systemic lupus erythematosus.

Genetic factors[8]

Lichen sclerosus (not necessarily genital lichen sclerosus) has been reported in families, including twins (identical and nonidentical), sisters, mothers and daughters, and a brother and sister. Note, however, that no consistent pattern of genetic inheritance has been identified.

Presence of human papillomaviruses

The presence of human papillomaviruses (HPVs) has been reported in some cases of childhood penile lichen sclerosus. Whether the lichen sclerosus is directly attributable to HPV infection, or if lichen sclerosus merely promotes HPV infection is unclear.

Patients with penile lichen sclerosus alone have not been demonstrated to have a higher incidence of HPV infection.

In two studies that included 23 and 11 children, HPV was identified in 52% and 64% of cases, respectively.[9, 10] However, HPV is more common in uncircumcised males, and the finding of HPV infection in such patients could be incidental.

A 2017 systematic review of 27 papers reporting the prevalence of HPV in lichen sclerosus revealed that HPV was present in 22% of lichen sclerosus cases.[11] It also highlighted HPV-16 as the most common genotype.

Other

In a study of 18 patients[12] with combined buccal mucosa grafting and genital skin flap reconstruction of extensive anterior urethral strictures, 16.7% of stricture cases were caused by BXO.

Epidemiology

Frequency

United States

Kizer et al[13] noted that of 153,432 male patients discharged from Brooke Army Medical Center, 108 (0.070%) had a diagnosis of balanitis xerotica obliterans (BXO). The age distribution was similar over a range of 2-90 years, with the exception of the third decade, when the incidence almost doubled. Black and Hispanic patients had twice the rate found in white patients (10.59 cases, 10.67 cases, and 5.07 cases per 10,000 patients, respectively).

International

The prevalence of male genital lichen sclerosus (balanitis xerotica obliterans [BXO]) has traditionally been estimated at 1 case per 300-1000 males. No recent studies confirm this estimate, but male genital lichen sclerosus is not considered a rare condition. Huntley et al[14] reported on 100 consecutive patients seen in pediatric urology clinics who were followed to discharge. Eighteen referrals for circumcision were for religious reasons. Of the other 82 patients, the main reason for referral was retractability or phimosis. Six patients were identified as having BXO, a condition that had not been suggested on referral. Epidemiological data continue to show that BXO can effect boys.[15, 16] Some in Italy claim that the incidence of BXO has been understated.[17]

In Austria, 75 boys younger than 10 years were treated for phimosis; phimosis grade 2 or 3 (schema by Kikiros) was suspected of being BXO. Boys were given either circumcision or conservative therapy with circumcision secondarily (only if therapy did not yield good results in the conservative group). A pathologist examined every circumcision specimen. Doctor performed circumcision primarily in 29 boys and secondarily in 17 boys (mean age, 3.7 y; range, 1-10 y). The pathologist found BXO, chronic inflammation, and normal histological results in 8 (17.4%), 26 (56.5%), and 12 (26.1%) of patients, respectively. The average follow up was approximately 8 months. Doctors did not report recurrences. BXO appeared to be more common than previously reported. The clinical appearance can be confusing in boys, and preoperative BXO suspicion failed to correlate with the final biopsy results.[18]

Race

Male genital lichen sclerosus (balanitis xerotica obliterans [BXO]) has no known predilection for any racial or ethnic group.

Sex

Male genital lichen sclerosus (balanitis xerotica obliterans [BXO]) occurs most frequently in persons who are uncircumcised and who are of middle age. One study[19] revealed that 51 (98%) of 52 patients clinically diagnosed with penile lichen sclerosus were uncircumcised.

Age

Although males with genital lichen sclerosus (balanitis xerotica obliterans [BXO]) are most frequently of middle age, the condition also may appear in children, ranging from young boys to adolescents.

The overall childhood incidence of BXO has been reported to be 5-6%.[20]

In 2019, a 10-year retrospective review of children aged 16 and younger undergoing circumcision revealed that BXO occurred in 91 (8.9%) of 1025 children, mostly in the group aged 5-10 years.[21]

The incidence of BXO in pediatric patients is higher than most physicians realize. Additionally, the incidence of BXO is high in boys with phimosis.[20, 22, 23]

Prognosis

Male genital lichen sclerosus is chronic and often progressive. Regression or improvement of atrophic areas is unexpected.

Malignancies have been reported to arise in penile lichen sclerosus lesions (rare); most common cancers are squamous cell carcinoma (SCC),[24] adenosquamous carcinoma, and verrucous carcinoma. A study of 86 uncircumcised men with genital lichen sclerosus revealed malignant changes (3 SCC, 1 SCC in situ, and 1 verrucous carcinoma) occurring in 5 (5.8%) subjects. The average time between diagnosis of lichen sclerosus and subsequent diagnosis of penile malignancy was 17 years.[25] Notably, 4 of the 5 patients with malignant changes were found by polymerase chain reaction to have evidence of HPV-16 in their tissue specimens. It has been suggested that lichen sclerosus may promote HPV infection and perhaps the development of SCC.[9]

 

Presentation

History

Early in its course, penile lichen sclerosus (balanitis xerotica obliterans [BXO]) is relatively asymptomatic with only mild visually observable changes of the penis and glans. Physical changes occur over months or years and may include color or textural changes. Early symptoms are more prevalent in uncircumcised patients.

Symptoms occurring with time and progression of penile lichen sclerosus are as follows:

  • Pruritus

  • Burning

  • Hypoesthesia of the glans penis

  • Dysuria

  • Painful erection with altered sexual function

  • Decrease in urinary force or stream caliber

  • Urethritis with or without discharge

Symptoms occurring in late penile lichen sclerosus (in uncircumcised patients) are as follows:

  • Phimosis (inability to retract the foreskin over the glans)

  • Paraphimosis (inability to return an already retracted foreskin back over the glans)

The development of multifocal squamous cell carcinoma (SCC) in persons with lichen sclerosus et atrophicus of the penis and hepatitis C virus infection has been reported. SCC of the penis arising from BXO alone has also been noted.

A urethral stone manifesting as a stop valve, a rare complication of BXO, has been reported.

In older patients, BXO with phimosis can be a cause of difficulty with urination; thus, older patients should be examined to see if they have BXO in they have symptoms of difficulty with urination.[26]

Physical Examination

Early penile lichen sclerosus (balanitis xerotica obliterans [BXO]) demonstrates only subtle physical findings (eg, mild, nonspecific erythema; mild hypopigmentation).

As the condition progresses, single or multiple discrete erythematous papules or macules progress and coalesce into atrophic ivory, white, or purple-white patches or plaques. Lesions most commonly affect the glans and prepuce. The frenulum, urethral meatus, fossa navicularis, penile shaft, and perianal areas may become involved. A sclerotic white ring at the tip of the prepuce is diagnostic at this stage. Erosions, fissures, petechiae, serous and hemorrhagic bullae, and telangiectasias of the glans have been reported, albeit uncommonly. It runs a relapsing and remitting course, with periods of quiescence, but is nonetheless progressive.{ref41]

With further disease progression, the glans may become adherent to the prepuce. The coronal sulcus and frenulum may be sclerotically destroyed. The urethral meatus may narrow to the point of urinary retention. Urinary retention may be severe enough to cause retrograde damage to the posterior urethra and to the bladder and kidneys. Significant urethral meatal narrowing has led to sloughing of the distal half centimeter of the urethra. Phimosis and paraphimosis of uncircumcised patients may occur at this late stage. Chronic disease may lead to atrophy of the glans.[27]

Seventeen percent of lichen sclerosus cases are extragenital, beginning as mild, nonspecific erythema with mild hypopigmentation.

In one case report[28] , BXO in a middle-aged man involved the entire anterior urethra and the scrotum. It manifested as a palpable nodular scrotal mass and caused obstructive voiding symptoms. He was treated with a staged urethroplasty.

Complications

Phimosis, paraphimosis, painful erection, urethral stenosis, urinary retention, and altered flow are the most common complications.[29]

As the disease progresses, urinary retention may be sufficient to lead to retrograde damage to the posterior urethra, bladder, and kidneys.

As previously noted, painful erections in some cases of male genital lichen sclerosus may limit sexual function.

Malignant transformation is estimated to occur in 4-8% of cases. A 2017 retrospective review found that 13.6% of patients with balanitis xerotica obliterans (BXO) had evidence of penile intraepithelial neoplasia.[6] Another retrospective study in Paraguay that examined surgical specimens for invasive squamous cell carcinoma found that 33% of cases had associated BXO.[30] A similar study in London found that 28% of 155 patients with penile squamous cell carcinoma had BXO.[31]

A long lag time has been observed between symptoms of BXO and diagnosis of penile squamous neoplasia, with Nasca et al reporting between 10 and 23 years.[25]

Common signs and symptoms of penile malignancy include nodule or tumor growth, ulceration, blistering, hematuria, erythema, pain, purulent discharge, bleeding, lymphadenopathy, and failure to respond to treatment for presumptive inflammatory or infectious balanitis. For this reason, close follow-up care is indicated in order to quickly diagnose any malignant changes.

Long-standing penile lichen sclerosus (BXO) resulting in renal impairment in a child that lead to a persistent but improved renal impairment after circumcision has been noted.[32]

 

DDx

Diagnostic Considerations

Also consider the following:

  • Phimosis
  • Balanitis
  • Buried penis
  • Zoon plasma cell balanitis

Goolamali and Pakianathan[33] reported penile carcinoma arising in balanitis xerotica obliterans (BXO) in a 46-year-old white man; thus, if BXO is suspected or has occurred in the past, penile carcinoma should be excluded during the examination.

Pseudoepitheliomatous keratotic and micaceous balanitis (PKMB) is a very rare papulosquamous dermatosis of the glans penis. PKMB presents in elderly, uncircumcised men as a slowly growing, coarsely scaling, micaceous, white-to-gold, laminated, well-demarcated plaque. The lesion may grow to involve the coronal sulcus and the distal penile shaft. Symptoms include phimosis, pain, and interference with sexual activity. PKMB is considered to be a premalignant condition. Nearly all reported patients have had malignant degeneration. Reported associated malignancies include SCC, verrucous carcinoma, and fibrosarcoma.

Differential Diagnoses

 

Workup

Laboratory Studies

A rapid protein reagin test helps exclude syphilis.

Procedures

Skin biopsy aids in the diagnosis of male genital lichen sclerosus (balanitis xerotica obliterans [BXO]).

Histologic Findings

Histopathologic changes of genital lichen sclerosus are similar to those of nongenital lichen sclerosus.

Epidermal findings include orthokeratosis, hyperkeratosis with follicular plugging, hyperkeratosis without follicular plugging, and stratum malpighii atrophy.

In early balanitis xerotica obliterans (BXO), moderate lymphocytic infiltrate in the superficial dermis and basal epidermis, associated with the epidermal basal vacuolar interface, is noted. As lesions develop, there is loss of elastic fibers in the papillary dermis, the epidermis becomes atrophic with hyperkeratosis, and subepidermal edema and displacement of the dermal bandlike inflammatory infiltrate downward occur. The edema is later replaced by fibrosis, forming a wide homogenous zone extending from the subepidermal layer to the mid dermis.[10] Both morphea and radiation dermatitis can produce similar changes in the superficial dermis, but the lymphoid band is absent.

Follicular plugging is not apparent in mucosal BXO. Significant dermal edema and homogenization of the collagen in the upper dermis occurs, with dilatation of blood and lymph vessels and a loss of elastic fibers.

The immune cells moving into areas of BXO include lymphocytes, plasma cells, and histiocytes in the mid dermis. The inflammatory infiltrate is less pronounced in long-standing lesions.

Lester and Swick in 2014 studied 66 biopsies of BXO,[34] 30 from females and 36 from males. Nine were extragenital and 57 were genital. Spongiosis was noted in 14, epidermal hyperplasia in 28, and squamous cell carcinoma in 7. Early/transitional lichen sclerosis was noted in 35, with epidermal basement membrane thickening (97%), hyperplasia (57%), and epidermotropism of lymphocytes (97%). Eosinophils occurred in 35 specimens (53%) contained eosinophils (23 early/transitional lichen sclerosis). Increased eosinophils were in men (P  = .074), and squamous cell carcinoma (P  =0.014) was predictive of eosinophil number. The researchers concluded that epidermotropism of lymphocytes, epidermal hyperplasia, and basement membrane thickening were useful features in pointing out early lichen sclerosis. Eosinophils commonly occurred in lichen sclerosis and were most common in genital male eruptions and in lichensclerosis associated with squamous cell carcinoma.

 

Treatment

Medical Care

No consistently effective treatment has been developed for penile lichen sclerosus (balanitis xerotica obliterans [BXO]); however, the therapies described below have varying degrees of reported success.

Topical and intralesional steroids have been used. Topical steroids can offer a reliable option only in the management of mild BXO limited to the prepuce in boys with minimal scar formation. Patients and their families must have realistic expectations with regard to the success of such treatments. Steroid-based creams are ineffective in persons with established scarring. Studies have shown that applying a potent topical steroid improves BXO in the histologically early and intermediate stages of disease and may inhibit further worsening in the late stages. Kiss[35] questioned the utility of topical steroid-based creams for the treatment of clinical BXO. Differences in success rates may relate to an unwillingness to use superpotent corticosteroids.

Ghysel et al reported on successful therapy with topical steroid application and skin stretching on prepubertal boys with unretractable foreskin and phimosis.[36]

Successful treatment of BXO with topical tacrolimus has been reported.

Etretinate therapy has been used, but it is no longer available; acitretin is the current equivalent.

Carbon dioxide laser treatment has been used.[37]

An interesting report notes the successful use of intralesional adalimumab, a medication for psoriasis among other things, for BXO.[38]

Ebert et al,[39] in a retrospective analysis of 13 children with BXO published in 2007, reported that the relapse rate was lower after topical tacrolimus therapy than with betamethasone therapy.

In a case series of 3 patients, 2 had softening of the skin and pruritus, tenderness, and inflammatory change resolution within 3 weeks of receiving oral and intramuscular penicillin. Dirithromycin at 500 mg/d abated BXO in a third patient; the BXO returned when dirithromycin was discontinued but it improved again upon resumption of therapy.

Further treatment, or treatment of circumcised patients, is more challenging.

Intraurethral steroids provide efficacious therapy for stricture disease in patients with biopsy-proven BXO before invasive surgery.[40]

Surgical Care

A variety of surgical techniques can be used to treat more severe penile lichen sclerosus (balanitis xerotica obliterans [BXO]).

Circumcision is indicated when phimosis or paraphimosis impair function. Topical steroids are recommended to be continued postoperatively, and there should be a low threshold to rebiopsy if any concerns arise regarding squamous neoplasia development. Complete circumcision is recommended, as partial circumcision is associated with recurrent disease in 50% of cases.[41]

Uncircumcised patients usually benefit from therapeutic circumcision. Provide regular follow-up care to observe any changes in involved areas suggestive of malignancy.

Foreskin preputioplasty combined with intralesional triamcinolone might be a tenable alternative as against circumcision to treat BXO.[42]

Consider surgical intervention for symptoms or signs of urethral meatal stenosis. Buccal mucosal graft (BMG) for BXO-induced urethral stricture can work.[29]

Dubey et al[43] report that in BXO-related strictures with a viable urethral plate, 1-stage dorsal onlay buccal mucosal urethroplasty achieves superb medium-term results. They also state that the intervention created a normal, wide-caliber, slitlike glans, and a 2-stage procedure provides effective treatment but is associated with a higher revision rate.

Full-thickness skin grafts from eyelids to penis, plus split-thickness grafts in chronic BXO have been reported.

Buccal mucosa appears to be a durable source of nongenital tissue for urethral replacement. Attention to detail in terms of graft harvest, graft preparation, and graft fixation helps to avoid major postoperative complications. Onlay grafts appear to be preferable to tube grafts, and patients with a diagnosis of BXO do not appear to be candidates for the 1-stage urethral reconstruction using buccal mucosa.

Circumferential laser vaporization for severe meatal stenosis secondary to BXO reportedly is effective.

In 2007, Levine et al[44] reported on buccal mucosa graft urethroplasty for anterior urethral stricture repair. They evaluated the impact of stricture location and lichen sclerosus on surgical outcome. When lichen sclerosus affects the penis, complete excision of the diseased urethra with multistage repair decreases the rate of stricture recurrence associated with a 1-stage repair.

Palminteri et al[45] treated 17 patients, performing y resurfacing or reconstruction of the glans penis for benign, premalignant, and malignant penile lesions (5 glans skinning and resurfacing; 5 glans amputation and reconstruction of the neoglans, and 7 partial penile amputation and reconstruction of the neoglans). Four patients had lichen sclerosus. Glans resurfacing and reconstruction were performed with the use of a skin graft harvested from the thigh. Patients who received glans resurfacing reported glandular sensory restoration and complete sexual ability. Patients receiving glansectomy or partial penectomy with neoglans reconstruction maintained sexual function and activity, albeit with reduced sensitivity secondary to glans/penile amputation. Palminteri et al concluded that glans resurfacing or reconstruction can ensure a normal-appearing and functional penis, without jeopardizing cancer control.

A review published in 2013 found that BXO likely is more common than believed, and, while circumcision is its primary treatment, topical or intralesional treatments can be co-adjuvants of treatment.[46]

Simsek et al in 2014 performed circular buccal mucosal urethroplasty in 15 males for BXO related to anterior urethral strictures.[47] Urethral catheter removal occurred within 2 weeks, and, during subsequent visits, cosmetic outcome, symptoms assessment, and uroflowmetry over 20.5 months (range, 4-96 mo) were measured. The 15 men manifested no recurrent stricture, a normal meatus, and no chordee or erectile dysfunction. Excellent functional and cosmetic results were achieved in all 15 patients. They concluded that for surgical treatment of meatal strictures, a circular mucosal graft technique restores a functional and cosmetic penis.

Consultations

Consider consultation with urologists for the following:

  • Therapeutic circumcision

  • Circumcision for symptomatic phimosis or paraphimosis

  • Significant narrowing or obstruction of the urethral meatus or changes in urinary flow

Activity

In some cases of male genital lichen sclerosus, painful erections may limit sexual function.

Prevention

Early circumcision may decrease the risk of developing male genital lichen sclerosus (balanitis xerotica obliterans BXO]); nearly all cases have been reported in uncircumcised patients.

Long-Term Monitoring

Provide regular follow-up care to observe any changes in involved areas suggestive of malignancy.

Regular follow-up is necessary in patients treated with topical steroids to ensure maintenance of normal skin texture and color and detection of any signs of steroid-related atrophy.

Regular follow-up post therapeutic circumcision is recommended to detect recurrence of the lesion. A low threshold to perform a biopsy on any concerning lesion is recommended to detect early squamous neoplasia.

Consider surgical intervention for symptoms or signs of urethral meatal stenosis.

Patients can be taught to dilate the urethral meatus at home if the penile lichen sclerosus (balanitis xerotica obliterans [BXO]) involves the meatus; this sometimes is useful.

 

Medication

Medication Summary

Topical steroids, especially superpotent topical steroids, are the mainstay of medical therapy. Zavras et al reported successful treatment of 1079 (91.1%) of 1185 boys with a diagnosis of phimosis using fluticasone propionate 0.05%, including boys with mild balanitis xerotica obliterans (BXO).[48]  Ultrapotent steroids are typically applied daily for the first 3-4 weeks, then on weekends.

Topical testosterone is mostly ineffective and is not discussed further. Etretinate has been used with limited success but is no longer available for prescription in the United States.

Topical corticosteroids

Class Summary

Topical corticosteroids help reduce inflammatory lesions and may reduce or resolve lesions.

Clobetasol (Temovate)

Clobetasol is a class I superpotent topical steroid; it suppresses mitosis and increases synthesis of proteins that decrease inflammation and cause vasoconstriction. Clobetasol is used in most studies dealing with treatment of lichen sclerosus.

Topical immunomodulators

Class Summary

Topical calcineurin inhibitors are immune suppressants that block early T-cell activation, degranulation of mast cells, and multiple cytokines.

Tacrolimus ointment 0.1% or 0.03% (Protopic)

The mechanism of action for tacrolimus ointment in atopic dermatitis is not known. It reduces itching and inflammation by suppressing the release of cytokines from T cells. It also inhibits transcription for genes that encode IL-3, IL-4, IL-5, GM-CSF, and TNF-alpha, all of which are involved in early stages of T-cell activation. Additionally, tacrolimus ointment may inhibit the release of preformed mediators from skin mast cells and basophils and may down-regulate expression of FCeRI on Langerhans cells. It can be used in patients aged 2 years or older. It is more expensive than topical corticosteroids. It is available as ointment in concentrations of 0.03 and 0.1%. Tacrolimus ointment is indicated only after other treatment options have failed.