Morphea (Localized Scleroderma)

Table I.

Optimal Therapeutic Approach for this Disease

There is no broad consensus on treatment approaches in morphea. In general, early inflammatory lesions respond best to any therapy and may even completely resolve. The more sclerotic or inactive the lesion the less likely therapy will be completely efficacious. Topical therapies are appropriate as monotherapy only in localized, nonprogressive morphea. Deep involvement, threatened or presence of functional limitation, and rapidly progressive disease are all indications for therapy aimed at shutting down the disease process and preventing extension of lesions (ie, phototherapy or systemic therapy).

Treatment decision is based on the following:

Subtype

Patients with linear or generalized morphea often present with rapid progression and are at risk for functional impairment.

Depth of involvement: Phototherapy or systemic immunosuppressives are indicated depending on depth of involvement and potential for functional impairment.

– Superficial to mid-dermis: topical or phototherapy

– Deep involvement if widespread or presence/potential for functional/cosmetic impairment: systemic therapy

Stage and activity (inflammatory, sclerotic, atrophic)

– Early, active disease is most responsive to therapy (signs of activity: erythema, lesion extension, itching, tingling)

– Early intervention with aggressive systemic immunosuppressive (esp, MTX) is indicated to shut down active disease, especially if there is great risk of lesion expansion and progression or deep involvement (linear and generalized subtypes).

– Later stages of morphea with predominant sclerosis or so-called “burnt out lesions” may respond to intralesional steroid injection if solitary, or phototherapy if more widespread. Softening of the skin, reduction of contractures and sustaining range of motion are important goals and may also be achieved with physical or occupational physical therapy. Surgery and skin grafting may be considered in severe cases of stable non-progressing single lesions with debilitating functional or cosmetic impairment (en coup de sabre or Parry Romberg).

There are case reports documenting the reactivation and rapid extension of surgically excised lesions, so this should only be undertaken in patients with long-standing inactive disease and with a full discussion of the potential risk. The same is true regarding the use of filler substance for atrophic lesions.

Presence or potential for complications

Potential for extensive tissue damage (pigmentary change, atrophy, contractures, etc) and lesions with higher risk for secondary problems (facial lesions, en coup de sabre, etc) require more aggressive treatment (Figure 8).

Concomitant disorders

Underlying liver disease or renal failure may be a contraindication for methotrexate and other systemic therapies. Collaboration with internists, pediatrics, or rheumatologists is crucial to providing best therapy for individuals with multiple illnesses.

Phototherapy (especially UVA1)

Currently, phototherapy is one of the best treatment options in morphea when it does not involve subcutis or below. The highest level of evidence is broad-band UVA (320 to 400nm wavelength), narrow-band UVB (wavelength centered around 311 nm), UVA1 (340 to 400nm wavelength). Due to a shorter wavelength, narrow-band UVB is useful in lesions affecting the superficial dermis, but of limited utility in deeper lesions due to lack of penetration.

UVA on the other hand has a greater depth of penetration and may even be effective in reducing inflammatory cytokine concentrations and endothelial cell dysfunction in skin lesions compared with UVB. UVA1 is divided into: low dose (20 to 40J/cm²), medium dose (40 to 80J/cm²) or high dose (80 to 120J/cm²).

UVA1 delivered 24 to 30 times in high or medium doses is superior to narrow band UVB or low dose UVA1, but efficacy in “burnt-out” lesions without the presence of inflammation and activity as well as in atrophic or deep subtypes is debatable. In these cases, or in patients with facial hemiatrophy (Parry Romberg) or eosinophilic fasciitis, systemic drugs are preferred.

Symptoms of skin tightening and inflammation should improve after 10 to 20 treatments as well as progression (start with a medium and increase to high dose; treatment is 3 to 5 days per week). Ideal dose and frequency of treatments have not been determined.

Side effects of UVA1 include transient headache, erythema, pruritus and hyperpigmentation of skin and morphea lesions in particular. Even smaller subtle lesions may become apparent after several treatment sessions due to development of hyperpigmentation. Concerns about carcinogenesis in patients receiving UVA1 phototherapy are legitimate, although an association has not been made to date. Advise patients to avoid extensive sun exposure and tanning beds and to be screened for cancerous lesions annually.

Methotrexate and systemic corticosteroids

Methotrexate (MTX) is one of the best systemic treatment options for morphea. Oral or intravenous (IV) glucocorticoids may be used along with methotrexate in rapidly progressive or inflammatory disease. Of note, optimum regimen for the use of methotrexate and/or glucocorticoids has not been established. Recommendations are based on current literature and the author’s experience.

Typical dose for children: 0.6mg/kg/week delivered orally or via subcutaneous injection.

Typical dose in adults: 15 to 25mg/week delivered orally or via subcutaneous injection

Until MTX takes effect, systemic corticosteroids may be used to rapidly shut down severely inflammatory, symptomatic, or progressive morphea (orally: 1mg/kg/d, or intravenous pulse: 30mg/kg/d for 3 days per month) for the first 3 months. Oral or parenteral (subcutaneous injection) forms of MTX are available. Frequent gastrointestinal upset may require switching to parenteral forms.

Pregnancy should be prevented during therapy and until 3 months after therapy because of the teratogenic effects of MTX. Widely available guidelines for appropriate monitoring of liver function, blood counts, and renal function should be observed. The most common side effects are nausea and gastrointestinal upset. For prolonged disease suppression patients often may have to stay on therapy for several years.

Corticosteroids

Topical steroids, although often prescribed, are of unclear benefit. Treating morphea at an early stage may require potent drugs or aggressive localized therapy to prevent spreading and progression, hence physicians should refrain from using topical steroids as a first-line therapeutic agent in cases of extensive, deep, or rapidly progressive morphea.

Intralesional triamcinolone (10mg/mL) once a month for 3 to 4 separate occasions may be beneficial in patients with solitary inflammatory sclerotic lesions and stable disease or as an adjunct to other therapy (triamcinolone acetonide 5 to 10mg/cc). This form of treatment is well tolerated, although not suitable for multiple lesions or large lesions.

Oral steroids (prednisone or methylprednisolone) are used during the initiation phase of MTX therapy, in combination with it, or in a solitary regimen in patients with contraindications to MTX and other systemic immunosuppressives (liver disease, kidney failure, anticipated pregnancy, low tolerance of MTX, etc). I recommend 1mg/kg initially, with a maximum of 60mg.

Vitamin D analogues

Vitamin D analogues are thought to influence keratinocyte differentiation, and promising studies justify their use in relatively superficial and no- progressive lesions (topical calcipotriene 0.005% ointment under occlusion two times per day).

Other treatment options with reported efficacy

– Mycophenolate mofetil

– Topical tacrolimus (0.1% twice a day) showed promising effects in small trials involving 13 patients. Especially erythematous lesions, which are thought to be inflammatory, were most responsive.

– Every patient should undergo occupational therapy and physical therapy (OT/PT) if contractures or limited range of motion are present.

– Cosmetic corrections and concomitant medical problems should be addressed in a multidisciplinary team of plastic surgeons, neurosurgeons, ear-nose-throat (ENT), rheumatologists, orthopedics and dermatologists.

There is one case report of a single patient with generalized morphea that is resistant to traditional therapy (including immunosuppression with cyclosporine), receiving imatinib. The off-label use of this tyrosine kinase inhibitor at a dose of 200mg per day for 6 months showed substantial improvement. After therapy cessation, no new lesions developed for 6 months.

Patient Management

DETERMINE SUBTYPE

Circumscribed: Close follow-up (linear and generalized morphea may present initially as circumscribed lesion). Additional evaluation is rarely needed

Linear

Head and face involvement: All patients: refer for ophthalmologic examination. Look for neurologic symptoms, jaw problems and dental malformation and displacement and refer as appropriate.

Extremity: Muscle pain or tightness, deep fixed lesion: MRI or US to determine subcutaneous, fascia, muscle or bone involvement.

Check CK and aldolase levels in peripheral blood. I usually check this if patients report any muscle pain, weakness, or tightness and clinically have deep bound down lesions in the area. I also consider MRI to image the area looking for muscle or fascial involvement, which might help localize a site to biopsy by general surgery if indicated.

A complete blood count (CBC) with differential is also helpful looking for eosinophilia in cases of eosinophilic fasciitis (EF). I usually take this as an indication for systemic immunosuppressive therapy and involve a pediatric or adult rheumatologist. Repeat imaging every 4 to 6 months to determine response to treatment.

Joint pain, stiffness, swelling or reduced weight bearing may indicate arthritis. (This may affect a joint underlying the morphea lesions or in an unaffected area.) Rheumatology consult may be indicated.

Decreased range of motion (ROM), contractures or limb length discrepancies would indicate the following:

– OT/PT not only for ROM, but also strengthening, proprioception, and balance

– Orthopedics consultation

– Rheumatology consultation

– Physical examinations with measurements of affected limbs every 6 months, looking for limb length descrepancy.

DETERMINE LEVEL OF DISEASE ACTIVITY USING THE FOLLOWING CRITERIA: New or increased lesion size over the past 3 months, presence of signs of disease activity (erythema, peripheral induration, pruritus, edema). Active lesions respond best to treatment. Inactive lesions (dermal/subcutaneous atrophy, pigmentary alteration, central sclerosis, residual functional impairment, no increase in lesion size or number over past 3 months) will not respond to medical therapy, but can benefit from supportive care and close monitoring for disease reactivation.

Each patient contact should be documented with simple digital photographs. These images, which are crucial in order to determine disease activity, progression and treatment success, should be reviewed during each visit

Phototherapy is safe and highly effective in many cases, although also time consuming and not readily available. Referring patients who live far away to temporary housing facilities and coordinating school and work schedules may be difficult.

Currently there is no curative therapeutic approach available, and there is general agreement among morphea experts that the systemic therapies suppress disease activity, as evidenced by reports of disease reactivation after cessation of therapy. Further, some patients experience a remitting/relapsing course. Thus management encompasses a complex interplay of risk vs benefit, minimizing side effects, and close patient follow-up. Patients also benefit from a multidisciplinary approach when severe disease is present.

At this time no laboratory tests are indicated to differentiate the various subtypes because there is no accepted biomarker for disease activity or severity. I order labs appropriate for a baseline evaluation if I am considering immunosuppressive therapy—CBC, complete metabolic panel (CMP), urinalysis (U/A,), purified protein derivitive (PPD) test for tuberculosis (TB). If the patient has other specific findings or symptoms that might indicate another connective tissue disorder or internal manifestations, I will order laboratory tests guided by those findings, ie, muscle pain tightness, creatinine phosphokinase (CPK), aldolase, MRI, CBC with differential looking for eosinophils.

Unusual Clinical Scenarios to Consider in Patient Management

Since the skin is usually the first organ affected by scleroderma, it is important to distinguish morphea from scleroderma, as they are different disorders with different prognoses. The predominant difficulty is in differentiating a generalized pansclerotic morphea patient who may present with dysphagia and dyspnea due to mechanical restriction from cutaneous sclerosis, not internal organ involvement. Further, these patients may present with edematous digits due to circumferential sclerosis of the forearms, but do not have true sclerodactyly/acrosclerosis.

Helpful clinical clues to differentiate pansclerotic morphea from scleroderma include that lesions spread from the trunk acrally, absence of Rayaud’s phenomenon, absence of nailfold capillary change, sparing of hands and digits, lack of characteristic antibodies associated with scleroderma, and absence of internal organ involvement.

What is the Evidence?

Vilela, FA, Carneiro, S, Ramos-e-Silva, M. “Treatment of morphea or localized scleroderma: review of the literature”. J Drugs Dermatol. vol. 9. 2010. pp. 1213-9. (The authors acknowledge that the treatment of morphea is controversial. They review the main agents utilized to improve lesions and associated symptoms.)

Laxer, RM, Zulian, F. “Localized scleroderma”. Curr Opin Rheumatol. vol. 18. 2006. pp. 606-13. (A large multicentre study coordinated by the Pediatric Rheumatology European Society has yielded important information on the epidemiology and clinical manifestations of juvenile localized scleroderma, especially as it pertains to systemic manifestations. Previous results using methotrexate and corticosteroidshave been confirmed. Studies on phototherapy have also demonstrated efficacy. Imiquimod has shown promise in an initial case series.)

Saxton-Daniels, S, Jacobe, HT. “An evaluation of long-term outcomes in adults with pediatric-onset morphea”. Arch Dermatol. vol. 146. 2010. pp. 1044-5. (The prevalence of morphea in childhood is not well established, but past reports suggest approximately 2/3 of linear morphea begins before age18, and 20–30% of morphea overall begins in childhood. Studies have described significant morbidity in children with morphea, but none have addressed the disease effects when they reach adulthood. From the Morphea Registry and DNA Repository at the University of Texas Southwestern Medical Center adults with pediatric onset morphea were identified. In contrast to other studies, 89% of our cohort had continued disease activity. Because of referral bias, prospective cohort studies are needed to determine accurate prevalence. Nonetheless, our data indicates there is a subset with active disease in adulthood who need life-long evaluation and repeated courses of aggressive treatment to prevent the significant morbidity noted in our group.)

York, NR, Jacobe, HT. “UVA1 phototherapy: a review of mechanism and therapeutic application”. Int J Dermatol. vol. 49. 2010. pp. 623-30. (Ultraviolet radiation (UVR) phototherapy has been associated with both deleterious and beneficial effects to patients with both localized and systemic skin disorders. Phototherapy is advantageous in diseases of the epidermis and dermis, as it provides the most direct approach minimizing systemic side effects. Most recently, ultraviolet A1 (UVA1)phototherapy has emerged as a specific UVR phototherapeutic mechanism. It has shown to be therapeutic in a number of sclerosing skin conditions and other dermatitides, in many cases proving to be more effective than other phototherapy modalities. Treatment advantages of UVA1 phototherapy include the ability to penetrate into the deep layers of the skin to affect changes on disease-causing T cells, as well as activation of endothelial cells to promote neovascularization. UVA1t herapy also has been shown to be relatively free of side effects associated with other phototherapy regimens, including erythema and cellular transformation. These properties make UVA1 phototherapy an important treatment option for many debilitating skin conditions.)

Kreuter, A, Krieg, T, Worm, M, Wenzel, J, Gambichler, T, Kuhn, A. “AWMF Guideline no”. 013/066. Diagnosis and therapy of circumscribed scleroderma. J Dtsch Dermatol Ges. vol. 7. 2009. pp. S1-14. (Localized scleroderma is a rare autoimmune disease with primary affection of the skin, and occasional involvement of the fat tissue, muscle, fascia, and bone. Depending on the clinical subtype, the spectrum of skin lesions ranges from singular plaque lesions to severe generalized or linear subtypes. which may lead to movement restrictions and permanent disability. ThisGerman S1-guideline proposes a classification of localized scleroderma that, considering the extent and depth of fibrosis, distinguishes limited, generalized, linear, and deep forms of localized scleroderma, together with its associated subtypes. The guideline includes a description of the pathogenesis, of differential diagnoses, and particular aspects of juvenile localized scleroderma, as well as recommendations for histopathologic, serologic, and biometric diagnostic procedures. Based on studies of topical and systemic treatments as well as phototherapy for localized scleroderma published in international literature, a treatment algorithm wasdeveloped that takes account of the different subtypes and the extent of disease.)

Zulian, F. “New developments in localized scleroderma”. Curr Opin Rheumatol. vol. 20. 2008. pp. 601-7. (The authors consider outcome measures for scleroderma. The also acknoledge that previous results, using methotrexate and phototherapy, have beenconfirmed. A successful use of bosentan, an endothelin receptor antagonist with vasodilatative and antifibrotic properties for refractory cutaneous ulcerations in pansclerotic morphea, opens new horizons of treatment.)

Leitenberger, JJ, Cayce, RL, Haley, RW, Adams-Huet, B, Bergstresser, PR, Jacobe, HT. “Distinct autoimmune syndromes in morphea: a review of 245 adult and pediatric cases”. Arch Dermatol. vol. 145. 2009. pp. 545-50. (In this retrospective review of 245 patients with morphea it was noted that high prevalences of concomitant and familial autoimmune disease, systemic manifestations, and antinuclear antibody positivity in the generalized and possibly mixed subtypes suggest that these are systemic autoimmune syndromes and not skin-only phenomena. This has implications for the management and treatment of patients with morphea.)

Zulian, F, Vallongo, C, Woo, P, Russo, R, Ruperto, N, Harper, J. “Localized scleroderma in childhood is not just a skin disease”. Arthritis Rheum. vol. 52. 2005. pp. 2873-81. (750 patients with morphea were studies. Extracutaneous manifestations of juvenile localized sclerodermadeveloped in almost one-fourth of the children in this study. These extracutaneous manifestations often were unrelated to the site of the skin lesions and sometimes were associated with multiple organ involvement. The risk of developing SSc was very low [1 patient]. This subgroup of patients with juvenile localized scleroderma should be evaluated extensively, treated more aggressively, and monitored carefully. In patients with extracutaneous involvement, the prevalence of antinuclear antibodies and rheumatoid factor was significantly higher than that among patients with only skin involvement. However, Scl-70 andanticentromere, markers of SSc, were not significantly increased.)

Weibel, L, Sampaio, MC, Visentin, MT, Howell, KJ, Woo, P, Harper, JI. “Evaluation of methotrexate and corticosteroids for the treatment of localized scleroderma (morphoea) in children”. Br J Dermatol. vol. 155. 2006. pp. 1013-20. (Treatment and outcome of 34 patients with LS were retrospectively analysed. Pulsed intravenous methylprednisolone was given, followed by oral prednisolone on a reducing regimen and maintenance treatment with methotrexate. We assessed treatment outcome clinically and by thermography and monitored adverse events. From the onset of treatment, the disease stopped progressing in 94% of the patients. In 16 (47%) patients therapy was discontinued when the disease was considered to be inactive clinically; however, seven (44%) of the 16 developed a relapse, necessitating repeat treatment.These data suggest that systemic corticosteroids and methotrexate in combination are beneficial and well tolerated in the treatment of children with LS. Because of the risk of relapse after discontinuing therapy, long-term monitoring is mandatory.)