Chapter 64. Morphea

Morphea is a chronic autoimmune disease characterized by sclerosis of the skin. The term “localized scleroderma” is also used in an attempt to highlight the systemic features of morphea. This causes confusion with systemic sclerosis (scleroderma) often resulting in unnecessary evaluation and anxiety. It is the opinion of the authors this term should be avoided. Morphea itself has a spectrum of manifestations ranging from skin only to multiple organ involvement. Of note, organ involvement in morphea is distinctly different from systemic sclerosis (Box 64-1).

Morphea has an estimated incidence of 2.7 per 100,000 with a female:male ratio of 2 to 3:1.1 Morphea is more common in Caucasians.2–5 The relative frequency of the different subtypes varies between studies. This is likely due to use of different classification systems. Twenty to thirty percent of morphea begins in childhood, but it can occur at any age.2–5 Linear morphea is the most common pediatric subtype (although all subtypes occur at any age).1,2,6 Twenty-five to eighty-seven percent of pediatric cases are linear morphea, with limb or trunk involvement in approximately 70%–80% and en coup de sabre (ECDS) or progressive facial hemiatrophy (PHA; formerly described as Parry–Rhomberg) in 22%–30%.1,2,4,5,7,8 In adults, circumscribed and generalized subtypes predominate. Deep morphea/morphea profunda is uncommon in both adults and children with a frequency of 2%–4%.1,2,4,7,8

Periods of disease activity vary from 3 to 6 years, but reactivation after periods of remission occurs in 20%.2,8 (eFig. 64-0.1). Others have a chronic course persisting for decades. The prognostic markers for recurrent or chronic disease have yet to be determined.

The etiology and pathogenesis of morphea is poorly understood. Most pathologic events ascribed to morphea are extrapolated from studies in systemic sclerosis (assuming the two disorders arise from the same etiology). Morphea probably arises from a genetic background that increases disease susceptibility, combined with other causative factors (infectious, environmental exposures) that modulate disease expression.

Like many autoimmune connective tissue diseases, morphea is likely a complex genetic disease. Familial clustering is rarely seen,5,9,10 and morphea is also associated with higher than expected rates of familial autoimmune disorders.5,11,12

Although there are no definitive associations, development of morphea lesions has been linked to local tissue trauma including radiation (eFig. 64-0.2), surgery, insect bites, and intramuscular injections.13 Although controversial, infectious agents have also been linked to lesion development.

Increasing amounts of evidence support autoimmune-mediated inflammation early in the course of morphea.14 Early morphea lesions are characterized by the influx of large amounts of mononuclear lymphocytes (usually activated T lymphocytes), plasma cells, and eosinophils.15 This is likely the result of autoimmunity, as there is widespread autoimmune reactivity in morphea patients (elevated ANAs, cytokines, and adhesion molecules).5,12,16 Morphea patients also have concomitant autoimmune disease at higher expected frequency than a healthy population.5,11

Vessel damage and upregulation of adhesion molecules (ICAM-1, VCAM 1, and E-selectin) occur related to the inflammatory cell infiltrate which facilitates local monocyte recruitment.17 These adhesion molecules are upregulated by cytokines classically associated with a Th2 immune response (Il-4, Il-1, and TNFs). Cytokines found in the sera and skin of morphea patients in increased concentration include IL-4, IL-6, and IL-8.18 These cytokines (especially IL-4) upregulate TGF-β, initiating a cascade of events resulting in increased production of collagen and other extracellular matrix components via induction of connective tissue growth factor, platelet-derived growth factor, and matrix metalloproteinases. These cytokines and growth factors inhibit interferon-γ (a suppressor of collagen synthesis and Th1-related cytokine). Chimerism or nonself cells may play a role in the pathogenesis of morphea by initiating a local inflammatory reaction.19

Morphea is currently divided into five subtypes (Table 64-1).20 Superficial or deep disease (involving subcutis, fascia, or below) may occur with any subtype. Morphea lesions may also occur with overlying lichen sclerosus change (Fig. 64-1).

Cutaneous Lesions

Stages of Cutaneous Lesions

(Fig. 64-2).

Morphea begins as erythematous plaques or patches, sometimes with a reticulated appearance. Later hypopigmented sclerotic plaques develop at the center of the lesion, surrounded by an erythematous or violaceous border (inflammatory stage) (Fig. 64-2A). Pain and/or itching can precede the initial skin findings. Sclerosis develops centrally, which turns into a shiny white color, as lesions expand with surrounding hyperpigmentation (sclerotic stage). There is loss of hair follicles, producing alopecia. Over months to years, the sclerotic plaque softens and becomes atrophic with hypo- or hyperpigmentation (atrophic stage) (Fig. 64-2B). The atrophic stage is associated with cigarette paper wrinkling (papillary dermis), cliff drop (dermal), or deep indentions (subcutis or deeper).

Circumscribed Morphea

Circumscribed morphea represents oval to round lesions undergoing the stages of activity described in the previous section that are not diffuse enough to meet criteria for generalized disease (Table 64-1). Patients with circumscribed morphea should be closely followed, as both linear and generalized morphea may begin with circumscribed lesions.

Atrophroderma of Pasini and Pierini are thought to be the residua of plaque-type morphea. The borders of the atrophoderma lesions have a “cliff-drop” appearance resembling “burnt-out” morphea lesions.

Generalized Morphea

Generalized morphea is characterized by more than or equal to four lesions on at least two of seven different anatomic sites. There are likely three variants of generalized morphea: (1) isomorphic, (2) symmetric, and (3) pansclerotic (Table 64-1; Figs. 64-3 and 64-4).21,22 In direct contrast to systemic scleroderma, generalized morphea does not present with acrosclerosis or sclerodactyly. Instead, lesions frequently begin on the trunk and spread acrally, sparing the fingers and toes (Fig. 64-4).

Linear Morphea

Linear morphea usually affects the extremities and face, but it can occur on the trunk (where it is often misclassified as circumscribed) (Table 64-1, Fig. 64-5A). The presence of multiple linear lesions is not uncommon. A recent study suggests that linear morphea may follow Blaschko's lines.23 Linear morphea may involve the dermis, subcutaneous tissue, muscle, or even underlying bone, causing significant deformities. Bone marrow inflammation has also been reported.24,25 ECDS “cut of the sword” may present as an atrophic band linear plaque on the forehead (Fig. 64-5B), extending to the scalp (where cicatricial alopecia occurs), brow, nose, and lip. Other linear lesions on the head and neck present on the temple or chin, and are generally hyperpigmented atrophic plaques (Fig. 64-5C). PHF is characterized by a slowly progressive, unilateral atrophy of skin, soft tissues, muscles, and/or bony structures. The atrophy may be accompanied by classic linear morphea lesions on the face or elsewhere.

Deep Morphea

Deep morphea, or morphea profunda, involves the deep dermis, subcutaneous tissue, fascia, and muscle. Plaques are poorly circumscribed and symmetrical (Fig. 64-6). The skin feels thickened and bound down to the underlying fascia and muscle. A “groove sign” (depression) may be present at the site of tendons and ligaments. Deep morphea lesions may underlie any clinical subtype of morphea, particularly linear and generalized, or occur alone.

EF, or Shulman syndrome, is a related disorder presenting with rapid onset of symmetric areas of pain and edema, usually on the extremities. EF may occur with cutaneous induration similar to morphea, or remain without skin involvement.

Related Physical Findings

Extracutaneous manifestations develop in 22%–56% of morphea patients.1,4,5,7,8,26 Articular and muscular (eFig. 64-6.1) involvement (arthritis, myalgias, neuropathies, and carpal tunnel syndrome) is the most common finding (12%) and can occur unrelated to skin lesions.11,27 Cutaneous disease itself produces limited range of motion, limb length discrepancy, joint deformity, and contracture (45%–56% linear morphea). Patients with lesions crossing joint lines are most at risk.8,26 ECDS is associated with neurologic and ocular complications (3.6%) including seizures, headaches, adnexal abnormalities (eyelids, eyelashes), uveitis, and episcleritis.11,27,28 Facial morphea may produce dental malocclusion, altered dentition, and atrophy of the tongue and salivary glands. Another possible finding is Raynaud phenomenon, although more strongly associated with systemic sclerosis.5

Laboratory Abnormalities

Serum Autoantibodies

Autoantibodies reported in patients with morphea include ANA, antisingle-stranded DNA, antidouble-stranded DNA, antihistone, antitopoisomerase IIα, antiphospholipid, anticentromere, anti-Scl-70, and rheumatoid factor (MMP-1).5,16,26,29–34 The clinical and prognostic significance of these autoantibodies remains unclear. ANA occur in 39%–80% of patients and are more common in patients with linear or generalized disease.5,8,16,26

Other Serum Abnormalities

Peripheral eosinophilia, hypergammaglobulinemia, and increased ESR/CRP may occur with active disease of any type, but particularly deep morphea (may correlate with disease activity).

Histopathology

Imaging Studies

MRI provides a complete assessment of the extent of disease, including depth of involvement and disease activity.25 This is especially helpful when deep involvement is suspected. It is also possible to evaluate the response to treatment, although not currently routine practice.

Ultrasonography (US) is a sensitive tool to evaluate or monitor tissue thickness, loss of subcutaneous fat and muscle, or other architectural alterations. Disease activity can be correlated with the detection of hyperemia and echogenicity.35 Discussion with the radiologist performing the MRI or US studies is crucial to adequately detect and evaluate change related to the morphea.

Children with morphea can have significant morbidity related to morphea, including effects on growth, function, and quality of life (fewer studies exist in adults). Muscle weakness may occur in affected extremities or face. Behavioral changes, learning disabilities, and seizure (sometimes preceding cutaneous lesions)36,37 have been reported in children with (and without) facial involvement. In addition, disfigurement and physical symptoms (fatigue, pain, itch) associated with morphea affect psychosocial development and play a substantial role in the quality of life for patients with morphea.

Pansclerotic morphea has been associated with an increased risk of squamous cell carcinoma due to chronic ulcers. The resulting sclerosis of the skin can cause significant contracture, and produces restrictive pulmonary defects and dysphagia. Circumferential sclerosis of the arms or legs may also produce compartment syndrome, bullae, and ulcers.

Morphea may coexist with other autoimmune diseases (systemic lupus erythematosis, vitiligo, primary biliary sclerosis, autoimmune hepatitis, Hashitmoto's thyroiditis, and myasthenia gravis).38–43 In particular, generalized morphea has been associated with an increased rate of autoimmune disease.5

Although morphea causes functional and aesthetic impairment, it is rarely life-threatening. Morphea may be self-limited, but frequently has a remitting relapsing or chronic course producing significant disease burden over time.12 (eFig. 64-0.1)

Overview

The natural history of morphea is poorly understood. At least some cases undergo spontaneous remission after a few years of activity. However, even when spontaneous remission occurs, residual damage created by active disease remains. In addition, new evidence suggests at least a subset of morphea patients have continued disease activity over many years, ultimately leading to extensive disease burden and related morbidity.12 Despite the large number of reported treatments, no consistent recommendations exist for therapy. This section aims to provide evidence-based algorithm for the rational evaluation and management of morphea patients (Figs. 64-7A and 64-7B).

Patient Evaluation

In determining which therapy is appropriate, the following must be considered:

• Disease Activity and Damage: Existing studies indicate that early, active disease is most responsive to any therapy.44 Indicators of active disease include development of new lesions or extension of existing lesions (photographs are critical), erythema and/or induration of the advancing edge of the lesion, patient reported symptoms such as itch or tingling. Disease damage (reversible or irreversible) includes pigmentary change, induration of the lesion center (controversial), atrophy (dermal, subcutaneous, muscle), contracture, limb length discrepancy, and scarring alopecia. Disease damage is much more difficult to treat and therapy should be aimed at preventing disease damage. Further, patients with active disease at risk for significant damage (facial lesions, PFH, lesions crossing joint lines, large BSA involvement, rapid progression) likely need aggressive therapy (phototherapy and/or systemic immunosuppresives).
• Depth of Involvement: Morphea involving the superficial to middermis would logically be amenable to topical therapy or phototherapy; however, involvement of the deep dermis and beyond should be treated systemically. Deep involvement can occur in all subtypes of morphea, but is especially prominent among linear and some generalized patients.
• Disease Progression: Many generalized and linear morphea patients are initially diagnosed with circumscribed morphea, but progress to have much more extensive disease.12 Therefore, patients who initially present with 1–3 plaques (which may be amenable to localized therapy) should be closely followed. If these patients progress, therapy should then be aimed at preventing further progression (i.e., phototherapy or systemic therapy).
• Systemic Involvement: Systemic involvement is usually an indication for systemic immunosuppressive therapy.
• Disease Subtype: Patients with linear and generalized (particularly those with rapid onset of confluent plaques) are likely at risk for severe, extensive disease and should be treated aggressively either with phototherapy or systemic immunosuppressives depending on the depth of involvement.

The diagnosis of morphea is usually made by the clinical appearance of the lesions. Histological examination may aid therapeutic decision-making because it is sometimes difficult to determine the degree of activity or depth of involvement by clinical examination alone. Biopsy of the advancing edge of a lesion may provide insight into both (eFig. 64-6.2). Biopsies should be taken from the inflammatory or indurated border or sclerotic center (indicate on pathology requisition) and include fat. For lesions with minimal clinical change, biopsy of site-matched unaffected skin is helpful. Although a large number of laboratory-based assessments are reported to reflect disease activity and prognosis in morphea, there are no widely accepted biomarkers for morphea. Consequently, laboratory-based tests are not recommended for evaluation morphea in the absence of specific signs and symptoms indicating the need for further assessment. Assessment via MRI and ultrasound is becoming increasingly useful for determination of lesion activity and depth and should be considered when deep morphea is present or suspected.

Specific Treatments

See Table 64-2.

Phototherapy

Phototherapy has the greatest evidence for efficacy (level 1, randomized controlled trials: broadband ultraviolet (UV) A, narrowband (NB) UVB, and UVA 1; level 2: PUVA systemic and topical).45–50 NB UVB should be considered for lesions affecting the superficial dermis (relatively thin on palpation or with sclerosis and inflammation in the papillary and superficial reticular dermis). UVA-based therapies are more appropriate for deeper dermal lesions due to greater depth of penetration. UVA-1 in particular has evidence for normalization of dermal collagen and effect on inflammation in morphea so is appropriate for both inflammatory and sclerotic disease.45 In the absence of access to UVA-1 phototherapy, use of broadband UVA is also supported by the literature.50 Disease is expected to improve (progression halted and erythema improved) after 10–20 treatments and most trials stopped after 20–30 treatments. Evidence suggests that patients continue to improve after cessation of therapy, and some authors recommend using a greater number of treatments30–50 for further therapeutic benefit. Uncontrolled trials demonstrated increased benefit with medium to high dose UVA-1 versus low dose, but controlled trials were less convincing. Optimum dose and regimen for UVA-1 phototherapy has yet to be determined. Phototherapy is likely ineffective for deep involvement (subcutis, fascia, muscle), and therefore should not be considered as primary therapy.

Vitamin D Derivatives

Only one study provides level-1 evidence on the effect of vitamin D derivatives in morphea, and it showed no difference between oral calcitriol and placebo.51 In fact, placebo and treatment groups improved equally. The authors also point out that the study was underpowered by their own calculations, making definitive conclusions regarding the efficacy of oral calcitriol difficult. The efficacy of topical vitamin D derivatives has been explored via uncontrolled trials and case reports52 (level-2 evidence) and showed improvement in most or all patients, albeit over several months of therapy (an interval in which lesions might improve independent of therapy). Importantly, calciprotriene was applied under occlusion in these studies.

Immunomodulators

Methotrexate with or Without Corticosteroids

The use of methotrexate (monotherapy) and methotrexate combined with systemic corticosteroids is effective based on level-2 evidence.28,44,53–55 Optimum dose and route, indications for addition of corticosteroids, and duration of therapy have not been determined. In most studies with combined therapy, corticosteroids are used for induction therapy either orally or via intravenous pulse (IVMP 30 mg/kg/day for 3 days per month or 1 mg/kg/day prednisone) over the first 3 months. Methotrexate is used as steroid sparing agent and started simultaneously (0.6 mg/kg/week in children or 15–25 mg/week in adults) and maintained for a prolonged period (1–2 years). Most study participants responded in a mean of 2–5 months. The best responders were all early in their disease course. Importantly, relapse was noted frequently after cessation of therapy, underscoring that therapy likely only suppresses disease activity.

Other Immunomodulators

Level-2 evidence suggests the use of occluded topical tacrolimus 0.1% ointment might be effective for active, inflammatory superficial plaque-type morphea.56 Recent case series utilizing oral mycophenolate mofetil indicate potential utility in patients refractory to methotrexate or sensitive to corticosteroid side effects.57 Case reports on the use of oral cyclosporine, bosentan, infliximab, and topical imiquimod have also reported some efficacy, but more definitive studies are lacking.

Antimicrobials

Despite the widespread use of antimicrobials in morphea (antibiotics and hydroxychloroquine), no published clinical trials exist.58 Literature supporting the use of antimalarials is limited to a case series in which two patients improved with hydroxychloroquine (while simultaneously receiving oral steroids and methotrexate).59 In a retrospective review, 7/11 patients continued to have active disease 3–153 months after starting hydroxychloroquine.4 At this time, the use of these agents in severe morphea is likely not indicated pending more definitive evidence of efficacy.

Lack of Evidence

The most commonly used treatment for morphea, topical steroids, shows no evidence for efficacy in the literature. There are also no studies investigating the use of intralesional steroids. In the hands of the authors, intralesional steroids have been extremely effective in treating circumscribed plaques or as an adjuvant for recalcitrant areas in patients receiving phototherapy or systemic treatment. Current evidence does not support the use of penicillamine or interferon-γ.60

Adjunctive Therapy

A significant number of morphea patients suffer irreversible sequelae. When these patients come to medical attention, they may no longer have disease activity, but rather damage from the past or a mixture of active disease and damage. Consequently, every morphea patient should be examined for the presence of limitation in range of motion, contracture, limb length discrepancy, or other functional impairment. In these cases, consultation with rheumatology, physical/occupational therapy, physical medicine and rehabilitation, plastic surgery, orthopedics, and oral maxillofacial surgery is highly recommended to maximize cosmesis, function, and minimize further damage.