Morphea through the ages

Introduction

Morphea, also referred to as localized scleroderma, is an immune-mediated fibrosing condition affecting the skin with variable extension to underlying structures. It presents most commonly in children between 2-14 years old, and adults in the fourth decade of life¹.

Pathogenesis

Our understanding of the pathogenesis of morphea is constantly being updated as we gain greater understanding of the disease. Microvascular injury in a predisposed individual is the first step in the pathogenesis of morphea, with multiple potential triggers implicated, including infections, drugs, and trauma¹. Cell adhesion molecules and interleukin-8 (IL-8) attract the lymphocytic infiltrate and activation of the T helper type 1 (Th1)/Th17 pathway leading to early inflammatory plaques. Multiple cytokines including IL-2, IL-6, IL-4 and IL-13 are involved, with increased levels correlating with the severity of disease in generalized and linear forms². IL-4 and IL-6 levels have also been shown to decrease in parallel with disease improvement. Activation of the Th2 pathway leads to fibrosis and damage. Conflicting evidence exists about the role of transforming growth factor (TGF-β ) in the pathogenesis of morphea.

Clinical Presentation

There are many different subtypes of morphea, and the appearance of plaques varies accordingly. In the inflammatory phase, plaque-type morphea lesions can be ovoid or linear, with varying degrees of erythema and induration depending on the depth of involvement (Figure 1). In children, early inflammatory plaques on the face can mimic a capillary malformation or sinus pericranium, a congenital venous anomaly in which epicranial veins connect to intracranial dural sinuses. Indurated circumscribed plaques may have a similar appearance to necrobiosis lipoidica or pretibial myxedema.

Figure 1. Photo of morphea on patient’s abdomen.

Plaques may progress over time to become more sclerotic and then finally atrophic, with hyper- and hypopigmentation being the most prominent features in burnt out lesions. Not all plaques transition through these 3 classic phases (early inflammation, subsequent sclerosis and final atrophy). In deep forms of morphea, epidermal changes may be absent.

Diagnosis and Work-up 

Consensus guidelines for the diagnosis and treatment of localized scleroderma have been published, including the 2019 EULAR consensus guidelines for juvenile localized scleroderma and the 2017 European Dermatology Forum guidelines^3,4.

The diagnosis of morphea can usually be made clinically, with biopsy required in cases that present with less-than-classic symptomology. Several classification systems have been proposed for morphea (Table 1)⁵. The Peterson classification consists of five groups: plaque, generalized, bullous, linear, and deep. The Laxer Criteria, proposed in 2006, differs in that it lacks a bullous variant and classifies deep involvement as a subtype of circumscribed morphea. Finally, the criteria proposed by the European Dermatology Forum has 6 subtypes and includes eosinophilic fasciitis. The most common presentation of morphea in children is linear, whereas in adults it is plaque. The Laxer criteria successfully classified 95% (n=900) patients in a recent study compared to 56% (n=533) and 52% (n=487) using the Peterson criteria and European Dermatology Forum classification respectively⁵.

Table 1: Classification Systems of Morphea; adapted from Prasad et al.5

Laboratory investigations should include markers of systemic involvement and baseline bloodwork for possible systemic treatment if indicated. Screening for extracutaneous manifestations, present in up to 25% of patients, should be directed based on the location of the morphea and signs or symptoms.

Several autoantibodies are more common in patients with morphea, however testing for these is only recommended if clinical suspicion exists for concurrent autoimmune conditions6. Elevated antinuclear antibody (ANA) levels are reported in 23–68% of patients, usually defined as titres at minimum >1:80. The combination of positive ANA with positive anti-histone or anti-single-stranded DNA (anti-ssDNA) was associated with more severe disease in a cohort of 187 adults and children with linear morphea, defined by functional limitations, extensive body surface area involvement, and high skin damage⁷. Rheumatoid factor, which is elevated in 3-16% of patients, was most common in a pediatric cohort of 750 patients and correlated with arthritis and musculoskeletal manifestations^6,8. Inflammatory markers are seldom elevated, although an increase in erythrocyte sedimentation rate (ESR) can be seen in children with joint involvement⁹. 

Lichen sclerosis may coexist with morphea, both genital (n=8) and extragenital (n=19), as reported in up to 6% of patients with morphea based on a cohort of 472 adults and children. These data suggest that, compared with lichen sclerosis in the general population, lichen sclerosis was significantly more frequent in patients with moprhea as indicated by an odds ratio of 18.1 in this cohort of patients. , Patients with morphea may benefit from careful screening questions and physical exam for concomitant lichen sclerosis¹⁰. 

Abnormal findings in the central nervous system (CNS), eyes, and teeth have been associated with morphea affecting the head across multiple studies11. A wide range of CNS findings have been reported in patients with morphea of the head, the most common being white matter lesions ipsilateral to skin plaques but reports also include contralateral anomalies. Patients with anomalies are not always symptomatic. Guidelines recommend a brain MRI for screening in this population^3,4. Imaging should include contrast, but vascular imaging is unlikely to help, and repeat imaging should be ordered if there is a change in symptoms¹¹.

Ocular manifestations are also most common in patients with facial lesions or those with CNS manifestations, and include anterior uveitis, episcleritis, enophthalmos, and lagophthalmos¹¹. A baseline ophthalmologic assessment with slit-lamp exam and ongoing re-assessment every 6-12 months is recommended. 

Dental changes including shortened roots, missing secondary teeth, and alveolar resorption have been reported on imaging in patients with en coup de sabre (ECDS) or Parry-Romberg Syndrome (PRS)¹¹ (Table 2).

Table 2: Potential Investigations/ Assessments that can be considered; courtesy of Cathryn Sibbald, MD

Although imaging is not routinely recommended for localized morphea of the head, it may be helpful as the use of MRI has been reported to demonstrate the extent or activity of disease beyond what is appreciable on clinical exam¹².

It is generally accepted that systemic sclerosis (SSc) is distinct from morphea and that it is quite rare for patients to have both. However, a systematic review and meta-analysis of 5 studies involving 1,082 patients ranging in mean age from 36 to 55 years and predominantly female reported the coexistence of SSc and morphea to be between 2.4 and 7.4% of patients¹³. Analysis also revealed that patients with both SSc and morphea tended to be ANA positive with Raynaud’s phenomenon and the authors postulate that these characteristics, along with presence of nailfold scleroderma patterns in a patient with morphea, should prompt further screening for possible SSc. 

Assessment

Multiple clinical tools have been investigated to assess the clinical severity and response to treatment, all with limitations.

One of the more common and validated scoring tools is the LoSCAT (Localized Scleroderma Cutaneous Assessment Tool), which includes a Skin Severity Index (LoSSI) and a Skin Damage Index (LoSDI)¹⁴. With this tool, markers of activity include new or enlarging lesions, erythema, and induration at the edges of plaques. Indices of damage include hyper- and hypopigmentation, subcutaneous and dermal atrophy, and central induration. Unfortunately, this tool does not include waxy white plaques which are also markers of active disease.. Photo-documentation is recommended along with the use of the LoSCAT assessment tool if possible⁴.

Less commonly adapted tools include infrared thermography and high frequency ultrasound. In addition to the need for equipment, limitations of these tools include low specificity of thermography and lack of standardization for ultrasound, explaining their lack of inclusion in guidelines^3,4.

Treatments

Topical treatment regimens are listed in Table 3. Both guidelines(the 2019 EULAR consensus guidelines for juvenile localized scleroderma and the 2017 European Dermatology Forum guidelines) include topical treatments as first-line options for plaques that are limited in size and depth (not extending deeper than dermis) ^3,4. Calcipotriol, tacrolimus and corticosteroids are all included despite a paucity of evidence supporting their use, and occlusion is suggested to enhance the efficacy of all⁴. Other agents with limited evidence include imiquimod, crisaborole, and hyaluronidase. 

Table 3: Topical treatments; adapted from LaChance et al.2

Topical treatments should be continued for a minimum of 3 months, as clinical response in sclerosis can take anywhere from 8-12 weeks. After 3 months, topical corticosteroid-based regimens are recommended to be used intermittently as opposed to continuously⁴. 

Improvement in plaque morphea with phototherapy has been described using both UVA and UVB wavelengths². UVA provides the advantage of potential collagenase activation and deeper penetration, although access may be limited in some centres. 

Systemic medications are recommended for active lesions that are widespread, rapidly progressive, with potential of causing joint contractures, or located on the face^3,4. A recent systematic review included 742 patients treated with systemic agents, with methotrexate and mycophenolate mofetil being the most commonly used immunosuppressants¹⁵. 

Methotrexate is considered a first-line agent in both children and adults. Systemic corticosteroids (methylprednisolone or prednisone) can be used adjunctively for the first 3-6 months of therapy. An evidence-based review of the use of systemic immunosuppressive therapies for the treatment of morphea included a comparison of the combination of methotrexate and steroids in children and adults with morphea, with all demonstrating better response with combination treatment¹⁵. 

Mycophenolate mofetil has demonstrated efficacy in patients who are refractory to methotrexate, in both pediatric and adult studies, with improvement documented in 87-91% of patients^16,17. In patients who have contraindications or a lack of clinical response, multiple different systemic agents have been used, all with limited evidence, listed in Table 4. 

Table 4: Systemic Treatments; adapted from Abduelmula et al.15
SC: subcutaneous

Surgical interventions can improve volume, symmetry and contour in patients, and include grafting of fat, bone and cartilage, or injectable fillers such as hyaluronic acid¹⁸. The optimal timing for surgical intervention is not uniformly agreed upon, but in general most clinicians advocate for waiting until the disease is inactive to minimize any risk of reactivation or relapse¹⁸.

Physiotherapy and manual therapy should be added to topical and systemic therapy in all types of morphea that result in restrictions of motion⁴. Massage and lymphatic drainage may also add benefit in sclerotic types of morphea.

Outcomes

The risk of relapse is as high as 30-45% in some cohorts^19,20. Older age at disease onset is a prognostic risk factor for relapse, with other potential predictive risk factors including linear disease on the limbs, presence of extracutaneous manifestations, and elevated ANA levels. It is recommended that systemic treatments be continued for at least 24 months, although some experts advocate treatment to continue for 3 years^3,4. 

Conclusion

More data is needed on long term outcomes, and hopefully current and future patient registries will help in gathering this important longitudinal data to help better inform treatment strategies as well as adding to current knowledge about pathogenesis and associations.