Morphea

overview of morphea

1. Morphea “ Localized scleroderma” By Mostafa A. Sanad

2. Introduction Localized scleroderma (LS), also called morphea,comprises a spectrum of sclerotic autoimmune diseases that primarily affect the skin,primarily of the dermis and subcutaneous fat, which ultimately leads to a scar-like sclerosis. Depending on the respective subtypes, LS might also involve adjacent tissues such as the fat, fascia, muscle, and bone. In contrast to systemic sclerosis, LS does not affect internal organs such as the lungs, heart,kidneys , or gastrointestinal tract. Although LS and systemic sclerosis ( SSc ) share similar pathogenetic pathways including the release of distinct proinflammatory cytokines and dysregulation of the connective tissue metabolism, both diseases rarely coexist , and transition from LS to SSc does not occur .

3. Epidemiology LS is a rare disease that seems to be most frequent in whites, but may affect all races. The prevalence (total number of affected patients per million)increases with age. It is approximately 500 per million at age 18 and 2200 at age 80 years1.The disease is more prevalent in women than in men (2.6 to 1 ). The disease may manifest at all ages, but the peak age of incidence essentially differs in the respective subtypes of LS. The most frequent subtype of LS,morphea , usually appears in adults between 40 and 50 years of age, whereas linear subtypes primarily present in childhood between 2 and 14 years of age. Several reports of familiar clustering and increased rates of other autoimmune diseases (e.g., Hashimoto’s thyroiditis , alopecia areata , vitiligo , and type 1 diabetes) in patients with LS are suggestive for a genetic component. However, in contrast to SSc , susceptibility genes for LS are still unknown.

4. Pathogenesis The hallmark feature of LS is overproduction of collagen and increased extracellular matrix deposition.Its exact initiation still remains unknown. It has been hypothesized that certain stimuli, e.g .,infections , trauma, radiation, or drugs might cause microvascular injuries that subsequently result in a release of various adhesion molecules. Upregulation of some of these adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 might induce T cell activation that in turn activate the release of key player profibrotic cytokines such as transforming growth factor-beta (TGF-b ),platelet-derived growth factor , connective tissue growth factor, and interleukin 4 , 6, and 8. This profibrotic pathway additionally includes a spectrum of chemokines that have demonstrated to significantly contribute to skin sclerosis.At the end, similar to SSc , activation of all of these proinflammatory and profibrotic signals lead to excessive collagen production and decrease of matrix metalloproteinases (MMP ) responsible for collagen degradation.

5. Pathogenesis Although much is known about the early inflammatory phase and the molecular mechanisms involved in the fibroblastic reaction of LS, little is known about the initial triggers of the disease. Among infectious agents, Borrelia organisms have been extensively studied on both sides of the Atlantic . Although high rates of Borrelia infections, in part using highly sensitive new detection techniques such as focus-floating microscopy,have been reported in LS patients from Europe,a variety of studies from the United States failed to demonstrate an association. Among the few drugs that have been reported to induce LS, most evidence exists for bleomycin , D- penicillamine , vitamin K1, and L-5 hydroxytryptophane plus carbidopa . Few reports exist on radiation-induced LS, which primarily occurs in women with breast carcinoma .

6. Classification and clinical characteristics of LS subtypes A German group of experts recently suggested a classification that considers the extent and depth of fibrosis and refers to the treatment of the respective subtypes.

7. Plaque-type The classical plaque type, is by far the most frequent subtype of LS, especially in adults. In the early active phase, morphea usually presents with oval-shaped lesions surrounded by an erythematous border (the so-called “lilac ring”). In the later stage of the disease, morphea lesions become hard and sclerotic in the center, with a whitish or ivory color. Older lesions may also become atrophic, hypo-, or hyperpigmented and, depending on the location of fibrosis, may also lead to hair loss and loss of the skin appendages. Morphea is frequently located on the trunk,especially the submammary region, and the transitional area between the hip and inguinal regions.

8. Plaque-type

9. Guttate morphea Guttate morphea is a rare subtype of morphea that presents with multiple yellowish or whitish, small sclerotic lesions with a shiny surface . Guttate morphea is predominantly located on the trunk. Early inflammatory lesions may simply present as erythematous maculae. Clinically and histopathologically , guttate morphea might be difficult to distinguish from extragenital lichen sclerosus .

10. Atrophoderma of Pasini and Pierini Atrophoderma of Pasini and Pierini is possibly an early abortive type of morphea . The recently described term “superficial morphea ” seems to be synonymous with atrophoderma of Pasini and Pierini . The clinical presentation of this subtype of LS, which frequently manifests in childhood, is characterized by symmetrical, single or multiple, sharply demarcated, hyperpigmented , nonindurated patches that are located on the trunk or extremities.

11. Nodular or keloid morphea Here, the inflammation of the dermis leads to thick, keloid -like nodules or streaks, clinically indistinguishable from indurated keloids .

12. Bullous morphea In some patients, especially those where sclerosis of the skin is associated with diffuse, rapidly progressive edema, lymphoceles may result from stasis of lymphatic fluid and may appear as bullae . This is rarely a feature of plaque-type morphea . It seems to be more frequent in generalized, disabling morphea or sclerodermoid GVHD. Bullous morphea has to be separated from mechanical blisters that may occur in the central scar and are secondary to impaired mechanical stability of the dermal–epidermal junction.

13. Generalized type Generalized LS is a more severe variant of LS.According to Laxer and Zulian , generalized LS is present in case of four or more indurated plaques of more than 3 cm in diameter, involving two or more of seven anatomic sites (head-neck, each extremity, anterior trunk, and posterior trunk). The most commonly affected sites are the trunk,thighs , and lumbosacral region. The plaques are often distributed symmetrically and can coalesce into larger lesions. A unique and very rare variant of the generalized type of LS is “disabling pansclerotic morphea .”Disabling pansclerotic morphea , predominantly occurring in childhood, may lead to extensive involvement of the skin, fat tissue, fascia, muscle,and bone, with only a limited tendency to regres sion of the fibrotic changes. Disabling pansclerotic morphea often results in severe contractures and poorly healing, large ulcerations, and skin necroses.

14. Eosinophilic fasciitis Eosinophilic fasciitis (also called Shulman syndrome) is nowadays considered by many experts to be a special subtype of generalized LS. A mechanical trauma often precedes the first manifestation of the disease. Clinically, eosinophilic fasciitis exclusively affects the extremities and presents with a rapid onset of symmetrical swelling of the skin. In the later stage of disease, lesions become more indurated and fibrotic, leading to the typical “ peau d’orange ”-like appearance. elevated sedimentation rate, and hypergammaglobulinemia remain critical elements of the syndrome. The diagnosis of eosinophilic fasciitis is suspected in a patient presenting with characteristic skin changes and consistent laboratory findings. It is confirmed with full-thickness biopsy or characteristic MRI findings

15. Linear Morphea Linear LS is by far most common subtype of LS in childhood. Linear LS is characterized by longitudinally arranged linear, band-like lesions that are predominantly located on the extremities.Evidence indicates that linear LS may follow the lines of Blaschko . In mild disease, the lesions may heal with residual hyperpigmentation . However, depending on the extent of the fibrotic process, linear LS may lead to severe growth retardation, muscle atrophy , flexion contractures, myositis and myalgia , arthritis and arthralgia , and psychological disability.

16. Linear Morphea

17. “ en coup de sabre ” and Parry–Romberg Syndrome The best known linear subtype of the disease is LS “en coup de sabre ”. It is located on the frontoparietal region of the head, usually ranging paramedian from the eyebrows into the hair-bearing scalp where it might cause scarring alopecia. Involvement of the underlying central nervous system (e.g., seizures, migraine, and headache) and abnormal ophthalmological findings (e.g., uveitis ) are common. Several authors have speculated that progressive facial hemiatrophy (also called Parry–Romberg syndrome) and LS “en coup de sabre” are variants of the same condition. Progressive facial hemiatrophy is clinically characterized by a primary atrophy of the subcutaneous tissue,muscle , and bone. Skin fibrosis is rare in this particular subtype. Progressive facial hemiatrophy often occurs in childhood or adolescence and may result in severe facial asymmetry. Occurrence of simultaneous linear LS “en coup de sabre” and progressive facial hemiatrophy is quite frequent,with a reported coincidence of up to 40%. In the classification proposed in this presentation,progressive facial hemiatrophy is listed under the linear subtypes of LS, although with exclusive involvement of extracutaneous structures, it may also be classified as a “deep subtype” of LS.

18. Deep morphea The deep type of LS, called deep morphea , is by far the most rare variant (<5% of patients). In deep morphea , the fibrotic process mainly affects the deeper layers of the connective tissue, i.e., fat tissue, fascia, and underlying muscle. Deep morphea lesions are typically arranged symmetrically and predominantly located on the extremities. Deep morphea may initiate during childhood and may sometimes manifest without any clinical signs of inflammation

19. Deep morphea

20. Differential diagnoses LS may present with a broad spectrum of subtypes and clinical stages of disease. Accordingly, a variety of different differential diagnoses should be considered . In daily routine, the physicians’ pivotal challenge is to differentiate LS from SSc . Importantly, typical facial (e.g., teleangiectases,beak -shaped nose, and microstomia ) and vascular (e.g., Raynaud’s phenomenon, pitting scars, and digital ulcers) features of SSc as well as highly specific serum antibodies (e.g., anticentromere antibodies and anti-Scl-70 antibodies) are absent in LS. The most relevant differential diagnoses for limited LS ( morphea ) are extragenital lichen sclerosus and acrodermatitis chronic atrophicans , for generalized LS chronic graft versus host disease,SSc , and nephrogenic systemic fibrosis, and for linear LS lupus erythematosus profundus and other types of panniculitis .

21. Serologic features High incidence of autoimmune phenomena has been reported in LS patients. Serum antinuclear antibodies, most of them with a homogenous pattern, have been detected in 20% to 80% of LS patients. Active childhood LS might be associated with antihistone antibodies, hypergammaglobulinemia , and eosinophilia . In patients with linear LS of the extremities with concomitant joint involvement, increased levels of rheumatoid factor may be present, and do sometimes correlate with the clinical degree of arthritis activity. Numerous cytokines (e.g., tumor necrosis factor-a, interleukin 2, 4, 6, 8, and 13) and soluble factors (e.g., CD23 or CD30) have been reported in LS patients, and some of them seem to correlate with the respective subtype and disease activity.However , none of them have so far been proven to be consistently useful for assessing disease activity or clinical course. The same applies to procollagen III peptide. Therefore, at present, treatment success in LS can purely be measured by clinical features.

22. Radiologic examination Patients with LS “en coup de sabre” and progressive facial hemiatrophy often suffer from neurological symptoms (e.g., migraine, headaches, and epilepsy). In these cases, cranial magnetic resonance imaging (MRI) should be considered to detect potential involvement of the central nervous system because subcortical calcifications and brain atrophy are common. Despite such abnormalities of the central nervous system, many patients are asymptomatic. In addition, MRI and computed tomography studies might be helpful for surgical planning (e.g., in LS “en coup de sabre”type ) and to detect muscle or bone involvement,for instance in linear LS of the extremities. Bone scintigraphy should be considered in cases with linear LS of the extremities that might have concomitant arthritis.

23. Treatment Topical therapy UV phototherapy Systemic therapy

24. Calcipotriol Topical therapy corticosteroid Although no well-performed studies exist on the use of topical corticosteroids, they are the mainstay of topical treatment in LS. Therapy with moderate to high-potent corticosteroids should be performed in the active phase of disease, and their application should be restricted to a total of 3 months. Intralesional steroid therapy might be performed in LS “en coup de sabre,” with injections into the active margin. So far, two uncontrolled studies exist on the use of topical calcipotriol in LS, in one of which calcipotriol 0.005% was administered along with low dose UVA1 phototherapy . In both studies,administration was performed twice daily. In the monotherapy study, calcipotriol 0.005% was applied under occlusion. Calcipotriol 0.005% should be considered for active inflammatory superficial types of LS with a low degree of sclerosis. Treatment should be performed twice daily for a minimum of 3 months.

25. Imiquimod Topical therapy calcineurin inhibitors A recent double- blind,placebo controlled pilot study has shown that topical tacrolimus significantly improves LS. Outcome measures in this study were the changes of surface area, a clinical score for erythema , induration , dyspigmentation , telangiectasia , and atrophy. Early inflammatory lesions resolved and late sclerotic lesions softened,whereas no effects were seen on preexisting skin atrophy. Thus, tacrolimus ointment might be an effective treatment option for active LS lesions. The topical immune response modifier imiquimod has been reported to significantly improve abnormal pigmentation, sclerosis, and erythema in LS. The mechanism of imiquimod action in LS might be explained by induction of interferon-g, which inhibits TGF-b, thereby exhibiting a broad antifibrotic Effect.

26. phototherapy The first experience of the successful use of UV phototherapy in LS has been reported in 1994. Since then, much information has been gained on the entire spectrum of antifibrotic and anti inflammatory effects of UV phototherapy in skin sclerosis. Because longer wavelengths in the UVA range (320–400 nm) penetrate deeper into the dermis than does UVB (280–320), most studies have focused on UVA. A number of uncontrolled studies on psoralen plus UVA (PUVA; a study on bath-PUVA with 17 patients and a study on cream-PUVA with four patients), broad-band UVA (three studies from Egypt with 15, 22, and 67 patients),and UVA1-phototherapy (six open uncontrolled studies with a total of 88 patients) have demonstrated that phototherapy is very effective in LS. Before initiating UV phototherapy in LS, it should be considered that UV rays only penetrate into the deep dermis. Therefore, UV phototherapy (in combination with topical treatment, e.g.,topical corticosteroids or topical vitamin D-analogs) is an effective treatment option for limited disease restricted to the skin, but not in LS subtypes with affection of deeper structures ( e.g.,fat tissue, fascia, muscle, or bone). Such subtypes require systemic therapy.

27. Systemic therapy corticosteroid Similar to topical corticosteroids, there is a paucity of data on systemic corticosteroids, although they are widely used agents in LS, particularly in linear,generalized , and deep subtypes. In the only published uncontrolled study on 17 patients with LS (corticosteroid dosage: 0.5–1.0 mg/kg body weight daily), a marked improvement was noticed in nearly all of the patients. Systemic corticosteroids are safe and effective in active lesions of LS,and should be considered in patients with severe disease affecting extracutaneous structures ( e.g.,fat tissue, fascia, muscle, and bone).Moreover, systemic corticosteroids are the first-line treatment option in eosinophilic fasciitis.

28. Systemic therapy MXT Among systemic treatment of LS, best evidence exists for the use of methotrexate (MTX). MTX inhibits several cytokines that play a central role in sclerotic skin diseases, such as interleukins 2, 4,and 6. Recently, a large randomized placebo-controlled study on 85 patients with childhood LS treated with oral corticosteroids and low-dose MTX confirmed the efficacy of this combination therapy for LS. Thus, MTX alone or in combination with corticosteroids are currently first-line options for LS, especially in linear, generalized, and deep subtypes.

29. Systemic therapy Recently, a small case series of seven MTXresistant LS patients treated with mycophenolate mofetil (MMF) has shown improvement of skin sclerosis and inflammation. In vitro studies have shown that MMF inhibits the proliferation of lymphocytes, but also of other cell types, including smooth muscle cells and fibroblasts, indicating that it has direct antifibrotic properties in addition to its well-known immunosuppressive effects.These preliminary observations make MMF an interesting new candidate for further clinical studies. Numerous other systemics have reported in cases of LS, including infliximab , bosentan , antimalarial drugs, imatinib , extracorporeal photopheresis,cyclosporine , and penicillin, but none of them has so far been confirmed in a larger number of subjects.