Materiały źródłowe

• #1 Morphea – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK559010/

  Morphea, also called localized scleroderma, is a rare inflammatory skin condition that can also affect the subcutaneous tissues. […] The etiology of morphea is unclear, but genetic predisposition, autoimmune dysregulation, and environmental factors play a role in the pathogenesis of morphea. […] The pathophysiology of morphea is vague, but there is evidence supporting the role of autoimmune dysregulation with abnormal cytokine production and vascular dysfunction in morphea. […] Excess collagen deposition in the dermis also plays a crucial role in morphea. […] The role of immune dysregulation is confirmed by the presence of inflammatory infiltrates in skin biopsies laden with eosinophils, lymphocytes, and plasma cells. […] IL-4 cytokine is detected at higher levels in patients with morphea.

• #1 Morphea: The 2023 update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9969991/

  Morphea, also known as localized scleroderma, is a chronic inflammatory connective tissue disorder with variable clinical presentations, that affects both adults and children. […] While the etiology is still unknown, many factors may contribute to disease development, including genetic predisposition, vascular dysregulation, TH1/TH2 imbalance with chemokines and cytokines associated with interferon- and profibrotic pathways as well as certain environmental factors. […] The pathogenesis of morphea is still not very well understood. A variety of factors, including genetics, environmental factors, such as infections, skin trauma, autoimmune dysregulation with abnormal cytokine production, and/or vascular dysfunction may play a role in the development of morphea. In general, three phases can be distinguished: (i) an early inflammatory phase, (ii) a fibrotic/sclerotic phase, and (iii) an atrophic phase.

• #1 Morphea: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1065782-overview

  Overproduction of collagen, particularly types I and III collagen, by fibroblasts in affected tissues is common to all forms of morphea, although the mechanism by which these fibroblasts are activated is unknown. […] Proposed factors involved in the pathogenesis of morphea include endothelial cell injury, immunologic (eg, T lymphocyte) and inflammatory activation, and dysregulation of collagen production. […] An autoimmune component is supported by the frequent presence of autoantibodies in affected individuals, as well as the association of morphea with other autoimmune diseases, including systemic lupus erythematosus, vitiligo, type 1 diabetes, and autoimmune thyroiditis. […] Endothelial cell injury is currently thought to be the inciting event in the pathogenesis of morphea. […] This injury results in increased levels of adhesion molecules (circulating intercellular adhesion molecule-1, vascular cell adhesion molecule 1, and E-selectin) and fibrogenic T-helper 2 cytokines such as interleukin (IL)4, IL-6, and transforming growth factor-beta (TGF-beta).

• #1 Morphea – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK559010/

  There is an increased presence of vascular cell adhesion molecule 1 (VCAM1) and intracellular cell adhesion molecule 1 (ICAM1) in patients with morphea, which facilitate the recruitment of T lymphocytes in the acute phase. […] CD-4 T helper cells play a significant role by producing IL-4 cytokine, which causes the upregulation of TGF-B. TGF-B stimulates fibroblast production of collagen and other extracellular matrix proteins.

• #1 Morphea: progress to date and the road ahead

  https://atm.amegroups.org/article/view/61306/html

  The precise pathogenesis of morphea is not completely understood. […] However, the dysregulated immune and fibrotic pathways that contribute to these changes have not yet been systematically studied. […] Although it is generally accepted that immune dysfunction is the principal component in the development of morphea, other factors are also thought to contribute to pathogenesis, including genetic predisposition, traumatic or environmental factors, and vascular dysfunction. […] Recent observations have supported the role of dysregulated immune pathways, particularly IFN gamma, demonstrating that CXCL9 and CXCL10 levels are associated with increased clinical measures of disease activity. […] Beyond CXCR3 ligands, other upstream and downstream pathways have also been implicated in the pathogenesis of morphea.

• #1 What Is New in Morphea—Narrative Review on Molecular Aspects and New Targeted Therapies

  https://www.mdpi.com/2077-0383/13/23/7134

  Studies suggest the existence of an imbalance in the Th lymphocyte population, with a predominance of Th2 over Th1 lymphocytes, which also favors fibrotic processes. […] The main regulator of the fibrosis process is TGF-β. An increase in its concentration causes an increase in the expression of collagen types I, III, VI, X, fibronectin and proteoglycans. […] Understanding the genetic basis of morphea is critical to uncovering the mechanisms underlying this disease and identifying potential treatment targets. […] Human leukocyte antigen (HLA) has been implicated as the most promising target in the pathogenesis of morphea, suggesting a genetic predisposition to the disease. […] Recent studies have highlighted the involvement of cutaneous mosaicism as a possible factor in morphea’s pathogenesis.

• #1 Morphea: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1065782-overview

  These cytokines recruit eosinophils, CD4+ T cells, and macrophages, which are present in early morphea lesions and in eosinophilic fasciitis. […] These cytokines and growth factors also increase fibroblast proliferation and induce synthesis of excess collagen and connective-tissue growth factor. […] TGF-beta also decreases production of proteases, inhibiting collagen breakdown. […] Connective-tissue growth factor is a soluble mediator that enhances and perpetuates the profibrotic effects of TGF-beta. […] The ultimate result of the endothelial injury and inflammatory cascade is increased collagen and extracellular matrix deposition. […] Other proposed pathophysiologic mechanisms in morphea include the formation of antimatrix metalloproteinase antibodies, as well as increased expression of insulinlike growth factor, which enhances collagen production.

• #1 What Is New in Morphea—Narrative Review on Molecular Aspects and New Targeted Therapies

  https://www.mdpi.com/2077-0383/13/23/7134

  Epigenetic factors are considered to be triggers of the morphea, next to environmental factors and genetic predisposition. […] Abnormal DNA methylation resulting in altered gene expression has been shown in many autoimmune disorders, including systemic scleroderma. […] MicroRNAs (miRNAs) are small non-coding RNAs that usually bind to complementary sequences in the 3′ untranslated regions (UTR) of mRNAs, which results in inhibiting their translation into protein. […] Morphea is characterized by skin fibrosis due to excessive deposition of type I collagen, and studies have shown that several miRNAs are regulators of this collagen expression. […] The pathophysiology of morphea is based in part on abnormal signaling via the platelet-derived growth factor (PDGF) and TNFβ, which appears to be one of the key processes in the inflammatory response in morphea and systemic scleroderma.

• #1 Morphoea (localised scleroderma, morphea)

  https://dermnetnz.org/topics/morphoea

  Morphoea (American spelling, morphea) is characterised by an area of inflammation and fibrosis (thickening and hardening) of the skin due to increased collagen deposition. […] The precise cause of morphoea is unknown. […] Localised genetic factors appear to play a role; for example, cutaneous mosaicism may important in linear morphoea, which follows Blaschko lines of epidermal development. […] Up to 40% of patients with severe forms of morphoea have a personal or family history of autoimmune disease (eg, thyroid disease, vitiligo) or rheumatologic disease (eg, rheumatoid arthritis). […] For unknown reasons, morphoea often develops after an external trigger such as: Insect bite or tick bite (the role of Borellia burgdorferi, cause of Lyme disease is controversial), Injection (eg, bleomycin, silicone) or vaccination, Repeated friction, Surgery, Radiotherapy, Penetrating wound, Extreme exercise, Repeated minor friction along the waistband, bra strap and inguinal region, in isomorphic disseminated plaque morphoea.

• #1 Morphoea (localised scleroderma, morphea)

  https://dermnetnz.org/topics/morphoea

  Trauma-related morphoea may occur at the affected site, or at unrelated distant sites. […] Any subtype of morphoea can affect connective tissue under the skin, such as the fat, fascia, muscle, bone, joints, or rarely brain (in craniofacial linear morphoea). Deep tissue involvement is a marker of severe disease. […] Eosinophilic fasciitis is a form of pansclerotic morphoea with deep fascial involvement. […] These extracutaneous manifestations imply that morphoea is a systemic inflammatory condition. […] Specific treatment decisions in morphoea are guided by the subtype of morphoea and its severity. […] Disease progression and treatment response can be monitored using photographs, the localized scleroderma cutaneous assessment tool(LoSCAT) and other highly specialised tests, such as infrared thermography. […] Morphoea can follow a protracted course, which can be relapsing and remitting, or chronically active.

• #1 ClinMed International Library | A case of Hemorrhagic Bullous Morphea | Journal of Dermatology Research and Therapy

  http://clinmedjournals.org/articles/ijdrt/journal-of-dermatology-research-and-therapy-ijdrt-1-011.php

  Bullous morphea is a rare form of localized scleroderma (morphea) characterized by bullae on or around an atrophic morphea plaque. […] The cause of bullae formation in morphea is multifactorial, with lymphatic obstruction from the sclerodermatous process being considered as the most likely cause. […] The pathogenesis of bullous morphea is still unknown, but several mechanisms have been proposed, such as inflammation, lymphangiectasis and immune-mediated aggression. […] The current belief is bullous lesions are more frequently observed on the lower extremities, which suggests that lymphatic obstruction, combined with increased hydrostatic pressure, leads to bullae formation. […] But Angel reported three cases of bullous morphea that did not show any histopathological feature suggestive of lymphatic blockage, so insisted some signs supporting local trauma as a cause. […] Pautrier also suggested that vascular changes like arterities and phlebosclerosis play role in bullae formation, so that hemorrhagic bullae can occur in bullous morphea, although rare. […] Daoud found that major basic protein is responsible for blister formation in at least some cases of morphea.

• #1 Postirradiation Morphea: Unique Presentation on the Breast | MDedge

  https://blogs.the-hospitalist.org/content/postirradiation-morphea-unique-presentation-breast

  Postirradiation morphea (PIM) is a rare but well-documented phenomenon that primarily occurs in breast cancer patients who have received radiation therapy; however, it also has been reported in patients who have received radiation therapy for lymphoma as well as endocervical, endometrial, and gastric carcinomas. Importantly, clinicians must be able to recognize and differentiate this condition from other causes of new-onset induration and erythema of the breast, such as cancer recurrence, a new primary malignancy, or inflammatory etiologies (eg, radiation or contact dermatitis). Typically, PIM presents months to years after radiation therapy as an erythematous patch within the irradiated area that progressively becomes indurated. […] Radiation therapy is an often overlooked cause of morphea. It was first described in 1905 but then rarely discussed until a 1989 case series of 9 patients, 7 of whom had received irradiation for breast cancer. Today, the increasing popularity of lumpectomy plus radiation therapy for treatment of early-stage breast cancer has led to a rise in PIM incidence. Estimates have indicated an incidence among previously irradiated breast cancer patients as high as 1 in 500 individuals, appreciably higher than that seen in the general population. Tissue changes occur as early as weeks or as late as 32 years after radiation treatment and are commonly mistaken for mastitis, such as in our case, as well as radiation dermatitis, radiation fibrosis, or malignant conditions.

• #1

  https://journals.lww.com/10.4103/0019-5154.190132

  It is thought that radiation initiates an initial inflammatory phase followed by burnt-out phase characterized by induration, fibroid retraction, and pigmentation. The pathophysiology is thought to be radiation-induced neoantigen formation that subsequently stimulates secretion of TGF-. TGF- strongly stimulates fibroblasts, collagen synthesis, and hence excessive fibrosis ensues. […] The prognosis of radiation-induced morphea is good and usually improves with wide variety of treatment modalities such as intralesional or systemic steroids, oral or topical antibiotics, antimalarials, and phototherapy. […] Regular monitoring of the patients receiving radiotherapy is recommended.

• #1 Postirradiation Morphea: Unique Presentation on the Breast | MDedge

  https://blogs.the-hospitalist.org/content/postirradiation-morphea-unique-presentation-breast

  In contrast to other radiation-induced skin conditions, development of PIM is independent of the presence or absence of adjuvant chemotherapy, type of radiation therapy, or the total radiation dose or fractionation number, with reported doses ranging from less than 20.0 Gy to up to 59.4 Gy and dose fractions ranging from 10 to 30. In 20% to 30% of cases, PIM extends beyond the radiation field, sometimes involving distant sites never exposed to high-energy rays. This observation suggests a mechanism reliant on more widespread cascade rather than solely local tissue damage. […] Prominent culture-negative, lymphoplasmacytic inflammation is another important diagnostic clue. Radiation dermatitis and fibrosis do not have the marked erythematous to violaceous hue seen in early morphea plaques. This color seen in early morphea plaques may be intense enough and in a geographic pattern, emulating a vascular lesion. However, a PubMed search of articles indexed for MEDLINE using the terms reticulate radiation morphea and livedo radiation morphea yielded no reports linking the reticulate erythema seen in our patient with early PIM. It is important to note that the histopathology findings in our patient were not entirely specific, and although there were some background changes that may have represented a sequela of radiation to the area (ie, the enlarged fibroblasts and increased number of vessels), there were foci suggestive of early sclerosing dermatitis. With clinical correlation, including the extension beyond the radiation field, these changes were best interpreted as early PIM. Therefore, our case demonstrated a novel presentation of a frequently underrecognized trigger for morphea. Although we favored a diagnosis of PIM, a fibrosing chronic radiation dermatitis could not be entirely excluded based on the clinical and histologic features.

• #1

  https://link.springer.com/article/10.1007/s10165-001-8063-1

  The objective of this study was to assess the importance of the free radical release process in the pathogenesis of localized scleroderma and compare it with that in systemic sclerosis. […] The free radical release process is as important in the pathogenesis of morphea as it is in systemic sclerosis, where it appears to be involved in the development of skin induration.

• #1 Morphea: progress to date and the road ahead

  https://atm.amegroups.org/article/view/61306/html

  There remains a critical need to define morphea pathogenesis more clearly in order to identify promising targets for mechanistic studies and therapeutic development. […] Further study using these state of the art approaches are necessary to gain a detailed, unbiased picture of upstream and downstream pathways in human skin that are likely implicated in morphea pathogenesis, particularly dysregulated IFN gamma mediated pathways, which appear particularly promising.

• #1 An acute bleomycin inflammatory and fibrotic mouse model of morphea is dependent upon CXCL9 and CXCR3 | medRxiv

  https://www.medrxiv.org/content/10.1101/19000844v1

  Morphea, or localized scleroderma, is characterized by an inflammatory phase followed by cutaneous fibrosis, which may lead to disfigurement and/or disability. […] Previous work from our group showed that the CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in lesional skin of morphea patients. […] Here, we used an acute inflammatory and fibrotic bleomycin mouse model of morphea to examine the role of the CXCR3 chemokine axis in pathogenesis. […] To determine whether these chemokines are mechanistically involved in pathogenesis, we induced fibrosis in CXCL9, CXCL10, or CXCR3 deficient mice and found that fibrosis is dependent on CXCL9 and CXCR3. […] Taken together, our studies provide evidence that acute intradermal bleomycin administration in mice can model inflammatory morphea, and that CXCL9 and its receptor CXCR3 are mechanistically involved in pathogenesis. […] CXCL9 drives acute morphea pathogenesis in mice.

• #1 Morphea: Evidence-based recommendations for treatment – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/morphea-evidence-based-recommendations-for-treatment/

  These three prospective studies suggest that treatment of morphea with systemic methotrexate and steroids is effective. […] MMF has been shown to have anti-proliferative and anti-fibrotic properties in in vitro and in vivo experiments. […] MMF therapy has resulted in a statistically significant improvement in skin scores in subjects with diffuse systemic sclerosis and improvement in retroperitoneal fibrosis. […] It is with consideration of the data, MMFs more favorable side-effect profile and anti-fibrotic properties that I recommend it in patients with potentially deforming disease who fail methotrexate and steroids. […] In conclusion, additional trials of therapeutic options for patients with morphea are needed.

• #2 Morphea: The 2023 update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9969991/

  Morphea, also known as localized scleroderma, is a chronic inflammatory connective tissue disorder with variable clinical presentations, that affects both adults and children. […] While the etiology is still unknown, many factors may contribute to disease development, including genetic predisposition, vascular dysregulation, TH1/TH2 imbalance with chemokines and cytokines associated with interferon- and profibrotic pathways as well as certain environmental factors. […] The pathogenesis of morphea is still not very well understood. A variety of factors, including genetics, environmental factors, such as infections, skin trauma, autoimmune dysregulation with abnormal cytokine production, and/or vascular dysfunction may play a role in the development of morphea. In general, three phases can be distinguished: (i) an early inflammatory phase, (ii) a fibrotic/sclerotic phase, and (iii) an atrophic phase.

• #2 Morphea: The 2023 update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9969991/

  In the early stage of morphea, a large number of mononuclear lymphocytes (primarily activated T lymphocytes but also macrophages), some plasma cells and eosinophils infiltrate the skin and surrounding blood vessels. […] Based on functional in vitro data and cytokine analysis (mostly in the serum of patients) it is suggested that a TH1/TH2 imbalance in morphea is propagating the disease. […] It is postulated that injury of the vascular endothelium and upregulation of adhesion molecules, such as E-selectin and VCAM-1 during the inflammatory stage facilitate the recruitment of T lymphocytes that are capable of producing profibrotic cytokines like IL-4, IL-6 and TGF-. […] Fibrosis plays a critical role in causing tissue damage in scleroderma and is accompanied by hardening of the skin from excessive cellular proliferation as well as deposition of collagen and other extracellular matrix components. […] Atrophy is a poorly understood pathogenic event that may persist long after the sclerotic phase of morphea.

• #2 What Is New in Morphea—Narrative Review on Molecular Aspects and New Targeted Therapies

  https://www.mdpi.com/2077-0383/13/23/7134

  The following insults are mentioned: trauma, infection, radiation or drugs (β-blockers, bleomycin, bromocriptine, D-penicillamine). They cause microvascular damage and secondary activation of T lymphocytes. […] Studies have confirmed that transforming growth factor β (TGF-β), interleukin IL-1β, IL-4, IL-6, IL-10, IL-27, interferon gamma (INF-γ) and, more recently, IL-17A are essential for inflammation and fibrosis. Ultimately, activation of these pro-inflammatory and fibrosis-inducing mediators leads to excessive collagen production and reduced production of metalloproteinases responsible for collagen degradation. […] The most likely earliest phenomenon underlying the pathogenesis of morphea is thought to be endothelial cell activation resulting from endothelial damage. […] Increased production of adhesion molecules such as ICAM-1, VCAM-1, E-selectin and P-selectin leads to increased recruitment of inflammatory cells, including T lymphocytes, monocytes and other immune cells.

• #2 What Is New in Morphea—Narrative Review on Molecular Aspects and New Targeted Therapies

  https://www.mdpi.com/2077-0383/13/23/7134

  Studies suggest the existence of an imbalance in the Th lymphocyte population, with a predominance of Th2 over Th1 lymphocytes, which also favors fibrotic processes. […] The main regulator of the fibrosis process is TGF-β. An increase in its concentration causes an increase in the expression of collagen types I, III, VI, X, fibronectin and proteoglycans. […] Understanding the genetic basis of morphea is critical to uncovering the mechanisms underlying this disease and identifying potential treatment targets. […] Human leukocyte antigen (HLA) has been implicated as the most promising target in the pathogenesis of morphea, suggesting a genetic predisposition to the disease. […] Recent studies have highlighted the involvement of cutaneous mosaicism as a possible factor in morphea’s pathogenesis.

• #2 Morphea: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1065782-overview

  These cytokines recruit eosinophils, CD4+ T cells, and macrophages, which are present in early morphea lesions and in eosinophilic fasciitis. […] These cytokines and growth factors also increase fibroblast proliferation and induce synthesis of excess collagen and connective-tissue growth factor. […] TGF-beta also decreases production of proteases, inhibiting collagen breakdown. […] Connective-tissue growth factor is a soluble mediator that enhances and perpetuates the profibrotic effects of TGF-beta. […] The ultimate result of the endothelial injury and inflammatory cascade is increased collagen and extracellular matrix deposition. […] Other proposed pathophysiologic mechanisms in morphea include the formation of antimatrix metalloproteinase antibodies, as well as increased expression of insulinlike growth factor, which enhances collagen production.

• #2 An acute bleomycin inflammatory and fibrotic mouse model of morphea is dependent upon CXCL9 and CXCR3 | medRxiv

  https://www.medrxiv.org/content/10.1101/19000844v1.full-text

  Morphea, or localized scleroderma, is characterized by an inflammatory phase followed by cutaneous fibrosis, which may lead to disfigurement and/or disability. Previous work from our group showed that the CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in lesional skin of morphea patients. Here, we used an acute inflammatory and fibrotic bleomycin mouse model of morphea to examine the role of the CXCR3 chemokine axis in pathogenesis. […] To determine whether these chemokines are mechanistically involved in pathogenesis, we induced fibrosis in CXCL9, CXCL10, or CXCR3 deficient mice and found that fibrosis is dependent on CXCL9 and CXCR3. […] Taken together, our studies provide evidence that acute intradermal bleomycin administration in mice can model inflammatory morphea, and that CXCL9 and its receptor CXCR3 are mechanistically involved in pathogenesis. […] We found that fibrosis in our mouse model of morphea is dependent on CXCL9 but not CXCL10. […] These studies indicate that acute intradermal bleomycin injection may be a model for inflammatory and fibrotic morphea, and that this disease process is dependent on CXCL9 and its receptor CXCR3.

• #2 Morphea: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1065782-overview

  Overproduction of collagen, particularly types I and III collagen, by fibroblasts in affected tissues is common to all forms of morphea, although the mechanism by which these fibroblasts are activated is unknown. […] Proposed factors involved in the pathogenesis of morphea include endothelial cell injury, immunologic (eg, T lymphocyte) and inflammatory activation, and dysregulation of collagen production. […] An autoimmune component is supported by the frequent presence of autoantibodies in affected individuals, as well as the association of morphea with other autoimmune diseases, including systemic lupus erythematosus, vitiligo, type 1 diabetes, and autoimmune thyroiditis. […] Endothelial cell injury is currently thought to be the inciting event in the pathogenesis of morphea. […] This injury results in increased levels of adhesion molecules (circulating intercellular adhesion molecule-1, vascular cell adhesion molecule 1, and E-selectin) and fibrogenic T-helper 2 cytokines such as interleukin (IL)4, IL-6, and transforming growth factor-beta (TGF-beta).

• #2 What Is New in Morphea—Narrative Review on Molecular Aspects and New Targeted Therapies

  https://www.mdpi.com/2077-0383/13/23/7134

  Epigenetic factors are considered to be triggers of the morphea, next to environmental factors and genetic predisposition. […] Abnormal DNA methylation resulting in altered gene expression has been shown in many autoimmune disorders, including systemic scleroderma. […] MicroRNAs (miRNAs) are small non-coding RNAs that usually bind to complementary sequences in the 3′ untranslated regions (UTR) of mRNAs, which results in inhibiting their translation into protein. […] Morphea is characterized by skin fibrosis due to excessive deposition of type I collagen, and studies have shown that several miRNAs are regulators of this collagen expression. […] The pathophysiology of morphea is based in part on abnormal signaling via the platelet-derived growth factor (PDGF) and TNFβ, which appears to be one of the key processes in the inflammatory response in morphea and systemic scleroderma.

• #2 Scleroderma-Morphea

  http://www.thedoctorsdoctor.com/diseases/scleroderma_morphea.htm

  Analysis of CSF and pathology obtained at brain biopsy provides evidence of an inflammatory process which may be amenable to immunosuppressive treatment. […] We propose that somatic mutations affecting vessels may predispose to increased endothelial cell apoptosis. This could lead to the development of an autoimmune response in some individuals, and the areas of localized scleroderma may be markers of susceptibility to autoimmune disease. […] A causative role of Borrelia burgdorferi infection has been controversially discussed, but no conclusive solution has yet been achieved. […] B burgdorferi infection may be relevant for the induction of a distinct autoimmune type of scleroderma; it may be called „Borrelia-associated early onset morphea” and is characterized by the combination of disease onset at younger age, infection with B burgdorferi, and evident autoimmune phenomena as reflected by high-titer antinuclear antibodies.

• #2

  https://journals.lww.com/10.4103/0019-5154.190132

  Morphea is a chronic autoimmune disease of multifactorial etiology characterized by sclerosis of skin. The etiology and pathogenesis are poorly understood. […] Development of morphea is linked to local tissue trauma, surgery, insect bites, intramuscular injections, and infections with Borrelia burgdorferi and cytomegalovirus. […] Autoimmunity is one of the central features of morphea. Several in vitro studies have shown abnormalities in fibroblasts from patients with morphea. […] Increased connective tissue growth factor gene expression also leads to fibrosis which is possibly mediated via activation of Smad and ERX1/2 pathways. […] Morphea postradiotherapy is a rare complication, with an estimated incidence of 1 in 500 patients, in contrast to that of morphea (of any etiology), which is 2.7/100,000 in the general population.

• #2 KoreaMed Synapse

  https://synapse.koreamed.org/articles/1045499

  Localized scleroderma (morphea) usually develops spontaneously, but the precise mechanisms underlying disease development are obscure. […] However, a significant number of reports suggest that external stimuli can induce morphea. […] Several external stimuli participate in morphea pathogenesis, including trauma or operative stress, irradiation, infections (viral infections and a Borelia infection), Bacille Calmette-Guerin vaccination, pregnancy, implantation of a silicon prosthesis, viral factors, toxic factors, and neurogenic factors. […] These observations strongly suggest that external physical stimuli can cause morphea. […] The precise mechanisms underlying these phenomena are unknown. […] Some speculations include that trauma may trigger the production and release of inflammatory mediators and/or fibrogenic cytokines, such as transforming growth factor-beta, from cells in the microenvironment of the traumatic lesion. This can result in the synthesis of excess collagen in susceptible individuals and lead to sclerosis at a local site. […] The reason why sclerosis but not fibrosis is induced with external stimuli and causes morphea in specific patients should be clarified in future studies.

• #2 ClinMed International Library | A case of Hemorrhagic Bullous Morphea | Journal of Dermatology Research and Therapy

  http://clinmedjournals.org/articles/ijdrt/journal-of-dermatology-research-and-therapy-ijdrt-1-011.php

  Bullous morphea is a rare form of localized scleroderma (morphea) characterized by bullae on or around an atrophic morphea plaque. […] The cause of bullae formation in morphea is multifactorial, with lymphatic obstruction from the sclerodermatous process being considered as the most likely cause. […] The pathogenesis of bullous morphea is still unknown, but several mechanisms have been proposed, such as inflammation, lymphangiectasis and immune-mediated aggression. […] The current belief is bullous lesions are more frequently observed on the lower extremities, which suggests that lymphatic obstruction, combined with increased hydrostatic pressure, leads to bullae formation. […] But Angel reported three cases of bullous morphea that did not show any histopathological feature suggestive of lymphatic blockage, so insisted some signs supporting local trauma as a cause. […] Pautrier also suggested that vascular changes like arterities and phlebosclerosis play role in bullae formation, so that hemorrhagic bullae can occur in bullous morphea, although rare. […] Daoud found that major basic protein is responsible for blister formation in at least some cases of morphea.

• #2

  https://journals.lww.com/10.4103/0019-5154.190132

  It is thought that radiation initiates an initial inflammatory phase followed by burnt-out phase characterized by induration, fibroid retraction, and pigmentation. The pathophysiology is thought to be radiation-induced neoantigen formation that subsequently stimulates secretion of TGF-. TGF- strongly stimulates fibroblasts, collagen synthesis, and hence excessive fibrosis ensues. […] The prognosis of radiation-induced morphea is good and usually improves with wide variety of treatment modalities such as intralesional or systemic steroids, oral or topical antibiotics, antimalarials, and phototherapy. […] Regular monitoring of the patients receiving radiotherapy is recommended.

• #2 Postirradiation Morphea: Unique Presentation on the Breast | MDedge

  https://blogs.the-hospitalist.org/content/postirradiation-morphea-unique-presentation-breast

  In contrast to other radiation-induced skin conditions, development of PIM is independent of the presence or absence of adjuvant chemotherapy, type of radiation therapy, or the total radiation dose or fractionation number, with reported doses ranging from less than 20.0 Gy to up to 59.4 Gy and dose fractions ranging from 10 to 30. In 20% to 30% of cases, PIM extends beyond the radiation field, sometimes involving distant sites never exposed to high-energy rays. This observation suggests a mechanism reliant on more widespread cascade rather than solely local tissue damage. […] Prominent culture-negative, lymphoplasmacytic inflammation is another important diagnostic clue. Radiation dermatitis and fibrosis do not have the marked erythematous to violaceous hue seen in early morphea plaques. This color seen in early morphea plaques may be intense enough and in a geographic pattern, emulating a vascular lesion. However, a PubMed search of articles indexed for MEDLINE using the terms reticulate radiation morphea and livedo radiation morphea yielded no reports linking the reticulate erythema seen in our patient with early PIM. It is important to note that the histopathology findings in our patient were not entirely specific, and although there were some background changes that may have represented a sequela of radiation to the area (ie, the enlarged fibroblasts and increased number of vessels), there were foci suggestive of early sclerosing dermatitis. With clinical correlation, including the extension beyond the radiation field, these changes were best interpreted as early PIM. Therefore, our case demonstrated a novel presentation of a frequently underrecognized trigger for morphea. Although we favored a diagnosis of PIM, a fibrosing chronic radiation dermatitis could not be entirely excluded based on the clinical and histologic features.

• #2 Bullous Morphea: Description of a New Case and Discussion of Etiologic and Pathogenic Factors in Bulla Formation | Actas Dermo-Sifiliográficas

  https://www.actasdermo.org/es-bullous-morphea-description-new-case-articulo-S1578219016302967

  Bullous morphea is a rare form of localized scleroderma. Since the description of the first case, numerous theories have been put forward on the origin of the blisters, but the actual mechanism by which they develop remains unclear. […] The most widely accepted theory on the origin of the blisters has been lymphatic obstruction due to lymphangiectasia caused by the underlying sclerotic changes. However, not all lesions of bullous morphea present lymphangiectasia on histology, nor do all cases of scleroderma with lymphangiectasia present blisters. […] Local trauma may be another etiologic and pathogenic factor, given the hemorrhagic content of some blisters and their frequent localization in areas of friction such as the legs and intertriginous areas. […] Some authors have suggested that eosinophils may play a role in this disease, while other postulate reactive oxygen species as a possible causative factor.

• #2 Autoantigen microarrays reveal myelin basic protein autoantibodies in morphea | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03246-5

  Morphea is an autoimmune, sclerosing skin disorder. Despite the recent emphasis on immune dysregulation in morphea, the role of autoantibodies in morphea pathogenesis or utility as biomarkers are poorly defined. […] Studies to date imply that B cells and autoantibodies may play a role in morphea pathogenesis. […] Although these studies suggest the possibility that these autoantibodies may be important for pathogenesis or as biomarkers, their role is poorly understood. […] We have identified anti-MBP as a potential antibody associated with morphea due to its increased expression in morphea compared to healthy controls and systemic sclerosis patients. […] The pathogenesis of morphea remains poorly understood and little is known about autoantibodies associated with morphea. […] The morphea cohort exhibited a significantly increased median net fluorescence intensity (NFI) for MBP of 133 compared to 15.5 in matched healthy controls (p0.01) and 45.5 in systemic sclerosis patients (p0.01).

• #2 Morphea: Evidence-based recommendations for treatment – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/morphea-evidence-based-recommendations-for-treatment/

  These three prospective studies suggest that treatment of morphea with systemic methotrexate and steroids is effective. […] MMF has been shown to have anti-proliferative and anti-fibrotic properties in in vitro and in vivo experiments. […] MMF therapy has resulted in a statistically significant improvement in skin scores in subjects with diffuse systemic sclerosis and improvement in retroperitoneal fibrosis. […] It is with consideration of the data, MMFs more favorable side-effect profile and anti-fibrotic properties that I recommend it in patients with potentially deforming disease who fail methotrexate and steroids. […] In conclusion, additional trials of therapeutic options for patients with morphea are needed.

• #3 Morphea: progress to date and the road ahead

  https://atm.amegroups.org/article/view/61306/html

  Morphea is a rare autoimmune condition causing inflammation and sclerosis of the skin and underlying soft tissue. […] The pathogenesis of morphea is incompletely understood and is an evolving area of research. Studies suggest a multifactorial etiology involving dysregulated immune and fibrotic pathways, with additional contributing factors including genetic predisposition, traumatic or environmental factors, and vascular dysregulation. […] Recent studies have demonstrated the role of dysregulated immune and fibrotic pathways in the pathogenesis of morphea, particularly interferon (IFN) gamma related pathways. […] While immune dysfunction is thought to play the primary role in morphea pathogenesis, there are other factors that may also contribute, including genetic predisposition, environmental factors, and vascular dysregulation.

• #3 Morphea – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK559010/

  Morphea, also called localized scleroderma, is a rare inflammatory skin condition that can also affect the subcutaneous tissues. […] The etiology of morphea is unclear, but genetic predisposition, autoimmune dysregulation, and environmental factors play a role in the pathogenesis of morphea. […] The pathophysiology of morphea is vague, but there is evidence supporting the role of autoimmune dysregulation with abnormal cytokine production and vascular dysfunction in morphea. […] Excess collagen deposition in the dermis also plays a crucial role in morphea. […] The role of immune dysregulation is confirmed by the presence of inflammatory infiltrates in skin biopsies laden with eosinophils, lymphocytes, and plasma cells. […] IL-4 cytokine is detected at higher levels in patients with morphea.

• #3 What Is New in Morphea—Narrative Review on Molecular Aspects and New Targeted Therapies

  https://www.mdpi.com/2077-0383/13/23/7134

  The following insults are mentioned: trauma, infection, radiation or drugs (β-blockers, bleomycin, bromocriptine, D-penicillamine). They cause microvascular damage and secondary activation of T lymphocytes. […] Studies have confirmed that transforming growth factor β (TGF-β), interleukin IL-1β, IL-4, IL-6, IL-10, IL-27, interferon gamma (INF-γ) and, more recently, IL-17A are essential for inflammation and fibrosis. Ultimately, activation of these pro-inflammatory and fibrosis-inducing mediators leads to excessive collagen production and reduced production of metalloproteinases responsible for collagen degradation. […] The most likely earliest phenomenon underlying the pathogenesis of morphea is thought to be endothelial cell activation resulting from endothelial damage. […] Increased production of adhesion molecules such as ICAM-1, VCAM-1, E-selectin and P-selectin leads to increased recruitment of inflammatory cells, including T lymphocytes, monocytes and other immune cells.

• #3 Morphea: a practical review of its diagnosis, classification and treatment

  http://www.scielo.org.mx/scielo.php?script=sci_arttext&pid=S0016-38132019000500483

  Morphea etiology and pathogenesis are not yet fully understood. Autoimmune, environmental factors and various events that trigger the production of cytokines are thought to be involved, including infections, radiation or trauma. […] The skin sclerosis process comprises three main events, which can be therapeutic targets: A primary microvascular lesion, with SVCAM-1 and sE-selectin elevation, which are indicators of endothelial activation; as well as expression of adhesion molecules, thickening of the basement membrane and intimal hyperplasia. […] Fibroblast function control by perivascular CD4+ T cells that produce interleukin-4 and transforming growth factor b, which are cytokines that direct differentiation towards the Th2 phenotype, recruit eosinophils (which can be found at morphea early stages) and modify the synthesis of collagen by fibroblasts.

• #3 Morphea: The 2023 update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9969991/

  In the early stage of morphea, a large number of mononuclear lymphocytes (primarily activated T lymphocytes but also macrophages), some plasma cells and eosinophils infiltrate the skin and surrounding blood vessels. […] Based on functional in vitro data and cytokine analysis (mostly in the serum of patients) it is suggested that a TH1/TH2 imbalance in morphea is propagating the disease. […] It is postulated that injury of the vascular endothelium and upregulation of adhesion molecules, such as E-selectin and VCAM-1 during the inflammatory stage facilitate the recruitment of T lymphocytes that are capable of producing profibrotic cytokines like IL-4, IL-6 and TGF-. […] Fibrosis plays a critical role in causing tissue damage in scleroderma and is accompanied by hardening of the skin from excessive cellular proliferation as well as deposition of collagen and other extracellular matrix components. […] Atrophy is a poorly understood pathogenic event that may persist long after the sclerotic phase of morphea.

• #3 Morphea: progress to date and the road ahead

  https://atm.amegroups.org/article/view/61306/html

  The precise pathogenesis of morphea is not completely understood. […] However, the dysregulated immune and fibrotic pathways that contribute to these changes have not yet been systematically studied. […] Although it is generally accepted that immune dysfunction is the principal component in the development of morphea, other factors are also thought to contribute to pathogenesis, including genetic predisposition, traumatic or environmental factors, and vascular dysfunction. […] Recent observations have supported the role of dysregulated immune pathways, particularly IFN gamma, demonstrating that CXCL9 and CXCL10 levels are associated with increased clinical measures of disease activity. […] Beyond CXCR3 ligands, other upstream and downstream pathways have also been implicated in the pathogenesis of morphea.

• #3

  https://link.springer.com/article/10.1007/s40257-017-0269-x

  Development of cutaneous or subcutaneous fibrosis is the key characteristic of morphea. Fibrosis is a result of excessive collagen synthesis and decreased degradation. Transforming growth factor-1 (TGF-1) has been shown to increase the expression of several collagen types and other extracellular matrix components in morphea and SSc. […] The pathogenesis of EF remains unknown. Numerous associations with potential etiological factors have been proposed in case reports.

• #3 Morphea – Wikipedia

  https://en.wikipedia.org/wiki/Morphea

  Case reports of morphea co-existing with other systemic autoimmune diseases such as primary biliary cirrhosis, vitiligo, and systemic lupus erythematosus lend support to morphea as an autoimmune disease. […] Borrelia burgdorferi infection may be relevant for the induction of a distinct autoimmune type of scleroderma; it may be called „Borrelia-associated early onset morphea” and is characterized by the combination of disease onset at younger age, infection with B. burgdorferi, and evident autoimmune phenomena as reflected by high-titer antinuclear antibodies.

• #4 Morphea: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1065782-overview

  Overproduction of collagen, particularly types I and III collagen, by fibroblasts in affected tissues is common to all forms of morphea, although the mechanism by which these fibroblasts are activated is unknown. […] Proposed factors involved in the pathogenesis of morphea include endothelial cell injury, immunologic (eg, T lymphocyte) and inflammatory activation, and dysregulation of collagen production. […] An autoimmune component is supported by the frequent presence of autoantibodies in affected individuals, as well as the association of morphea with other autoimmune diseases, including systemic lupus erythematosus, vitiligo, type 1 diabetes, and autoimmune thyroiditis. […] Endothelial cell injury is currently thought to be the inciting event in the pathogenesis of morphea. […] This injury results in increased levels of adhesion molecules (circulating intercellular adhesion molecule-1, vascular cell adhesion molecule 1, and E-selectin) and fibrogenic T-helper 2 cytokines such as interleukin (IL)4, IL-6, and transforming growth factor-beta (TGF-beta).

• #5 Morphea – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/morphea/symptoms-causes/syc-20375283

  Morphea is a rare skin condition characterized by small red or purple patches that develop firm white or ivory centers. The affected skin becomes tight and less flexible. […] The cause of morphea is unknown. It may be caused by an unusual reaction of your immune system. In people at increased risk of morphea, it could be triggered by injury to the affected area, medications, chemical toxins, an infection or radiation therapy. […] Morphea affects the skin and underlying tissue and sometimes bone. The condition generally lasts several years and then improves or at times disappears by itself. It may leave scars or areas of darkened or discolored skin. It is possible for morphea to recur.

• #5 What Is New in Morphea—Narrative Review on Molecular Aspects and New Targeted Therapies

  https://www.mdpi.com/2077-0383/13/23/7134

  The following insults are mentioned: trauma, infection, radiation or drugs (β-blockers, bleomycin, bromocriptine, D-penicillamine). They cause microvascular damage and secondary activation of T lymphocytes. […] Studies have confirmed that transforming growth factor β (TGF-β), interleukin IL-1β, IL-4, IL-6, IL-10, IL-27, interferon gamma (INF-γ) and, more recently, IL-17A are essential for inflammation and fibrosis. Ultimately, activation of these pro-inflammatory and fibrosis-inducing mediators leads to excessive collagen production and reduced production of metalloproteinases responsible for collagen degradation. […] The most likely earliest phenomenon underlying the pathogenesis of morphea is thought to be endothelial cell activation resulting from endothelial damage. […] Increased production of adhesion molecules such as ICAM-1, VCAM-1, E-selectin and P-selectin leads to increased recruitment of inflammatory cells, including T lymphocytes, monocytes and other immune cells.

• #6 Morphea: The 2023 update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9969991/

  In the early stage of morphea, a large number of mononuclear lymphocytes (primarily activated T lymphocytes but also macrophages), some plasma cells and eosinophils infiltrate the skin and surrounding blood vessels. […] Based on functional in vitro data and cytokine analysis (mostly in the serum of patients) it is suggested that a TH1/TH2 imbalance in morphea is propagating the disease. […] It is postulated that injury of the vascular endothelium and upregulation of adhesion molecules, such as E-selectin and VCAM-1 during the inflammatory stage facilitate the recruitment of T lymphocytes that are capable of producing profibrotic cytokines like IL-4, IL-6 and TGF-. […] Fibrosis plays a critical role in causing tissue damage in scleroderma and is accompanied by hardening of the skin from excessive cellular proliferation as well as deposition of collagen and other extracellular matrix components. […] Atrophy is a poorly understood pathogenic event that may persist long after the sclerotic phase of morphea.

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