Morphea is a rare, autoimmune, clinically heterogeneous sclerosing disorder of the skin and subcutaneous structures.³ Morphea is more common in whites and women, has an equal prevalence in children and adults, and an estimated incidence of 0.4 to 2.7 per 100,000 people.³ Morphea presents as five clinical subtypes of disease: circumscribed (with superficial and deep variants), linear (with superficial and deep variants), generalized (defined as four or more plaques larger than 3 cm in diameter on two or more body surface regions, also with superficial and deep variants), mixed variant (combination of circumscribed and linear, or linear and generalized), and pansclerotic (sclerosis that spans the epidermis and subcutaneous tissues and involves all body surface areas other than the fingers and toes). Morphea is characterized as having an “active phase” (when patients are developing new lesions, have expansion of existing lesions, or demonstrate signs of inflammation on clinical exam) and a “damage” or “burnt-out phase” (when no new lesions are forming, lesion size is stable, and there are no clinical signs of inflammation). All subtypes of morphea present with sclerotic plaques clinically resembling scars, with varying amounts of surrounding inflammation (Fig. 3-1).

Histopathologically, early lesions of morphea reveal perivascular infiltrates composed of plasma cells and lymphocytes and increase in collagen deposition (Fig. 3-2). In late lesions of morphea, the inflammatory infiltrate remits,
and the dermis and subcutaneous fat are replaced by thick, pale sclerotic collagen bundles (Fig. 3-3). Dermal appendages and blood vessels are replaced by collagen.

The pathogenesis of morphea is incompletely understood at this time. Patients with morphea are likely to have an underlying genetic predisposition based on familial clustering with other autoimmune diseases and specific human leukocyte antigen (HLA) subtypes identified as predisposing factors.⁴,⁵ Several environmental factors have been postulated to be part of the pathogenesis of disease, including Lyme disease, trauma, radiation, medications, and viral infections.⁶ Autoantibodies may also be a part of the pathogenesis. Patients with morphea frequently have positive antinuclear antibodies (ANAs), single-stranded
DNA antibodies, antihistone antibodies, rheumatoid factor, and anti-topoisomerase IIα antibodies.³ The sclerosis in morphea lesions is thought to be initiated by vascular injury via environmental exposure or autoantibodies. Endothelial injury causes release of cytokines that cause increased expression of vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selectin.³ The result is an initial inflammatory response characterized by T_H1⁺ cells, interleukin (IL)-2, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α).⁷ Profibrotic cytokines such as IL-4 and -6 and TGF-β are expressed, which recruit eosinophils, CD4⁺ T cells, and macrophages.³ Expression of IL-6 is thought to transition the T_H1⁺ environment to a T_H17 environment, and then ultimately a T_H2⁺ environment characterized by IL-4 and -13.⁷ This prosclerotic environment results in increases in collagen, fibronectin, and proteoglycan and a decrease in proteases.

Treatment of morphea is determined based on subtype and phase.⁶ Active circumscribed morphea is typically treated with topical immunosuppressants or phototherapy. Active linear morphea is typically treated with systemic immunosuppressants. Active generalized and pansclerotic morphea are typically treated with phototherapy or systemic immunosuppressants. Treatment of the damage phase of morphea is limited by lack of data. Case reports of fillers, lasers, and fat transplants to correct contractures and disfigurement have been published.⁸,⁹,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶,¹⁷,¹⁸

Lichen sclerosus (LS) is a rare sclerosing disorder with a predilection for anogenital skin. LS commonly occurs in patients with morphea and may be a morphea variant. LS is much more common in women than in men and has a bimodal onset (prepubertal children and postmenopausal women).¹⁹ Patients with LS are more likely to have a personal history of additional autoimmune diseases, such as vitiligo and autoimmune thyroiditis, and a family history of autoimmunity than healthy controls.¹⁹ LS presents with white sclerotic plaques, typically on the anogenital skin (Fig. 3-4). The degree of sclerosis can be severe, leading to functional impairment including dysuria, constipation, and sexual dysfunction. The pathogenesis of the disease is not elucidated to date; however, genetics (particularly associations with HLAs), autoimmunity (development of anti-extracellular matrix 1 antibodies), hormones, and recurrent irritation have been proposed to serve pathogenic roles.¹⁹ The chronic inflammation associated with LS leads to vulvar intraepithelial neoplasia (VIN), which increases the risk of development of anogenital squamous cell carcinoma (SCC). Patients with LS should be monitored closely for this potential complication.²⁰,²¹ LS is typically treated with superpotent topical steroids. Adherence to topical steroid maintenance therapy has been shown to decrease the risk of VIN and SCC.²²

Systemic Sclerosis is a rare autoimmune sclerosing disorder of the skin and internal organs with an estimated prevalence of 150 to 300 cases per million.²³ Systemic sclerosis is subdivided into two clinically distinct phenotypes: limited cutaneous systemic sclerosis (LcSScl) and diffuse cutaneous systemic sclerosis (DcSScl).²⁴ Both phenotypes are characterized by Raynaud’s phenomenon, positive ANA, nailfold capillary changes (dilation and hemorrhage in early stages and nailfold capillary drop out and irregular arborizing vessels in later stages), sclerodactyly, and a high risk of interstitial lung disease. The patterns of skin sclerosis, autoantibodies, and additional organ involvement in the phenotypic subsets differ in the following ways. Patients with LcSScl have sclerosis that is distal to the elbows and knees, though the head and neck may also be involved. By definition, patients with DcSScl have sclerosis that extends proximal to the elbows and knees. Patients with LcSScl are more likely to have anti-centromere antibodies, whereas patients with DcSScl are more likely to express anti-Scl 70 (also called anti-topoisomerase) antibodies, and
anti-RNA polymerase III antibodies (Table 3-2). Patients with LcSScl are more likely to develop isolated pulmonary artery hypertension (which is sclerosis of the pulmonary artery), whereas patients with DcSScl are more likely to develop renal crisis, likely due to sclerosis of the arcuate and intralobular arteries in the glomeruli.²⁵ The organ sclerosis that occurs in systemic sclerosis results in high morbidity and mortality.

The pathophysiology of systemic sclerosis is exceedingly complex and incompletely understood. In broad strokes, it is felt that genetics (polymorphisms in HLA class II gene region, IRF5, CD247, BANK1, STAT4, TNFSF4, BLK, C8orf13, IL–23R, and TBX21 genes)²⁶,²⁷ and environmental factors (exposure to vinyl chloride, silica dust and organic solvents, medications such as bleomycin, pentazocine, cocaine, and viruses)²⁷ instigate an inflammatory response that is initially targeted against blood vessels. Endothelial cell damage results in upregulation of cellular adhesion molecules (VCAM, ICAM, E-selectin), chemokines (CCL 2,5,7,17,22,27, CXCL8), recruitment and activation of platelets, altered capillary permeability, and vasoconstriction (via endothelin-1).²,²⁸ The cellular adhesion molecules and chemokines recruit perivascular CD3⁺ and CD4⁺ mononuclear cells that express CD45, HLA-DR, and the IL-2 receptor and which secrete fibrogenic cytokines and chemokines (IL-1, -2, -4, -5, -6, -8, -12, -13, -17, TNF-α, and IFN-α and IFN-γ).²,⁷,²⁶,²⁹ These lesional T cells have restricted specificities representative of oligoclonal T-cell expansion.² Systemic sclerosis is ultimately characterized by a shift in the T_H1 to T_H2 cytokine balance, favoring T_H2 cytokines.² Production of these cytokines results in inflammation, and recruitment and activation of fibroblasts and myofibroblasts, which make collagen 1, 3, 6, 7, fibronectin, and glycosaminoglycans (GAGs), resulting in fibrosis.³⁰ The signaling that results in overproduction of collagens, fibronectin, and GAGs in systemic sclerosis is multifaceted and involves TGF-β signaling through SMAD and SMAD-independent pathways, platelet-derived growth factor receptors (PDGFRc), canonical Wnt signaling, sonic hedgehog (SHH) signaling, aberrations in Notch signaling, microRNA signaling (particularly miR29 and miR29a), histone modifications,³⁰,³¹ and alterations in transcription factors (SP1, SMAD3, ETS1, early growth response 1, CCAAT-binding factor, SP3, CCAAT/enhancer binding protein, Y box-binding protein 1, c-KROX, and FLI-1).² Additionally, B-cell dysfunction may contribute to fibrosis by not only making pathogenic autoantibodies, but by secreting IL-6, which directly stimulates fibroblasts.²

DP is a relatively common fibroproliferative disorder of the aponeurotic fascial fibers of the palm of the hand that ultimately results in flexion contractures of the fingers (Fig. 3-5). DP is most common in men of Northern European descent.³³ The development of Dupuytren’s is divided into three stages (1) the proliferation phase—during which fibroblasts gather within the fascial fibers; (2) the involutional phase—during which fibroblasts align along the lines of tension and differentiate into myofibroblasts;
and (3) the residual phase—during which collagen formation predominates.³³

The pathogenesis of DP is incompletely understood and is likely due to an interplay of genetic predisposition and environmental factors. Genetic factors are believed to play a strong role in disease development, with heritability estimated as high as 80% in the Danish population.³³,³⁴ Genome-wide association studies have revealed relevant mutations in genes within the Wnt pathway (WNT4, WNT2, WNT7B, RSPO2).³⁵ HLA associations including HLADrB3, HLA A1 B8 Dr3, HLA DRB1^*15³³; changes in TGF-β signaling secondary to single nucleotide polymorphisms (SNPs) in the gene encoding transcription factor Zf9; and a heteroplasmic mutation located within the mitochondrial 16s ribosomal RNA region have been described.³³ Changes in microRNA expression that affect Wnt and β-catenin signaling have been discovered,³³,³⁶ and a lack of downregulation of connexins 26, 30 and 43 has also been demonstrated.³² Associated environmental factors include smoking, diabetes, and alcohol use.³³,³⁶ Either through these genetic and environmental changes or other mechanisms that have yet to be described, changes occur in the immune system including the formation of autoantibodies to collagens 1 through 4, autoreactive T cells, and severe dysregulation of molecular pathways involved in wound healing and fibrosis including upregulation of TGF-β, IL-1, β-fibroblast growth factor (FGF), PDGF; increased production of collagen, periostin, tenascin, β-catenin, α5β1, fibronectin, and proteoglycan 4; and dysregulation of matrix metalloproteinases (MMPs).³³ DP is often treated with injection of collagenase from Clostridium histolyticum and surgery for recalcitrant cases.

Peyronie’s disease (PD) is caused by fibrosis of the tunica albuginea of the penis, resulting in penile curvature. PD is estimated to affect up to 9% men, with incidence increasing with age.³⁷ PD begins with an active phase, during which the patient has pain with erections, and develops progressive curvature of the penis. The quiescent phase follows a mean of 18 months later. During the quiescent phase, the penile deformity remains stable, but there is resolution of the pain.³⁷ The pathogenesis of PD is hypothesized to be due to abnormal wound healing induced by microbleeding within the tunica albuginea after microtrauma to the penis.³⁷,³⁸ It is hypothesized that the fibrin produced with microbleeding recruits inflammatory cells and platelets, which produce inflammatory cytokines (TGF-β, PDGF, FGF, IL-1, TNF-α, plasminogen activator inhibitor-1), cause oxidative stress and ultimately excessive collagen deposition.³⁸ Gene expression patterns for genes regulating collagen degradation, ossification, and myofibroblast differentiation have been shown to be similar in DP and PD.³⁹ Overlap of DP and PD happens in 10% to 40% of patients.³⁸ PD is treated with injection of collagenase derived from C. histolyticum and surgery for refractory cases.

Plantar fibromatosis (Ledderhose disease) is the development of superficial collagen nodules within the nonweight-bearing medial band of the plantar aponeurosis (Fig. 3-6).⁴⁰,⁴¹ Like DP it is associated with diabetes, with alcohol overuse, and in men.⁴⁰,⁴¹ Plantar fibromatosis often coexists with DP and PD. The pathogenesis of plantar fibromatosis to date has not been investigated. It is assumed that the pathogenic mechanisms of DP are similar to those causing plantar fibromatosis. Plantar fibromatosis is not treated unless patients experience pain. If the nodules are painful or limit mobility, conservative treatments include anti-inflammatories, cortisone injections, physical therapy, and orthotics. For those patients with refractory disease, radiotherapy, surgery, and extracorporeal shock wave therapy are therapeutic options, although recurrence rates are high.⁴⁰

Knuckle pads are asymptomatic nodules over the extensor proximal interphalangeal (PIP) joints that usually appear
between the ages of 15 and 30 years (Fig. 3-7).⁴² Knuckle pads have been observed to occur concomitantly with other superficial fibromatoses, although their pathogenesis has not been studied. Knuckle pads are a cutaneous finding of Bart-Pumphrey syndrome (knuckle pads, leukonychia, palmoplantar keratoderma, and deafness caused by an autosomal dominant mutation in the GJB2 gene). Histologically, the nodules are made up of fibroblasts and collagen. Due to their asymptomatic nature and difficult-to-treat location, knuckle pads are not usually treated.

Pachydermodactyly (PDD) is asymptomatic thickening of the periarticular skin of the PIPs.⁴³ PDD is most common in adolescent men and is thought to be caused by repetitive friction to the lateral fingers due to obsessive compulsive behaviors, work, or sports. The pathogenesis is unknown. PDD may be mistaken for inflammatory arthritis. PDD should be painless and noninflammatory, and involved joints should have full range of motion.⁴³ Hand radiographs can distinguish PDD from pachydermoperiostosis.⁴³ Histopathologically, there is a thickened epidermis with increased fibroblasts and collagen deposition in the dermis. There is no reliable treatment for PDD, although avoidance of repetitive trauma may decrease disease progression.

Nodular fasciitis, also referred to as pseudosarcomatous fasciitis, is a rapidly growing, painful, benign fascial tumor most commonly seen in young adults.⁴¹,⁴⁴ Nodular fasciitis typically presents on the upper extremity (usually the forearm), with trunk, head and neck, and lower extremity involvement occurring with decreasing frequency. When nodular fasciitis occurs in children, it may more commonly present on the head and neck.⁴⁵ The pathogenesis of nodular fasciitis is incompletely understood; however, a fusion gene of MYH9-USP6 has recently been described.⁴⁶ MYH9 is a nonmuscle myosin class II gene found in fibroblasts, endothelial cells, macrophages, and leukocytes.⁴⁶ MYH9 encodes a protein involved in cell motility, shape, and cytokinesis.⁴⁶ USP6 is a deubiquitinating enzyme involved in intracellular trafficking, protein turnover, cell transformation, and inflammatory signaling.⁴⁶ Histopathologically, nodular fasciitis is made up of fibroblasts and myofibroblasts, and mitotic figures are common. Nodular fasciitis may spontaneously regress. Excision results in cure, with an estimated rate of local recurrence at 2%.⁴¹

Ainhum, also referred to as dactylolysis spontanea, is the name for a fibrous band that develops around the fifth toes of patients of African descent and ultimately results in arterial narrowing, bone absorption, and finally autoamputation.⁴⁷,⁴⁸ Ainhum rarely involves digits other than the fifth toe. Ainhum is most common in people of African descent, but also occurs in Asia, South and Central America, and the United States.⁴⁷,⁴⁸ The highest incidence is in Nigeria.⁴⁸ The pathogenesis is unknown. No autoimmune diseases, genetic diseases, nor infectious diseases have been associated with ainhum. Histopathology reveals hyperkeratosis, acanthosis, a lymphocytic infiltration made mostly of T cells, increased fibroblasts, and collagen.⁴⁷ If diagnosed early enough, the fibrous band can be injected with steroids or resected in an effort to save the involved toe(s).

Scleredema is characterized by woody induration of the skin caused by increase in collagen bundles and deposition of GAGs. Three clinical subsets of scleredema have been described: (1) scleredema secondary to diabetes mellitus, (2) scleredema secondary to infection, and (3) scleredema secondary to a monoclonal gammopathy.⁴⁹ Scleredema secondary to diabetes occurs most commonly in men with long-standing, poorly controlled diabetes with concomitant microvascular complications. The onset of the disease is slow, progressive, and chronic. The posterior neck and upper back and chest are the most commonly involved sites (Fig. 3-8). Scleredema secondary to infection can occur after any febrile illness, but most commonly after streptococcal infection. Onset is sudden and most commonly involves the head and neck, although the trunk, upper extremities, and oropharynx may be involved. Scleredema secondary to infection often self-resolves over months. Scleredema secondary to monoclonal gammopathy (usually IgG and IgA) most commonly involves the neck, upper back, and chest, although head and neck involvement has also been reported. Onset is slow, but the condition is progressive
and tends to be refractory to treatment.⁴⁹ Histopathological findings are the same in all three subsets and include a normal epidermis, a normal number of fibroblasts, and a dermis that is thickened due to an increase in collagen bundles and deposition of GAGs. The pathophysiology of scleredema is not understood and has been incompletely studied. It is postulated that in scleredema secondary to diabetes there is nonenzymatic glycosylation of dermal collagen, which potentially activates fibroblasts resulting in increased collagen production and increased GAGs.⁵⁰ It is hypothesized that the scleredema that occurs in the setting of a monoclonal gammopathy is due to paraprotein stimulation of fibroblasts.

Scleromyxedema, also referred to as generalized lichen myxedematosus, is a rare mucinosis associated with monoclonal gammopathy, usually IgG lambda. Less than 10% of patients with scleromyxedema develop overt myeloma. Scleromyxedema presents with sheets of 2 to 3 mm firm, waxy, flesh-colored papules on the face (resulting in leonine facies), the ears, the dorsal hands, and the trunk (resulting in Shar-Pei sign) (Fig. 3-9).⁵¹,⁵² Systemic involvement occurs frequently and may include dysphagia, myopathy, arthritis, carpal tunnel syndrome, central nervous system disruption (encephalopathy, coma, stroke, seizures, psychosis), obstructive or restrictive pulmonary disease, heart block, pericardial effusions, and cardiomyopathy.⁵¹,⁵² Histopathologically, the papules reveal increased numbers of fibroblasts, increased GAGs, and increased collagen. The pathogenesis of scleromyxedema remains unknown. It is assumed that monoclonal gammopathy is involved in the pathogenesis by increasing IL-1, TNF, and TGB-β, which stimulate fibroblasts to make more GAGs and collagen. However, the paraprotein itself is not enough to stimulate fibroblasts, and paraprotein levels do not correlate with disease severity. Scleromyxedema may be treated with intravenous immunoglobulin, thalidomide, or antimyeloma medications.

Sclerema neonatorum is a rare subtype of lobular panniculitis. Sclerema neonatorum presents as firm, cool to the touch, mottled and violaceous, “bound-down” plaques on the buttocks, thighs, and trunk of preterm, severely ill newborns.⁵³ Histologically sclerema neonatorum has a lobular inflammatory infiltrate in the subcutaneous fat with needle-shaped crystals within the adipocytes.⁵³ The pathogenesis of sclerema neonatorum is unknown.⁵³ Exchange transfusion in the setting of sclerema neonatorum and sepsis may decrease mortality. Treatment is otherwise supportive. The pathogenesis of sclerema neonatorum does not include an increase of fibroblasts or fibroblast activation but rather occurs secondary to inflammation of the subcutaneous fat.