An 80-year-old Caucasian gentleman presented to dermatology for a rash on his bilateral anterior lower extremities. The patient reported that his skin changes began 8 months before as a red, flat rash, accompanied by swelling of the lower extremities. He also complained that his skin "felt thick" but was otherwise asymptomatic, and he had not treated it with anything before presenting to dermatology. His primary care provider had diagnosed him with lipodermatosclerosis 1 month before presentation in dermatology.
The patient had no history of deep venous thrombosis, vascular insufficiency, superficial thrombophlebitis, lower extremity claudication, varicose veins, or stasis dermatitis.
He was in good health, with a past medical history significant only for hypercholesterolemia and an abdominal hernia 3 years before. He had no history of thyroid disorder, diabetes, renal disease, or known exposure to gadolinium.
On presentation, he was a well-appearing, older gentleman, in no acute distress. On bilateral lower extremities, from knee to ankle, he had ill-defined hyperpigmented plaques with central hypopigmentation. The skin felt thick and bound down. There were smaller erythematous, bound-down plaques on the thighs. On the forearms, he had small, discrete bound-down violaceous plaques.
The initial workup included liver profile, basic metabolic profile, complete blood count, rheumatoid factor, and protein electrophoresis, which were all within normal limits. His antinuclear antibody was elevated at 1:160 and was speckled, and his C-reactive protein was elevated at 7.
No biopsy was performed; diagnosis was made based on clinical findings. He was started on clobetasol (0.05%) ointment and calcipotriene (0.005%) cream, both twice daily to all affected areas. One week later, his disease was no worse but had not improved with topical treatment.
It was recommended that oral therapy be initiated. A test dose of methotrexate (MTX; 10 mg) by mouth once a week for 2 weeks was given. His liver profile was reassessed during this trial treatment and remained normal.
After 2 weeks of methotrexate and continued topical therapy, the plaques on his arms were improving. After 1 month of treatment, the erythema around the plaques on both arms and legs had resolved, and all lesions were less indurated and firm than at initial presentation.
At the time of publication the patient was continuing to see improvement in skin thickness, firmness, and erythema and was currently tolerating the methotrexate and topical treatments without laboratory abnormalities or other problems.
WHAT'S YOUR DIAGNOSIS?
B. Nephrogenic fibrosing dermopathy
C. Systemic sclerosis
Lipodermatosclerosis is a form of panniculitis or inflammation of the subcutaneous fat, which is seen in patients with chronic venous insufficiency (Moschella & Hurley, 1992). Patients usually present with skin induration, hyperpigmentation, swelling, erythema, and narrowing of the distal lower leg near the ankle, which is known as inverted champagne bottle or bowling pin appearance (Bolognia, Jorizzo, & Rapini, 2008; Walsh & Santa Cruz, 2010). There may be small, white, scarred areas, known as atrophie blanche (Bolognia et al., 2008). The overlying skin can be warm, tender, and scaly, leading to the frequent misdiagnosis of cellulitis (Moschella & Hurley, 1992).
Lipodermatosclerosis usually occurs in people over 40, without inciting illness or trauma (Moschella & Hurley, 1992). The cause is not completely understood but is related to venous hypertension and venous insufficiency, and it occurs more commonly in people who are obese. Some patients present with recurrent episodes of painful inflammation of the lower extremities, often just proximal to the ankle (Bolognia et al., 2008).
The diagnosis can usually be made clinically but can be confirmed with a skin biopsy. Primary management of lipodermatosclerosis consists of compression therapy to correct venous stasis. Other components of therapy and management include sclerotherapy, weight reduction, oral pentoxifylline to increase blood flow, topical steroids or intralesional steroids to reduce inflammation, and topical capsaicin for pain relief (Bolognia et al., 2008).
Nephrogenic Fibrosing Dermopathy
Nephrogenic fibrosing dermopathy is a fibrosing disease of the skin and internal organs, distinct from scleroderma and scleromyxedema (Bolognia et al., 2008). It is only seen in patients with renal insufficiency who have received imaging studies with gadolinium, a contrast dye. Gadolinium can be found in tissue samples of patients with NSD (Pryor et al., 2007).
NSD usually has a gradual onset with development of induration, thickening, and hardening of the skin, with hyperpigmentation. The skin is often shiny, with a woody consistency, and the classic peau d'orange appearance (Bolognia et al., 2008).
Skin changes are most readily appreciated on the extremities, followed by the trunk; the face is almost never involved. Yellow palmar papules have been reported, as have yellow scleral plaques (Pryor et al., 2007).
NSD is a debilitating and sometimes fatal disease. Patients complain of burning, itching, swelling, and hardening and tightening of the skin. Joint complaints are common, with difficulty moving or straightening the arms, hands, legs or feet (Bolognia et al., 2008). Patients may have muscle weakness and bone pain, especially involving the hipbones or ribs (Bolognia et al., 2008; Pryor et al., 2007).
The most successful treatment appears to be extracorporeal photopheresis (Bolognia et al., 2008); however, for most patients, the disease is progressive and slow to respond to treatment (Schieren et al., 2009).
Systemic sclerosis is an autoimmune systemic connective tissue disease whose pathogenesis is only partially understood (Bolognia et al., 2008). There are three main changes in systemic sclerosis: induration and thickening of skin (scleroderma), abnormalities of both microvasculature (telangiectasia) and large vessels (Raynaud's phenomenon), and fibrotic degenerative changes in various organs, such as heart, lungs, kidneys, and gastrointestinal tract (Bolognia et al., 2008).
Systemic sclerosis can have many different presentations. Patients may have involvement of the skin only, internal organs only, or both skin and internal organs. Because of the various presenting symptoms, diagnosis is often difficult at the onset (Bolognia et al., 2008).
Raynaud's phenomenon is the most common initial complaint; the second most common complaint is symmetric painless edema or thickening of the skin of the digits, known as sausaging of the digits (Moschella & Hurley, 1992). Patients may also complain of pruritus, difficulty in swallowing, shortness of breath, palpitations, joint pain or swelling, or myositis (Bolognia et al., 2008; Moschella & Hurley, 1992).
No definite therapy has been shown to slow or stop progression of skin or visceral disease. Treatment is tailored to organ involvement. Pruritus can be ameliorated by topical camphor or menthol, emollients, psoralen plus UVA treatment, or UVA-1 phototherapy (Bolognia et al., 2008).
Numerous oral therapies have been proposed and tested, many without effect. d-Penicillamine, interferon, photopheresis, corticosteroids, methotrexate, chlorambucil, cyclosporine, tacrolimus, thalidomide, intravenous cyclophosphamide, statins, immunosuppressive drugs with stem cell transplantation, and imatinib have been investigated. Results are varied, and no one therapy has shown consistent benefit. Whichever therapy is initiated, care should be multidisciplinary, including dermatology, pulmonology, nephrology, radiology, cardiology, and orthopedic surgery (Bolognia et al., 2008).
Scleredema is an uncommon disorder of progressive, nonpitting induration of the skin. Although it does not typically affect the arms and legs, it is discussed here because it presents with tightening and induration of the skin, similar to the complaints of our patient. Scleredema usually occurs on the face, neck, and upper back, and patients report difficulty smiling, opening the mouth, and wrinkling the forehead (Moschella & Hurley, 1992).
Scleredema may be associated with an acute antecedent febrile illness, most often streptococcal infection, diabetes mellitus, blood dyscrasia, and, rarely, multiple myeloma. Although generally considered to be a benign, self-limited skin condition, scleredema may be persistent and can involve the viscera (Bolognia et al., 2008).
Primary lesions are ill-defined, woody, nonpitting, indurated plaques that may clinically mimic edema. There may be erythema, hyperpigmentation, and/or peau d'orange appearance. The epidermis overlying affected areas wrinkles when pinched (Bolognia et al., 2008).
Streptococcal throat culture and antistreptolysin-O titer should be obtained, in addition to fasting glucose, glycosylated hemoglobin, and serum protein electrophoresis (Bolognia et al., 2008).
Although the name implies sclerosis and edema, neither is present on histology. Instead, there is mucin deposition between dermal collagen bundles, seen mostly in the deep dermis (Moschella & Hurley, 1992).
Treatment with appropriate antibiotic therapy should be initiated for patients with documented or suspected infection. Evaluation and treatment for blood dyscrasia and diabetes should be completed (Bolognia et al., 2008).
Myxedema is a primary disorder of mucin, in which there is deposition of hyaluronic acid in the dermis and subcutis, usually because of thyroid disease. This diagnosis should be considered in a patient presenting with skin induration of the pretibial area (Moschella & Hurley, 1992).
Patients present with sharply circumscribed nodules or plaques over the anterior lower legs, usually bilaterally (Bolognia et al., 2008). Lesions can extend to any part of the legs and lower abdomen. Lesions are skin-colored to yellow-brown, nonpitting, and waxy. Follicular pores may be dilated, resulting in the peau d'orange appearance. Small plaques are asymptomatic, but as lesions enlarge, they become painful (Bolognia et al., 2008; Moschella & Hurley, 1992). Cosmesis may be a concern.
Onset of disease is usually within 1-2 years of diagnosis of Graves' disease. Myxedema in the absence of Graves' disease is rare (Bolognia et al., 2008; Moschella & Hurley, 1992).
Workup should include thyrotropin levels, which may be abnormally high or low, and long-acting thyroid stimulator, which is elevated in 50% of patients (Bolognia et al., 2008). Skin biopsy shows deposition of mucin in the reticular dermis and separation of collagen bundles into individual fibers (Bolognia et al., 2008; Moschella & Hurley, 1992).
First line treatment is usually compression wraps or stockings with 20-40 mm Hg of pressure and topical corticosteroids under occlusion. If topical corticosteroids are ineffective, intralesional corticosteroids may be helpful. Ideal management includes collaboration between dermatology and endocrinology (Bolognia et al., 2008).
Morphea: The Answer Is Morphea
Morphea or localized scleroderma, is a skin disorder characterized by excessive collagen deposition, which leads to thickening of the dermis and/or subcutaneous tissue (Chung, Lin, Furst, & Fiorentino, 2006). Lack of features such as Raynaud's phenomenon, telangiectasia, and progressive internal organ involvement differentiate morphea from systemic scleroderma (Zulian, 2004).
Only 0.9%-5.7% of patients with morphea develop systemic scleroderma. The development of Raynaud's phenomenon and nail fold capillary changes may raise a red flag to the clinician, indicating that the patient with morphea is developing systemic scleroderma. The four major types of morphea are plaque, generalized, linear, and deep. The classification is based on clinical presentation and depth of tissue involvement (Zulian, 2004).
The incidence of morphea has been estimated as 25 cases per 1 million people per year. Adults and children are equally affected by this condition, but the presentations differ. Most adults present with plaque-type lesions, and most children present with linear morphea. All races are affected, but Caucasians are more often plagued with this disease than African Americans. Women are affected three times more than men (Nguyen, 2010).
It is thought that morphea and systemic scleroderma are triggered by distinct events: morphea being caused by a local trigger within the skin and systemic scleroderma being caused by a generalized trigger. Specific triggers of morphea are yet to be identified (Bolognia et al., 2008).
Despite the different triggering events, the development of sclerosis in morphea and systemic scleroderma seems to follow a common pathway. Three components are thought to be responsible for the development of sclerosis: vascular damage, activated T cells, and altered connective tissue production (Bolognia et al., 2008).
Usually morphea is asymptomatic. Twenty percent of patients experience extracutaneous symptoms, such as arthralgias, dysphasia, dyspnea, seizures, headaches, cranial nerve palsies, trigeminal neuralgia, eye pain, or visual changes (Nguyen, 2010).
The most common and benign type of morphea is plaque-type morphea. It presents as well-demarcated, oval-shaped, indurated plaques that range from 1 cm to greater than 10 cm in diameter. The lesions are relatively superficial, mostly involving the dermis and not the subcutaneous tissue. Sometimes a violaceous border (lilac ring) surrounds the indurated region. As the disease progresses, sclerosis develops centrally and progresses peripherally. Eventually, the lesions become smooth and shiny, with loss of hair follicles and sweat glands. Hyperpigmentation also develops. The plaques are usually distributed on the trunk, less likely on the extremities, and usually spare the face (Nguyen, 2010).
Several variations of plaque-type morphea exist. Guttate morphea is characterized by multiple sharply demarcated lesions, less than 1 cm in diameter. These lesions are usually sclerotic and whitish in color, with an appearance similar to that of extragenital lichen sclerosis. Guttate morphea differs from lichen sclerosis in that it lacks epidermal atrophy and follicular plugging (Nguyen, 2010).
Keloidal (nodular) morphea is rare and is characterized by keloid-like nodules in the setting of typical plaque-type morphea (Nguyen, 2010).
Atrophoderma of Pasini and Pierini is characterized by burnt-out plaque-type lesions located on the trunk, axillae, and inner thighs, which are hyperpigmented and indurated, with depressed well-defined cliff-drop borders (Nguyen, 2010).
Bullous morphea is thought to result from stasis of lymphatic fluid due to the sclerodermatous process. It is characterized by tense bullae, which develop overlying plaque-type linear or deep morphea lesions (Nguyen, 2010).
Linear morphea is similar to deep morphea, but it occurs in a linear pattern, sometimes following Blaschko lines. The lesions usually occur on the lower extremities; however, if they occur on the upper extremities or head, they are distributed on the frontal portion of the head or upper extremities. They appear as hyperpigmented, atrophic, linear patches. Frontoparietal linear morphea, also known as en coup de sabre can result in scarring alopecia if the scalp and/or eyebrows are involved (Soma & Fujimoto, 1998).
Deep morphea, also know as morphea profunda, involves the fat and fascia. Characterized by symmetrically distributed ill-defined, bound-down, sclerotic plaques with a cobblestone or pseudocellulite appearance. The lesions lack the color changes of typical plaque-type morphea because of the deeper level of inflammation. During the late stages of the disease, the groove sign is present, which is a depression along the course of a vein and/or between muscle groups (Nguyen, 2010).
Eosinophilic fasciitis is sometimes thought to be a variant of morphea. It mostly involves the fascia, causing an acute onset of symmetric pain and edema of the trunk or extremities. It precedes progressive induration, with an appearance similar to that of deep morphea (Nguyen, 2010).
The exact etiology of morphea is unknown, but an autoimmune mechanism has been suggested. Generalized morphea has the highest association with systemic autoimmune disease and a positive antinuclear antibody. Often, different morphea subtypes exist in the same patient, which suggests that all subtypes share a similar underlying process. Other than autoimmune etiology, there are other ideas of what may cause morphea. Morphea has been known to occur at sites of previous radiation therapy. This has been seen 1 month to 20 years after irradiation (Nguyen, 2010). Some researchers suggest that chimerism may be a cause of morphea (Zulian, 2008).
Various infections, such as Epstein-Barr virus, varicella, measles, hepatitis B, and borreliosis, have been proposed as possible triggers. There have been reports of morphea-like lesions occurring after bacillus Calmette-Guerin; tetanus; and measles, mumps, and rubella vaccinations (Nguyen, 2010).
Rarely, medications have induced morphea. Examples include bleomycin, d-penicillamine, l-5-hydroxytryptophan, and balicatib (Peroni et al., 2008). Trauma, hormones, and genetics have all been linked to the disease, as well (Nguyen, 2010).
The differential diagnosis for morphea includes lipodermatosclerosis, systemic sclerosis, myxedema, scleredema, primary systemic amyloidosis, ataxia-telangiectasia, atrophoderma of Pasini and Pierini, eosinophilia-myalgia syndrome, eosinophilic fasciitis, graft versus host disease, keloid and hypertrophic scar, lichen sclerosus et atrophicus, nephrogenic fibrosing dermopathy, inflammatory granuloma annulare, interstitial and granulomatous dermatitis, erythema migrans, fixed drug eruption, Sweet's syndrome (early), and interstitial mycosis fungoides (Nguyen, 2010).
Laboratory studies are not very helpful in the diagnosis of morphea but should be considered on a case-to-case basis. Complete blood count and erythrocyte sedimentation rate results are usually normal (Nguyen, 2010). Immunoglobulin G and immunoglobulin M may be increased, especially in deep morphea. The significance of serum autoantibodies is unclear, and they are commonly present in all types of morphea (Nguyen, 2010).
Diagnostic imaging studies have greater value in monitoring disease activity and invasion of underlying structures than in making the initial diagnosis. Although morphea can be diagnosed clinically, a biopsy is useful in confirming the diagnosis and identifying the depth of involvement. A deep punch biopsy is usually sufficient to diagnose plaque-type and generalized morphea. The exact location of the biopsy should be noted and documented, because different histologic features are seen in the center of the lesion versus the border. An incisional biopsy down to muscle is needed to diagnose linear and deep morphea to assess fascial involvement (Nguyen, 2010).
The goal of treatment is to decrease inflammation in early disease and to prevent sclerosis in advanced disease. Plaque-type morphea may gradually spontaneously resolve in 3-5 years (Nguyen, 2010).
Superpotent topical steroids, topical calcipotriene, topical tacrolimus ointment, imiquimod cream, and intralesional corticosteroids have all been beneficial at reducing inflammation, induration, and erythema (Nguyen, 2010).
Patients with disabling generalized, linear, or deep morphea usually require more aggressive treatment with oral medications. Systemic corticosteroids are helpful for the inflammatory phases but have little effect once sclerosis is established (Nguyen, 2010).
Rapidly progressive morphea has been successfully treated using high-dose corticosteroids in combination with once weekly low-dose methotrexate (Nguyen, 2010).
There is little evidence in the literature to support the use of hydroxychloroquine, but broadband UVA, long-wavelength UVA-1, and psoralen plus UVA have shown marked clinical improvement in morphea. Case reports of treatment with extracorporeal photopheresis, photodynamic therapy, and pulsed dye laser seem promising, but larger studies are needed.