Scleredema

INTRODUCTION — Scleredema (synonym: scleredema adultorum of Buschke) is a rare, sclerotic skin disease that usually occurs in association with diabetes mellitus, infection (particularly streptococcal infection of the upper respiratory tract in children), or monoclonal gammopathy. Scleredema is characterized by the development of diffuse, woody induration of the skin and primarily affects the upper body (picture 1A-C).

The clinical course of scleredema varies from spontaneous resolution within several months, which often occurs in scleredema that follows a streptococcal upper respiratory infection, to persistent and progressive disease. Data on the treatment options for scleredema are primarily limited to case reports; therefore, the best approach to treatment remains unclear.

The clinical features, diagnosis, and management of scleredema will be discussed here. Other sclerotic disorders of the skin, such as systemic sclerosis (scleroderma) and scleromyxedema are distinct from scleredema. Overviews of these disorders are provided separately. (See "Scleromyxedema" and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

EPIDEMIOLOGY — The exact prevalence of scleredema is not known. Although scleredema is generally considered a rare disorder, the possibility that scleredema is underrecognized is suggested by a prospective study of 484 patients with diabetes in California that found a prevalence of scleredema of 2.5 percent [1]. A smaller Kuwaiti study found an even higher prevalence of scleredema in diabetic patients; among 100 patients with diabetes, scleredema was diagnosed in 14 percent [2].

Scleredema affects all racial and ethnic groups, and there is no clear sex difference in predilection for the disease [3]. Both children and adults may develop scleredema [4,5]; however, the age distribution for scleredema varies with the subtype of disease. (See 'Etiology' below.)

ETIOLOGY — Scleredema primarily occurs in association with three classes of disorders:

●Diabetes mellitus (synonym: scleredema diabeticorum)

●Infection (usually streptococcal infection of the upper respiratory tract and often associated with fever)

●Monoclonal gammopathies (eg, monoclonal gammopathy of uncertain significance, multiple myeloma, Waldenström macroglobulinemia)

Diabetes mellitus-associated scleredema, which is considered the most common form of the disease, primarily affects adults, particularly middle-aged obese individuals [6]. In a retrospective chart review in which 30 of 44 patients (68 percent) with scleredema had diabetes mellitus, the mean patient age was 54 years and the male to female ratio among patients with diabetes mellitus was 2.3:1 [6]. In contrast, scleredema related to infection predominantly affects young adults and children. Scleredema associated with monoclonal gammopathy is the least common presentation of scleredema and almost exclusively occurs in adults. Expectations for the clinical course of scleredema differ based upon the associated disease. (See 'Clinical features' below.)

There are rare reports linking scleredema to other disorders. Examples include human immunodeficiency virus infection [7], AIDS-related lipodystrophy syndrome [8], carcinoid tumor [9], malignant insulinoma [10], carcinoma of the gall bladder [11], rheumatoid arthritis and Sjögren syndrome [12], and primary hyperparathyroidism [13]. Occasionally, a link between the onset of scleredema and another disorder is not detected.

PATHOGENESIS — The pathogenesis of scleredema is largely unknown. In scleredema associated with diabetes, irreversible glycosylation of collagen, as well as alterations in collagenase activity, might lead to excessive accumulation of collagen and mucin [14]. Moreover, profibrotic effects due to hypoxia and microvascular damage have been suggested [15]. In scleredema not associated with diabetes, direct effects of streptococcal hypersensitivity or paraproteinemia might lead to increased collagen production.

CLINICAL FEATURES — Scleredema clinically presents as widespread, diffuse, woody induration of the skin (picture 1A-C). A slight erythema and "peau d'orange" appearance of the skin might be present as well. The severity of disease can range from mild skin induration that is barely noticed by the patient to more extensive involvement resulting in impaired mobility.

The clinical presentation and course of scleredema is influenced by the etiology:

●Scleredema associated with diabetes mellitus – The onset of diabetes mellitus-associated scleredema is usually subtle and slowly progressive. Typically affected areas include the posterior neck, interscapular region of the upper back, and chest, whereas the extremities are usually spared [3]. The condition tends to be chronic.

●Scleredema following infection – Infection-associated scleredema is characterized by a more sudden onset. Symptoms of scleredema tend to begin a few weeks after the preceding infection [16,17]. The condition predominantly affects the cervicofacial region, but may, in a later stage of disease, also include the trunk and upper extremities. In more severe forms, involvement of the mouth and pharynx can occur, leading to dysphagia and dysphonia. Post-streptococcal scleredema often shows complete clinical regression after several months [18]. Scleredema following infection predominantly occurs in children and young adults.

●Scleredema associated with monoclonal gammopathy – Clinical findings of this subtype are very similar to scleredema associated with diabetes mellitus. The disease is characterized by slow onset and slow progression; spontaneous regression usually does not occur [19,20].

In most patients, symptoms and signs of scleredema remain limited to the skin. Systemic involvement of scleredema is rare and mostly occurs in severe disease. Ocular (ocular muscle palsy), gastrointestinal (dysphagia), respiratory (dysphonia), muscular (myositis), and cardiac symptoms have been reported in the literature [3,4,21-23]. Infrequently, death has occurred as a consequence of systemic involvement [23,24].

HISTOPATHOLOGY — The histopathologic findings of scleredema are not pathognomonic, but when detected in conjunction with the clinical findings, are valuable for diagnosis. Key histopathologic findings in scleredema include [25]:

●Normal epidermis

●Thickened reticular dermis demonstrating marked swelling of collagen bundles that appear separated from one another by a variable amount of mucin (picture 2)

●Absence of fibroblast proliferation

Although the epidermis is usually unaffected in scleredema, the dermis can be three to four times thicker than normal. The absence of fibroblast proliferation in the dermis is useful for distinguishing scleredema from scleromyxedema and nephrogenic systemic fibrosis, in which fibroblast proliferation is characteristically seen. (See "Scleromyxedema", section on 'Histopathology' and "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease", section on 'Pathogenesis'.)

In addition to these findings, elastic fibers are often reduced in number [25]. Slight perivascular and periadnexal lymphocytic infiltrates also may be present. The subcutaneous fat tissue may be involved, demonstrating replacement of fat by thickened collagen bundles.

In case of systemic involvement, mucin deposition might also be present in the respective tissue (eg, skeletal muscle or heart). In a patient with scleredema, multiple myeloma, and heart failure, post-mortem examination revealed mucopolysaccharide deposition in the myocardium [26].

DIAGNOSIS — The characteristic clinical findings together with the patient’s medical history usually raise suspicion for scleredema. The diagnosis should be considered in patients who present with progressive woody induration of the skin that begins on the neck or upper trunk, particularly in the setting of diabetes, recent streptococcal upper respiratory infection, or monoclonal gammopathy. A skin biopsy should be performed to confirm the diagnosis and laboratory studies can be useful for identifying the associated disease.

History and physical examination — The patient history is useful for identifying a history of a preceding infection, diabetes mellitus, or monoclonal gammopathy in patients with clinical findings suggestive of scleredema, information that is helpful for estimating the expected course of the disease. A review of systems should also be performed to aid in the recognition of less common associated disorders (eg, malignancy) and rare systemic manifestations of scleredema.

A full skin examination should be performed to determine the extent of involvement and to evaluate for the presence of signs suggestive of a different sclerotic skin disease. Although no validated clinical scores exist for assessing the severity of scleredema, some clinicians utilize the Rodnan skin score for systemic sclerosis to document the extent of disease (figure 1). In addition, physical limitations secondary to scleredema can be assessed through asking the patient to demonstrate range of motion of the neck and upper extremities.

Skin biopsy — A skin biopsy should always be performed to confirm the clinical diagnosis and to rule out other diseases that might resemble scleredema. The biopsy must be sufficiently deep, as scleredema primarily involves the dermis and frequently extends to the subcutis. Thus, an incisional biopsy or a 6 mm or larger punch biopsy that includes subcutaneous fat is our preferred biopsy procedure. (See "Skin biopsy techniques", section on 'Punch biopsy'.)

Laboratory studies — No specific blood parameters exist for the diagnosis of scleredema. However, considering the three major etiologies of scleredema, serologic testing can be useful for identifying the associated disorder. Our typical laboratory workup includes:

●Antistreptolysin O (ASO) titer to evaluate for recent streptococcal infection

●Fasting plasma glucose or glycated hemoglobin (A1C) to evaluate for diabetes mellitus

●Serum protein electrophoresis and immunofixation to evaluate for monoclonal gammopathies

DIFFERENTIAL DIAGNOSIS — Several sclerotic disorders can share clinical features with scleredema. Careful clinical examination and review of the histopathological findings, as well as some laboratory studies are useful for distinguishing these conditions from scleredema. The most relevant disorders in the differential diagnosis of scleredema are:

●Systemic sclerosis – Systemic sclerosis (SSc) is a severe autoimmune disease that may affect the skin and internal organs such as the lungs, heart, kidneys, and gastrointestinal tract. SSc is divided into limited and diffuse disease, depending on the clinical features and serologic findings. Most SSc patients have antinuclear antibodies, and extractable nuclear antibodies such as anti-SCL-70 and anticentromere antibodies are highly specific to the disease. Unlike scleredema, skin sclerosis in SSc usually begins at the hands and distal extremities, leading in some cases to painful finger ulcerations. Facial manifestations of SSc include microstomia, facial telangiectasias, and mask-like skin on the face. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

●Scleromyxedema – Scleromyxedema is a rare condition characterized by massive deposition of mucin in the skin. Scleromyxedema is almost exclusively associated with monoclonal gammopathy. Clinically, scleromyxedema appears as erythematous, firm papules that coalesce into large, sclerotic plaques [3,27]. Typically-affected areas include the head (especially the glabella region, posterior auricular area, and neck) and the extremities (picture 3A-B). Internal organs can be involved. Unlike scleredema, fibroblast proliferation in the dermis is a characteristic histopathologic feature of scleromyxedema. (See "Scleromyxedema".)

●Generalized morphea – Generalized morphea (or generalized, localized scleroderma) is a subtype of localized scleroderma that affects more than three anatomical areas of the body. The most commonly affected sites are the trunk, thighs, and lumbosacral region (picture 4). The plaques are often distributed symmetrically and can coalesce into larger lesions [28]. (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults", section on 'Clinical manifestations'.)

●Eosinophilic fasciitis (Shulman syndrome) – Eosinophilic fasciitis (EF) is a rare fibrotic disease characterized by a rapid onset of symmetric edematous swelling of the proximal extremities. In the later stage of disease, lesions become more indurated and fibrotic, leading to the typical "peau d'orange"-like appearance (picture 5). Mechanical trauma often precedes the first manifestation of the disease. The histopathologic changes of EF are located in the fascia and fat tissue. Peripheral blood and tissue eosinophilia, hypergammaglobulinemia, and elevated C-reactive protein and erythrocyte sedimentation rate are typical for EF. (See "Eosinophilic fasciitis".)

●Nephrogenic systemic fibrosis – Nephrogenic systemic fibrosis (NSF) is a rare fibrotic disorder in individuals with acute or chronic kidney insufficiency induced by gadolinium-containing contrast agents. NSF is clinically characterized by rapid confluent sclerotic plaques that predominantly affect the extremities and may lead to severe joint contractures (picture 6). NSF is a progressive condition that can also affect the internal organs. The typical histopathology of NSF is characterized by thickened collagen bundles (extending into the subcutaneous fat tissue, fascia, and muscle) separated by large clefts and surrounded by CD34+ fibrocytes [3,29]. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)

Examples of other disorders that are occasionally in the differential diagnosis include lymphedema, cardiac or renal edema, radiation-induced skin fibrosis, and graft-versus-host disease.

TREATMENT — There is a lack of clarity on the best approach to the treatment of scleredema. Evidence on the efficacy of treatments such as phototherapy, immunosuppressants, radiation therapy, and physical therapy is primarily limited to observations documented in case reports and case series. No single treatment appears to be uniformly effective, and guidelines for treatment are mainly based on expert opinion [30].

Our approach — The uncertainty about the efficacy of treatments for scleredema supports a careful approach to treatment. Because the condition is benign and often asymptomatic, treatment of scleredema is not always necessary; we typically reserve treatment for patients who develop signs of functional impairment or have otherwise symptomatic disease. In addition, the prognostic differences between scleredema associated with upper respiratory infection and other forms of scleredema lead us to approach the management of these patients differently.

Scleredema associated with upper respiratory infection — Poststreptococcal scleredema often resolves within several months. Therefore, deferring treatment (a "wait and see" strategy), with the exception of physical therapy, is our preferred option for the initial management of these patients. Active infections that warrant treatment should be treated appropriately. We refer patients to physical therapy in an attempt to minimize the development of functional limitations during the active phase of the disease. (See 'Physical therapy' below.)

Therapeutic interventions used for other patients with scleredema may be attempted if signs of improvement are not evident within several months. Similar to other patients with scleredema, our first-line therapeutic intervention for patients with scleredema associated with upper respiratory infection is phototherapy. (See 'Clinical features' above and 'Scleredema related to other disorders' below.)

Scleredema related to other disorders — Scleredema that is not associated with upper respiratory infection usually exhibits a protracted course. Thus, treatment often is attempted in patients who develop physical limitations or who experience other bothersome symptoms related to scleredema. Our preferred initial regimen for patients with scleredema consists of physical therapy and phototherapy. We also ensure that the associated condition (eg, diabetes mellitus) is appropriately managed, though it has not been confirmed whether treatment of the associated disease impacts the clinical course of scleredema [17,31].

Physical therapy — Although frequently used in the management of patients with sclerotic skin disorders, little data exist on the value of physical therapy in scleredema. We refer all patients with scleredema to physical therapy in an attempt to minimize functional limitations related to reduced joint mobility. In a case report, combination treatment with ultrasonic massage and physical therapy seemed to improve mobility in a patient with diabetes mellitus-associated scleredema [32].

Phototherapy — Phototherapy is our preferred initial treatment for scleredema based upon a retrospective study and case reports documenting improvement in the clinical manifestations of scleredema with this therapy, the benefit from phototherapy observed in other sclerotic skin diseases, and the overall well-tolerated nature of phototherapy [6,33-39]. (See "Morphea (localized scleroderma) in adults: Management", section on 'Phototherapy'.)

Although studies to compare the efficacies of the various types of phototherapy have not been performed, ultraviolet A1 (UVA1) phototherapy is generally considered the preferred mode of phototherapy for sclerotic skin disease. Compared with broadband and narrowband UVB phototherapy (290 to 320 nm and 311 nm, respectively), the longer wavelengths of light administered during UVA1 phototherapy (340 to 400 nm) penetrate more deeply into the dermis. In addition, UVA1 eliminates the erythema-inducing and less-deeply penetrating shorter wavelengths of light included in broadband UVA phototherapy (320 to 400 nm). The mechanisms of action of UVA1 and other forms of phototherapy in sclerotic skin diseases are not fully understood, but may involve upregulation of matrix metalloproteinases or modulation of cytokines that promote collagen production [40]. (See "UVA1 phototherapy" and "Morphea (localized scleroderma) in adults: Management", section on 'Phototherapy'.)

Support for the use of UVA1 in scleredema is derived from observations in several patients who demonstrated moderate to marked improvement during UVA1 therapy [6,34-38]. As an example, in a series of five patients with scleredema who were treated with low-dose (20 to 30 J/cm²) or medium-dose UVA1 (50 to 60 J/cm²), four patients achieved at least 50 percent improvement [35]. Treatment is usually administered two to five times per week. The optimal treatment regimen remains unclear. Our preferred initial treatment course is medium-dose UVA1 given three to five times weekly.

Although initial signs of improvement are evident in some patients after fewer than 10 UVA1 treatments [36,37], more than 30 treatments may be necessary to achieve satisfactory results [40]. We typically prescribe an initial course of 40 treatments. Relapses after treatment cessation have been reported [40].

The availability of UVA1 phototherapy is primarily limited to academic centers, meaning that treatment with UVA1 is not always practical or feasible. Improvement in scleredema during psoralen plus UVA (PUVA) phototherapy [6,41-44] or narrowband UVB (311 nm) phototherapy [45] has been reported, and these modalities represent additional types of phototherapy that may be beneficial in scleredema. Treatment with PUVA requires the administration of a photosensitizer prior to light treatment; apparent benefit from PUVA has been reported in patients given the photosensitizer orally, in a bath, or as a topical cream [41-44].

Data on combination treatment with phototherapy and medical therapy are limited. Responses to broadband UVA or PUVA given in conjunction with oral colchicine have been documented in a few patients [46,47].

Adverse effects of phototherapy include erythema, blistering, pruritus, and accelerated skin aging. Increased risk for squamous cell carcinoma has been observed in patients receiving very high numbers of PUVA treatments for psoriasis. The impact of UVA1 treatment on risk for skin cancer is unclear. (See "UVA1 phototherapy" and "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Adverse effects' and "UVB phototherapy (broadband and narrowband)", section on 'Short- and long-term adverse effects'.)

Other interventions — A variety of other therapeutic interventions have been reported to be effective for scleredema in individual patients, including immunosuppressive drugs, radiation, and other therapies. Because of concern for treatment-related adverse effects, and consistent with the approach recommended in European Dermatology S1 guidelines, we reserve treatment with immunosuppressants and radiation for patients with persistent, debilitating disease who have failed or cannot receive phototherapy [6,30].

Immunosuppressants — Immunosuppressive agents that have appeared to be effective in a few patients with scleredema have included methotrexate, cyclosporine, and systemic glucocorticoids (eg, dexamethasone pulse therapy or high-dose intravenous glucocorticoids) [16,48-50].

The potential for severe adverse effects should be carefully considered prior to the initiation of immunosuppressive therapy. For example, the use of systemic glucocorticoids should be avoided in scleredema associated with diabetes mellitus.

Radiation — Electron-beam therapy has been linked to improvement in scleredema in several case reports, including patients who previously failed immunosuppression and other treatments [51-55]. The long-term efficacy of electron beam treatment is unclear; although sustained remission for two years after treatment has occurred [54], relapses within one to two years also have been reported [51].

The mechanism of action of radiation therapy in scleredema is unknown. It has been postulated that an inhibitory effect on fibroblasts or other cells that contribute to connective tissue or mucin production may play a role [51].

Acute adverse effects of electron-beam therapy include skin burns or irritation, pruritus, and fatigue. Long-term adverse effects include chronic skin changes and increased risk for cutaneous malignancy.

Other — Several other therapies have appeared beneficial for the management of scleredema in case reports, including intravenous immunoglobulins in poststreptococcal scleredema and paraproteinemia-associated scleredema; factor XIII infusions, prostaglandin E1, allopurinol, tamoxifen, and extracorporeal shock wave therapy combined with triamcinolone acetonide intralesional injections in diabetic scleredema; and thalidomide or bortezomib in multiple myeloma-associated disease [56-64]. Extracorporeal photophoresis, a treatment that has seemed useful in other sclerotic skin diseases, appeared to be beneficial in a patient with scleredema associated with paraproteinemia [65]. Additional data are necessary to confirm the efficacy of all of these treatments.

PROGNOSIS AND FOLLOW-UP — The course of scleredema varies. While many patients who develop scleredema after streptococcal infection experience spontaneous resolution, other patients experience a prolonged and slowly progressive disease course [6]. Depending on the severity of skin involvement, symptoms can range from only a mild sensation of stiffness to extensive sclerotic changes resulting in reduced mobility and significant disability. Scleredema generally is not life threatening. Fatalities resulting from scleredema are rare, and have appeared to result from cardiac or respiratory involvement [23,24].

We follow patients with scleredema periodically. Patients with active, progressing disease are reexamined at least every three months to determine whether alterations to the management plan are needed. We reexamine patients with stable disease at least once yearly.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Scleredema in adults".)

SUMMARY AND RECOMMENDATIONS

●Scleredema is a sclerotic skin disease that most often occurs in association with diabetes mellitus, infection (particularly streptococcal infection of the upper respiratory tract), or monoclonal gammopathy. Both children and adults may develop scleredema. The pathogenesis of scleredema is unclear. (See 'Epidemiology' above and 'Pathogenesis' above.)

●The clinical manifestations of scleredema typically occur on the upper body and manifest as diffuse, woody induration of the skin (picture 1A-C). Slight erythema or a peau d’orange appearance of the skin may be present. Slow progressive involvement of the posterior neck and upper back is common. In patients with scleredema associated with upper respiratory infection, the cervicofacial region often is the initial site of involvement. (See 'Clinical features' above.)

●The clinical course of scleredema varies. Spontaneous resolution often occurs in patients with poststreptococcal scleredema, whereas in other patients, the disease is usually progressive and chronic. (See 'Clinical features' above.)

●The diagnosis of scleredema is made by review of the patient history, physical examination, and skin biopsy. Laboratory studies are useful for detecting the presence of an associated disease. (See 'Diagnosis' above.)

●Data are limited for the treatment of scleredema preventing definitive conclusions about treatment efficacy. In an attempt to minimize the development of functional limitations we refer all patients to physical therapy. (See 'Treatment' above.)

●For scleredema that is not functionally limiting or otherwise symptomatic, additional treatment is not necessary. In addition, because of the likelihood of spontaneous resolution of post-streptococcal scleredema, the initiation of treatment other than physical therapy can be delayed in this population. (See 'Our approach' above and 'Scleredema associated with upper respiratory infection' above.)

●For patients with functionally limiting or symptomatic scleredema that is not expected to resolve spontaneously, we suggest initial treatment with phototherapy (Grade 2C). When available, we prefer to use UVA1 phototherapy. Improvement in scleredema has also been reported with PUVA and narrowband UVB phototherapy. (See 'Scleredema related to other disorders' above.)

●Other interventions such as immunosuppressive medications and radiation therapy have been reported to be effective in small numbers of patients with scleredema. Due to concern for adverse effects, we reserve these therapies for patients with persistent, debilitating disease who fail or cannot receive phototherapy. (See 'Other interventions' above.)