Scleredema 

Updated: Mar 15, 2019
Author: Lisa K Pappas-Taffer, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Scleredema is an uncommon, but likely underrecognized, fibromucinous connective-tissue disease. It is characterized clinically by woody induration and hardening of the skin that results from excessive mucin deposition between thickened collagen bundles in the skin's dermis. The term scleredema is a misnomer because neither sclerosis nor edema is found on microscopic examination.

There are three clinical forms of scleredema, which are classified by their associated condition. Scleredema may be associated with a history of an antecedent infection (type 1), a blood dyscrasia (type 2), or diabetes mellitus (type 3). Each of these clinical forms has a different history, course, and prognosis. There are also rare reports of scleredema associated with other disorders, as well as occurring independent of an associated disorder. Additional reported associations include the following:

  • Hyperparathyroidism[1]

  • Rheumatoid arthritis and Sjögren syndrome[2]

  • HIV disease and AIDS–related lipodystrophy syndrome[3]

  • Malignant insulinoma[4]

  • Carcinoid of the gall bladder[5]

  • Carcinoid tumor[6]

  • Lichen sclerosus[7]

Scleredema can be a self-resolving or a persistent skin condition. It is typically considered benign, but it can involve internal organs and rarely may result in death. There is no standard therapeutic protocol, as therapeutic success in the literature is limited to case reports.

Pathophysiology

Increased deposition of collagen and mucin (hyaluronic acid, an acid mucopolysaccharide) is seen in this condition; however, the causative mechanism is unknown.

Theories for diabetes-associated scleredema include accumulation of collagen as the result of irreversible collagen glycosylation and resistance to degradation by collagenase; alternatively, increased collagen synthesis due to excess insulin stimulation, microvascular damage, and hypoxia has been suggested.

Theories for nondiabetic scleredema include molecular mimicry, in which streptococcal antigens cross-react with components of the dermis resulting in an antigen-antibody reaction.  

Etiology

The cause of scleredema is unknown; however, it is associated with a number of conditions. Many patients have no history of an acute antecedent illness. Note the following:

  • Febrile illness with streptococcal infections[8, 9] : An upper respiratory tract infection (typically pharyngitis) is the most common cause of scleredema in patients with type 1 scleredema. Scleredema following scabies infestation, as a result of superinfection with Streptococcus, has been reported.[10]

  • Other infections: The onset of scleredema has also been associated with cytomegalovirus infection, influenza, measles, pertussis, mumps, diphtheria, typhus fever, encephalitis, and dental abscesses.

  • Myelomatous disorders[11, 12] : A subset of patients with type 2 scleredema has shown a well-established relationship between scleredema with paraproteins and multiple myeloma. One analysis of 52 patients with group 2 scleredema revealed 25% had plasma cell dyscrasia, including 3 patients with multiple myeloma and 10 with monoclonal gammopathy of unknown significance.[13]

  • Diabetes mellitus[14, 15] : Patients usually have a longstanding history of diabetes, often poorly controlled.

  • Trauma: Rare reports exist of scleredema occurring after trauma to the affected area. One report has described geometric scleredema due to mechanical stress.[16]

  • Drug reaction: In 2005, scleredema was reported in association with the use of infliximab; although rare, treating physicians should consider the possibility of an adverse drug reaction as the underlying etiology.[17]

Epidemiology

Frequency

Worldwide, scleredema is rare, although diabetes-related scleredema is likely underreported.[18, 19]

Race

No racial predilection is reported for scleredema.

Sex

A female preponderance is reported for scleredema, with a female-to-male ratio of 2:1 for non–diabetes-related scleredema. Adult-onset diabetes associated scleredema is much more common in men, with a male-to-female ratio of 10:1.

Age

Scleredema occurs in individuals of all ages, ranging from infancy to adulthood.[20] Although scleredema is sometimes referred to as scleredema adultorum, 50% of scleredema cases occur in individuals younger than 20 years. The majority of childhood cases are postinfectious and self-resolving.[21, 22]

Prognosis

The course of scleredema is unpredictable. Patients with type 1 scleredema, particularly pediatric patients, typically have a self-limited course, with the disease resolving in 6 months to 2 years. However, a number of reports exist in which these patients had a protracted course or, rarely, long-term cardiac or skeletal muscle involvement. Patients with types 2 and 3 typically have a slowly progressive or unremitting course over many years. Reports of relapses following apparent improvement also exist.

Typically, scleredema is a benign process limited to the skin. The skin changes of scleredema can cause limitations of movement. Rarely, this can include reductions in joint mobility, difficulty opening eyes or mouth, or restrictive lung disease in extensive trunk involvement.

Although the disorder is usually restricted to the skin, the tongue, pharynx, esophagus, skeletal muscle, and cardiac muscle may rarely be affected. Rare case reports of morbidity due to extracutaneous collagen and mucin deposition include the following:

  • Tongue involvement: Unlike scleroderma, the tongue has been reported in scleredema, resulting in dysarthria and difficulty with mastication and tongue protrusion.

  • Cardiac involvement: This may result in cardiomyopathy, heart failure, arrhythmias, pericardial effusion, and unexplained murmurs.[13, 21]

  • Other organs involvement: Skeletal muscles, ocular muscles, the pharynx, the liver, parotid glands, pleurae, the peritoneum, and the spleen reportedly may be involved.

  • Esophageal involvement: In one report, a patient with scleredema developed dysphagia, presumably from scleredema of the upper part of the esophagus. Esophageal biopsy was not performed on this patient.[23]

Death from scleredema is rare. However, reports have described patients dying from the complications of cardiac or respiratory involvement.[13, 24]

 

Presentation

History

Patients report stiff or hard skin. The rapidity of onset and locations of involvement differ based on the clinical subgroup. A thorough history regarding preceding illnesses, history of diabetes, and a review of systems should be performed to help identify less commonly associated extracutaneous manifestations (lungs, heart, trouble eating or talking, or muscle weakness) or, rarely, reported associations with malignancies.

Scleredema can be categorized into three clinical subgroups. Each has a different history, course, and prognosis. Note the following:

Type 1, postinfectious

This subgroup was historically referred to as scleredema adultorum. However, this is considered by some to be a misnomer because most pediatric patients fall into this group. Patients report a hardening of the skin a few weeks after a febrile illness, most commonly an upper or lower respiratory tract streptococcal infection.[25] The skin hardening progresses rapidly, first involving the face and neck, then spreading distally to involve the trunk and proximal upper limbs in a symmetric manner. Hands and feet are typically spared. Complications may include difficulty in smiling, opening the mouth, limited range of motion, and, in severe cases, involvement of the pharynx or tongue can lead to dysphagia or dysphonia. The condition usually clears spontaneously in 6 months to 2 years. The duration is not affected by the use of antibiotics.

Type 2, associated plasma dyscrasia

This subgroup includes patients whose disease tends to occur insidiously, progressing slowly over many years, with no history of preceding illness. Rimon et al identified 52 cases of type 2 scleredema in the world literature from 1963 to 1986, of which 25% had plasma cell dyscrasias, including 3 with multiple myeloma and 10 with monoclonal gammopathy of unknown significance. They also noted that the gammopathies were diagnosed on average 10 years after the onset of scleredema skin changes.[13] IgG monoclonal gammopathy is most common, followed by an IgA type. Spontaneous remission is much less likely to occur than in the type 1 subgroup.

Type 3, associated diabetes mellitus (scleredema diabeticorum)

This subtype of scleredema tends to occur more often in middle-aged males (at a reported 10:1 ratio), often obese, with longstanding, often uncontrolled, diabetes mellitus. In a 2015 multicenter study, 30 (68%) of 44 patients with scleredema had poorly controlled diabetes, with a type 2‒to‒type 1 ratio of 6.5:1.[26] Subtle skin hardening of the upper back begins in an insidious manner, progressing slowly over many years, to involve the upper back, neck, and shoulders with associated erythema; often, a pebbled appearance may evolve. Patients typically experience a more protracted course that is refractory to therapy. Control of the hyperglycemia does not improve the scleredema.[27]

Physical Examination

Scleredema presents as ill-defined, woody, nonpitting, indurated plaques. Generalized cases may clinically mimic edema. Erythema, hyperpigmentation, and/or a peau-d'-orange appearance of the affected areas may be present. The taught skin may appear shiny, and, when pinched, firmness is appreciated with noted wrinkling of overlying epidermis.

Scleredema is usually most evident in the upper part of the body, specifically the face, the neck, the trunk, and the extremities in type 1 and 2 subgroups. However, a case of scleredema confined to the thighs[28] and a case of scleredema confined to the periocular region[29] have been reported. Hands and feet are typically spared in scleredema, in contrast to systemic sclerosis, which has sclerodactyly. Scleredema patients with extensive facial involvement may appear expressionless and may have difficulty in opening their mouths. They may have difficulty with tongue protrusion.

Physical examination should include evaluation of range of motion of the neck, upper extremities, and tongue. Auscultation of the heart and lungs should also be performed.

Note the images below:

Middle-aged man who has diabetes with scleredema o Middle-aged man who has diabetes with scleredema on the upper part of the back.
Middle-aged man who has diabetes with scleredema o Middle-aged man who has diabetes with scleredema on the upper part of the back.

Complications

Complications include the following:

  • Limited range of motion
  • Poor wound healing
  • Recurrent skin infections
  • Restrictive lung disease
  • Dysarthria
  • Dysphagia
  • Difficulty in closing the eyes
  • Death (rare)
 

DDx

 

Workup

Laboratory Studies

Laboratory studies can be helpful to identify an associated condition:

A throat culture should be obtained in scleredema patients to exclude group A streptococcal infection.

Antistreptolysin-O (ASO) titers should be obtained in scleredema patients to exclude a recent infection with group A streptococci in a patient without clinically apparent pharyngitis or other infectious etiology.

Fasting blood glucose or glycosylated hemoglobin (A1C) measurements should be obtained in scleredema patients to rule out diabetes mellitus.

Serum protein electrophoresis (SPEP) and immunofixation should be performed in scleredema patients to exclude a monoclonal gammopathy. Both paraproteinemias (also known as monoclonal gammopathies) and multiple myelomas have been reported in patients with scleredema (type 2). The most commonly identified paraprotein is IgG having a kappa light chain; however, an IgA type can occur. Blood dyscrasias usually appear several years after the onset of scleredema. The interval between diagnosis of scleredema and the detection of paraprotein can occur before, concurrently, or after the diagnosis of scleredema. In one report, a delayed paraproteinemia was detected on average up to 10 years following the diagnosis of scleredema.[13] However, other sources quote a median detection of paraproteinemia 2.5 years after diagnosis.

Imaging Studies

No imaging studies are necessary for the diagnosis of scleredema.

Isolated case reports have described scleredema occurring in association with internal malignancies (eg, carcinoma of the gall bladder,[5] malignant insulinoma,[30] carcinoid tumor[6] ). Imaging studies are warranted if this is suggested based on clinical findings.

Some investigators have proposed ultrasonic imaging of skin thickness in scleredema patients as a method to monitor the response to therapy. Computed tomography may demonstrate induration in the involved soft tissues, although it is not often necessary. MRI may highlight the involved areas as well, and some have advocated for MRI usage to determine the extent of disease and monitor progression in select cases.[31]

Other Tests

A punch biopsy or incisional biopsy of lesional skin that extends to include subcutaneous fat is recommended.

Histologic Findings

The histopathologic analysis reveals a normal epidermis with a thickened dermis and increased spaces between large collagen bundles. The space results from increased deposition of mucopolysaccharide (hyaluronic acid) in the dermis. The mucin is more prominent in the deep dermis. In some cases, mucin is better detected in unfixed sections stained at a pH of 7.0 with toluidine blue, or in tissue fixed with 0.05% or 1% cetylpyridinium chloride solution and stained with Alcian blue at a pH of 2.5.

Appendiceal structures in scleredema remain unchanged (unlike scleroderma) and there is an absence of a fibroblast proliferation (unlike scleromyxedema or nephrogenic systemic fibrosis).

 

Treatment

Medical Care

Treatment is unnecessary for postinfectious scleredema as it is typically self-limited. However, in rapidly progressive, fulminant cases, systemic therapy is recommended.[32] Physical therapy, intravenous immunoglobulin, or UVA-1 phototherapy could be considered.

Types 2 and 3 scleredema associated with a monoclonal gammopathy or diabetes typically does not regress spontaneously, and no therapy is consistently effective. Most therapeutic successes described are limited to single case reports or small case series; there are no comparative data and no approved algorithm for scleredema treatment. Expert opinion also differs. In general, it is agreed that treatment of an identified cause is warranted. For type 1 scleredema, antimicrobial agents are used if indicated. For type 2 scleredema, annual screening for a lymphoproliferative disorder, and for those with a monoclonal gammopathy, referral to a hematologist are, indicated. Physical therapy should be considered for all types. However, expert opinion often differs based on personal experience. In a 2017 publication of the European dermatology forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, first-line recommendations were UVA-1 phototherapy or psoralen with UVA (PUVA).[33]

Treatments described in case reports and small case series

A number of therapies, including systemic steroids,[26, 34, 35] cyclosporine,[26, 36] methotrexate,[37] high-dose penicillin,[15, 26] penicillamine, electron beam,[38, 39] and glycemic control with prostaglandin E1 (PGE1)[14] have been reported with mixed success. A report using tamoxifen for its antifibrotic properties noted improvements in two patients.[40] Incidental improvement was noted in one case of scleredema during allopurinol therapy.[41] A 2018 report described three cases of successful treatment with tranilast.[42]

Case reports in the literature describe improvement with UVA-1 phototherapy,[26, 43, 44] narrow-band UVB phototherapy,[45, 46] and PUVA either administered systemically or topically.[26, 47, 48, 49, 50] Case reports also describe these successfully used in combination with colchicine,[51, 52] methotrexate,[53] and physiotherapy.[54] In the authors’ experience, narrow-band UVB phototherapy was not successful.

Physical modalities, such as ultrasonic massage with physical therapy, may improve range of motion and quality of life for some patients alone or in combination with other therapies.[55]

In cases associated with myeloma, chemotherapy directed at the hematologic malignancy has been reported to result in concomitant improvement of the skin disease.[56] For patients with paraproteinemia, extracorporeal photophoresis has been used.[57]

Multiple reports described efficacy with intravenous immunoglobulin therapy in postinfectious, diabetic, and monoclonal gammopathy–associated scleredema that were refractory to more standard therapies.[58, 59, 60]

A 2015 multicenter retrospective review of associations and treatment response among 44 patients was published, finding some response to physiotherapies, systemic steroids, UVA-1, PUVA, and a few combination therapies in a limited number of patients.[26]

Treatment of associated conditions

Appropriate antibiotic therapy should be started in scleredema patients if infection is detected, although antibiotics do not appear to shorten the course of skin findings in scleredema.[61]

Treatment of detected blood dyscrasias or diabetes mellitus should be completed.

Consultations

Consultation with a dermatologist to confirm the diagnosis is recommended.

Consultation with a hematologist may be necessary. Refer patients in cases of detected blood dyscrasias and/or monoclonal gammopathies.

Consultation with a physical therapist may be necessary. Refer patients with range-of-motion difficulties. Prompt attention to physical therapy can potentially reduce long-term range-of-motion limitations.

Diet

No restrictions are necessary.

Activity

No restrictions are necessary.

Long-Term Monitoring

Patients with longstanding scleredema should be periodically monitored using the results of serum protein and immunoprotein electrophoresis to detect the development of paraproteinemia or myeloma. Blood dyscrasias may occur several years after the onset of scleredema.

 

Medication

Medication Summary

There are no comparative data and no approved algorithm for scleredema treatment. Treatments described in case reports and small case series are described in Medical Care.