Are You Confident of the Diagnosis?
Characteristic findings on physical examination
The diagnosis of scleromyxedema is based upon the following clinico-pathologic criteria: 1) Generalized papular and sclerodermoid eruption; 2) Microscopic triad including mucin deposition, fibrosis and fibroblast proliferation; 3) Monoclonal gammopathy; absence of a thyroid disorder.
Scleromyxedema affects both genders and any ethnic background, with a predilection for middle-aged adults in their fifties. It is clinically characterized by a widespread symmetric eruption of 2-to-3 mm firm, waxy, dome-shaped or flat-topped papules, commonly over the hands, forearms, head and neck region, upper trunk, and thighs (Figure 1, Figure 2). The papules are closely spaced and often arranged in a striking linear array and the surrounding skin is indurated.
A pathognomonic sign is thickening of the glabella with deep longitudinal furrowing, giving the patient a leonine-like facial appearance (Figure 3). Retroauricular papular involvement is characteristic. Erythema, edema, and a brownish discoloration also may be seen in the involved areas; pruritus is not uncommon and a Koebner phenomenon, in response to scratching, may be present. The mucous membranes and scalp are spared.
Depending on the rapidity of onset and the degree of involvement, patients may be either initially asymptomatic or notice that their skin becomes thick and hard. The face shows a diffuse erythema with induration, coarsening, and grooving both in the forehead lines and in lateral portions of the chin. As the disease progresses, erythematous and infiltrated plaques with sclerodermoid induration, sclerodactyly and decreased motility of the mouth and joints occur.
As virtually all patients have acral skin induration, a central depression surrounded by an elevated rim on the proximal interphalangeal joints is referred to as the “doughnut sign.” Inquire whether the patient has other cutaneous manifestations as scleromyxedema is commonly associated with extracutaneous involvement leading to significant co-morbidity.
Expected results of diagnostic studies
When the disease is clinically suspected, we have to consider two further steps for confirmation: a skin biopsy and serum electrophoresis with immunofixation. The latter reveals the presence of a serum paraprotein (usually 7S-IgG) with lambda light chains.
Histopathology shows the microscopic triad of a diffuse deposit of mucin in the upper and mid-reticular dermis easily confirmed with an alcian blue or iron colloidal stain, an increase in collagen deposition and a marked proliferation of irregularly arranged fibroblast (Figure 4, Figure 5). Thyroid function test results are normal. Findings of other laboratory tests are usually normal, except in cases of specific extracutaneous symptoms where specific organ systems are affected. Further evaluation of these organs would then be warranted.
There is little value in imaging studies, although high-resolution cutaneous ultrasonography may become a useful diagnostic and disease activity monitoring tool for skin thickening.
The main differential diagnosis of scleromyxedema includes the following entities: 1) scleroderma (systemic sclerosis); 2) scleredema; and 3) nephrogenic systemic fibrosis. The presence of diffuse waxy papules in linear arrays and in a characteristic distribution on the glabellum and posterior auricular area and the IgG monoclonal gammopathy play in favor of a diagnosis of scleromyxedema.
In particular, nephrogenic systemic fibrosis, which develops in individuals with renal dysfunction and exposure to gadolinium, may have mucin and fibroblastic proliferation in biopsy specimens, but patients usually lack both facial involvement (commonly seen in scleromyxedema) and paraproteinemia. In the setting of mucinosis, scleromyxedema should be differentiated from the localized variants of lichen myxedematosus (Table I). In the past, the terms lichen myxedematosus, papular mucinosis, and scleromyxedema have been used interchangeably to describe the same disorder. This is not the case.
A spectrum of disease appears to exist, with the more localized, less severe forms in the absence of systemic manifestations, which are generally called lichen myxedematosus or papular mucinosis, and the more sclerodermoid, generalized form, which is referred to as scleromyxedema. The differential is not only a matter of semantics but is important for prognostic and therapeutic purposes.
|Scleromyxedema||Localized variants of lichen myxedematosus|
|Generalized papular eruption and sclerodermoid features||Papular eruption (or nodules and/or plaques due to confluence of papules)|
|Microscopic triad (mucin deposition, fibroblast proliferation, fibrosis)||Mucin deposition with variable fibroblast proliferation|
|Monoclonal gammopathy||Absence of monoclonal gammopathy|
|Absence of thyroid disorder||Absence of thyroid disorder|
Who is at Risk for Developing this Disease?
Patients with monoclonal gammopathy, especially of IgG lambda type but also IgG kappa type are at risk of developing scleromyxedema. This is a rare event, however, as monoclonal gammopathy of undetermined significance is common and reported in approximately 3% of persons older than 70 years while scleromyxedema is an uncommon disease, affecting middle-aged adults with only a few small series of patients and about 170 cases reported in the literature.
What is the Cause of the Disease?
The etiopathogenesis of scleromyxedema is unknown. The significance of the monoclonal gammopathy is a matter of debate.
Paraprotein levels do not correlate with either the extent or the progression of the disease. In addition, while sera from patients with scleromyxedema enhance fibroblast proliferation in vitro, an immunoglobulin purified from paraprotein-containing sera fails to do so, suggesting a pathogenetic role for circulating factors other than the paraprotein.
For example, circulating cytokines such as interleukin (IL)-1, TNF, and TGF-β are known to stimulate glycosaminoglycan synthesis in the skin or heparin sulfate proteoglycan obtained from scleromyxedema papules has been demonstrated to promote fibroblast growth factor activity.
Clinical remission of scleromyxedema following autologous hematopoietic stem cell transplantation points to the bone marrow as a source of these circulating factors. Lastly, the development of scleromyxedema following a cutaneous granulomatous reaction to intradermal injections of hyaluronic gel suggests the possibility of a human adjuvant disease.
Systemic Implications and Complications
Hematologic disorder in scleromyxedema patients includes a monoclonal gammopathy that is a diagnostic criterion, usually of IgG lambda-type. Although a mild plasmacytosis may be found in the bone marrow, scleromyxedema progresses to multiple myeloma in less than 10% of cases.
The musculoskeletal system is affected in 27% of patients, presenting with varying degrees of proximal muscle weakness, elevation of muscle enzymes, and inflammatory electromyographic findings.
Pulmonary involvement may manifest as obstructive or restrictive lung involvement in 17% of patients.
Central and peripheral nervous system involves 10% of patients and includes an unexplained encephalopathy with coma following a flu-like illness (dermato-neuro syndrome) and paresthesias. Arthralgias, arthropathies and carpal tunnel syndrome occur in 10% of cases.
Gastrointestinal involvement presents as progressive dysphagia due to esophageal induration.
Cardiovascular, renal and ocular manifestations may also occur. Mucin may fill the walls of myocardial blood vessels as well as the interstitium of the kidney, pancreas, adrenal glands and nerves.
In dermatoneural syndrome, brain autopsy has not been contributory and the pathogenetic basis of the encephalopathy remains obscure. Involvement of central nervous system, heart, kidney and the progression to overt myeloma worsens the prognosis.
Treatment options for scleromyxedema are summarized in Table II.
|Medical Treatment Surgical Procedures Physical Modalities|
|Topical and intralesional corticosterois|
|IVIG (intravenous immunoglobulin)|
|Chemotherapeutic agents (melphalan)|
|Granulocyte colony-stimulating factor|
|Autologous stem cell transplantation|
Optimal Therapeutic Approach for this Disease
There is no evidence to support any specific treatment for scleromyxedema because of lack of randomized clinical trials, limited number of case reports, incomplete understanding of the disease pathophysiology and variability of response to different therapeutic modalities.
In the past, monthly courses of melphalan were often the therapy of choice, targeting the plasma cell dyscrasia. This alkylating agent can result in some clinical improvement, but it has also been implicated in 30% of the deaths secondary to its induction of hematologic malignancies and septic complications. Other chemotherapeutic agents (eg, cyclophosphamide, methotrexate, chlorambucil, 2-chlorodesoxyadenosine) have been tried, but with no better results and similar side effects.
Intravenous immunoglobulins are an effective and relatively safe treatment for both cutaneous and extracutaneous manifestations of scleromyxedema, and especially in acute worsening of the clinical condition with neurologic symptoms. This is our first treatment of choice. The dose varies from 0.5 g to 2g/kg body weight, once monthly. The treatment usually results in almost total regression of skin papules, improvement of skin stiffness and mouth opening, increase in articular motility and reduction of sclerodactyly. The therapeutic response, however, is not permanent and maintenance infusions spaced out to every 2 months are required.
Although the mechanism of action is not fully understood, an immunomodulatory action has been proposed that includes neutralization of circulating autoantibodies by antiidiotype antibodies, functional blockade of Fc receptors on macrophages, inhibition of complement-mediated damage, modulation of the production of cytokines and cytokine antagonists with an antifibrotic mechanism, neutralization of pathogens involved in the cause of autoimmune disease, blockade of CD95 (Fas ligand) with inhibition of apoptosis.
Systemic steroids and/or thalidomide are considered our second choice of treatment. Prednisone or dexamethasone seems to target both the paraprotein production and the hyperactive fibroblasts through its immunosuppressive and anti-fibroblast effects.
Dexamethasone is an oral, long-acting corticosteroid with nearly 8 times more glucocorticoid potency than prednisone. Oral high-dose dexamethasone 40mg once daily for 4 days is given by consecutive weekly cycles each month for a total of 6 cycles. A maintenance therapy of 40mg once daily for 4 days every month is continued. This regimen is commonly used in the treatment of multiple myeloma.
Prednisone is usually started at a dose of 1/mg/kg/day until adequate clinical response occurs (usually at least 1 month); then, it is slowly tapered to a maintenance therapy of 10 mg on alternate days, according to the persistence of the improvement.
Thalidomide at doses of 100 to 300mg has also been shown to improve symptoms of scleromyxedema for its antiangiogenic, anti-inflammatory and immunomodulatory properties, including reduction in the plasma concentration of the monoclonal immunoglobulin, but the teratogenicity and risk of potentially irreversible peripheral neuropathy limit its use.
Autologous peripheral blood stem cell transplantation has been reported to produce dramatic results in some patients and can be considered as a third line of treatment. Although not a curative treatment, it may be used before alkylating agents that could adversely affect the ability to collect stem cells. Other therapies targeting plasma cell dyscrasia such as lenalidomide and bortezomib have been tried with variable results and non-negligible side effects. Systemic retinoids, especially isotretinoin, gave good results only on an anecdotal basis (0.50 to 0.75 mg/kg/day). Interferon-α has led to paradoxical effects, with both improvement and worsening of the disease.
In our opinion, the use of potentially toxic drugs should be limited to patients who are disfigured, disabled, or very ill. Skin-limited cases will be managed less aggressively than those yielding functional impairment, and the use of ultrapotent topical corticosteroids (such as clobetasol) or topical calcineurin inhibitors (such as tacrolimus 0.1% ointment) can be considered. For resistant or nodular areas, intralesional steroids (triamcinolone 10mg/cc) are helpful.
The use of combinations of therapeutic modalities for any potential synergistic effect should be tried, especially in recalcitrant and disabling cases.
Dysarthria and a flu-like illness may herald coma, and the patient should be promptly admitted to hospital for close observation.
Lastly, on occasion, spontaneous improvement and clinical resolution, even after 15 years, have been described. This event has never been observed in our experience.
Explain the chronic and unpredictable course of scleromyxedema to the patients so that they understand that there is no specific definitive treatment and the therapeutic response varies. Even after a good initial response, the disease tends to relapse after withdrawal of the therapy and a maintenance treatment is required.
A good approach is to determine how severe scleromyxedema is, what degree of extracutaneous involvement occurs, and what effect it is having on the patient’s quality of life. Skin-limited cases will be managed less aggressively. A high-resolution ultrasound or MRI performed at baseline, repeated annually, to measure dermal thickness, is of value in objectively determining if a patient is responding to therapy.
The risks of any potential systemic treatment must be carefully weighed against potential benefit and discussed with the patient. Patients requiring systemic, potentially aggressive treatments (systemic corticosteroids, IVIG, thalidomide, cytotoxic agents, etc) need to be seen repeatedly for the appropriate monitoring for that drug or modality. Referral to a hematologist-oncologist or rheumatologist familiar with the use of cytotoxic agents is warranted. Due to its unpredictable course, patients with skin-limited disease need to be seen periodically (every 3 months).
The serum protein electrophoresis should be repeated annually, and, if there is any concern for a rise in the level of monoclonal protein, patient should be sent to a hematologist. A quantitative immunoglobulin measurement to follow up the progress of the monoclonal gammopathy can be done.
An endpoint to treatment is difficult to achieve as recurrence is almost always the rule after withdrawal of the therapy. A maintenance therapy should be scheduled on a regular basis according to the patient‘s response, compliance and side effects.
Unusual Clinical Scenarios to Consider in Patient Management
Remember that although rare, unusual presentations of scleromyxedema may occur. Monoclonal gammopathy may be lacking in appoximately 10% of patients with scleromyxedema and overlapping features with localized lichen myxedematosus may occur (atypical forms). Under these circumstances, a careful follow-up and assessment of immunoelectrophoresis is important.
Histologically, scleromyxedema may present with an unusual granulomatous pattern reminiscent of interstitial granuloma annulare, which expands the spectrum of the disease and highlights the difficulty in diagnosing this disabling condition. This granulomatous pattern could represent a histiocytic response to the monoclonal gammopathy as it has been previously suggested for the granulomatous response to lymphomas.
Anti-TNF therapies (infliximab, adalimumab, etanercept) could be taken into consideration in the future as TNF has been proved to stimulate mucin production from fibroblast in vitro.
What is the Evidence?
Rongioletti, F, Smoller, BR. Clinical and pathological aspects of skin diseases in endocrine, metabolic, nutritional and deposition disease. 2010. pp. 139-52. (A thorough up-to-date review of the cutaneous mucinoses including the details on the diagnosis and management of scleromyxedema, and the associations with other systemic manifestations.)
Rongioletti, F, Rebora, A, Bolognia, JL, Jorizzo, JL, Rapini, RP. “Mucinoses”. Dermatology. 2008. pp. 611-21. (Etiopathogenesis, clinical and pathologic presentations, differential diagnoses, treatment and prognosis of scleromyxedema are reviewed.)
Cokonis Georgakis, CD, Falasca, G, Georgakis, A, Heymann, WR. “Scleromyxedema”. Clin Dermatol. vol. 24. 2006. pp. 493-7. (Another good review of the main aspects of scleromyxedema.)
Rongioletti, F. “Lichen myxedematosus (papular mucinosis): new concepts and perspectives for an old disease”. Semin Cutan Med Surg. vol. 25. 2006. pp. 100-4. (The new classification of lichen myxedematosus and the importance in differentiating scleromyxedema from localized lichen myxedematosus for therapeutic and diagnostic purposes are presented.)
Dinneen, AM, Dicken, CH. “Scleromyxedema”. J Am Acad Dermatol. vol. 33. 1995. pp. 37-43. (One of the largest series of scleromyxedema patients ever reported with important information on the extracutaneous manifestations, outcome, response to therapy and consequences with alkylating agents.)
Rey, JB, Luria, RB. “Treatment of scleromyxedema and the dermatoneuro syndrome with intravenous immunoglobulin”. J Am Acad Dermatol. vol. 60. 2009. pp. 1037-41. (Increasing evidence supports intravenous immunoglobulin as an effective and relatively safe treatment for both cutaneous and extracutaneous manifestations of scleromyxedema, including the dermatoneuro syndrome.)
Rongioletti, F, Cozzani, E, Parodi, A. “Scleromyxedema with an interstitial granulomatous-like pattern: a rare histologic variant mimicking granuloma annulare”. J Cutan Pathol. vol. 37. 2010. pp. 1084-7. (Anecdotal report of an unusual histologic presentation of scleromyxedema mimicking a granulomatous disease.)
Ataergin, S, Arpaci, F, Demiriz, M, Ozet, A. “Transient efficacy of double high-dose chemotherapy and autologous peripheral stem cell transplantation, immunoglobulin, thalidomide, and bortezomib in the treatment of scleromyxedema”. Am J Clin Dermatol. vol. 9. 2008. pp. 271-3. (Aggressive therapies for scleromyxedema, such those used for multiple myeloma, are valid but burdened by side effects and transient efficacy.)
Efthimiou, P, Blanco, M. “Intravenous gammaglobulin and thalidomide may be an effective therapeutic combination in refractory scleromyxedema: case report and discussion of the literature”. Semin Arthritis Rheum. vol. 38. 2008. pp. 188-94. (The use of combinations of therapeutic modalities for any potential synergistic effect can be tried, especially in recalcitrant and disabling cases.)
Blum, M, Wigley, FM, Hummers, LK. “Scleromyxedema: a case series highlighting long-term outcomes of treatment with intravenous mmunoglobulin (IVIG)”. Medicine (Baltimore). vol. 87. 2008. pp. 10-20. (The therapeutic benefit and the long-term use of IVIG in a series of patients is highlighted.)
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