Scleromyxedema

INTRODUCTION — Scleromyxedema, also known as diffuse/generalized and sclerodermoid lichen myxedematosus or Arndt-Gottron disease, is a primary cutaneous mucinosis characterized by a generalized, papular and sclerodermoid, cutaneous eruption that usually occurs in association with monoclonal gammopathy [1]. Affected patients develop numerous waxy, firm papules and plaques that demonstrate mucin deposition, increased fibroblast proliferation, and fibrosis on histologic examination. Systemic manifestations may involve the cardiovascular, gastrointestinal, pulmonary, musculoskeletal, renal, or nervous systems and may lead to significant morbidity and mortality.

Scleromyxedema should be distinguished from localized lichen myxedematosus, a form of lichen myxedematosus that presents with waxy, firm papules and plaques involving limited areas. Unlike scleromyxedema, sclerotic features, systemic involvement, and monoclonal gammopathy are absent in localized lichen myxedematosus. Scleroderma and scleredema are additional disorders that present with sclerodermoid features but are unrelated to scleromyxedema. Scleromyxedema is also distinct from myxedema of thyroid disease.

●(See "Localized lichen myxedematosus".)

●(See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

●(See "Scleredema".)

●(See "Clinical manifestations of hypothyroidism".)

The clinical features, diagnosis, and management of scleromyxedema will be reviewed here.

EPIDEMIOLOGY — Scleromyxedema is a rare disease that usually affects middle-aged adults between the ages of 30 and 80 years with no race or sex predominance [1]. In a multicenter, retrospective study of 30 patients with scleromyxedema, the mean age of affected patients was 59 years [1]. This illness is extremely rare in infants and young children.

PATHOGENESIS — The pathogenesis of scleromyxedema is unknown. The significance of the associated monoclonal gammopathy and the underlying plasma cell clone is debated. The main hypothesis is that circulating cytokines, such as interleukin (IL) 1, tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta, known to stimulate glycosaminoglycan synthesis and fibroblast proliferation in the skin, could play a role [2-4].

A promoting role of TGF-beta has also been identified in case series by analysis of RNA in involved skin tissue [5,6]. New insights were added by a study in which abnormally high secretion of IL-4, a profibrotic cytokine, was found in serum from scleromyxedema patients, suggesting a chronic Th2-skewed T cell response against an unknown target antigen [7]. The same study also found that both CD4+ and CD8+ T cells from patients with scleromyxedema present a profound deficiency (even after stimulation) of the production of interferon-gamma and IL-17 with respect to healthy donor control cells. Involvement of interferon pathways has been previously suggested, and the role of interferon-gamma in scleromyxedema could be related to the lack of its inhibitory effect on both proliferation and extracellular matrix production by fibroblasts.

Clinical remission of scleromyxedema following autologous stem cell transplantation suggests that the bone marrow may be a source of these circulating factors [2,8]. (See 'Severe and refractory disease' below.)

Many authors have also suggested that paraproteins themselves may be pathogenic, acting as autoantibodies that stimulate fibroblasts to proliferate and overproduce mucin. However, data conflict on the relevance of this theory. Although serum isolated from patients with scleromyxedema has enhanced fibroblast proliferation in some in vitro studies [9,10], one of these studies also found that purified immunoglobulin from the serum did not stimulate fibroblast growth [9]. In addition, a study in which serum from a patient with scleromyxedema was found to increase production of hyaluronic acid (a component of mucin) and prostaglandin E by fibroblast cultures did not find a stimulatory effect of the serum on fibroblast proliferation [11]. Moreover, paraprotein levels usually do not correlate with the severity of disease, disease progression, or the response to treatment [1]. Only on anecdotal basis has the complete resolution of skin lesions coincided with the normalization of the bone marrow and the disappearance of the paraprotein [12].

Additional theories on the pathogenesis of scleromyxedema have been proposed. It has been suggested that an intrinsic abnormality of scleromyxedema fibroblasts may result in increased glycosaminoglycan synthesis [13]. In addition, case reports documenting the development of scleromyxedema following a cutaneous, granulomatous reaction after intradermal hyaluronic gel injections [14] or after breast silicone implantation [1] may suggest a type of autoimmune syndrome induced by adjuvants.

CLINICAL FINDINGS — The clinical manifestations of scleromyxedema include both cutaneous and extracutaneous features.

Cutaneous manifestations — The characteristic skin finding in scleromyxedema is a widespread eruption of 2 to 3 mm, firm, waxy, closely spaced, dome-shaped or flat-topped papules involving the hands, forearms, head, neck, upper trunk, and thighs (picture 1A-B) [2,3]. Papules are often arranged in a strikingly linear array, and the surrounding skin is shiny and indurate (ie, sclerodermoid) in appearance (picture 2). Rarely, nontender subcutaneous nodules are present. The glabella is typically involved with deep, longitudinal furrows that produce the characteristic leonine face (picture 3). Deep furrowing also is typically evident on the trunk or limbs associated with redundant skin folds (known as "Shar-Pei sign") (picture 1C). Erythema, edema, and a brownish discoloration may be seen in the involved areas; pruritus is not uncommon.

Eyebrow, axillary, and pubic hair may be sparse in patients with scleromyxedema. The mucous membranes are spared. As the condition progresses, erythematous and infiltrated plaques may appear with skin stiffening, sclerodactyly, and decreased motility of the mouth and joints. On the proximal interphalangeal joints, a central depression surrounded by an elevated rim (due to skin thickening) can be seen and is referred to as the "doughnut sign" (picture 4). Unlike scleroderma, telangiectasias and calcinosis are absent. Although rare, the Raynaud phenomenon occurs.

Extracutaneous manifestations — Patients with scleromyxedema can have a number of internal manifestations, including neurologic, rheumatologic, cardiovascular, gastrointestinal, pulmonary, and renal manifestations of the disease. In a multicenter, retrospective study of 30 patients with scleromyxedema, the most common extracutaneous manifestations were neurologic abnormalities (30 percent of patients), rheumatologic abnormalities (25 percent of patients), and cardiac abnormalities (22 percent of patients) [1]. In a retrospective study of 33 patients with scleromyxedema from France, the most frequent complications were carpal tunnel syndrome and arthralgia, occurring in 33 and 27 percent of patients, respectively [5].

●Neurologic – Neurologic complications may involve the peripheral nervous system (eg, carpal tunnel syndrome or peripheral sensory and motor neuropathy) or the central nervous system (eg, memory loss, vertigo, gait problems, stroke, seizures, psychosis, or "dermato-neuro syndrome") [5,15,16]. Carpal tunnel syndrome is thought to be due to either deposition of glycosaminoglycans in the carpal tunnel or to a direct toxic effect in the median nerve [17]. The dermato-neuro syndrome is an occasionally lethal, acute, neurologic complication characterized by fever, confusion, dysarthria, lethargy, convulsions, and coma [16,18]. The dermato-neuro syndrome often is preceded by flu-like symptoms. In the French series, 18 percent of patients had dermato-neuro syndrome [5].

●Rheumatologic – Rheumatologic manifestations are characterized by arthralgias or arthritis of the peripheral joints, especially of the hands, with noninflammatory synovial fluids [19]. A severe, destructive polyarthritis resembling rheumatoid arthritis also has been reported [20]. Proximal or generalized weakness due to inflammatory myopathy and fibromyalgia is common and usually occurs several months or years after the onset of skin involvement [4,21]. In these patients, muscle biopsy reveals a necrotizing and vacuolar myopathy; interstitial inflammatory infiltrates are found uncommonly and may cause confusion with polymyositis. A few cases of true dermatomyositis have been described in association with scleromyxedema [22]. Spontaneous or interferon alfa-induced rhabdomyolysis is an additional rare finding [23,24].

●Cardiovascular – Cardiovascular abnormalities with congestive heart failure, myocardial ischemia, heart block, and pericardial effusion may occur [1,25,26]. Valvular mucin deposition has been described in a case report [27].

●Gastrointestinal – Dysphagia is the most common gastrointestinal manifestation and is related to esophageal dysmotility mainly localized to the upper esophagus [28]. Dysphagia is most commonly found in patients with an associated myopathy. Nasal regurgitation may also occur [28].

●Respiratory – Dyspnea on exertion is the most common pulmonary finding, due to obstructive or restrictive pathology [28-30]. In addition, hoarseness and aspiration may occur due to laryngeal involvement with decreased epiglottis and vocal cord mobility [31].

●Renal – Involvement of the kidney, characterized by a scleroderma renal crisis-like acute renal failure, is a rare event [32].

●Ocular – Infrequently, corneal opacities and ectropion are seen.

The pathogenesis of the extracutaneous manifestations of scleromyxedema is unclear. It has been suggested that mucin deposition in various organs may be the cause, although mucin is not consistently found on autopsy in fatal cases [33,34].

In dermato-neuro syndrome, brain autopsy has not been contributory, and the pathogenic basis of the encephalopathy remains obscure [16]. It has been proposed that an increased blood viscosity with impaired microcirculation due to paraproteinemia may result in encephalopathy. A pathogenic role for immunoglobulin G (IgG) crossing a damaged blood-brain barrier, mediated by increased interleukin (IL) 6 production, has also been suggested [16,35]. Some authors have proposed viral infection-associated elevation of IL-6 as a contributing factor. Supportive observations include the frequent association of the syndrome with a flu-like prodrome or upper respiratory infection symptoms and reports of the onset of dermato-neuro syndrome in conjunction with influenza or coronavirus disease 2019 (COVID-19) [36-38].

ASSOCIATED DISORDERS — Scleromyxedema is usually associated with monoclonal gammopathy. The monoclonal protein is most commonly IgG-lambda [1,5,28,29]. However, less frequently, a different monoclonal protein type is present [28]. Patients with scleromyxedema in the absence of monoclonal gammopathy are considered to have an atypical form of the disease. (See "Diagnosis of monoclonal gammopathy of undetermined significance" and "Clinical course and management of monoclonal gammopathy of undetermined significance".)

A mild plasmacytosis may be found in the bone marrow of patients with scleromyxedema. However, the disease is estimated to progress to multiple myeloma in less than 10 percent of cases, similar to monoclonal gammopathy of undetermined significance [4]. Anecdotal associations with hematologic malignancies (such as Hodgkin and non-Hodgkin lymphomas, Waldenström macroglobulinemia, lymphoid leukemia, and myelomonocytic leukemia) or visceral carcinomas have been reported [1,39-41]. Although treatment of the primary cancer may result in the regression of the skin lesions, no clear association with any specific noniatrogenic neoplasm has been identified. Most hemolymphoproliferative malignancies in these patients are iatrogenic and associated with the use of melphalan treatment [28].

CLINICAL COURSE — Scleromyxedema follows a chronic, progressive, and sometimes unpredictable course [3]. Depending on the rapidity of onset and the degree of involvement, patients may be either initially asymptomatic or may notice that skin becomes thick and hard and that the face shows a diffuse induration and coarsening in the forehead lines and in lateral portions of the chin. As the disease progresses (usually over the course of years and, occasionally, over the course of several months), a diffuse, sclerodermoid induration with overlying papules, sclerodactyly, and decreased motility of the mouth and joints occurs. Our experience suggests that spontaneous resolution does not occur; however, at least one case of apparent spontaneous resolution has been reported [42].

Systemic consequences of scleromyxedema may result in death [1,33]. In a case series in which follow-up was available for 21 patients with scleromyxedema (mean follow-up time 33.5 months, range 2 months to 11 years), at the end of follow-up, 5 patients (23.8 percent) died, whereas 12 patients were alive with disease and 4 patients were alive without disease [1]. Death was caused by extracutaneous complications of scleromyxedema, including dermato-neuro syndrome (two patients) and myocardial insufficiency due to endocardial mucin deposition (one patient) or by an associated myeloid leukemia (one patient) or Hodgkin lymphoma (one patient). A better prognosis was reported in a French study in which the overall survival of all 33 patients with scleromyxedema was 97 percent at three years [5].

Death also may occur as a side effect of treatment. In particular, treatment with melphalan has been associated with death from complications of sepsis and hematologic malignancies [28]. In the French study, one patient died of severe sepsis and specific heart involvement following chemotherapy treatment with bortezomib, melphalan, and dexamethasone [5].

HISTOPATHOLOGY — Scleromyxedema is characterized by a triad of microscopic features that includes (picture 5A-B) [43,44]:

●A diffuse deposit of mucin composed primarily of hyaluronic acid in the upper and mid-reticular dermis; the presence of mucin can be confirmed with an Alcian blue stain (pH 2.5) or a colloidal iron stain and hyaluronidase digestion (picture 6).

●An increase in collagen deposition.

●A marked proliferation of irregularly arranged fibroblasts.

The epidermis may be normal or thinned by the presence of the underlying mucin and fibrosis; the hair follicles may be atrophic, and a slight perivascular, superficial, lymphoplasmacytic infiltrate is often present. Sweat gland proliferations are found occasionally [45]. The elastic fibers are fragmented and decreased in number, explaining the clinical presentation of redundant skin folds on a sclerodermoid background [46].

An interstitial, granuloma annulare-like pattern has been described in cutaneous biopsy specimens from patients with scleromyxedema, occurring in approximately 25 percent of the specimens [47,48]. This histologic pattern is characterized by a diffuse, interstitial proliferation of blue-gray histiocytes (CD68+, CD163+), giant cells, and lymphocytes within the papillary and mid-reticular dermis forming loose granulomas among collagen fibers and mucin deposits.

Histologic specimens from extracutaneous sites may demonstrate mucin deposition among myocardial cells and in the walls of myocardial blood vessels as well as in the interstitium of the kidney, lungs, pancreas, adrenal glands, and nerves [26,34]. Lymph node involvement with infiltration by numerous fibroblasts surrounded by mucin and collagen deposits has been observed [49]. Mucin has not been found in brain autopsies of patients who died of dermato-neuro syndrome.

DIAGNOSIS — The diagnosis of scleromyxedema is based upon the recognition of the following clinicopathologic criteria:

●Generalized, papular and sclerodermoid eruption

●Microscopic triad, including mucin deposition, fibrosis, and fibroblast proliferation, or, less frequently, an interstitial granulomatous-like pattern

●Monoclonal gammopathy

●Absence of thyroid disorder

Atypical forms of scleromyxedema include scleromyxedema in the absence of monoclonal gammopathy or scleromyxedema demonstrating an interstitial granulomatous-like pattern on histopathology. (See 'Associated disorders' above and 'Histopathology' above.)

Patient history — The patient history is useful for identifying symptoms suggestive of extracutaneous involvement and functional limitations secondary to the disease. Patients should be asked about arthralgia, paresthesia, pain, and numbness of the hands (suggestive of associated carpal tunnel syndrome), weakness (suggestive of muscular involvement), dysphagia (suggestive of associated esophageal dysmotility), and dyspnea on exertion (suggestive of pulmonary involvement).

Physical examination — A full skin examination should be performed in patients with suspected scleromyxedema to determine the extent of skin involvement and to identify signs that support the diagnosis or suggest a different disease. Findings of a widespread, papular eruption accompanied by skin induration (particularly involving the hands, face, or around the mouth) and edematous fingers and hands should raise suspicion for the diagnosis.

There is not a standardized method for grading the severity of cutaneous involvement in scleromyxedema. We have found the modified Rodnan skin score, a scoring system often used to assess the severity of skin involvement in systemic sclerosis (scleroderma), useful for following and documenting the severity of disease [50]. (See "Pretreatment evaluation of adults with systemic sclerosis (scleroderma)", section on 'Skin involvement'.)

Skin biopsy — Skin biopsy is the mainstay for diagnosis and should be performed on a group of papules with underlying thickening. A 4 or 5 mm punch biopsy is sufficient for diagnosis. Key findings include mucin deposition, fibrosis, and fibroblast proliferation. (See "Skin biopsy techniques", section on 'Punch biopsy' and 'Histopathology' above.)

Immunofluorescence studies are not contributory to the diagnosis of scleromyxedema and are usually negative [51]. Anecdotally, scanty granular IgG along the epidermal basement membrane and IgG and C1q focally along the connective tissue fibers in the dermis of clinically involved skin have been detected [52].

Laboratory tests — The workup of patients with suspected scleromyxedema should include the following laboratory studies to determine whether the diagnostic criteria are met:

●Serum protein immunoelectrophoresis and immunofixation and serum free light chain assay to evaluate for monoclonal gammopathy

●Thyroid studies to rule out myxedema of thyroid disease (see "Laboratory assessment of thyroid function")

Serum protein immunofixation generally reveals the presence of a monoclonal protein, most commonly IgG-lambda type [1]. Thyroid function test results are normal.

We routinely obtain additional laboratory studies to evaluate for signs of systemic disease, including a complete blood count, comprehensive metabolic panel, muscle enzymes, and urinalysis.

Additional tests — There is little value in imaging studies for the diagnosis of scleromyxedema, although high-resolution cutaneous ultrasonography may become a useful diagnostic and disease activity monitoring tool for skin thickening.

Dermoscopy is nonspecific, showing rice grain-like structures corresponding to papules. Reflectance confocal microscopy features include dermal stellate cells, bright fibers, and dark areas, corresponding to the classical triad of fibroblast proliferation, increased collagen deposition, and mucin deposits, respectively [53]. (See "Overview of dermoscopy".)

Although not necessary for diagnosis, nail fold videocapillaroscopy is normal or nonspecific in scleromyxedema [54]. This differs from scleroderma, in which megacapillaries and decreased capillary density are characteristic features.

In patients who exhibit symptoms suggestive of extracutaneous disease, the corresponding internal organs should be evaluated. As examples, esophageal manometry can be useful for evaluating patients with dysphagia, and pulmonary function studies, including spirometry for forced vital capacity and quantification of diffusing capacity for carbon monoxide, are appropriate for patients with dyspnea. In dermato-neuro syndrome, lumbar puncture and magnetic resonance imaging typically reveal normal findings; however, electroencephalogram results may be consistent with toxic or metabolic encephalopathy [16]. (See 'Extracutaneous manifestations' above.)

DIFFERENTIAL DIAGNOSIS — The major disorders in the differential diagnosis of scleromyxedema are scleroderma (systemic sclerosis), scleredema, and nephrogenic systemic fibrosis [55]. Other disorders characterized by sclerodermoid skin changes may also enter the differential diagnosis (table 1) (see "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Causes of scleroderma-like skin changes'):

●Systemic sclerosis – Characteristic cutaneous findings of systemic sclerosis include skin thickening or hardening that begins on the fingers, hands, or face with centripetal extension in the absence of papules. Raynaud phenomenon is present in more than 90 percent of patients and antecedes the sclerosis of fingers. Associated cutaneous findings include telangiectasia, digital ischemic ulcers, and calcinosis. Nailfold capillaroscopy is useful for early diagnosis of systemic sclerosis, showing dilated and giant capillaries, hemorrhages, disorganized vascular arrays, ramified/bushy capillaries, and capillary losses. Systemic scleroderma is associated with specific autoantibody profiles, including anti-Scl70 or anticentromere antibody. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Cutaneous manifestations'.)

Although patients with scleromyxedema may have symptoms that mimic scleroderma, such as sclerodactyly, the Raynaud phenomenon (rarely), and esophageal dysmotility, clinical and laboratory features distinguish the two diseases. The presence of diffuse, waxy papules in linear arrays and in a characteristic distribution that includes the glabella and posterior auricular area, the involvement of the middle portion of the back (always spared in scleroderma), and the presence of an IgG monoclonal gammopathy all favor a diagnosis of scleromyxedema. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

●Scleredema – Scleredema (also known as scleredema adultorum of Buschke) is characterized by a symmetrical, nonpitting induration of the skin that typically begins on the neck and later spreads to the shoulders and upper part of the trunk with occasional erythema (picture 7). Scleredema is typically associated with a history of an antecedent upper respiratory infection, diabetes mellitus, or blood dyscrasia [2]. The histologic findings of scleromyxedema and scleredema differ; the fibroblast proliferation that is evident in histologic specimens of scleromyxedema is absent in scleredema [56]. (See "Scleredema".)

●Nephrogenic systemic fibrosis – Nephrogenic systemic fibrosis, which develops in individuals with renal dysfunction and exposure to gadolinium, can have a similar histologic appearance to scleromyxedema, with findings of mucin and fibroblastic proliferation in biopsy specimens. Common cutaneous findings of this condition include bilateral, symmetric, fibrotic, indurated papules, plaques, or subcutaneous nodules that begin on the distal extremities prior to progressing proximally (picture 8). Patients may also develop muscle, joint, internal organ, or scleral involvement.

Clinical correlation is useful for distinguishing the two diseases. Unlike scleromyxedema, facial involvement (common in scleromyxedema), the presence of widespread papules, and monoclonal gammopathy are not features of nephrogenic systemic fibrosis. Scleral plaques have not been reported in scleromyxedema. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)

Importantly, scleromyxedema should be differentiated from the localized variants of lichen myxedematosus. In the past, the terms "papular mucinosis," "lichen myxedematosus," and "scleromyxedema" were often used indiscriminately. Although scleromyxedema and the localized type of lichen myxedematosus (including subtypes such as acral persistent papular mucinosis, discrete lichen myxedematosus, papular mucinosis of infancy, and nodular lichen myxedematosus) belong to the same disease spectrum, it is important to make a distinction between the two disorders because of differences in prognosis and the approach to therapy [2,3]. Historically, most patients reported in the literature to have lichen myxedematosus or papular mucinosis without specification of the disease subtype appear to have had scleromyxedema with monoclonal gammopathy. Occasionally, patients have overlapping or atypical features and fall in between scleromyxedema and localized lichen myxedematosus [3]. (See "Localized lichen myxedematosus".)

TREATMENT — Although treatment of scleromyxedema is recommended to minimize risk for the development of complications, a paucity of high-quality studies on the efficacy of treatments for scleromyxedema and an incomplete understanding of the pathogenesis of the disorder have prevented the development of definitive guidelines on the best approach to treatment. No randomized trials have evaluated therapies for scleromyxedema, and data are primarily limited to case reports and case series due to the rarity of the disease. No specific treatment appears to be uniformly effective or curative, and the relative efficacies of the treatments that have been utilized remain unclear.

As a consequence of the limited data on therapies for scleromyxedema, opinions vary on the preferred approach to treatment. In all cases, consideration of the risk-benefit ratio of treatment is important for selecting an appropriate therapeutic regimen; both scleromyxedema and its therapies may induce life-threatening side effects.

Complete resolution of the manifestations of scleromyxedema is the goal of treatment but is not always feasible. Marked improvement in papules and skin thickening is generally considered a successful response for skin disease [50]. Our typical approach to the treatment of scleromyxedema will be reviewed here. Consideration of patient characteristics, patient preferences, clinician experience, and treatment accessibility may support other approaches to treatment. Of note, successful treatment of scleromyxedema does not appear to require the resolution of the associated paraproteinemia.

Preferred initial therapy — Systemic therapy is the treatment method of choice for patients with scleromyxedema. Intravenous immunoglobulin (IVIG) is our first choice for therapy based upon multiple case reports and case series that support its efficacy and the generally well-tolerated nature of this nonimmunosuppressive treatment [5,50,57]. For those patients who cannot receive IVIG, systemic glucocorticoids and immunomodulatory drugs (thalidomide or lenalidomide) are our preferred initial systemic therapies. (See 'Failure of initial therapy' below.)

In the past, melphalan, a chemotherapeutic agent given with the intent to treat the associated plasma cell dyscrasia, was often considered first-line treatment for scleromyxedema. However, concerns regarding serious adverse effects, including hematologic malignancies and opportunistic infections, contributed to a desire for other less toxic first-line therapies for scleromyxedema.

Intravenous immunoglobulin (IVIG) — The mechanism through which IVIG improves scleromyxedema is unclear. Suggested mechanisms focus on the immunomodulatory effects of IVIG, including neutralization of circulating autoantibodies by anti-idiotype antibodies, functional blockade of fragment crystallizable receptors on macrophages, and inhibition of fibrosis via modulation of the production of cytokines and cytokine antagonists [58,59].

Administration — IVIG is usually administered at the dose of 2 g/kg per month divided over two to four consecutive days per month according to the preparation and concentration of IVIG. Improvement in skin and extracutaneous symptoms, especially rheumatologic symptoms, often is evident after the first one or two cycles of IVIG [1,60,61]. In our experience, almost all patients exhibit at least partial improvement within four to six cycles. Patients with an unsatisfactory response to IVIG after six cycles are typically transitioned to other therapies. (See 'Failure of initial therapy' below.)

Lower doses of IVIG may also be effective. A patient with skin-limited disease who had failed to respond to systemic glucocorticoids, extracorporeal photophoresis, and interferon had a reduction in clinical findings within two cycles of IVIG given at a dose of 0.5 g/kg given over five days at four-week intervals [60].

Although remissions persisting for a few months to three years after cessation of IVIG infusions have been reported, the response to IVIG is usually transient [29,61,62]. Maintenance IVIG cycles every six to eight weeks are generally required to maintain remission [61]. We typically administer IVIG over two to four days at a dose of 2 g/kg of IVIG every six weeks or 1.5 g/kg of IVIG every four weeks.

Drawbacks of IVIG treatment are its high cost and the time-consuming administration. The use of more concentrated IVIG, reducing the time of administration to two days, has improved the management of the disease. Possible side effects are skin flushes, hand dermatitis, arthralgias, myalgias, fever, headache, thoracic or abdominal pain, nausea, and tachycardia. Myocardial ischemia and death secondary to suspected myocardial infarction have been reported in scleromyxedema patients with known cardiac risk factors during treatment with IVIG [1,63]. However, the side effects experienced by patients receiving IVIG for scleromyxedema generally have been mild and self-limited [64]. The adverse effects of IVIG are reviewed in greater detail separately. (See "Intravenous immune globulin: Adverse effects".)

Efficacy — Data on the efficacy and safety of IVIG are primarily limited to case reports and case series; no randomized trials have been performed [1,5,6,29]. Examples of published reports that have offered support for the efficacy of IVIG for this disease include:

●In a retrospective study, 13 of 31 patients (42 percent) with scleromyxedema (without features of dermato-neuro syndrome or mucinous cardiac involvement) treated with IVIG (2 g/kg monthly for the first six months) as a first- or second-line therapy achieved a complete clinical response [5]. Patients were treated with IVIG for a median of 16 months.

●In a review of eight adults with scleromyxedema who were treated with monthly cycles of IVIG (2 g/kg per cycle divided over two to five days), two achieved a complete response and six achieved a partial response after up to six cycles of IVIG [29]. Treatment was followed by maintenance therapy every 6 to 12 weeks as needed.

●In a multicenter, retrospective study of 30 patients with scleromyxedema, three of the six patients treated with IVIG (2 g/kg per monthly cycle) achieved complete clinical remissions [1]. The three remaining patients achieved partial responses.

In the first study, a complete clinical response was defined as complete clinical improvement from baseline. In the latter two studies, complete responses were defined as an absence of systemic symptoms or skin findings of scleromyxedema, and partial responses consisted of a decrease in skin changes and improvement in systemic symptoms. In these and other reports, responders to IVIG have included both patients who received IVIG as initial treatment and patients who had previously failed other therapies [1,5,29,61,65].

Failure of initial therapy — When treatment with IVIG is not an option or yields an insufficient response, we institute other therapies. Systemic glucocorticoids and thalidomide are our preferred next-line treatments. Systemic glucocorticoids and thalidomide can be given alone. More often, we add one of these agents to IVIG therapy because of the favorable results we have observed with combination therapy.

Selection between systemic glucocorticoids and thalidomide is based upon consideration of factors such as patient comorbidities, tolerability, drug availability, and clinician comfort. Most often we use systemic glucocorticoids first; if the response is insufficient, we begin thalidomide.

Patients with severe disease who cannot be successfully managed with IVIG, thalidomide, and/or systemic glucocorticoids are candidates for trials of more aggressive interventions. (See 'Severe and refractory disease' below.)

Systemic glucocorticoids — Systemic glucocorticoids have been used for scleromyxedema as monotherapy or in conjunction with chemotherapeutic agents [66,67]. It is postulated that benefit from systemic glucocorticoids may result from immunosuppressive and antifibroblast effects of these agents [68].

Administration — Our preferred regimen for systemic glucocorticoid therapy is prednisone (0.5 to 1 mg/kg per day) until the desired therapeutic effect is reached. Responses usually occur within four weeks. Then, we begin to slowly taper the glucocorticoid dose to the lowest dose necessary to maintain the response to treatment. If patients fail to respond within four to six weeks, we consider treatment ineffective and typically transition to thalidomide.

The adverse effects of systemic glucocorticoid therapy are reviewed separately. (See "Major adverse effects of systemic glucocorticoids".)

Efficacy — Data on the efficacy of systemic glucocorticoids in scleromyxedema are limited to case reports. Prednisone (0.5 to 1 mg/kg per day), prednisolone (0.3 to 0.5 mg/kg per day), and oral high-dose dexamethasone (40 mg once daily for four days per week during three consecutive weeks each month) have been associated with improvement in cutaneous manifestations of scleromyxedema in individual patients [68-70]. The associated paraproteinemia may or may not improve in patients in whom systemic glucocorticoid therapy induces remission of scleromyxedema [69,70]. Failure of systemic glucocorticoid therapy to improve scleromyxedema has also been reported [1].

Immunomodulatory drugs (thalidomide or lenalidomide) — The mechanism of action of thalidomide in scleromyxedema is unknown. Immunomodulatory effects on proinflammatory and profibrotic cytokines and antiangiogenic properties may contribute to inhibition of fibrosis [71].

Lenalidomide, a thalidomide derivative with a more favorable side effect profile, may be a reasonable alternative to thalidomide. Disadvantages of lenalidomide compared with thalidomide include higher cost and less data on the efficacy of this therapy.

Administration — Treatment with thalidomide should begin at a dose of 50 to 100 mg per day. The dose is slowly increased according to clinical response and tolerance up to 150 to 400 mg per day. Clinical improvement is expected within two to three months, and a change in therapy is appropriate for patients who do not exhibit improvement within this period. (See 'Severe and refractory disease' below.)

Once a satisfactory response to thalidomide is achieved, the lowest dose effective for maintaining improvement is used for maintenance therapy.

Teratogenicity and peripheral neuropathy are side effects of thalidomide that can limit the use of this therapy. Patients should be monitored for the development of peripheral neuropathy during treatment. In the United States, patient and provider participation in a Risk Evaluation and Mitigation Strategy program (www.thalomidrems.com), a program aimed to prevent the use of thalidomide during pregnancy, is required for the use of this medication. Other potential adverse effects of thalidomide include drowsiness, constipation, thrombosis, and leukopenia.

Lenalidomide is usually used at a dose of 10 to 25 mg per day for three weeks per month, starting with the lower dose. Once response is achieved, the lenalidomide dose can be reduced to the lowest dose effective for maintaining improvement.

Examples of potential adverse effects of lenalidomide include teratogenicity, thrombocytopenia, neutropenia, and thrombosis. In the United States, lenalidomide is available under a restricted distribution program (Revlimid REMS). Peripheral neuropathy, sedation, and constipation occur to a lesser extent with lenalidomide compared with thalidomide.

Efficacy — Multiple case reports have documented improvement in the cutaneous manifestations of scleromyxedema following treatment with thalidomide [72-77]. Improvement in systemic manifestations [77] and serum paraprotein levels [72] have also been reported in some patients. Thalidomide may be a useful adjunct to IVIG therapy; the addition of thalidomide to IVIG appeared to be useful for decreasing the frequency of IVIG treatment in a case report [71].

A few case reports and series have documented the use of lenalidomide. In a retrospective study, treatment of three patients with IVIG-refractory scleromyxedema with lenalidomide, dexamethasone, and IVIG was associated with partial clinical responses and complete hematologic responses in all patients [5]. In case reports, lenalidomide (25 mg per day for three weeks per month) appeared beneficial when used in combination with IVIG in one patient [78] but failed to induce clinical improvement when used in combination with dexamethasone in another patient [13].

Severe and refractory disease — Patients who fail to achieve sufficient improvement with the therapies above may benefit from interventions aimed at treating the associated plasma cell dyscrasia.

Examples of therapeutic options we typically reserve for these patients include bortezomib with dexamethasone, autologous stem cell transplantation, and melphalan. Data are limited on the efficacy of these therapies for cutaneous and extracutaneous manifestations of scleromyxedema. In addition, the response to these treatments is variable and relapse may occur. Thus, the risks associated with these therapies must be considered carefully prior to treatment.

Our typical approach to severe disease that has failed to respond to IVIG, systemic glucocorticoids, and immunomodulatory drugs starts with bortezomib and dexamethasone therapy. Poor responders are candidates for autologous stem cell transplantation. We generally avoid melphalan because of concern for serious hematologic toxicity, including malignancy (see "Melphalan: Drug information"):

●Bortezomib and dexamethasone – Combination therapy with bortezomib and dexamethasone has been associated with rapid improvement in cutaneous manifestations and constitutional symptoms of scleromyxedema in case reports, including a patient who relapsed after autologous stem cell transplantation [13,79]. A successful response was also observed in a patient treated with bortezomib and dexamethasone in combination with thalidomide [12].

Our typical regimen involves bortezomib given at a dose of 1.3 mg/m² (maximum of 2 mg per dose) on days 1, 8, 15, and 22. Dexamethasone (40 mg per dose) is given on days 1, 8, 15, and 22. A total of six cycles are given over a period of six months. In very refractory cases, thalidomide may be added, given at a dose of 100 mg per day for the first 14 days followed by 200 mg per day for the next seven days, similar to a protocol used for myeloma. (See "Multiple myeloma: Initial treatment".)

●Autologous stem cell transplantation – Multiple cases of scleromyxedema treated with autologous stem cell transplantation have been reported since the initial report of a complete remission in 2001 [8]. In a review of 17 reported cases of scleromyxedema treated with autologous stem cell transplantation published between 2001 and 2011, complete remissions (resolution of all clinical symptoms, skin abnormality, and serum paraprotein) were attained by 10 patients (59 percent) and partial remissions were attained by 5 patients (29 percent) [80]. However, only two of the complete responders remained in remission after follow-up periods ranging between 14 and >60 months.

●Melphalan – Although melphalan was often considered a first-line treatment for scleromyxedema in the past, the potential for drug-related serious adverse events limits the use of this agent. A review of 17 patients who received melphalan for scleromyxedema (1 to 4 mg per day or cyclic therapy) at a single medical center found that although 12 patients had improvement of skin disease with therapy, improvement was temporary in 8 patients and 9 patients died of hematologic malignancy or septic complications that were considered related to therapy [28].

Dermato-neuro syndrome — The approach to patients with dermato-neuro syndrome is not standardized, and various treatments have seemed to yield benefit in case reports. Examples include IVIG [65], systemic glucocorticoids plus plasmapheresis or IVIG [18,81], systemic glucocorticoids plus cyclophosphamide and plasmapheresis [5,15], melphalan plus IVIG, and bortezomib plus dexamethasone [82]. Spontaneous improvement also has been reported [16].

Our typical initial approach consists of IVIG (2 g per kg per month) with dexamethasone pulse therapy (intravenous dexamethasone [100 mg per day] given for three consecutive days per month). This may be followed by the addition of plasmapheresis (every other day for 10 days) for patients who do not improve within two cycles of IVIG and dexamethasone therapy.

Other therapies — Case reports have documented clinical improvement in patients treated with topical betamethasone and topical dimethyl sulfoxide [83], topical and intralesional corticosteroid therapy [84], oral isotretinoin [85,86], acitretin [1], interferon-alfa [87], hydroxychloroquine [1], cyclosporine [88], and chemotherapeutic agents, including cyclophosphamide [89], methotrexate [21,90], chlorambucil [91], and 2-chlorodesoxyadenosine [92]. The efficacies of these agents for scleromyxedema remain to be confirmed. Of note, treatment with interferon-alfa was associated with worsening of symptoms in a woman with localized lichen myxedematosus [93].

Ultraviolet A1 (UVA1) or psoralen plus ultraviolet A (PUVA) phototherapy [94], Grenz ray [33,95], and total skin electron beam therapy [96] have also been reported to improve cutaneous manifestations of scleromyxedema in case reports. These therapies do not have an impact on paraproteinemia and systemic involvement. Of note, accidental excessive exposure to ultraviolet B (UVB) has appeared to exacerbate the disease in one patient [97]. Allogeneic hematopoietic cell transplant has also been tried with success in a patient with refractory disease [98].

Tumor necrosis factor (TNF)-alpha inhibitors may not be useful. TNF-alpha has been suggested as a profibrotic cytokine that may be implicated in the pathogenesis of scleromyxedema, and a patient in whom IVIG lost efficacy failed to respond to infliximab [99].

Cosmetic interventions — Case reports suggest that facial disfigurement can be treated with dermabrasion plus surgery or carbon dioxide laser with good cosmetic results [100,101]. These procedures do not affect systemic manifestations of scleromyxedema.

PROGNOSIS AND FOLLOW-UP — Scleromyxedema is a disease with an unpredictable but usually progressive and disabling course in the absence of successful treatment. Even when therapy is successful, long-term maintenance therapy usually is required since relapse commonly occurs upon the discontinuation of treatment. Death may result from complications of extracutaneous involvement or adverse effects of therapy. (See 'Clinical course' above.)

Because of the various cutaneous and extracutaneous manifestations of scleromyxedema, a multispecialty team often is needed for the optimal management of these patients. Depending on the manifestations present, dermatologists, hematologists, cardiologists, pulmonologists, gastroenterologists, hand surgeons, and other specialists can be valuable for managing affected patients.

The unpredictable course of scleromyxedema, the variable response to treatment, and the common occurrence of relapse demand close, long-term follow-up of these patients. We usually reassess patients once per month with a full skin examination, review of systems, and reevaluation of the therapeutic regimen. Serologic studies, including assessment of the status of the associated monoclonal gammopathy, are not useful for monitoring disease activity.

Patients should be cautioned that development of neurologic symptoms (eg, dysarthria) and flu-like illness may be the initial signs of dermato-neuro syndrome. Patients with such symptoms should be admitted to the hospital for close observation, evaluation, and eventually admission to the intensive care unit.

Follow-up data on patients treated for scleromyxedema are limited, but relapse after treatment appears to be common. Most patients treated with IVIG require continued therapy to remain in remission [29,61]. Frequent relapses have also been reported following autologous bone marrow transplantation and melphalan therapy [28,80]. No treatment has been identified that definitively cures the disease.

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: Scleromyxedema and localized lichen myxedematosus".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Scleromyxedema is an uncommon, diffuse/generalized, papular and cutaneous eruption that usually occurs in association with monoclonal gammopathy and may have accompanying systemic features. The disorder typically affects adults. There is no sex predilection.

●Pathogenesis – The pathogenesis of scleromyxedema is unknown, but circulating cytokines, such as interleukin (IL) 1, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, and IL-4, known to stimulate glycosaminoglycan synthesis and fibroblast proliferation in the skin, seem to play a role. (See 'Epidemiology' above and 'Pathogenesis' above and 'Associated disorders' above.)

●Clinical findings – The cutaneous manifestations of scleromyxedema consist of widespread, waxy papules and indurated plaques (picture 1A-C). Progressive cutaneous involvement can lead to decreased motility of the mouth and joints. Extracutaneous involvement in scleromyxedema can present with a variety of manifestations. Neurologic, musculoskeletal, cardiac, gastrointestinal, respiratory, or renal abnormalities may develop. (See 'Clinical findings' above.)

●Clinical course – The clinical course of scleromyxedema is chronic and progressive. Cutaneous and extracutaneous involvement can lead to significant morbidity. Death may result from complications related to extracutaneous involvement, such as dermato-neuro syndrome, or adverse effects of therapy. (See 'Clinical course' above.)

●Diagnosis – The diagnosis of scleromyxedema is based upon recognition of consistent clinical, pathologic, and laboratory findings. The presence of the following features is supportive of the diagnosis (see 'Diagnosis' above):

•Diffuse/generalized, papular and sclerodermoid eruption

•Microscopic triad, including mucin deposition, fibrosis, and fibroblast proliferation, or, less frequently, an interstitial granulomatous-like pattern

•Monoclonal gammopathy

•Absence of thyroid disorder

●Treatment – There is a paucity of data on the treatment options for scleromyxedema. The available data consist primarily of case reports and case series. Thus, there are no definitive guidelines on the best approach to treatment (see 'Treatment' above):

•Initial treatment – Patients with scleromyxedema generally require systemic therapy. We suggest intravenous immunoglobulin (IVIG) as initial treatment (Grade 2C). Systemic glucocorticoids and immunomodulatory drugs (thalidomide or lenalidomide) are alternative treatment options that may also be used in conjunction with IVIG therapy. (See 'Treatment' above.)

•Severe and refractory disease – Patients who fail to respond to IVIG, systemic glucocorticoids, or immunomodulatory drugs may benefit from other therapies. Examples of treatment options for severe and refractory disease include bortezomib plus dexamethasone, autologous stem cell transplantation, and melphalan. The risk-benefit ratios of treatment must be carefully considered prior to therapy. (See 'Severe and refractory disease' above.)

●Prognosis – Recurrence of scleromyxedema is common after withdrawal of an effective therapy. Long-term maintenance treatment usually is required, and close clinical follow-up is necessary. (See 'Prognosis and follow-up' above.)