New insights on scleromyxedema

Abstract

Scleromyxedema is a rare fibromucinous disorders, with several clinical and pathological overlaps with scleroderma and scleredema. Etiopathogenesis remains uncovered, and no explanation has been provided either for the origin of mucin deposition or for the paraprotein role. The disease does not show gender predilection and affects mainly middle-age adults. The course is unpredictable, and prognosis remains guarded for renal, cardiac, and neurologic complications, especially in the setting of dermato-neuro syndrome. A valuable recent progress is the consensus definition of diagnostic criteria and lines of treatment, which hold the promise to improve the early recognition and management of this rare condition worldwide. High-dose intravenous immunoglobulin has been suggested as the first-line treatment either alone or associated with systemic steroids and/or thalidomide. In very recalcitrant cases, adjunctive bortezomib and/or autologous stem cell transplant might be considered. Melphalan treatment was associated with very toxic side effects and actually is no longer recommended.

Introduction

Scleromyxedema is a rare fibromucinous disease of unknown etiology, classified as the generalized form of primary cutaneous mucinosis. It is characteristically associated with a monoclonal gammopathy, mostly of immunoglobulin G (IgG) lambda type, while thyroid function should be within normal range to exclude generalized or pretibial myxedema.^1–4 The disease affects adults in their 5–6 decade of age, without gender predilection or ethnic background. ¹ It is included among sclerodermoid- or scleroderma-like disorders for the symmetrical progressive skin induration, especially on the extremities and face. ² However, distinctive features include the presence of firm, translucent papules as elementary lesions, absence of Raynaud’s phenomenon or autoimmunity alterations in respect to systemic sclerosis and no correlation with diabetes or infections in the differential diagnosis with scleredema (Table 1).

Table 1.

Differential diagnosis of scleromyxedema.

Disease	Clinical manifestations	Histopathological findings
Systemic sclerosis	Presence of Raynaud’s phenomenon, telangiectasias, or calcinosis. Abnormal nail fold capillaries Autoimmunity at laboratory assessment	Absent or scanty mucin deposition. Extensive fibrosis, from reticular dermis through subcutis, with deep perivascular lymphoplasmocytic infiltrate
Scleredema adultorum of Buschke	Patients with diabetes or history of upper tract respiratory infections, or monoclonal gammopathy	Mucin deposits are interstitial, intermingled between fenestrated collagen bundles. The reticular dermis is up to three times thickened than normal
Nephrogenic systemic fibrosis	Gadolinium exposure in patients with severe renal insufficiency	Extensive mucin deposition and fibrosis throughout the reticular dermis and subcutis, with additional thick elastic fibers oriented parallel to the collagen bundles, dystrophic calcification, bone metaplasia and sclerotic bodies
Radiotherapy-induced skin thickening	History of radiotherapy and lesions limited to the exposed areas	No mucin deposition
Graft versus host disease	History of hemopoietic cell transplantation	Similar to scleroderma
Cutaneous amyloidosis	Pruritic papules on the shins	Dermal material stains with Congo red dye
Myxedema	Thyroid function abnormalities	Large amounts of mucin in the dermis, without increased fibroblasts; more pronounced epidermal alterations, with follicular plugging, hyperkeratosis, and eventual papillomatosis and acanthosis
Lichen myxedematosus variants	Localized skin involvement and different prognosis	Mucin deposition in upper dermis but variable fibroblasts activation and limited fibrosis
Granuloma annulare	Annular papular eruption, without prominent skin induration	Granulomatous pattern, with palisading histiocytes around necrobiotic collagen, and presence of neutrophils in the infiltrate and fibrin deposition
Interstitial granulomatous drug reaction	Exposure to drug intake	Characteristic interface dermatitis with vacuolar degeneration and variable lymphocytic atypia in the infiltrate
Other histiocytic disorders	Different history and clinical features	Specific histopathologic findings

The course is usually progressive and disabling and may lead to marked morbidity or even death.^1,4–8 There are several systemic implications due to scleromyxedema, including renal, cardiac, pulmonary, and neurologic involvement, especially in the form of dermato-neuro syndrome.^1,8–13 Unfortunately, the response to current treatments is not permanent, and the prognosis is further worsened by the sudden occurrence of hematological malignancies, and septic complications.^1,4,9

Etiopathogenesis

The primum movens of the disease remains uncovered, with no explanations for the two pathognomonic pathological findings: mucin deposition and fibroblasts activation with fibrosis. An intrinsic abnormality of fibroblasts has never been identified,^8,14 while the quantification of the mucin deposits is not apparently related to the disease severity.^{1,4,6–8,10–13} The demonstration that patients’ serum stimulates the fibroblasts proliferation and glycosaminoglycans synthesis in vitro supports the hypothesis of pathogenetic circulating cytokines. ¹⁵ Major promoters of glycosaminoglycans synthesis are interleukin (IL)-1, IL-6, tumor necrosis factor alpha and beta, as well as the transforming growth factor beta (TGF-b), ¹ but no releasing source has been identified. Implication of the bone marrow stroma and aberrant plasma cell clones were not confirmed; although in several patients, the autologous stem cell transplantation (ASCT) was very effective in the disease control. ¹⁶ The purified paraprotein failed to stimulate fibroblasts in an experimental model. ¹⁵ The monoclonal gammopathy is not obligate, as atypical scleromyxedema cases lack this criterion. ¹ It is otherwise noteworthy that patients without hematological dyscrasia evince a more favorable course and response to conventional immunosuppressants, such as cyclosporine, betamethasone, and methotrexate.^17,18 Thus, a negative prognostic significance has been granted to the gammopathy occurrence.^1,4,13

Whatever primarily causes the disease, immune suppression is an effective measure to control the process. In the past, very cytotoxic treatment with melphalan was considered the gold standard, but high-dose intravenous immunoglobulin G (hd-IVIgG) treatment is as much effective, without considerable side effects in the long-term administration.^19,20 Several mechanisms of actions have been evoked to explain how IVIg therapy interferes with the fibroblast proliferation and fibrogenesis in scleromyxedema: inhibition of aberrant plasma cells and cytokines release, paraprotein linkage, and block of the activated complement cascade. The more specific activity is the demonstration in an experimental model of the IVIg capacity to decrease the type I collagen gene expression and consequent collagen depositions. ²¹ Other documented inhibitory effects on fibrosis might depend on the downregulation of TGF-b, endothelin-1, and connective tissue growth factor expression, as well as the metalloproteinase activity. ²² The IVIg batches are usually in reach of anti-fibroblast antibodies and Fas-legand, the latter being a potent cell apoptosis inducer. ²³ Besides all these interesting findings, the therapeutic effect of IVIg is only temporary, and relapses occur at dismission.

Additional triggering factors have been seldom reported, which include the role of adjuvants related to breast silicone implantation and injected dermal fillers.^24,25 Treatment of concomitants hepatitis C virus with interferon and ribavirin was also effective on the scleromyxedema manifestations in a patient. ²⁶

Clinical manifestations

Primary cutaneous mucinosis is a distinctive skin disorder, which includes a generalized form, represented by scleromyxedema, and several localized forms, named papular mucinosis and “lichen myxedematosus.” ¹ The prognostic significance of the purely cutaneous form is completely different, although the clinical and histopathological features are hardly distinguishable, and categorization relies on the systemic symptoms’ absence. ⁵

Cutaneous manifestations are characterized by two different findings: the diffuse papular eruption and the underlying skin induration, with predilection for the dorsal aspects of the hands, forearms, head, neck, upper trunk, and thighs. The closely spaced papules are characteristically small, 2–3 mm in diameter, skin colored with a waxy appearance, dome-shaped or flat-topped, and often linearly arranged (Figure 1). Subcutaneous nodules are sometimes also present.^1,6 Not only the underlying skin but also other distant large areas, such as the trunk, are characterized by the other pathognomonic finding, very similar to scleroderma, consistent of the erythematous and edematous induration of the skin, with a variable surface appearance, from shiny to a brownish discoloration.^1,6 Consistency at palpation is hardened fibromatous. The skin hardening, with loose elasticity is responsible for several signs:

Figure 1.

Typical scleromyxedema papules with linear arrangement, and “doughnut sign,” on the dorsum of the hand, and fingers.

1. The “doughnut sign,” on the proximal interphalangeal joints, consisting of a central depression surrounded by an elevated rim of thickened skin. Progression to stiffening and decreased joints motility can lead to sclerodactyly, which is differentiated from scleroderma by the absence of the Raynaud’s phenomenon, telangiectasias, or calcinosis.^2,6,27

2. The “shar-pei sign,” on the trunk and radix of the limbs (Figure 2), which consists of deep longitudinal furrowing, very similar to the dog skin, giving the name to the sign.

3. The “leonine face,” on the glabella (Figure 3).

Figure 2.

The “Shar-pei sign” on the lower back.

Figure 3.

Typical “leonine face.”

The tiny firm papules are usually present in another very peculiar site of involvement, which is the auricle (Figure 4). A decrease for eyebrows, and axillary and pubic hair is common.^1,6 Mucous membranes are not involved in scleromyxedema, but skin induration around orifice might reduce motility.^1,6

Figure 4.

Auricle involvement with typical papules and skin induration.

Itching is common, and may be responsible of a Koebner phenomenon. ¹

For the quantification of the disease severity, a modification of the scleroderma skin scoring has been recently proposed, ²⁸ named the modified Rodnan score system for scleromyxedema (mRSSS), which assesses in a spot area the skin thickening, papules extension, severity of erythema, presence of pruritus or paresthesia, and repeat the measure in 20 different body districts. The complexity of this scoring system limits the indication to experimental subset and clinical trials.

Extracutaneous manifestations in scleromyxedema are frequent, but a direct association with the pathogenic process was documented in very few cases, by the presence of mucin deposition in the internal organ biopsy or autopsy,^1,10–12 and probably they include unrelated comorbidities. ⁶ Normal thyroidal function is a diagnostic criterion, which exclude other forms of mucinosis.^1–6

The monoclonal gammopathy, with lambda light chains IgG prevalence, is present in about 90% of patients, ¹ and the absence of this involvement defines the “atypical scleromyxedema” cases, which otherwise shows a more favorable prognosis.^{14,17,18,29,30} The possible evolution of the gammopathy into multiple myeloma is described in less than 10% of patients.^1,4,7

Other extracutaneous manifestations occur in about 70% of patients, and include musculoskeletal, neurologic, cardiac, pulmonary, and gastrointestinal symptoms.^1,4,7,8,13

The involvement of the nervous system affects 10%–30% of patients with scleromyxedema, but majority of symptoms not specific, varying from acute psychosis to cognitive disorders, stroke, peripheral neuropathy, and carpal tunnel syndrome.^1,15,31,32 A peculiar dramatic complication of scleromyxedema is the dermato-neuro syndrome, which manifests as a sudden state of altered consciousness, loss of gait, with fever, evolving to convulsions and coma, which are potentially fatal.^1,6,33,34 The onset is often announced by a flu-like prodrome, which in the absence of other predictive criteria recommend close monitoring, and prompt intervention in any patients with scleromyxedema.^6,33 The pathogenesis of the dermato-neuro syndrome is uncovered, and the few information come from autopsy: no mucin deposition was found, and brain histopathologic findings varied from near normal ¹⁷ to mild demyelination and gliosis.^12,31 An increased blood viscosity and consequent alteration of the central nervous system circulation has been postulated, probably related to the paraprotein level and/or increased leukocyte aggregation. ¹⁷ The role on an altered immunologic, if not autoimmune response is suggested by the efficacy of corticosteroids, and/or hd-IVIgG treatments. ³⁴

About 25% of patients manifest musculoskeletal symptoms, including arthralgia/arthritis of the peripheral joints, inflammatory myopathy, as well as fibromyalgia.^1,4,7

Potentially fatal cardiovascular manifestations occur in 22% of the patients, from myocardial ischemia to congestive heart failure, heart block, and pericardial effusion. ¹

Dyspnea due to obstructive or restrictive lung involvement is reported in about 17% of scleromyxedema patients. ⁴

Gastrointestinal manifestations are uncommon, but upper esophageal dysmotility, with dysphagia is reported. ³⁵ Renal involvement is a rare event, but potentially fatal for acute renal failure, very similar to the scleroderma-like crisis.^1,10

Retinal vasculitis and macular edema in course of scleromyxedema have recently been reported. ³⁶

The association with visceral malignancies has not been confirmed by multicenter studies, and previous observations were probably related to the aggressive melphalan therapy.^1,4,7 Besides, the proposal to consider scleromyxedema among paraneoplastic syndromes has been renewed by the recent observations of thymus and gastric carcinoma occurrence.^37,38

Diagnosis

Scleromyxedema is diagnosed upon clinical, pathologic, and laboratory findings. Recent consensus ¹³ has defined the diagnostic criteria, and at least three of the findings are necessary to confirm the diagnosis:

1. Presence of generalized papular and sclerodermoid manifestations;

2. Monoclonal gammopathy documentation;

3. Characteristic microscopic findings;

4. Absence of thyroid pathology.

All clinical criteria have been already exposed, while the other very fundamental criterion is the pathological characterization of the disease, which include two possible presentations: the classic microscopic triad and the interstitial granuloma annulare–like pattern.^3,6,39,40

The microscopic pathologic triad is defined by the presence of dermal mucin deposition, increased collagen accumulation, and fibroblast proliferation (Figure 5). ³ Mucin characteristically accumulates in the upper and mid-reticular dermis in scleromyxedema and is composed of hyaluronic acid, which is alcian blue-positive at pH 2.5, digested by hyaluronidase, while Congo red and periodic acid Schiff stains are negative. ⁴⁰ The second pathologic clue is the increased number of dermal fibroblasts, stellate or spindle-shaped, associated with thickened collagen bundles, irregularly arranged. Accompanying fragmentation and decreased number of the elastic fibers explains the occurrence of the loose redundant skin folds, especially on the back skin causing the shar-pei sign. ¹ The above epidermis might appear normal, slightly hyperkeratotic with acanthosis or thinned by the underlying mucin and fibrosis. Other additional microscopic findings include atrophic hair follicles, eccrine sweat glands proliferation, a mild superficial perivascular lymphoplasmacytic infiltrate, and dermal eosinophilia. ¹

Figure 5.

Pathologic triad characterized by dermal mucin, increased fibroblasts and fibrosis (Hematoxylin & Eosin stain; magnification ×10); Alcian PAS stain–positive mucin deposition in the dermis (magnification ×10).

A second histological pattern has been described, which consists of a band-like CD68+ histiocytic infiltrate, in the papillary or mid-dermis, mimicking the interstitial granuloma annulare findings. ⁴⁰ Distinction is subtle, but in scleromyxedema help the absence of prominent palisading histiocytes surrounding collagen necrosis, scanty fibrin deposition, or neutrophils infiltration. Another entity that should be differentiated from scleromyxedema under the microscope is the interstitial granulomatous drug reaction, which usually presents an additional vacuolar interface dermatitis, with lymphoid atypia.^3,6 Other rare histiocytic disorders are excluded on the base of anamnestic and clinical information. The role of the granulomatous component in the scleromyxedema pathogenesis is unclear, but reminds of similar findings described in lymphomas, where unidentified antigens are supposed to trigger a granulomatous anomalous immune response. ⁴¹

Usually, it is not necessary to perform direct immunofluorescence examination in scleromyxedema, although some authors reported the presence of a scanty granular IgG deposition along the epidermal basement membrane and focal IgG and complement positivity in the connective tissue. ⁴²

Abnormal mucin deposition usually occurs also in the lymph nodes, heart, kidney, lungs, pancreas, adrenal glands, and nerves.^1,3,6,8,12

The role of imaging is not consolidated in this rare condition, but high-frequency skin ultrasonography (13 Hz) candidates have a useful tool to measure the affected skin thickness ⁴³ to monitor the disease activity and eventual response to treatment.

Differential diagnosis

Very similar clinical and pathology manifestations (Table 1) are the localized variants of the primary cutaneous mucinosis, which include the discrete lichen myxedematosus, the papular mucinosis of infancy, the acral persistent papular mucinosis and nodular lichen myxedematosus. ⁵ The very limited skin involvement and benign prognosis help the differentiation from scleromyxedema.

Buschke’s scleredema of adultorum is associated with diabetes and microscopically characterized by marked interstitial mucin deposition, intermingled between fenestrated collagen bundles, in three times thickened reticular dermis. The other principal sclerodermoid disease is the nephrogenic systemic fibrosis, but gadolinium exposure in patients with severe renal insufficiency is a very pathognomonic history. ² Under the microscope, variable amounts of mucin are depicted, extending to the subcutis, with thick elastic fibers oriented parallel to the collagen bundles, dystrophic calcification, and sclerotic bodies, also known as elasto-collagenous balls. As regards differential from scleroderma, the detection of the typical papular lesions addresses the diagnosis of scleromyxedema, besides the acral skin induration common to both diseases. In minimal initial acral involvement, histopathological examination excludes the presence of mucin deposition in scleroderma. Moreover, history of Raynaud phenomenon, abnormal nail fold capillaries, as well as positive autoimmune findings are characteristic of systemic sclerosis, while always absent in scleromyxedema.^2,13

Therapy

No randomized clinical trials are available for this rare condition, and no specific treatment has proven permanent response, as relapses are frequent at dismissing. A practical treatment algorithm has been proposed on the recent European guidelines on sclerosing skin diseases, with first- and second-line approaches. ¹³

First-line treatment is represented by high-dose intravenous immunoglobulins (hd-IVIg), at the standard dosage of 2 g/Kg of bodyweight, which has proven high efficacy rate on skin and extracutaneous manifestations, including the dermato-neuro syndrome.^{1,13,20,21,35,44–49} Total dosage is divided into 4 or 5 days per cycle of treatment, and the cycle is repeated every 4 weeks, taking into consideration the IgG half-life elimination, with usually complete clearance in 21 days. ⁶ Skin assessment should be performed before starting the treatment and thereafter every three cycles. ¹⁹ If no valuable clinical response occurs within 6 months, the therapy should be discontinued. By converse, when skin improvement is assessed, the interval between the infusions can be gradually increased to 6 weeks. ¹³

The treatment is usually well tolerated, with mild side effects, usually depending on too fast infusion rate: skin eruption, tachycardia, nausea, thorax or abdominal pain, and arthralgia. ⁶ Exclusion of IgA deficiency and anti-IgA antibodies is mandatory to avoid the risk of anaphylaxis. Lower dosage per day and slow infusion rate are recommended in patients with severe kidney or heart involvement, concomitant medications, as well as in elderly patients. Worsening of kidney insufficiency and myocardial ischemia are rare events, but to be considered.^49–52 Severe events requiring dismission include septic meningitis, haemolytic anemia, and thrombosis. ⁶

Long-term treatment is usually required, and relapses occur in a variable time-lapse, from few months to 3 years cessation of intravenous immunoglobulin infusions. ⁶ If clinical response is not optimal or efficacy progressively reduced, combination with systemic corticosteroids, thalidomide, and more recently lenalidomide has been proposed.^{1,6,23,30,51–58}

Second-line treatments include same drugs as monotherapy, that is, systemic corticosteroids, thalidomide, or lenalidomide. ¹³ Systemic corticosteroids dosage varies following the active principle: 0.5–1 mg/kg/day of prednisone, 0.3–0.5 mg/kg/day of prednisolone, or dexamethasone 40 mg once daily for 4 days per week during three consecutive weeks each month.^6,13,19 Thalidomide dosage is usually gradually increased from 50–100 mg daily to 150–400 mg, while lenalidomide dosage is 25 mg/day for 3 weeks/month.^6,13,57,59

Third line of treatment is considered in very refractory disease and is represented by peripheral blood ASCT associated with dexamethasone.^13,46 Unfortunately, treatment with ASCT is not efficacious in case of dermato-neuro syndrome, ⁶⁰ and association of bortezomib and dexamethasone has been suggested.^44,61–63 Limited experience characterize other treatments, such as oral retinoids, interferon-alfa, cyclosporine, hydroxychloroquine, ultraviolet radiation A1 (UVA-1), or psoralen and ultraviolet A (PUVA) phototherapy, Grenz rays, and total skin electron-beam therapy.^13,63

Current guidelines do not recommend the use of potentially toxic drugs, ¹³ such as melphalan, although considered golden standard in the past years.^8,64–66 The Mayo Clinic experience documented a high rate of fatal adverse effects, including hematologic malignancies, especially acute leukemia, opportunistic infections, as well as congestive heart failure. ⁸ Combination of melphalan treatment with dexamethasone, followed by thalidomide has been recently suggested for very refractory and disabling cases. ⁶⁷ Other chemotherapeutic agents showed no better efficacy than melphalan and similar toxicity: cyclophosphamide, methotrexate, chlorambucil, and 2-chlorodeoxyadenosine.^4,8,13,63

Local treatment might be considered in very limited disease, ⁹ or associated to systemic therapy with auxiliary improvements. Several experiences document the usefulness of topical high-potency corticosteroids and/or calcineurin inhibitors, such as of tacrolimus, inhibiting TGF-induced collagen synthesis.^1,8,68,69 A certain cosmetic improvement is reported for facial disfigurement, with dermabrasion or carbon dioxide laser treatments.^70–72

Conclusion

Knowledge of the disease has increased worldwide, but understanding of the pathogenetic mechanisms that subtend skin mucinosis and fibrosis, as well as the role of monoclonal gammopathy remains a challenge. Information about the patient’s cytokines profiling, and variations during the course of the disease or in response to treatment are missing. Advances in pathogenesis might point out target treatments, to go behind long-term control of symptoms and deferred progression. A major limitation is the rarity of the disease, but an important recently achieved goal has been the definition of diagnostic criteria as well as treatment recommendations. Imaging improvement, especially high-frequency ultrasonography is expected to provide more objective quantification of the disease severity and activity, with eventual documentation of treatment efficacy. Actually, IVIg is considered the best therapeutic option with few side effects. Novel therapies are warrant, and as with actual options, the prognosis of scleromyxedema remains guarded, and quality of life limited by the disabling progressive course in the majority of patients.