INTRODUCTION — Pretibial myxedema (also called localized myxedema, thyroid dermopathy, or infiltrative dermopathy) is an infrequent manifestation of Graves' disease. It forms the third component of the classical triad of Graves' disease (goiter, orbitopathy, and pretibial myxedema). However, it is not restricted to the pretibial area and may involve the ankle and dorsum of the foot and may present on the elbows, knees, upper back, and neck [1]. Pretibial myxedema used to occur in up to 5 percent of patients with Graves' disease and 15 percent of patients with Graves' disease and orbitopathy [2,3], but the incidence of pretibial myxedema has declined considerably, probably because the diagnosis of Graves' hyperthyroidism is now established much earlier, and antithyroid therapy is initiated sooner. The prevalence of pretibial myxedema with thyroid eye disease has been reported as 0.15 per 10,000 persons [4].
The clinical manifestations, diagnosis, and treatment of pretibial myxedema will be reviewed here. Other clinical manifestations and the treatment of Graves' disease are reviewed separately.
●(See "Overview of the clinical manifestations of hyperthyroidism in adults".)
●(See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment".)
●(See "Clinical features and diagnosis of thyroid eye disease".)
●(See "Treatment of thyroid eye disease".)
PATHOLOGY AND PATHOGENESIS — Pretibial myxedema results from the accumulation in the dermis of glycosaminoglycans (GAG), especially hyaluronic acid, secreted by fibroblasts under the stimulation of local cytokines. The cytokines arise from a lymphocytic infiltration, which is best seen in early lesions. The resulting characteristic pathologic changes are mucinous edema and the fragmentation of collagen fibers with deposition of acid mucopolysaccharides (hyaluronic acid) in the papillary and reticular dermis, with subsequent extension into deeper tissue [1,5]. An increased number of fibroblasts have been reported [5]. Clinically, one sees non-pitting edema of the dermis, due both to the hydrophilic nature of these substances and secondarily to compression of dermal lymphatics [6] and fragmentation of dermal collagen fibers.
The etiology of pretibial myxedema is not proven but is considered similar to the retroorbital manifestation of Graves' eye disease. Patients with pretibial myxedema almost always have Graves' orbitopathy, and such patients characteristically have very high serum concentrations of thyroid-stimulating hormone (TSH) receptor antibodies compared with patients with fewer manifestations of Graves' disease and also compared with patients who have severe eye disease without pretibial myxedema.
The demonstration of TSH receptor protein expression by normal dermal fibroblasts has raised the possibility that TSH-receptor antibodies and/or antigen-specific T cells initiate the inflammatory response, which stimulates the production of GAG by these cells, as seen in the accompanying Graves' orbitopathy [7,8]. Cytokines such as tumor necrosis factor alpha and gamma interferon induce GAG release from fibroblasts and may also be secreted by Th1 type T cells activated by the fibroblast TSH receptor antigen [7-9]. The role of insulin-like growth factor 1 (IGF-1) and the IGF-1 receptor (IGF-1R), which appear to be critical to the development of Graves' eye disease (by enhancing the effects of the TSH receptor antibodies) has not been critically explored in pretibial myxedema. However, dermal fibroblasts have the same in vitro characteristics as retroorbital fibroblasts in this regard, so this phenomenon of cross-talk between the TSH receptor and the IGF-1R can be assumed to be important in this condition as well [10].
An etiologic role for TSH receptor antibodies and TSH receptor-specific T cells could also explain the occasional worsening of dermopathy after trauma, surgery, and radioiodine therapy for hyperthyroidism [11]. Among them, trauma to the pretibial region may be the most common precipitating factor initiating an inflammatory response [12,13], and it has been seen occasionally after thyroid surgery [14]. Tobacco use may also be a risk factor for the development of dermopathy, similar to its role in increasing the risk for thyroid eye disease [3]. (See "Clinical features and diagnosis of thyroid eye disease".)
CLINICAL FEATURES — Pretibial myxedema is characterized by bilateral, asymmetric, non-pitting, scaly thickening and induration of the skin, most commonly as one or a few well-demarcated papules or nodules several centimeters in diameter [15]. They may be violaceous or slightly pigmented (yellow-brown) and often have an orange-peel appearance. The lesions are usually asymptomatic but may be pruritic or even painful. The most frequent location of pretibial myxedema is over the lower legs, especially the pretibial areas or the dorsum of the foot (picture 1 and picture 2) and may be accompanied by persistent lymphedema. Rarely, the fingers and hands, elbows, arms, or face are affected [16]. The lesions usually appear over a period of several months and then stabilize or, in some cases, regress spontaneously. In rare patients, however, the lesions progress to involve the legs, feet, or hands completely, resulting in a form reminiscent of elephantiasis (picture 3) and leaving the patient severely disabled. The skin is thickened, woody, firm, with non-pitting edema, skin fibrosis, and verrucous nodules [2,15].
In a retrospective study of 178 patients followed for an average of 7.9 years, the following was noted [17]:
●Non-pitting edema was the most prevalent form of dermopathy (43 percent)
●The pretibial area was most commonly involved (99 percent)
●Virtually all patients had coexisting ophthalmopathy (97 percent)
Pretibial myxedema is rarely the presenting feature of autoimmune thyroid disease (ie, rarely preceding abnormalities in thyroid function tests) [2,18]. The development of pretibial myxedema is not related to thyroid function, and patients may be hyperthyroid, euthyroid, or hypothyroid at the time of presentation [15]. Patients may have other signs of hyperthyroidism, including clubbing of the fingers and osteoarthropathy of the phalanges of the hands and feet (thyroid acropachy), or symptoms and signs of hyperthyroidism may be absent. (See "Overview of the clinical manifestations of hyperthyroidism in adults".)
Patients with pretibial myxedema almost always have Graves' orbitopathy. Specific ocular findings in patients with coexisting Graves' orbitopathy may include periorbital edema, conjunctival injection and edema, proptosis, and extraocular muscle dysfunction. (See "Clinical features and diagnosis of thyroid eye disease".)
TSH receptor antibodies are persistently highly elevated in almost 100 percent of patients with Graves' disease and pretibial myxedema [15].
DIAGNOSIS — The diagnosis of pretibial myxedema is based upon the history and the characteristic clinical appearance of the skin lesion (the location, non-pitting nature, and distinct borders of the lesions). Punch biopsy is rarely necessary for diagnosis, particularly when the characteristic skin lesion develops in a patient with active hyperthyroidism or history of hyperthyroidism and Graves' ophthalmopathy. Punch biopsy of the skin may be necessary in patients who present with skin lesions in the absence of active hyperthyroidism or history of autoimmune thyroid disease, but this will usually turn out not to be pretibial myxedema. Glycosaminoglycans (GAG) can be detected on hematoxylin and eosin staining and confirmed with alcian blue, colloidal iron, or toluidine blue. Periodic acid-Schiff reaction (PAS) is negative.
DIFFERENTIAL DIAGNOSIS — Pretibial myxedema may resemble the skin lesions caused by inflammatory dermatoses, such as stasis dermatitis from chronic lymphatic and venous obstruction of the legs, chronic dermatitis, and cutaneous mucinosis (in patients with lupus erythematosus, dermatomyositis, scleroderma). It may also resemble lichen amyloidosis, hypertrophic lichen planus, and necrobiosis lipoidica diabeticorum. However, when the patient is known to have Graves' disease, none of these skin diseases in the differential diagnosis are likely to apply. (See "Stasis dermatitis" and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults" and "Overview of cutaneous lupus erythematosus" and "Lichen planus" and "Necrobiosis lipoidica".)
TREATMENT — Some patients with pretibial myxedema do not seek treatment because the extent of the lesions is limited and they are asymptomatic. The usual indications for treatment are pruritus, local discomfort, the unsightly appearance of the lesions, or progression of lesions. However, it is reasonable to treat all new lesions in the hope of preventing them from becoming more chronic because treatment is less effective in chronic disease [3,19]. The treatment approach described below is based upon case series and clinical experience [19-21].
●Nonpharmacologic – Nonpharmacologic treatment includes minimizing risk factors, such as sensibly avoiding tobacco, reducing weight, and normalizing thyroid function. Normalization of thyroid function does not necessarily improve pretibial myxedema [1]. However, severe disease is most often encountered in patients with longstanding untreated Graves' thyroid disease. Some experts advocate the use of compression stockings (20 to 30 mmHg) to improve lymphedema [1,3,15]. For more severe cases, some have recommended intensive treatment of coexisting lymphedema with physiotherapy [3].
●Pharmacologic – For initial pharmacologic therapy, medium- to high-potency topical corticosteroids with or without occlusion or intralesional corticosteroids are our suggested approach (table 1). We use the topical application of a glucocorticoid ointment covered by an occlusive dressing (eg, 0.025% fluocinolone acetonide) under plastic wrap nightly or every other night. We use intralesional corticosteroids if there is no improvement with topical treatment after 4 to 12 weeks, especially for plaque and nodular forms of dermopathy. Once the lesions regress, the frequency of glucocorticoid application can be reduced. Resistant lesions may require systemic glucocorticoid therapy while some cases can spontaneously resolve after several years.
In a randomized trial comparing seven injection sessions of intralesional triamcinolone acetate administered every three days versus every seven days in 110 patients with pretibial myxedema, complete response rates at end of treatment were similar (87.3 versus 90.9 percent) [22]. After 3.5 years of follow-up, recurrence rates were 31.2 and 32 percent, respectively. The dose of triamcinolone acetonide acetate injection (50 mg/5 mL) was calculated according to 8 mg triamcinolone acetonide acetate per 2 cm-diameter circle area at each session, but the total dose was not more than 100 mg at each session in a patient.
Longstanding pretibial myxedema may be quite resistant to all therapy. A number of case reports have suggested that the addition of pentoxifylline may be helpful in resistant cases [23]. This drug prevents the proliferation of fibroblasts. In other case reports, B cell depletion with rituximab and plasmapheresis were found to be helpful in severely affected patients [24-27]. Immunomodulatory therapy with intravenous immune globulin has been reported to be effective in an uncontrolled case series [28]. An insulin-like growth factor 1 receptor (IGF-1R) blocking monoclonal antibody is also under investigation after a case report of successfully treating a patient with pretibial myxedema [29]. Surgical excision has been tried, but as described above, such trauma almost always precipitates a recurrence of the disease and should not be attempted.
LONG-TERM OUTCOME — Little is documented about long-term outcomes in patients with pretibial myxedema. However, in a retrospective study of 178 patients followed for an average of 7.9 years, more severe cases, which were treated with topical glucocorticoids, occurred in 54 percent [17]. Patients with milder forms (40 percent) did not receive any therapy. Overall, 50 percent of patients had moderate improvement or complete remission, while 50 percent had minimal or no improvement. Patients who were untreated had a tendency for better outcome, but these were the patients with milder disease. All five patients with the most severe disease (elephantiasis) were less likely to have remission despite treatment with steroids.
SUMMARY AND RECOMMENDATIONS
●Pretibial myxedema results from the accumulation in the dermis of glycosaminoglycans (GAG), especially hyaluronic acid, secreted by fibroblasts under the stimulation of cytokines. The demonstration of thyroid-stimulating hormone (TSH) receptor protein expression by normal dermal fibroblasts raises the possibility that TSH-receptor antibodies and/or antigen-specific T cells initiate the inflammatory response, which stimulates the production of glycosaminoglycans by these cells. It is likely that the insulin-like growth factor 1 receptor (IGF-1R) contributes to the activity of the TSH receptor antibodies. (See 'Pathology and pathogenesis' above.)
●Pretibial myxedema is characterized by non-pitting, scaly thickening and induration of the skin, most frequently located over the lower legs, especially the pretibial areas or the dorsum of the foot (picture 1 and picture 2). Rarely, the fingers and hands, elbows, arms, or face are affected. (See 'Clinical features' above.)
●The diagnosis of pretibial myxedema is based upon a history of Graves' disease and the characteristic clinical appearance of the skin lesion (the location, non-pitting nature, and distinct borders of the lesions). Punch biopsy is rarely necessary for diagnosis, particularly when the characteristic skin lesion develops in a patient with active hyperthyroidism or history of hyperthyroidism and Graves' ophthalmopathy. (See 'Diagnosis' above.)
●Pretibial myxedema may resemble the skin lesions caused by inflammatory dermatoses, such as stasis dermatitis from chronic lymphatic and venous obstruction of the legs, chronic dermatitis, and cutaneous mucinosis (in patients with lupus erythematosus, dermatomyositis, scleroderma). (See 'Differential diagnosis' above.)
●The usual indications for treatment are pruritus, local discomfort, or the unsightly appearance of the lesions. However, it is reasonable to treat all new lesions in the hope of preventing them from becoming more chronic. (See 'Treatment' above.)
●Treatment includes minimizing risk factors, such as sensibly avoiding tobacco, reducing weight, and normalizing thyroid function. As initial therapy for pretibial myxedema, we suggest topical application of a medium- to high- potency glucocorticoid ointment (Grade 2C). We typically use fluocinolone acetonide (0.025%) under plastic wrap nightly or every other night (table 1). We use intralesional corticosteroids if there is no improvement with topical treatment. (See 'Treatment' above.)
