ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid disease

Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid disease
Literature review current through: Jan 2024.
This topic last updated: Mar 21, 2023.

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 thyroid eye disease [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 thyroid eye disease. Patients with pretibial myxedema almost always have thyroid eye disease, 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 (TSHR) 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 eye disease [7,8]. Infiltrating plasma cells in these lesions have been shown to secrete TSHR autoantibodies [9]. T cell-derived cytokines, such as tumor necrosis factor alpha (TNF-alpha) and gamma interferon, induce GAG release from fibroblasts after being activated by the fibroblast TSHR antigen [7,8,10]. In thyroid eye disease, there is significant crosstalk between the TSHR and the insulin-like growth factor 1 (IGF-1) receptor in orbital fibroblasts, such that activation of the TSHR by TSHR autoantibodies can lead to IGF-1 receptor signal transduction, and a synergistic effect on GAG production occurs after activation of both receptors. The role of IGF-1 and the IGF-1 receptor has not been explored in pretibial myxedema. Dermal fibroblasts have the same in vitro characteristics as retroorbital fibroblasts, so the phenomenon of cross-talk between the TSH receptor and the IGF-1 receptor can be assumed to be important in this condition as well [11]. (See "Clinical features and diagnosis of thyroid eye disease", section on 'Pathogenesis'.)

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 [12,13]. Among them, trauma to the pretibial region may be the most common precipitating factor initiating an inflammatory response [14,15], and it has been seen occasionally after thyroid surgery [16]. 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, but the evidence for a distinct action is not strong [3]. (See "Clinical features and diagnosis of thyroid eye disease", section on 'Risk factors'.)

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 up to several centimeters in diameter [17]. They may be violaceous or slightly pigmented (yellow-brown) and often have an orange-peel appearance. The skin is woody, firm, and fibrosed around the verrucous nodules [2,17]. 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 [18].

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.

In a retrospective study of 178 patients followed for an average of 7.9 years, the following was noted [19]:

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 thyroid eye disease (97 percent)

Pretibial myxedema is rarely the presenting feature of autoimmune thyroid disease (ie, rarely preceding abnormalities in thyroid function tests) [2,20]. The development of pretibial myxedema is not related to thyroid function, and patients may be hyperthyroid, euthyroid, or hypothyroid at the time of presentation [17]. 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 thyroid eye disease. Features may include periorbital edema, conjunctival injection and edema, proptosis, and extraocular muscle dysfunction. These findings are typical of but often more severe than the findings in patients with thyroid eye disease without pretibial myxedema. (See "Clinical features and diagnosis of thyroid eye disease".)

TSH receptor antibodies are highly elevated in almost 100 percent of patients with Graves' disease and pretibial myxedema [17]. The antibodies usually remain persistently elevated.

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 thyroid eye disease. 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 progression of lesions, 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 because treatment is less effective in chronic disease [3,21]. The treatment approach described below is based upon case series and clinical experience [21-23].

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 [1,3,17]. For more severe cases, some have recommended intensive treatment of coexisting lymphedema with physiotherapy [3].

Note that surgical excision has been tried in the past, but as described above, such trauma almost always precipitates a recurrence of the disease and should not be attempted. (See 'Pathology and pathogenesis' above.)

Pharmacologic

Initial treatment: High-potency corticosteroids – 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 corticosteroid ointment covered by an occlusive dressing (eg, 0.025% fluocinolone acetonide) under plastic wrap nightly or every other night.

If there is no improvement with topical treatment after 4 to 12 weeks, we switch to intralesional corticosteroids every three days, especially for plaque and nodular forms of dermopathy. After the lesions regress, the frequency of corticosteroid application can be reduced. Note that 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) [24]. 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.

Resistant disease – Patients who have corticosteroid-resistant disease or who present with longstanding pretibial myxedema may benefit from a different approach. For most patients with resistant disease, we prefer a trial of teprotumumab, given the shared pathogenesis of thyroid eye disease and pretibial myxedema and randomized trial evidence of efficacy in thyroid eye disease. (See "Treatment of thyroid eye disease", section on 'Teprotumumab'.)

For corticosteroid-resistant pretibial myxedema, there are only case reports describing the efficacy of the different approaches:

-In case reports, teprotumumab, an insulin-like growth factor 1 receptor (IGF-1R) blocking monoclonal antibody, was shown to be effective in refractory disease [25-27]. Another report also showed improvement with teprotumumab, but not all patients had refractory disease [28].

-A number of case reports have suggested that the addition of pentoxifylline may be helpful in resistant cases [29]. 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 [30-33].

-In an uncontrolled case series, immunomodulatory therapy with intravenous immune globulin has been reported to be effective [34].

LONG-TERM OUTCOME — Little is documented about long-term outcomes in patients with pretibial myxedema. In a retrospective study of 178 patients followed for an average of 7.9 years, 54 percent of patients had more severe disease and received therapy (primarily topical corticosteroids) whereas the remaining patients with milder forms of disease did not receive any therapy [19]. 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

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 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.)

Clinical features – 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.)

Diagnosis – 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.)

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). (See 'Differential diagnosis' above.)

Treatment

Indications – The usual indications for treatment are progression of lesions, 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.)

Nonpharmacologic – Treatment includes minimizing risk factors, such as sensibly avoiding tobacco, reducing weight, and normalizing thyroid function. (See 'Treatment' above.)

Initial pharmacologic therapy – 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 every three days if there is no improvement with topical treatment. (See 'Treatment' above.)

Resistant disease – For persistently severe corticosteroid-resistant disease, we suggest teprotumumab rather than another agent (Grade 2C). This suggestion is based on the shared pathogenesis of thyroid eye disease and pretibial myxedema, case reports of efficacy in pretibial myxedema, and randomized trial evidence of efficacy in thyroid eye disease. (See 'Treatment' above and "Treatment of thyroid eye disease", section on 'Teprotumumab'.)

  1. Doshi DN, Blyumin ML, Kimball AB. Cutaneous manifestations of thyroid disease. Clin Dermatol 2008; 26:283.
  2. Fatourechi V, Pajouhi M, Fransway AF. Dermopathy of Graves disease (pretibial myxedema). Review of 150 cases. Medicine (Baltimore) 1994; 73:1.
  3. Fatourechi V. Thyroid dermopathy and acropachy. Best Pract Res Clin Endocrinol Metab 2012; 26:553.
  4. Perros P, Hegedüs L, Bartalena L, et al. Graves' orbitopathy as a rare disease in Europe: a European Group on Graves' Orbitopathy (EUGOGO) position statement. Orphanet J Rare Dis 2017; 12:72.
  5. Shishido M, Kuroda K, Tsukifuji R, et al. A case of pretibial myxedema associated with Graves' disease: an immunohistochemical study of serum-derived hyaluronan-associated protein. J Dermatol 1995; 22:948.
  6. Bull RH, Coburn PR, Mortimer PS. Pretibial myxoedema: a manifestation of lymphoedema? Lancet 1993; 341:403.
  7. Ajjan RA, Watson PF, Weetman AP. Cytokines and thyroid function. Adv Neuroimmunol 1996; 6:359.
  8. Kahaly G, Förster G, Hansen C. Glycosaminoglycans in thyroid eye disease. Thyroid 1998; 8:429.
  9. Chen X, Dong J, Zhang L, et al. Local immune microenvironment of skin may play an important role in the development of pretibial myxedema. Exp Dermatol 2021; 30:1820.
  10. Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med 1993; 329:1468.
  11. Davies TF, Andersen S, Latif R, et al. Graves' disease. Nat Rev Dis Primers 2020; 6:52.
  12. Harvey RD, Metcalfe RA, Morteo C, et al. Acute pre-tibial myxoedema following radioiodine therapy for thyrotoxic Graves' disease. Clin Endocrinol (Oxf) 1995; 42:657.
  13. Fatourechi V. Pretibial myxedema: pathophysiology and treatment options. Am J Clin Dermatol 2005; 6:295.
  14. Rapoport B, Alsabeh R, Aftergood D, McLachlan SM. Elephantiasic pretibial myxedema: insight into and a hypothesis regarding the pathogenesis of the extrathyroidal manifestations of Graves' disease. Thyroid 2000; 10:685.
  15. Davies TF. Trauma and pressure explain the clinical presentation of the Graves' disease triad. Thyroid 2000; 10:629.
  16. Syed AA, Jones NA, Perros P. Medical image. Acute pretibial myxoedema following thyroidectomy for Graves' disease. N Z Med J 2008; 121:108.
  17. Ai J, Leonhardt JM, Heymann WR. Autoimmune thyroid diseases: etiology, pathogenesis, and dermatologic manifestations. J Am Acad Dermatol 2003; 48:641.
  18. Lan C, Wang Y, Zeng X, et al. Morphological Diversity of Pretibial Myxedema and Its Mechanism of Evolving Process and Outcome: A Retrospective Study of 216 Cases. J Thyroid Res 2016; 2016:2652174.
  19. Schwartz KM, Fatourechi V, Ahmed DD, Pond GR. Dermopathy of Graves' disease (pretibial myxedema): long-term outcome. J Clin Endocrinol Metab 2002; 87:438.
  20. Pujol RM, Monmany J, Bagué S, Alomar A. Graves' disease presenting as localized myxoedematous infiltration in a smallpox vaccination scar. Clin Exp Dermatol 2000; 25:132.
  21. Takasu N, Higa H, Kinjou Y. Treatment of pretibial myxedema (PTM) with topical steroid ointment application with sealing cover (steroid occlusive dressing technique: steroid ODT) in Graves' patients. Intern Med 2010; 49:665.
  22. Kriss JP, Pleshakov V, Rosenblum A, Sharp G. Therapy with occlusive dressings of pretibial myxedema with fluocinolone acetonide. J Clin Endocrinol Metab 1967; 27:595.
  23. Volden G. Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid occlusive dressing. Acta Derm Venereol 1992; 72:69.
  24. Lan C, Li C, Chen W, et al. A Randomized Controlled Trial of Intralesional Glucocorticoid for Treating Pretibial Myxedema. J Clin Med Res 2015; 7:862.
  25. Varma A, Rheeman C, Levitt J. Resolution of pretibial myxedema with teprotumumab in a patient with Graves disease. JAAD Case Rep 2020; 6:1281.
  26. Petit L, Catinis A, Richard E, Silverberg J. A case of pretibial myxedema treated with teprotumumab. JAAD Case Rep 2021; 16:134.
  27. Washington A, Nam H, Pitch M, et al. Improvement of Pretibial Myxedema Following Administration of Teprotumumab. J Drugs Dermatol 2022; 21:1252.
  28. Mervis JS, Maeng MM, Kirsner RS, Wester ST. Teprotumumab as a novel treatment for pretibial myxoedema. Br J Dermatol 2022; 187:795.
  29. Engin B, Gümüşel M, Ozdemir M, Cakir M. Successful combined pentoxifylline and intralesional triamcinolone acetonide treatment of severe pretibial myxedema. Dermatol Online J 2007; 13:16.
  30. Heyes C, Nolan R, Leahy M, Gebauer K. Treatment-resistant elephantiasic thyroid dermopathy responding to rituximab and plasmapheresis. Australas J Dermatol 2012; 53:e1.
  31. Mitchell AL, Gan EH, Morris M, et al. The effect of B cell depletion therapy on anti-TSH receptor antibodies and clinical outcome in glucocorticoid-refractory Graves' orbitopathy. Clin Endocrinol (Oxf) 2013; 79:437.
  32. Kotwal A, Turcu AF, Sonawane V, et al. Clinical Experience with Rituximab and Intravenous Immunoglobulin for Pretibial Myxedema: A Case Series. Thyroid 2019; 29:692.
  33. Gubbi S, Araque KA, Avadhanula S, et al. Combined Immunosuppressive Therapy for Severe Graves Dermopathy. Ann Intern Med 2021; 174:1478.
  34. Antonelli A, Navarranne A, Palla R, et al. Pretibial myxedema and high-dose intravenous immunoglobulin treatment. Thyroid 1994; 4:399.
Topic 7826 Version 14.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟