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Teprotumumab: An eye-opening advance for pretibial myxedema?


DII small banner By Warren R. Heymann, MD
May 8, 2017


pretibial myxedema
Histologic images of PME. (A, Hematoxylin-eosin stain; original magnification, ×40. B, Colloidal iron stain; original magnification, ×100.)
Credit: JAAD
Having just completed the chapter on the treatment of pretibial myxedema (PTM, also known as thyroid dermopathy) for the upcoming 5th edition of Treatment of Skin Disease (which I edit with my esteemed colleagues Mark Lebwohl, John Berth-Jones, and Ian Coulson), I am amazed at how little progress there has been for this disorder since we published the first edition. The first-line treatments are still corticosteroids — high potency topical steroids (with our without occlusion) or intralesional steroid injections. Second-line treatment adds pentoxifylline. Third-line therapies, many of variable efficacies, include IVIG, octreotide, plasmapheresis with rituximab, cytotoxic agents, UVA1, radiation, and surgery. (1)

PTM occurs in 0.5–4.3% of patients with Graves disease and occasionally in Hashimoto’s thyroiditis. It usually appears after the onset of thyroid-associated ophthalmopathy (TAO). PTM can be classified into four morphologic variants: non-pitting edema, plaque, nodular, and elephantiasic forms. Histopathological features of PTM include epidermal hyperkeratosis, accumulation of glycosaminoglycans (GAG), predominantly hyaluronic acid in the dermis, and lymphocytic infiltration. The pathogenesis of PTM is unknown, but is likely a due to a combination of immunological, cellular, genetic and mechanical factors (2). Thyroid-stimulating hormone receptor antibodies are the principal autoantibodies for Graves disease, TAO and PTM. (2)
 
Although some cases of PTM may be dramatic and debilitating, it is TAO that is of greatest concern. According to Weiler: “Thyroid eye disease is a complex autoimmune disease with the pathogenesis becoming more clearly understood; however, it is not completely comprehended. While the underlying molecular mechanism of thyroid eye disease is multifaceted, the activation of autoantibodies to thyroid stimulating hormone (TSH, thyrotropin) receptors (TSHR) seems to be the inciting event. In patients with Graves’ hyperthyroidism, there is an over-expression of TSHR in the retrobulbar tissue compared to controls, particularly in orbital fibroblasts, which are integral in the pathogenesis of thyroid eye disease. Upon activation, orbital fibroblasts proliferate and secrete pro-inflammatory cytokines and hydrophilic hyaluronan into the interstitial space. These processes result in a large osmotic pressure gradient in the orbit, leading to increased fluid accumulation between the muscle fibres.” (3)
 
Although TSHR is the main autoantigen for patients with TAO (and PTM), insulin-like growth factor-I receptor (IGF-IR), a tyrosine kinase receptor, has recently been proposed as a second antigen that participates in the pathogenesis of TAO. This theory based on its interactions with anti-IGF-IR antibodies generated in Graves disease, its apparent physical and functional complex formation with TSHR, and its involvement in TSHR post-receptor signaling. (4)

The hypothesis of inhibiting fibroblast production of hyaluronic acid by anti-IGF-I therapies is not new. Octreotide, a long-acting synthetic somatostatin analogue with IGF-I antagonistic properties has been used successfully (by oral or intralesional administration) in a few cases of PTM, but not others. (1)
 
Currently, corticosteroids are the main treatment for TAO. Smith et al conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves’ ophthalmopathy-specific quality-of-life questionnaire. Adverse events were assessed. In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes; adjusting medication for diabetes controlled this event. Teprotumumab could also be associated with muscle spasms and diarrhea, particularly in patients with gastrointestinal disease; however, no mechanistic link has been established. The authors concluded that for patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (5) There was no mention of dermatologic findings of the patients enrolled in this trial.

It is reasonable to assume that dermal fibroblasts behave similarly to orbital fibroblasts in the context of autoimmune thyroid disease. Any novel therapy that can enhance the lives of patients with severe, recalcitrant pretibial myxedema would be welcome. I look forward to seeing a study utilizing teprotumumab for PTM in the near future.

1. Ghazi ER, Heymann WR. Pretibial myxedema. In Lebwohl MG, Heymann WR, Berth-Jones J, Coulson I (eds). Treatment of Skin Disease. Elsevier, London (in press).
2. Chen X, et al. Efficacy of trimodality therapy for pretibial myxedema: A case series of 20 patients. Acta Derm Venereol 2016; 96: 714-5.
3. Weiler D. Thyroid eye disease: A review. Clin Exp Optom 2017; 100: 20-5.
4. Smith TJ, Janssen JA. Building the case for insulin-like growth factor receptor-I involvement in thyroid-associated ophthalmopathy. Front Endocrinol (Lausanne) 2017; 7:167.
5. Smith TJ, et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med 2017; 376: 1748-61.

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