Abstract
Background:
Pretibial dermopathy (PTD) is a rare, disfiguring manifestation of Graves’ disease. The shared pathophysiology with thyroid eye disease (TED), centered on fibroblast activation via a thyroid-stimulating hormone receptor and insulin-like growth factor-1 receptor (IGF-1R) complex, provides a strong rationale for using the IGF-1R inhibitor, teprotumumab.
Methods:
We present a case series of five patients with severe PTD and concomitant TED who were treated with teprotumumab. A review of reported cases in the literature was also conducted.
Results:
All patients experienced significant clinical improvement, including regression of skin thickening as well as enhanced functional capacity. Side effects included mild hearing loss, muscle cramps, and fatigue. One patient experienced a severe gastrointestinal event requiring treatment discontinuation, while those experiencing a recurrence of PTD, responded to a second course of therapy.
Conclusions:
Teprotumumab showed promising efficacy in the treatment of PTD. Further studies are needed to confirm its durability and safety.
Introduction
Pretibial dermopathy (PTD) is an autoimmune skin manifestation with an incidence of 0.5–4.3% reported in patients with Graves’ disease (GD). 1 The condition typically follows the development of thyroid eye disease (TED) and shares a similar pathophysiology: stimulation of fibroblasts through activation of thyroid-stimulating hormone receptors (TSHRs) by thyrotropin (TSH) receptor antibodies (TRAb), leading to the accumulation of glycosaminoglycans in the dermis and subcutis. 1 PTD commonly presents as nonpitting edema and skin thickening, predominantly affecting the pretibial area. 2 In severe cases, PTD can result in cosmetic disfigurement and functional impairment, such as reduced mobility, and may also be associated with thyroid acropathy. 3
Various treatments have been proposed, including compression stockings, intermittent pump compression, plasmapheresis, and several immunomodulatory therapies (rituximab and intravenous immunoglobulin), unfortunately, all with disappointing results.4–6 Currently, intralesional or topical corticosteroid is the mainstay for therapy. 7 However, efficacy is often limited, with patients experiencing inadequate response, as observed in the present cases. 5 This highlights the need for more effective therapeutic options.
Teprotumumab, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor and the only FDA-approved medical therapy for TED, targets the shared pathophysiological mechanism involving TSHR and IGF-1R cross-talk that drives fibroblast activation and tissue remodeling. 8 While its safety is known, its efficacy in PTD remains underinvestigated.
Here, we present five patients with severe PTD treated with teprotumumab, resulting in substantial clinical and functional improvement. We also reviewed prior cases reported in the literature to better characterize the clinical utility, durability, and safety profile of this therapeutic option.
Methods
This retrospective case series included five patients treated at the Mayo Clinic for PTD with teprotumumab. Laboratory assessments included serum TSH, free thyroxine (fT4), and thyroid antibody profiles. TRAb was measured using a second-generation electrochemiluminescence immunoassay (Roche Diagnostics), with a reference range of 0.00–1.75 IU/L. Thyroid-stimulating immunoglobulin (TSI) was quantified using a recombinant bioassay (Thyretain®) utilizing Chinese hamster ovary cells transfected with a chimeric human TSH receptor (Mc4-CHO) and a luciferase reporter gene. The assay measures cAMP production via chemiluminescence, reported as a TSI index; the reference range is ≤ 1.3 TSI Index.
This series was deemed exempt from the requirement of specific informed consent by the Mayo Clinic Institutional Review Board (24-006236) due to its retrospective nature and the use of de-identified data. All included patients had provided Minnesota Research Authorization for the use of their medical records for research purposes. Strict de-identification protocols were followed for all clinical images presented.
Case 1
An 83-year-old female with a past medical history of GD for 26 years, treated with radioactive iodine (RAI) and thyroidectomy, presented with PTD and moderate inactive TED that developed 15 years after RAI therapy.
On physical examination, she was hypertensive (141/89 mm Hg) but in no acute distress. She had asymmetrical proptosis of 22 mm in the left eye and 18 mm in the right eye, right lid retraction, and left lid ptosis. The skin of her toes, ankles, and lower extremities bilaterally up to the knees appeared thickened, with reddish/brownish discoloration and nodular lesions, but without ulcerations or evidence of infection.
Laboratory testing showed a TSH of 2.5 mIU/L, fT4 of 1.4 ng/dL, total triiodothyronine of 73 ng/dL, TSI of 5.7, and TRAb > 40 IU/L.
Previous treatment with compression stockings and local steroid creams was unsuccessful with the progression of PTD up to her knees bilaterally along with papillomatous changes over her toes and ankles (Fig. 1A). This resulted in debilitating pain and limited mobility. The decision was made to initiate teprotumumab to treat both her TED and PTD. She completed a full 8-infusion course (7 years after PTD diagnosis). Following treatment, particularly after 4 infusions, she experienced a significant clinical improvement in her PTD with a notable regression of the lower extremity skin changes (Fig. 1B). She reported decreased heaviness in her legs, increased skin elasticity, and improved ankle mobility and overall functional capacity. Side effects included hair loss, muscle aches, and mild hearing loss. She was monitored for two years. Her eye symptoms initially improved, but intermittent diplopia soon followed, and she underwent left upper-lid ptosis repair. When PTD gradually recurred, teprotumumab was restarted with improvement in both PTD and TED, but it was discontinued after one infusion due to renewed hearing loss.
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Case 2
A 66-year-old male with a 13-year history of GD and papillary thyroid carcinoma, treated with thyroidectomy and RAI remnant ablation, presented with progressive PTD alongside moderate severity and active TED that developed following RAI.
On examination, he had normal vital signs, significant proptosis of 35 mm bilaterally, conjunctival injection, erythematous changes over the left upper and lower eyelids, and lagophthalmos bilaterally. The lower extremities showed significant papulonodular skin changes in both feet.
Laboratory testing included a TSH of 1.7 mIU/L, an fT4 of 1.7 ng/dL, a thyroglobulin tumor marker of < 0.1 ng/mL, a TSI of 3, and a TRAb of 26 IU/L.
The patient had undergone two surgical reduction procedures on the dorsum of both feet with skin grafting 7 years earlier. Despite this intervention, his PTD progressed over the next year, with increased accumulation of deposits on his feet, predominantly on the left, and recurrent enlargement of his preexistent PTD areas (Fig. 1C).
The patient was initiated on teprotumumab (11 years after PTD diagnosis) for both TED and PTD, with significant improvement in his functional capacity after completing the initial full course of therapy. However, 18 months later, he experienced a recurrence of his PTD, with his feet gradually enlarging, which resulted in a decline in his balance. He started a second course of teprotumumab and showed again notable improvement after only four infusions (Fig. 1D) as well as minor improvement in his proptosis. The completion of his second course, however, was halted due to the development of gastrointestinal side effects, including severe diarrhea causing subsequent hospitalization. While the etiology of these side effects remains unclear, this patient had no prior or subsequent diagnosis of IBD, and the symptoms resolved after teprotumumab discontinuation. 14 months post-treatment, he reported increased leg tightness with worsening of dermopathy and increased eye blurriness. He was subsequently started on a third course of teprotumumab of which his symptoms improved after 4 infusions. However, he self-discontinued the infusions due to lack of further benefit, with his proptosis and blurriness remaining stable. He has an upcoming follow-up at the TED clinic for further evaluation.
Case 3
A 71-year-old female with a history of GD diagnosed 10 years prior presented with severe PTD and TED, both of which developed within a year of receiving RAI therapy.
On examination she had normal vital signs. There was bilateral lid retraction, mild conjunctival injection in the right eye, pronounced lagophthalmos, and asymmetrical bilateral proptosis of 24 mm on the left and 21 mm on right. Her PTD was severe, extending from the mid-shin downwards to her feet bilaterally; it was circumferential in the shin area and papular over her toes with no obvious ulceration (Fig. 1E).
Laboratory testing showed a TSH of 1.3 mIU/L, fT4 of 1.6 ng/dl, TRAB of 3.21 IU/L, and TSI of 5.6.
While her TED had been treated with multiple ocular surgeries, her PTD had been unsuccessfully managed with compression stockings and intralesional steroids. Given disease progression, she was started on teprotumumab 8 years after the first PTD diagnosis.
The patient completed a full course of teprotumumab with significant clinical improvement, particularly after the first 4 infusions, with a marked decrease in the volume of the skin changes in her lower extremities (Fig. 1F). She reported functional gains, stating that her “shoes felt looser” and that she experienced “significant improvement in mobility.” She did not note any pertinent side effects. She was monitored for 4 years after treatment with stable symptoms. She noted moderate, sustained improvement in her ocular symptoms; no subsequent management for TED was pursued.
Case 4
A 78-year-old female with a past medical history of GD for 8 years, treated with RAI, presented for management of her TED that developed 2 years after RAI and PTD.
On examination, she had normal vital signs and had a small thyroid of around 5 g with no tenderness or nodularity. There were significant ocular inflammatory changes, including swelling of the eyelids, conjunctival injection, chemosis, bilateral lagophthalmos, and proptosis of 24 mm on the left side and 25 mm on the right side. In addition, she had a 4 cm single plaque of PTD in the left mid-shin area with no ulceration.
Laboratory testing showed a TSH of 13.1 mIU/L, an fT4 of 1.5 ng/dl, a TRAB of 28 IU/L, and a TSI of 6.6.
Her TED became inactive, and she underwent orbital decompression surgery, which was complicated by the development of double vision. Shortly after surgery, she developed worsening of her PTD and was found to have extensive circumferential involvement that extended two-thirds of the way up over her shins to the dorsal aspect of both feet as well as involvement of her toes with notable discoloration. This severe PTD was treated with topical corticosteroids with no improvement.
Due to progressive PTD, refractory to treatment, and persistent proptosis, she was started on teprotumumab, with treatment initiation 1 year after PTD diagnosis. After completing 8 infusions, she noticed significant improvement. She reported that reduction, in swelling allowed her to “wear jeans and sandals that she had not fit into in the past” and noted an improvement in the discoloration of her lower extremities. Side effects included mild fatigue and “head-cold”-like symptoms. She initially reported improvement in proptosis and diplopia; however, she experienced worsening ptosis and underwent bilateral eyelid repair one year later. Regarding her PTD, she was monitored for two years following treatment, during which she had slowly worsening symptoms. She is now using compression stockings, with her condition currently stable.
Case 5
A 71-year-old woman with a history of GD treated with RAI 8 years ago presented with progressive PTD alongside moderate severity, inactive TED that began shortly after RAI.
On examination, her vital signs revealed mild hypertension. Ocular assessment revealed bilateral features consistent with TED, including proptosis of 28 mm on the right side and 27 mm on the left side with bilateral lid retraction. Cutaneous findings included prominent nodular lesions involving the bilateral pretibial area and toes (Fig. 1G).
Laboratory testing revealed a TSH of 1.17 mIU/L, an fT4 of 1.1 ng/dL, and a TRAb of 36 IU/L.
Signs of dermopathy appeared 2 years following GD diagnosis. Prior management included compression stockings and topical corticosteroids, both of which failed to yield improvement.
Four years after the onset of PTD, she started teprotumumab with a full 8-infusion course, targeting both TED and PTD. Following treatment, she reported substantial clinical improvement, including near-complete resolution of her dermopathy plaques, softer skin texture, and enhanced mobility of the affected areas (Fig. 1H). She did experience side effects, including muscle cramps, borderline hyperglycemia, and intermittent left-sided tinnitus, that fully resolved. She was followed for two years after treatment, during which her symptoms remained unchanged. She also experienced significant improvement in her ocular signs and symptoms, and these have likewise remained stable.
Discussion
This case series adds five compelling examples to the growing evidence supporting the utility of teprotumumab for the treatment of severe PTD. All patients experienced clinical and functional improvements, consistent with prior reports.
The likely explanation for teprotumumab’s noted efficacy in PTD stems from its shared pathophysiology with TED. 9 Specifically, crosstalk between IGF-1R and TSHR in fibroblasts promotes glycosaminoglycan accumulation and tissue expansion. 1 Histopathologic evaluation of patients with pretibial myxedema demonstrated an excess accumulation of hyaluronan in the reticular dermis and subcutaneous tissues, as well as lymphocytic infiltration. These changes are thought to be due to overactivation of dermal fibroblasts by TSI antibodies. 1 By inhibiting IGF-1R, teprotumumab disrupts this cascade, explaining its therapeutic effect in both conditions, 10 as demonstrated concurrently in our case series.
A review of the literature identified 14 patients treated with teprotumumab for PTD (Table 1).11–20 Including our series, data are now available for 19 patients, and all patients had PTD alongside TED. The collective evidence indicates a consistent pattern of rapid and significant response, often after only two to three infusions, as emphasized by one series. 13 Another case report of a 66-year-old female with PTD refractory to oral steroids and diuretic therapy noted rapid improvement with teprotumumab within 2 doses and complete resolution by the end of the 8th infusion. 18 These cases align regarding type of benefit: marked improvement in skin texture (softening) and volume, along with significant functional gains, such as improved mobility and the ability to wear shoes and clothing that previously did not fit, indicating an overall improvement in quality of life.
Review of Reported PTD Cases Treated with Teprotumumab in Literature as Well as Present Case Series
N/A, information not available.
These cases also underline important aspects about response durability. While most previous reports show remission lasting 12–18 months, recurrence can occur earlier; one published case relapsed at five months. 18 In our series, one patient experienced recurrence at 18 months and required a second treatment course. This suggests, as in TED, that flares may occur after drug clearance.
Furthermore, the safety profile observed in our series is largely consistent with that established in the pivotal TED trials, with muscle spasms, fatigue, and mild hearing loss being the most common adverse events. We note that one of our cases had severe gastrointestinal side effects, but their etiology remained uncertain given concomitant hepatic pathology. We also note, not surprisingly, that RAI treatment was used in all cases, reinforcing the need to consider the impact of this treatment on development/deterioration of TED along with increased TRAb and, likely, increase risk for PTD.
While our findings are consistent with previously published individual case reports, our series reports consecutive cases, aiming to eliminate potential reporting bias, and tries to define a time pattern for response and flare, if one is present.
This retrospective case series has inherent limitations, including the absence of a control group and possible reporting bias. Another major challenge in evaluating PTD treatment highlighted by our review is the lack of standardized, objective outcome measures; current assessments rely heavily on subjective reports and photographic comparisons. To improve clinical evaluation and research, future efforts should focus on developing validated, quantitative tools. While randomized trials may be difficult due to the rarity of severe PTD, prospective multicenter patient registries could provide valuable data on treatment efficacy, durability, and safety, while also supporting the adoption of objective metrics. This would help establish a stronger evidence base for the use of teprotumumab or other evolving therapies for thyroid autoimmunity in PTD.
In conclusion, this case series adds to the growing evidence that teprotumumab is a promising treatment for PTD. Although randomized controlled trials are ideal, the rarity of PTD limits their feasibility. Further observational studies are needed to confirm these findings and further improve treatment options for these patients, currently served rather dismally by the available therapies.
Authors’ Contributions
D.H.: Conceptualization (supporting), original draft (lead), writing—review and editing (equal); S.S.-O.: Original draft (supporting), writing-review and editing (equal), supervision; D.T.-T.: Original draft (supporting), writing—review and editing (equal), supervision; M.N.S.: Conceptualization (lead), original draft (equal), writing—review and editing (equal), supervision.
Footnotes
Author Disclosure Statement
No competing financial interests exist.
Funding Information
M.N.S.’s institution received research grants from Immunovant (#00014749-REN05) and Viridian (#00027041), and he received consulting fees from Merida, Minghui Pharma, Genentech, Ethyreal Bio, BioHaven, Lassen, Tr1X and ArgenX (over the last 12 months).