Key words
thyroid eye disease - proptosis - treatment - insulin-like growth factor I receptor
- monoclonal antibody - teprotumumab
Introduction
Thyroid-associated ophthalmopathy (TAO aka Gravesʼ ophthalmopathy/orbitopathy or thyroid
eye disease TED) represents the ocular manifestation of thyroid autoimmunity, most
commonly occurring in Graves’ disease (GD) [1]
[2]. TAO is often related to hyperthyroidism, but it is still not clear how hyperthyroidism
influences TAO. It can also occur in other autoimmune thyroid diseases, including
hypothyroidism, normal thyroid function, and Hashimoto's thyroiditis [3]
[4]. TAO often appears within 18 months following a GD diagnosis [5]. TAO is characterized by inflammation in the retrobulbar tissues, increased adipogenesis,
and accumulation of extraocular intramuscular glycosaminoglycans (GAGs) leading to
expansion and remodeling of orbital contents [6]. Common symptoms may include eye pain, excessive lacrimation, photophobia, blurry
vision, and diplopia. TAO can cause eyelid withdrawal, exophthalmos, chemical reactions,
periorbital edema, and changes in eye movement. Severe TAO can cause exposure keratopathy,
diplopia, and compressive optic neuropathy, even loss of vision. Modifiable risk factors
for the development or progression of TAO include smoking, radioactive iodine (RAI),
and uncontrolled hypothyroidism or hyperthyroidism [7]. The ideal TAO treatment is based on the pathogenic mechanism, which can rapidly
reduce inflammation, improve exophthalmos and diplopia, reduce the need for surgical
intervention, and restore the quality of life of patients [3]. Immune cross-reaction of thyroid and orbital antigens is a possible mechanism of
Graves’ ophthalmopathy, in which co-expression of thyroid stimulating hormone receptor
(TSHR) and insulin growth factor-1 receptor (IGF-1R) on orbital fibroblasts plays
a key role [8]. In vitro studies of orbital fibroblasts and fibrocytes show that IGF-IR-inhibitory
antibodies can attenuate the actions of IGF-I, thyrotropin, thyroid-stimulating immunoglobulins,
and immunoglobulins isolated from patients with Graves’ disease [9]
[10].
Treatments for TAO
Glucocorticoid
Glucocorticoid has been the main treatment for Graves’ ophthalmopathy. European Group
on Graves’ orbitopathy (EUGOGO) currently recommend IV-GCs as a first-line treatment
for active moderate to severe GO [11]. A meta-analysis of randomized clinical trials clearly demonstrates that intravenous
methylprednisolone shock therapy (IVMP) has higher efficacy and fewer side effects
than oral prednisone [12]. At the same cumulative dose, the weekly dose of GCs seems to be better than the
daily dose, and they found a significantly greater response rate for the weekly protocol
vs the daily protocol at the 12th week (76.92 vs. 41.03%; p = 0.0025) [13]. Compared with the 12-week protocol, the 4-week alternative with the same cumulative
dose of 4.5 g was less effective (41 vs. 77%) and had more side effects [13]. For moderate-to-severe TAO, EUGOGO recommends 500 mg GCs once weekly for 6 weeks
and 250 mg once weekly for 6 weeks (cumulative dose 4.5 g) [14]. Although glucocorticoids are usually used to treat TAO, there are currently not
enough placebo-controlled trials to prove their efficacy. Generally, glucocorticoids
can control orbital inflammation, reduce edema, improve soft tissue lesions (redness
and swelling of the eyelids and conjunctiva), and eye muscle movement, but they are
less effective in reducing exophthalmos and diplopia. In the maximum randomized controlled
trial (RCT) using three different cumulative doses of IV-GCs (2.25 g, 4.98 g, 7.47
g methylprednisolone), the average reduction in exophthalmos was less than 1 mm even
with the highest dose [15]. However, this RCT did not take into account the natural course of TAO, and there
was no placebo control. Approximately 10–20% of clinically active and severe TAO patients
may not respond to glucocorticoids and/or relapse after withdrawal [15]. Potential side effects and contraindications of glucocorticoids remain an important
consideration, and dose-dependent effects make it difficult to balance increased clinical
efficacy with higher doses and greater risk of side effects [15]
[16]. In addition to the common side effects of glucocorticoids, such as Cushing syndrome,
hyperglycemia, hypertension, osteoporosis and so on, there are also cases of IVMP
related to acute and serious hepatic injury, even leading to fatal hepatic failure,
recommended that the cumulative dose of IVMP should not exceed 8 g [17].
Orbital radiotherapy
Orbital radiotherapy is a useful therapy, which seems to be effective for ocular dyskinesia,
especially in recent cases, but has little effect on exophthalmos and long-term extraocular
muscle dysfunction [18]. RCTs from Amsterdam clearly show efficacy on motility [19] and also on soft tissue in less affected patients [20]. Also retrospective in nature but with high patient numbers and uniform inclusion
criteria the study from Johnson at al. showed that 16 Gy and 20 Gy are more effective
on improvement of motility than lower doses [21]. Another retrospective study revealed that orbital irradiation had a significant
additional benefit to iv. steroids on improvement of motility [22]. And even the CIRTED study revealed in the secondary outcomes in the so called ophthalmopathy
index (the severity index) that the combined therapy of azathioprin and orbital irradiation
reached nearly significance (p = 0.06) while no therapy alone. However this study
suffered from to many drop outs [23].
Orbital surgery
Orbital decompression is often used as a secondary treatment if there is a poor response
to corticosteroids or the need to avoid corticosteroid complications [24]. Surgery is required in the acute phase of TAO where there is immediate danger to
vision (e. g., optic neuropathy). A variety of procedures for surgical decompression
include balanced decompression, medial and floor decompression, lateral wall decompression,
and orbital fat decompression. Orbital surgery may cause recurrence of ophthalmopathy
and may cause or aggravate diplopia [25]. Garrity at al. showed even with the now outdated technology of transanthral decompression
that inflammation improved in more than 80% of the patients due to the reduction of
congestion [26]. Even basic science has clearly shown that from a certain point onwards, congestion-related
hypoxia plays a significant role in the progression of GO [27]. So, recurrence of ophthalmopathy is rather rare.
Immunotherapy and biotherapy
Antiproliferative agent
Based on these issues, new therapies targeting the pathogenesis of TAO is essential
to advance the treatment and improve clinical efficacy. CIRTED trial shows that it
is potentially beneficial of combining steroids and azathioprine, but drawing final
conclusions is limited by the high number of people who dropped out of the study [23]. Mycophenolate mofetil (MMF) has been shown to have a beneficial therapeutic effect
in inflammatory and autoimmune diseases. Post-hoc analysis of MINGO trial suggested
that addition of mycophenolate with methylprednisolone improved rate of response to
therapy in patients with active and moderate-to-severe TAO and had potential effects
in preventing long-term recurrence after steroids discontinuation. But the addition
of mycophenolate did not prevent dysthyroid optic neuropathy or improve the severity
of proptosis [28].
Etanercept
In several autoimmune diseases, including TAO, TNF-α (Tumor Necrosis Factor-α) has
a significant role [29]. Etanercept is a large molecule, a genetically engineered anti-TNF compound consisting
of receptors that bind TNF. Binding to TNF-α, it inhibits its function in autoimmune
diseases (rheumatoid arthritis, ankylosing spondylitis, psoriasis, etc.) [30]. Paridaens et al. have explored that etanercept may suppress the clinical symptoms
in TAO, but that was an uncontrolled study. Further studies are required to investigate
the efficacy and safety of this treatment [31].
Tocilizumab
Targeted biotherapy will bring a new hope; rituximab (anti-CD20) and tocilizumab (anti-IL-6)
appear to reduce inflammation and improve exophthalmos [32]. IL-6 is a pleiotropic cytokine produced by a wide variety of immune and nonimmune
cells, including leukocytes, macrophages ,fibroblasts, and many different tumor cells
[33]. Tocilizumab is a humanized anti-IL-6R monoclonal antibody (mAb), approved for the
treatment of rheumatoid arthritis (RA) [34] and systemic juvenile idiopathic arthritis [35]. Salvi M et al. observed that in GD patients with active inflammatory TAO, the IL-6
system is activated, and serum sIL-6R concentrations were higher than those in patients
with inactive TAO [36]. Several prospective studies manifested that Tocilizumab may significantly improve
the clinical features of patients with active TAO refractory to corticosteroids [37]
[38].
Rituximab
Rituximab (RTX), is a chimeric monoclonal antibody targeting CD20, a membrane-embedded
protein expressed on the surface of B cell [39]. Because RTX depletes CD20 B cells, it has been considered that RTX may be effective
for treating TAO. A few studies support that rituximab is conducive to deplete peripheral
B-cell, reduce disease activity, permit a decreased administration of systemic steroid
and induce long-term remission of TAO. Furthermore low-dose rituximab (100 mg) is
also effective and patients are exposed to lower risks of potentially severe side
effects [40]
[41]. A retrospective study showed that RTX offered limited and partial improvement for
active moderate-to-severe TAO with a long duration of disease [42]. But another randomized controlled trial of rituximab had reported conflicting results.
Stan et al. concluded that rituximab has no additional benefit to patients compared
to placebo. Note that 10 patients (4 in RTX group and 6 in the placebo, p <0.33) treated
with corticosteroids had completed therapy at least 1.5 months prior to trial enrollment
and all patients reported worsening of the disease after corticosteroids were discontinued
[43]. Because of these conflicting results, the role of rituximab in moderate-to-severe
TAO remains to be defined by a larger, multicenter RCT [44].
Therapy targeting TSHR
A small molecule TSHR antagonist (NCGC00229600) reduce the productions of cAMP, pAkt,
and HA, which are activated via TSHR signaling and are vital to the pathogenesis of
TAO. It may be beneficial to TAO with therapeutic potential [45]. The human monoclonal autoantibody K1–70 binds to the TSHR with high affinity and
blocks TSHR cyclic AMP stimulation by TSH and thyroid stimulating autoantibodies.
The study from Furmaniak et al. aimed to provide important toxicity, safety and pharmacokinetics
information to design the first in human clinical trial with K1–70 [46]. Marcinkowski et al. showed that S37a, a novel highly selective inhibitor for the
TSHR, not only inhibits the TSHR activation by thyrotropin itself but also activation
by monoclonal TSAb M22 (human), KSAb1 (murine), and the allosteric small-molecule
agonist C2. It has promising potential for further development for the treatment of
TAO [47].
Teprotumumab
Teprotumumab (TMB) is a fully recombinant human monoclonal antibody of immunoglobulin
G1 that binds to the cysteine-rich region of insulin-like growth factor-1 receptor
(IGF-IR) with high affinity and specificity [10]
[48]. Kumar suggested that blocking IGF-1R with a monoclonal antibody (mAb) may reduce
TSHR and IGF-1R dependent signaling, thereby blocking pathological activity initiated
by both receptors [49]. Although teprotumumab is specific for IGF-1R, Smith and his colleagues have shown
that it can also inhibit the signaling of TSH-R in vitro because the two receptors
form a physical complex [50].
Chen’s study is consistent with previous reports. The expression of IGF-1R and TSHR
on the surface of untreated fibroblasts is relatively high [51]
[52]. It showed that Teprotumumab does not interfere with the detection of either receptor
on the cell surface [10]. Then they investigated teprotumumab does not alter IGF-1R expression after incubation
and found a significant decrease in surface IGF-1R levels after 12 hours [10]. Because IGF-1R and TSHR form a physical complex [9], the effect of teprotumumab on TSHR display was also investigated. Similar to IGF-1R,
TSHR levels declined after treatment with teprotumumab, reaching a nadir after 12
hours [10]. Fibrocytes from GD patients also showed a significant reduction in surface IGF-1R
and TSHR due to teprotumumab treatment [10].
Previous studies have shown that IL-6 and IL-8 seem to be related to the pathogenesis
of TAO [53]
[54]. Subsequently, Chen H et al. detected the molecular mechanism of Teprotumumab's
effect on bTSH-induced cytokines in fibroblasts of healthy donors and GD patients.
The mAb failed to alter basal steady-state IL-6 and IL-8 mRNA levels. TSH increased
IL-6 transcripts in fibrocytes from healthy donors and patients with GD by 400-fold
and 2000-fold respectively. Teprotumumab significantly inhibited the induction by
bTSH of IL-6 mRNA in fibrocytes from healthy donors and patients with GD (p <0.001
and p <0.0001). Similar results were observed in the measurement of IL-8 mRNA [10]. Meanwhile, teprotumumab partially blocked the Akt phosphorylation induced by TSH
and IGF-1 [10]
[55].
Recent studies have shown that teprotumumab, as a pharmacological and functional inhibitor,
blocks the activation of IGF-1R through its endogenous ligands (IGF-1 and IGF-2),
and causes receptor internalization [32]
[48]
[56]. TMB exerts its pharmacological effects through functional inhibition of the IGF-1R
pathway, leading to complete closure of IGF-1R signaling by a combination of two mechanisms:
upon binding to the cysteine-rich domain of human IGF-1R, TMB blocks the binding pocket
for both endogenous ligands, IGF-1 and IGF-2, and prevents them from activating the
IGF-1R signaling cascade; and binding of TMB induces internalization and subsequent
degradation of IGF-1R, in vitro and in vivo, resulting in cell surface accessible
95% reduction in body protein [32].
Two multicenter, double-blind, randomized, placebo-controlled trials based on basic
researches had showed that it significantly reduced the degree of exophthalmos [57]
[58].
The primary endpoints in studies about the immunotherapies of TAO usually include
reduction of clinical activity score (CAS). Secondary end points usually include clinically
significant improvement in proptosis, lid fissure width, diplopia score, lagophthalmos,
disease severity, changes in those parameters, orbital fat/ muscle volume and quality-of-life,
each item of the clinical activity score, patient self-assessment and so on [28]
[42]
[43]. In most studies it is sufficient to achieve the primary outcome with an improvement
in the disease activity. Only a few studies call for an improvement in exophthalmos
or mobility mandatory to reach primary outcome. Primary and secondary outcomes in
teprotumumab RCTs will be introduced in detail in the following sections.
How IGF-1R Antibody Act on the Treatment of TAO?
How IGF-1R Antibody Act on the Treatment of TAO?
TSHR as Autoantigen in TAO
At the heart of Graves’ disease is the loss of immune tolerance to the thyroid stimulating
hormone receptor (TSHR) and the production of activated antibodies against this receptor
protein, known as thyroid stimulating immunoglobulin (TSI) [2]
[59], these autoantibodies can be detected in most GD patients with or without eye disease
[60]. TSH is expressed by the orbital fibrocyte [51]
[61], which suggests that it may be involved in ophthalmopathy. The expression of TSH
receptor in orbital fibroblasts and preadipocytes was relatively low, but increased
with retro-orbital adipocyte differentiation [51]. The expression in the active stage was higher than that in the inactive stage,
which was directly related to IL-1β [62]. CD34+ fibroblasts from bone marrow were detected in the orbital tissue of TAO,
but not in the normal orbit [51]. TSHR expressed by fibroblasts is functional and can upregulate the expression of
cytokines IL-6 and TNF-α [51]. CD40-CD40L activating orbital fibroblasts may be an important mechanism for upregulation
of local orbital IL-6 and IL-8 expression, and induce orbital fibroblasts to synthesize
excess hyaluronic acid [63]
[64]. A monoclonal TSHR-stimulating antibody M22 stimulates hyaluronic acid secretion
and M22 was specific for TSHR [65].
It has been reported that TSI levels may be associated with disease activity and predict
whether patients may develop into serious diseases in the future [66]. However, although antibody levels in patients with more severe and active TAO appear
to be higher, the utility of TSI levels as a clinical management guideline has not
been established in appropriate controlled studies [48]. In some severe cases, undetectable TSI [60]
[67], suggests that there may be additional autoantigens to play a role in TAO.
IGF-1R as Autoantigen in TAO
Insulin-like growth factor-1 receptor (IGF-IR) is a membrane tyrosine kinase receptor
that plays a role in cell growth and metabolism [68], it also regulates immune function and may be used as a therapeutic target in autoimmune
diseases [6]
[69]. Recent studies provide evidences for the role of IGF-1R in the pathogenesis of
GO [48]
[70].
Weightman and his colleagues provided the first clue that IGF-IR might be involved
in TAO [71]. They speculated that immunoglobulin (GD-IgG) stimulation of fibroblasts and extraocular
muscle cells may act through IGF-IR [71]. IgG collected from patients with GD, whet her or not manifested as TAO, can replace
the IGF-I radiolabeled on the surface binding site of orbital fibroblasts transplanted
from extraocular muscle tissue. In contrast, IgG in the healthy control failed to
change the binding of IGF-I to cells [71].
Subsequent study supported the presence of antibodies against IGF-1R, in which it
was found that IgG from GD patients induced the expression of T-cell chemokines in
auto fibroblasts from thyroid, orbit and skin. These effects did not exist in normal
control fibroblasts [72]. These IgG were later shown to target IGF-1R [73]. This triggers local inflammatory and immune responses, leading to fibroblast proliferation
and differentiation, tissue expansion, extracellular matrix augmentation, edema, and
extensive orbital tissue remodeling [69]
[74].
Smith’s basic research identified the important role of IGF-1R [10]
[50], which described the overexpression of IGF-1R in fibroblasts and its activation
by IgG in Graves’ disease, leading to inappropriate expression of inflammatory factors,
production of hyaluronic acid and cell activation in Graves’ orbital fibroblasts,
which lack of function in the culture of healthy donors [74]
[75]. Many subsequent studies have demonstrated the central role of orbital fibroblasts
and the overexpression of IGF-1R in Graves patients [9]
[75]
[76].
Pritchard et al. used the inhibitory anti-IGF-IR antibody 1H7 or DN mutant receptor
486/STOP transfected into GD fibroblasts to block IGF-IR activity, which could block
GD-IgG-dependent increases in IL-16 and RANTES expression [73]. The signaling pathway that mediates the action of GD IgG in these cells has been
mapped to Akt/FRAP/mTOR/p70sk6 [72]. This signaling leads to the induction of two T-cell chemokines, IL-16 and RANTES,
which are not found in healthy human fibroblasts [72]. In addition, Tsui et al. demonstrated that 1H7 can attenuate the ERK signal transduction
initiated by TSHR in TAO orbital fibroblasts [9]. Subsequent vitro studies of orbital fibroblasts and fibroblasts showed that the
antibody inhibiting IGF-IR could weaken the effects of IGF-I, thyrotropin and thyroid-stimulating
immunoglobulin [9]
[10]. Furthermore, functional IGF-1R was found in professional immune cells, including
lymphocytes (B cells and T cells) and monocytes, which indicated that IGF-1R may play
a role not only in the pathogenesis of GO, but also in the immune system [48].
Based on these findings, several attempts to test the functional autoantibody (IGF-1RAb)
against IGF-1R have yielded conflicting results, and some have questioned the existence
and significance of IGF-1RAb [77]
[78]
[79]
[80]
[81]
[82]
[83]
[84]. IGF-1R antibodies are unlikely to be a useful biomarker because they are only found
in a quarter of Graves’ patients, regardless of the presence or absence of TAO [85].
TSHR and IGF-1R complex
Proving the physical and functional interaction of IGF-1R and TSH-R is the key to
the ultimate treatment. Studies by Tramontano et al. provided preliminary clues to
the possible functional interaction between IGF1 and TSH, with IGF-1 enhancing the
effect of TSH in culture on thyroid epithelial cells FRTL-5, including cell proliferation
and DNA synthesis [86]. Conditional knockout of the IGF-1R gene in the thyroid gland significantly reduces
its response to TSH [87]. The two receptors signaling pathways overlap, indicating the potential for functional
interactions between receptor proteins [88]
[89]. Tsui et al. found that the two proteins actually interact physically, which directly
proved that IGF- 1R and TSHR form a protein complex, and IGF-1R was trans activated
by the complex [9]. Inhibition of IGF-IR activity in orbital fibroblasts, fibroblasts, or thyroid epithelial
cells leads to decreased activation of both receptors [9]
[48], supporting the role of IGF-1R in the pathogenesis of GO. In general, they are called
GD immunoglobulin G (GD IgG). Whether their activity is caused by TSI or by a unique
anti IGFIR antibody, altering their interaction with orbital autoantigens or altering
the signal events generated by these antibody antigen interactions seems to be a potentially
useful therapeutic target. M22 stimulates hyaluronic acid secretion, Neumann et al
latest study showed that M22 binds to TSHR but does not bind to IGF-1R and provided
additional evidence that immunoglobulins from patients with GO (GO-Igs) do not directly
activate IGF1R. Stimulation of HA secretion initiated by TSHR activation is independent
of autocrine/paracrine effects of IGF1 generation [65].
Therapeutic Trials of Teprotumumab in TAO
Therapeutic Trials of Teprotumumab in TAO
Phase II
Smith et al. conducted a multicenter, double-blind, randomized, placebo-controlled
trial (NCT 01868997) to conclude the effectiveness and safety of teprotumumab in patients
with moderate-to-severe active TAO [57]. A total of 88 patients were randomly assigned to receive either placebo or active
drugs. The primary outcome was the response in the study eye compared with placebo.
This end point comprised a reduction of 2 mm or more in proptosis in the study eye
and a reduction of 2 points or more in the Clinical Activity Score at 24th week. Secondary
outcomes, measured as continuous variables, included proptosis, the Clinical Activity
Score, and results on the Graves’ ophthalmopathy–specific quality-of-life questionnaire.
In the trial, 29 of the 42 patients (69%) who received teprotumumab had a response
at week 24, while 9 of the 45 patients (20%) who received placebo responded (p <0.001).
The time to first response was shorter and the fraction of patients achieving response
was higher in the teprotumumab group at weeks 6, 12 and 18 (p <0.001 at all comparisons).
In addition, QoL and visual function of TMB group were prominently improved at all
assessment time points, which was higher than that of placebo. The remarkable reduction
of proptosis was similar to the report after decompression surgery [25]
[90]. However, orbital surgery may lead to the recurrence of ophthalmopathy and may cause
or aggravate diplopia [25]
[57]
[91]. No significant reduction in proptosis had been reported in any previous placebo-controlled
trials of other drugs for TAO.
Phase III
A randomized, double-blind, placebo-controlled, multicenter phase 3 trial (NCT 03298867)
of teprotumumab had been completed which including 41 patients assigned to the teprotumumab
group and 42 to the placebo group [58]. It was similar to that of the phase 2 trial in which 8 infusions of teprotumumab
or placebo were administered over a 24 week. The difference is that assessment time
point was simplified to a proptosis reduction of >2 mm in the examined eye only at
week 24. At week 24, the percentage of patients in teprotumumab group with a proptosis
response was higher than with placebo (83 vs.10%, p <0.001). And the secondary outcomes
among the patients in the teprotumumab group were significantly better than in the
placebo group. The orbital imaging performed in the six patients in the teprotumumab
group (at one trial site) indicated reductions in extraocular muscle volume, orbital
fat volume, or both. In phase 2 trial, orbital imaging was not performed and it was
not possible to determine which orbital tissues were affected by teprotumumab. Another
limitation is lack of long-term follow-up. The collection of data on the durability
of efficacy and relapses are ongoing in either trial. In the phase 2 trial, the efficacy
of teprotumumab was maintained for up to 48 weeks of follow-up in most of the patients
who had a proptosis response and a diplopia response. An extension of the phase 3
OPTIC trial, OPTIC-X (NCT03461211), is currently ongoing for patients who did not
have a proptosis response and have a relapse during the follow-up period.
Safety of Teprotumumab
In the phase 2 clinical trial, the only adverse event related to the drug was hyperglycemia
in diabetic patients; the event was controlled by adjusting the diabetic drug [57]. In the phase 3 trial, most adverse events were mild or moderate in the teprotumumab
group; including muscle spasm, nausea, alopecia, diarrhea, fatigue, hyperglycemia,
hearing impairment, dry skin, dysgeusia, and headache. One of the two serious events
is that an infusion reaction leading to treatment discontinuation [58]. Several monoclonal antibodies against IGF-1R have been tested in clinical trials
to look forward to their therapeutic effects on various types of cancer. Although
the therapeutic effects of these drugs are disappointing, they generally show satisfactory
safety [92]. Ma and Zhang summarized the adverse reactions of anti IGF-1R monoclonal antibody
in tumor treatment. The total incidence of hyperglycemia was 14.4%, but metformin
and other hypoglycemic drugs seemed to be easy to control [93]. A complicated mechanism to explain hyperglycemia is as follows: Besides tumor cells,
IGF-IR monoclonal antibodies also act on normal tissues. Most of all, IGF-IRs in the
hypothalamic-pituitary axis that are involved in homeostatic feedback control is also
targeted. This reduces the feedback inhibition of growth hormone secretion, thus lead
to elevation in growth hormone (GH). Elevation of GH can cause insulin resistance
in classic insulin target organs, increased gluconeogenesis, and thus leading to elevations
in glucose concentrations. This in turn results in increased insulin secretion which
commonly corrects hyperglycemia to some extent [93]. Thrombocytopenia, neutropenia, anemia, and fatigue reported in previous cancer
studies were not observed in patients with ophthalmopathy [93]
[94].
Although some IGF-1R monoclonal antibodies have shown good safety in the targeted
treatment of tumor, the population of teprotumumab is limited, and the new immunomodulator
still has potentially fatal risks, including serious infection, malignant tumor, etc.
In view of these potential adverse events, immunomodulatory therapy must be performed
in experienced centers that can safely monitor and manage potential serious adverse
events.
Current Situation
Based on the positive results over two randomized clinical trials, the Food and Drug
Administration (FDA) and Dermatology and Ophthalmology Drug Advisory Committee(DODAC)
unanimously supported teprotumumab in the treatment of active Thyroid-associated ophthalmopathy
which potential benefits outweigh the risks.
Discussion
The completed trial was designed to examine the effectiveness and safety of IGF-IR
inhibition in active TAO. It could not address the issue of whether this therapeutic
strategy might also be effective in stable disease. Whether teprotumumab is effective
and safe in inactive patients still needs to be evaluated.
Stable normal thyroid function may contribute to the spontaneous improvement of mild
TAO and may help to optimize the potential reactivity of immunosuppressive therapy
[95]
[96]. Therefore, whether there is difference in the therapeutic effect of Teprotumumab
on moderate-to-severe active TAO with normal thyroid function or dysthyroidism is
not sure.
Further studies that directly compare teprotumumab with current first-line therapy
rather than placebos will help to confirm the superiority of its efficacy.
Thyroid skin lesions occur in 1–4% of Gravesʼ disease patients, and almost always
in patients with severe ophthalmopathy [97]. The mechanism of pretibial myxedema is not clear. TSHR is also expressed in fibroblasts
with pretibial myxedema. Is there IGF-1R and TSH-R complex in the anterior tibial
tissue, and is Teprotumumab beneficial to pretibial myxedema?
There are many IGF-1R monoclonal antibodies, but it is not sure whether Teprotumumab
has physical/biological characteristics, which makes its clinical efficacy and safety
different from other IGF-1R antibodies. Another mAb 1H7 blocked by IGF-1R can also
attenuate TSHR activated signal transduction in TAO orbital fibroblasts [9].
Conclusion
In the last few years, so many new findings have emerged that now allow targeted therapy.
IGF-1R as an autoantigen may be a mechanism for thyroid-associated ophthalmopathy.
The apparent effectiveness and relative security of teprotumumab offer hope for improving
the quality of life for ophthalmopathy patients. The drug has achieved registration
by the U.S. FDA. It is possible that some patients may achieve substantial benefit
and durable enough as to lessen the need for many remedial surgeries. In addition,
a longer follow-up period would allow investigators to assess clinical and subjective
improvements in diplopia and proptosis. Additional studies, including an extension
of the phase III OPTIC trial, OPTIC-X (NCT03461211), are currently underway.
