Abstract
Standardization of treatment outcomes in randomized clinical trials (RCTs) for active, moderate-to-severe Graves’ orbitopathy (GO) is needed to make results of different RCTs comparable and to draw sound conclusions on the efficacy of a given treatment. Both subjective patient-reported outcome (PRO) and objective clinician-reported outcome (CRO) are important in this regard. In this paper, it is proposed that primary PRO should be the evaluation of treatment-related changes in the quality of life by the use of a validated and disease-specific questionnaire (GO-QoL). The proposed primary CRO is a revised composite index, which includes only objective items and provides an overall assessment of the effects of treatment. Secondary outcomes should also be provided in RCTs to show the effects of treatment on individual features of GO, as well on persistence of activity (by the 7-item Clinical Activity Score), safety, relapses of GO, need for subsequent medical and/or surgical treatments, and other indicators (orbital volume, cytokines, TSH receptor antibody levels). Assessment of the overall response to treatment by primary and secondary outcomes should be made 3 months after treatment completion.
Introduction
Ever since the report of Lord Brain in 1955, glucocorticoids have been the mainstay in the medical treatment of Graves’ orbitopathy (GO) [1]. Intravenous glucocorticoid (IVGC) therapy is much more efficacious than placebo [2] and, because more effective than oral GC therapy, is recommended as first-line treatment for active, moderate-to-severe GO in current guidelines [3]. Novel treatment modalities that might be as efficacious as steroids or even better, have become available in the last few years. Rituximab is a promising agent, although conflicting outcomes have been reported [4, 5]. Teprotumumab and tocilizumab have potent efficacy as tested in placebo-controlled, randomized clinical trials (RCTs) [6, 7], but a head-to-head comparison of these agents with IVGC has not been done yet. It is expected that a number of RCTs will be published in the near future evaluating which of these novel agents can replace steroids by demonstrating greater efficacy, better safety, and greater cost-effectiveness. One should hope the outcomes of these various RCTs are directly comparable to each other. This hope seems rather illusory as outcome measures differ substantially in the aforementioned RCTs [2, 4-7]. The aim of the present paper is to propose primary and secondary outcome measures for standard use in the treatment of active, moderate-to-severe GO.
The FDA provides “Drug Development Tools” qualification programs that help to optimize drug development and evaluation [8]. The FDA distinguishes between clinician-reported outcomes (CRO) based on clinical observation and interpretation by a trained clinician, and patient-reported outcomes (PRO) based on a report that comes directly from the patient about the status of the patient’s symptoms or functioning without amendment or interpretation of the patient’s response by a clinician or anyone else [9]. Discrepancies between PRO and CRO can be explained by the fact that the degree of daily functioning and general health as perceived by the patient is not only determined by the severity of signs and symptoms but also by the characteristics of the individual and the environment, such as expectations, coping ability, motivation, social support, and the physician-patient relationship [10]. Assessment of PRO can be of important additional value in the description of disease severity because they highlight a different outcome level of interest. PRO can be important indicators of treatment success and are especially useful in the evaluation of treatments that include side effects [11]. Regulatory authorities consequently ask quite frequently for both subjective outcome assessment (by PRO) and objective outcome assessment (by CRO) as qualification for the efficacy of a drug.
Methods
We followed a practical guideline how to select outcome measurement instruments for inclusion in a “Core Outcome Set” (Table 1) [12, 13]. The construct of interest is the outcome of treatment of active, moderate-to-severe GO. We searched the literature to find existing outcome measurement instruments published between 2000 and 2020. For PRO, we restricted ourselves to disease-specific quality-of-life (QoL) questionnaires and disregarded the less sensitive general QoL questionnaires. For CRO, we confined ourselves to RCTs in patients with active, moderate-to-severe GO. The quality of identified outcome measurements was evaluated as far as possible by criteria given by the COSMIN consortium and the FDA (Table 1) [9, 13-16]. Outcome measurement instruments were eligible for inclusion in the “Core Outcome Set” if there was at least high-quality evidence for good content validity and good internal consistency (or evidence for test-retest reliability) and if the instrument was feasible [13]. High quality rating of evidence in this context is defined as consistent findings in multiple studies of at least good quality OR 1 study of excellent quality AND a total sample size of ≥100 patients [13]. We selected 1 PRO as subjective primary outcome measure and 1 CRO as objective primary outcome measure for inclusion in the “Core Outcome Set.”
Primary Outcomes
Patient-Reported Outcomes
A literature search identified 7 disease-specific PRO instruments used in GO (Table 2) [17-23]. The GO-QoL contains 16 questions, 8 on the consequences of double vision and decreased visual acuity on visual functioning and 8 on the psychosocial consequences of a changed appearance. The questions are answered on a 3-point Likert scale (1 point for “yes, seriously limited,” 2 points for “yes, a little limited,” and 3 points for “no, not limited at all”). The points given to questions 1–8 and 9–16 are added up to obtain 2 raw scores ranging from 8 to 24 points. The 2 raw scores are then transformed to 2 total scores, 1 for visual functioning and 1 for appearance, by the formula: total score = (raw score − 8)/16 × 100. The range is from 0 to 100, higher scores indicating better health (online suppl. Table 1; see online Supplementary Materials) [17].
Characteristics of PRO used in clinical trials of patients with GO
Test-retest reliability was evaluated in 89 GO patients [24]. Mean difference on visual functioning scale was 4.0 and on appearance scale 2.5. Substantial intraclass correlation coefficients (0.83 for visual functioning and 0.87 for appearance) reflect that errors of measurement are relatively small. Internal consistency is demonstrated by principal component analysis and high Cronbach’s α for both summary scores [17]. Evidence of content validity has been described in detail [17]. Questions considered relevant for GO patients were discussed with patients and experienced physicians. The questionnaire was subsequently evaluated in 112 consecutive GO patients, encompassing the whole spectrum of mild-to-severe GO and from active to inactive GO. Correlations of the 2 GO-QoL scales with clinical characteristics support construct validity. This is illustrated by a significant increase in the visual functioning score from 27.1 to 47.4 (p = 0.01) but not in the appearance score (from 51 to 55, NS) after orbital decompression for dysthyroid optic neuropathy (DON); in contrast, after decompression for disfiguring exophthalmos, the change in visual functioning score was not significant (from 64.8 to 68.0, NS), whereas the appearance score increased significantly from 44.7 to 55.8 (p < 0.001) [25]. Longitudinal construct validity is derived from a 12-year follow-up study in GO patients [26]. Ability to detect change was ascertained for both nonsurgical and surgical treatments [25, 27]. Based on effect sizes, changes in GO-QoL scores of about 20 points could be interpreted as a large effect, of about 10 points as small to moderate effects, and of 3–4 points as very small effects. A minimal clinically important difference in either GO-QoL scale can be considered 6–10 points. The GO-QoL was originally phrased in Dutch language, requiring cross-cultural validation for application in other languages and societies. Translation into English and validation in English-speaking patients have been described in detail [28]. Except for the item “bicycling,” which may be less relevant outside Holland, there were no major problems. Answers “never learned to ride a bike” or “no driver’s license” are scored as missing values. When there are missing values for some items, GO-QoL scores are calculated by the formula: Total score = (raw score − #)/2 × # times 100 (in which # is the number of completed items) [28]. The recent CIRTED trial further validated the English version of the GO-QoL [29]. The GO-QoL is now available in 19 languages: Chinese [30-32], Danish, Dutch, English, French, Georgian, German [33], Greek, Italian, Korean [34], Persian [35], Polish [36], Portuguese [37], Romanian, Russian, Serbian, Spanish [38], Swedish, and Turkish (some can be downloaded for free from www.eugogo.eu). Formal validation of the translated versions has been published for the English, Persian, Polish, and Portuguese versions of the GO-QoL [29, 35-37]. The GO-QoL finally satisfies feasibility criteria. The questionnaire is handed over to the patient prior to the consultation, while sitting in the waiting room. It takes about 3 min to complete the GO-QoL [22].
A German TAO-QoL (Thyroid-Associated Ophthalmopathy – QoL) questionnaire had 90 items [18]. Its development was based on contributions from clinicians, without input of patients; content validity is thus low. Construct validation has not been performed. Internal consistency is low in view of a low Cronbach’s α of 0.63 in a study among 104 patients undergoing orbital decompression [39]. Scores did not correlate with clinical variables.
The GO-QLS (GO Quality-of-Life Scale) was developed in the USA [19]. The original questionnaire contained 105 items, derived from the SF-12, DSQL (Dermatology-Specific Quality of Life), NEI-VFG (National Eye Institute Visual Function Questionnaire), and visual functions specific to GO. The questionnaire was completed by 253 GO patients and “validated by administering it to 33 healthy subjects.” Patients had no conceptual input, raising doubt about the content validity. To select the most appropriate items for the GO-QLS, a pool of candidate items was based on appropriate response scales, no excessive skewness, few missing values, and face validity for their applicability. Items were selected that correlated best and discriminated best with GO severity scales and possessed good face validity. Items were assigned points based on correlation rank (best 10 received 10–1 points), discriminating rank (best 10 received 10–1 points), and good face validity (3 points). Items that exceeded 10 points were included in the GO-QLS. The proposed GO-QLS (scaled from 0 to 100) consists of 9 questions. The internal consistency of the scale is good (Cronbach’s α of 0.89). The correlation between GO-QLS and GO severity scores is reasonable: Pearson’s correlation coefficients with clinical severity outcomes regarding neuropathy, cosmesis, myopathy, and keratopathy are −0.49, −0.32, −0.28, and −0.21, respectively [19].
The 25-item NEI-VFQ (National Eye Institute Visual Function Questionnaire) was evaluated for its potential suitability to measure HRQL in 30 GO patients, although it was not specifically designed for this purpose [20]. More than two-thirds of GO patients thought the instrument lacked items relevant to their disease, such as altered appearance and ocular discomfort. Patients with diplopia had lower scores than patients without diplopia [20], and scores were lower in the presence of DON than in the absence of DON [40]. There is strong doubt about the validity, reliability, and responsiveness of the NEI VFQ-25 in GO [41].
ThyPRO (Thyroid PRO) measures a range of QoL aspects relevant to patients with benign thyroid diseases (hyperthyroidism, hypothyroidism, goiter, and GO), as identified during patient and expert interviews [21]. It consists of 84 items summarized in 13 scales. Each item is rated on a 0–4 Likert scale, from no problems/symptoms = 0 to severe problems/symptoms = 4. The average score of items in a scale is divided by 4 and multiplied by 100 to yield thirteen 0–100 scales, with higher scores indicating worse health status. One of the 13 ThyPRO scales is on eye symptoms. Among the sample of 66 hyperthyroid patients treated to become euthyroid, 9 (14%) had GO; their ThyPRO score on subscale eye symptoms changed from baseline 19 ± 22 to 13 ± 15 at 6 months [42]. Further data on the item GO are not available. ThyPRO demonstrated good responsiveness in patients with hyperthyroidism, autoimmune hypothyroidism, or nontoxic goiter [42], but its responsiveness to specific treatment of GO cannot be judged properly. Its overall good measurement properties thus do not apply to GO [21, 42-45], and the ratings of ThyPRO in Table 2 are therefore given within brackets. Feasibility of the ThyPRO might become better with the introduction of a short version [46] and the use of electronic questionnaires [47].
The TED-QoL (Thyroid Eye Disease QoL) is a 3-item questionnaire designed in Canada [22]. The 3 questions are as follows: How is your eye disease currently interfering with your overall quality of life? How is your eye disease currently affecting your ability to carry out daily activities? How is your eye disease currently affecting your satisfaction with your appearance? Patients are asked to answer on a scale from 0 (does not interfere) to 10 (completely interferes). Content validity was assessed through a pilot study and interviews with specialists and patients. Construct validity was ascertained in 100 new consecutive GO patients through correlation between items on the TED-QoL and on GO-QoL and GO-QLS. TED-QoL correlated strongly with the other questionnaires for corresponding items: Pearson’s correlations were 0.71 and 0.62 for appearance, 0.69 and 0.66 for visual functioning, and 0.53 for overall QoL. Intraclass correlation coefficients demonstrated good test-retest reliability of the 3 questionnaires – TED-QoL: 0.81, 0.74, and 0.87; GO-QoL: 0.81 and 0.82; and GO-QLS: 0.74, 0.86, and 0.67. There is only moderate correlation between items on all 3 questionnaires and GO severity assessed by VISA scores [22]. Responsiveness of the TED-QoL to rehabilitative surgery (orbital decompression, strabismus surgery, and palpebral aperture narrowing) is good as assessed from pre- and postoperative scores for the same subjects [48]. TED-QoL is significantly faster to complete (1.6 min vs. GO-QoL 3.1 min vs. GO-QLS 2.7 min, p < 0.0001) [22].
The OX-TED (Oxford-Thyroid Eye Disease) QoL questionnaire consists of 7 questions, each with a score out of 10, with 1 indicating no concerns and 10 indicating major concerns. The higher the total score (maximum 70), the greater the impact of GO on the patient’s QoL [23]. There are no data how OX-TED was developed or validated, nor on measurement properties. In 12 patients with active GO who were treated early with low-dose rituximab, the average total score was 45 prior to treatment, decreasing nonsignificantly to 37 post-treatment at an average follow-up of 6 months.
Epicrises
There have been 2 systematic reviews on PRO in the field of GO [49, 50]. The first was published in 2004 and evaluated 31 questionnaires for people with vision impairments. Only a few questionnaires demonstrated sufficient psychometric quality. The results section states “The GO-QoL for people with Graves’ ophthalmopathy is the questionnaire that rates best on our criteria overall, with a ‘+’ for most aspects” [49]. The second was published in 2016 and evaluated 23 questionnaires on thyroid-specific HRQL. In the conclusion section, the authors state “After reviewing the present literature and critically examining published HRQL instruments, the ThyPRO, GO-QoL and ThyTSQ were the three with the greatest number of positive ratings according to nine quality assessment criteria of measurement properties. The ThyPRO was recommended to assess HRQL in patients with benign thyroid disease while the overall measurement properties of GO-QoL and ThyTSQ were satisfactory in measuring HRQL in GO and hypothyroidism, respectively” [50].The authors of the TED-QoL also suggest to use the GO-QoL in research as it enquires about a larger range of issues and is less prone to measurement error than a 3-item questionnaire might be [22]. EUGOGO made recommendations for assessing response to intervention in clinical trials in 2006, and the GO-QoL was recommended for assessment of the PRO as a primary outcome [51]. The recommendation was included in the formal ETA/EUGOGO guidelines for the management of GO in 2016 [3]. These recommendations are all in line with our analysis of the properties of the 7 PRO instruments in GO (Table 2). The GO-QoL clearly emerges as the instrument with the best overall quality. The GO-QoL has been used successfully as PRO to assess subjective primary outcome in 8 RCTs: in mild GO (comparing selenium with placebo) [52], in active, moderate-to-severe GO (comparing intravenous with oral methylprednisolone) [53], comparing different doses of IVGC [54], comparing rituximab with IVGC [4], comparing IVGC with or without mycophenolate [55], comparing teprotumumab with placebo [6], comparing tocilizumab with placebo [7], and in the CIRTED trial comparing oral prednisone with orbital irradiation, azathioprine, and placebo [29]. Using the notation of the GRADE system [56], we recommend the use of the GO-QoL as PRO for all interventions in active, moderate-to-severe GO (1, ØØØØ). This is not to say the GO-QoL should be used only in immunosuppressive treatment modalities for GO. On the contrary, the GO-QoL has been applied successfully as PRO for nonmedical treatment options as well, like orbital bony decompression [25, 57-59], orbital fat decompression [60], orbital bony + fat decompression [61], strabismus surgery [25, 27, 62], eyelid surgery [25], and orbital irradiation [25, 63].
Clinician-Reported Outcome
The following are the objective features that should be considered for CRO at baseline and in evaluating treatment outcomes in patients with active, moderate-to-severe GO.
Eyelid Aperture
This is the vertical distance between lid margins in millimeter in the mid-pupil position. The patient should look in primary position, sitting relaxed and with distant fixation. In addition, upper and lower eyelid position relative to the limbus might be indicated. The least significant change (increase/decrease) in eyelid aperture should be 2 mm [51].
Exophthalmos
This defines protrusion of the eyes, usually measured by a Hertel exophthalmometer, using the same intercanthal distance at baseline and follow-up visits. Exophthalmos is present when exophthalmometer readings are ≥3 mm above the upper normal values [51, 64]. Normal values are different in different ethnic groups (Asians < Caucasians < black people). The least significant change in exophthalmos (increase/decrease) should be 2 mm [51].
Extraocular Muscle Function
Subjective diplopia scores have been proposed, such as the Bahn-Gorman score [65]. They are useful in daily clinical practice, but, being patient dependent, do not fulfill criteria for objective CRO. Objective measures of extraocular muscle function include the prism cover test, the field of binocular vision, and the uniocular fields of fixation (ductions). While the former are useful when both eyes are involved [64], ductions independently assess ocular excursions in 4–6 directions of gaze in each eye using bowl or arc perimeter and expressing them in degrees [64]. Accordingly, ductions should be reported, the least significant change (increase/decrease) being 8° in at least 1 direction of gaze [51].
Visual Function
DON is absent in the definition of moderate-to severe GO: its presence categorizes GO as sight-threatening (or very severe) [3]. However, optic nerve involvement should be assessed at baseline by determination of best-corrected visual acuity, color vision, visual field, optic disc appearance, and relative afferent pupillary defect. In the evaluation of treatment outcome, appearance of significant abnormalities in 1 or more of the above features should be regarded as treatment failure and progression of GO from moderate-to-severe to sight-threatening (or very severe).
Corneal changes (punctate keratopathy or corneal ulcers) may occur but should be regarded as secondary to globe exposure. The presence of corneal breakdown moves GO from moderate-to-severe to sight-threatening (or very severe) and represents an emergency situation [3].
Soft Tissue Changes
Soft tissue changes, without the subjective pain (either spontaneous or with gaze), and therefore including eyelid edema, eyelid erythema, edema of caruncle, conjunctival hyperemia, chemosis, could be considered, if based on comparison with a color picture atlas, as objective manifestations and, therefore, be included in the CRO. In other words, a new 5-item Clinical Activity Score (CAS) might replace the non-fully objective 7-item CAS (see Secondary Outcomes section). GO should be considered active if CAS is ≥3/5. An 1-point change in the 5-item CAS might be regarded as significant.
Table 3 reports RCTs of the management of active, moderate-to-severe GO published in the period 2000–2020 (2, 4–7, 53–55, 66–81). Primary outcomes to define response to a given treatment were very heterogeneous. In some instances [4, 5, 7, 68-71, 74, 75], the 7-item CAS changes defined response as the only primary outcome or one of them. In many instances, the primary outcome was defined by a composite index, which included both objective measures (lid aperture, exophthalmos, and eye motility) and CAS changes; in the first study on teprotumumab [6], the primary outcome to define response was a composite index consisting of a decrease in exophthalmos of ≥2 mm plus a decrease in the CAS of ≥2 points. In the second study on teprotumumab from same multicenter consortium, given the striking effect on exophthalmos shown in the first study, the primary outcome was represented only by a decrease in exophthalmos ≥2 mm [81]. Only in 1 study [54] did changes in the QoL, assessed by the disease-validated GO-QoL questionnaire, represent a primary outcome contributing to definition of response to treatment. Secondary outcomes were also heterogeneous, including both subjective and objective features and were not always the same (Table 3). In some cases, CAS changes, included in the composite index (primary outcome), were also independently evaluated among secondary outcomes; in other words, they were counted twice. This is to some extent conceivable, because inactivation of GO (CAS change) is part of an overall response, which includes modifications in objective features. However, objective and subjective (or semi-subjective) features should be kept distinct.
Primary outcomes used to define positive response to immunosuppressive therapies for active, moderate-to-severe GO in randomized clinical trials
A revised composite index as a representation of the overall objective response to treatment for moderate-to-severe and active GO might be composed as follows:
The revised composite index is illustrated in Table 4. A response to treatment might be considered positive in the case of an improvement of at least 2 of the above features in 1 eye, without concomitant deterioration in the other eye. Deterioration would be defined by the occurrence of DON or worsening of at least 2 of the 4 components of the revised composite index. Deterioration represents at any time an indication to move to other treatments, either medical or surgical. In an attempt to verify whether the above modification of the composite index is feasible, we reevaluated the results of an RCT on the use on different doses of IVGC [54] with the revised composite index and compared them with data obtained using the original composite index. For this purpose, we pooled the 3 groups of patients (n = 159) treated with a low-dose, medium-dose, or high-dose IVGC regimen. Figure 1 shows that the number of responders did not significantly differ, suggesting that changes in the revised composite index, entirely objective, very well describe the overall changes in the different components of GO.
Proposal for revision of the composite index as primary objective treatment outcome for active, moderate-to-severe Graves’ orbitopathy
Evaluation of the revised composite index. Data from Bartalena et al. [54] were reanalyzed using the original composite index and the revised composite index (see Table 4). For this purpose, all the enrolled patients (n = 159), included in 3 groups given low-dose, medium-dose, high-dose intravenous glucocorticoids were pooled. Number of responders using the original composite index and the revised composite index were not significantly different.
Citation: European Thyroid Journal 9, 1_Suppl; 10.1159/000510700
It may be argued that a composite index might not faithfully or completely reflect what happened to the patient’s eyes. For example, inflammatory manifestations might improve but extraocular muscle dysfunction, heralded by diplopia, might persist. Or extraocular muscle dysfunction and inflammation might subside, while exophthalmos might be only partially affected by treatment. This objection is correct but can be overcome by arguing that residual manifestations have an inevitable impact on the QoL of patients, which would be unveiled and underscored by the PRO using GO-QoL. This brings us back to the central and fundamental role of patient self-assessment.
Secondary Outcomes
Clinical Activity Score
The natural history of GO encompasses an initial inflammatory phase (active disease), followed by a static phase (plateau), and finally by a progressive regression of inflammation (burnt-out or inactive disease) [82]. In most cases, inactivation of GO by no means implies complete restitutio ad integrum, and therefore, rehabilitative surgery is often required after medical treatment in patients who have had full-blown, moderate-to-severe and active GO [3]. The active phase of the disease is generally responsive to immunosuppressive treatments, which are completely useless in the inactive phase [3]. The CAS is a tool introduced more than 30 years ago by Mourits et al. [83] to differentiate inflammatory (active) GO from non-inflammatory (inactive GO). The original CAS included 10 items, the last 3 of which are indicative of recent progression of the ocular disease, but less useful for evaluating the effects of treatment. In the 7-item CAS, 1 point is attributed to each item (eyelid edema, eyelid hyperemia, conjunctival hyperemia, chemosis, caruncle edema, spontaneous ocular pain, and gaze-evoked pain), if present; therefore, the CAS (sum of the points) can range from 0 (no activity) to 7 (maximal activity). Active GO is defined by a CAS ≥ 3/7 [3]. The CAS was originally intended as a tool to identify patients who had a high chance of responding to immunosuppressive treatment [84], and in a more recent study by Yang et al. [85], it proved to be also a good predictor for additional immunosuppressive treatments or additional rehabilitative surgeries in patients who had not responded satisfactorily to a first course of immunosuppressive treatment. As mentioned above, changes in the CAS have been largely used as a primary treatment outcome measure in many randomized and non-randomized studies of the management of active, moderate-to-severe GO. Undoubtedly, the CAS is a very simple tool that can be used by an endocrinologist or an ophthalmologist in the office, both in the initial assessment and in follow-up visits, also outside specialized centers. The CAS has, however, some limitations, including: (i) it is binary (present/absent), with no possibility to grade changes in severity of each item; (ii) it may be difficult to distinguish inflammatory from congestive changes and, therefore, it may not always accurately reflect inflammation/activity of the disease; and (iii) it does not predict the possible development of DON. On the other hand, some of these limitations can be overcome. With the exception of pain, either at rest or with eye movements, which is entirely subjective (patient dependent), the other 5 items can be made objective if patient’s soft tissue changes are compared with a picture atlas (see the color picture atlas available on the EUGOGO website at www.eugogo.eu). This comparison may also help distinguish soft tissue changes due to inflammation from those related to congestion. Thus, if the 7-item CAS cannot be included, as a whole, either in PRO or in CRO, a revised 5-item CAS, without spontaneous and gaze-provoked ocular pain, can be included in the CRO, as suggested in a previous paragraph. Accordingly, we suggest that when evaluating treatment outcomes in both observational and RCTs, (i) changes in the 7-item CAS should not be considered as a primary treatment outcome and (ii) changes in the revised 5-item CAS can be included in the primary CRO as part of the revised composite index. The 7-item CAS maintains its validity as a secondary outcome to orientate the treatment strategy toward additional immunosuppressive treatments (CAS ≥ 3/7) or rehabilitative surgical procedures (CAS < 3/7).
Individual Items of GO and Other Indicators
In addition to an overall assessment of treatment outcome, report of details of individual ocular features should be included among secondary outcomes, thereby contributing to identify, in the context of a generally favorable (or unfavorable) response to a given treatment, which objective components were more (or less) responsive. See, for example, the apparently striking difference (in the absence of a head-to-head comparative study) in terms of exophthalmos decrease in patients treated with teprotumumab [7, 81] or IVGC [54]. These individual items may include eyelid aperture, exophthalmos, subjective and objective eye motility abnormalities, intraocular pressure, optic nerve involvement, orbital volume assessment, measurement of TSH receptor antibodies, or markers of inflammation (e.g., cytokines). But they may also include assessment of the effects of treatment on disease-related psychosocial well-being and public health relevance [33].
Adverse Events
Adverse events of IVGC, the current first-line treatment for active, moderate-to-severe GO, are well known and can be short-term or long-term [86, 87]. Less is known about novel immunosuppressive agents, such as rituximab, tocilizumab, and teprotumumab, particularly in the long-term. Therefore, adverse events should be carefully reported, as an integral part of the evaluation of the effects of treatment. In our opinion, they should be mentioned among secondary outcomes to allow a precise cost/benefit evaluation. A standardized tool to report adverse events is represented by the medical dictionary for regulatory affairs (MedDRA), recommended by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) [88]. By this tool, both the number and severity of adverse events should be reported in detail.
When Should Treatment Outcomes Be Assessed?
Treatment outcome assessment also needs to be standardized. Some studies report assessment of the primary outcome and response to treatment at the end of drug therapy. But this time point is extremely variable because duration of treatment varies from 3 months for IVGC [54] and tocilizumab [7], 6 months for mycophenolate [55] and teprotumumab [6, 81], or 1 day to 2 weeks for rituximab [4, 5]. Response to IVGC may observed early but also be delayed [89]. Relapse of GO or its progression to sight-threatening forms may occur after a response to treatment has been considered positive at a too early evaluation [54]. For these reasons, it seems reasonable to propose that in future RCTs for active, moderate-to-severe GO assessment of response by primary outcomes and secondary outcomes be carried out 3 months after treatment has been completed.
Discussion
In the last 20 years, the field of management of active, moderate-to-severe GO has witnessed a renewed interest driven by application of old drugs to this disease, combination therapies, or development of novel, biological agents providing promising results. Comparison of different studies and different drugs is extremely difficult due to the heterogeneity of reporting results. Therefore, we aimed at introducing a standardized way of evaluating treatment outcomes to overcome the above difficulties.
Objective ocular changes are extremely important, and it is fundamental to know which components of GO (inflammatory changes, exophthalmos, eye motility, and visual acuity), if not all, are influenced by therapy. In this regard, an overall evaluation of the objective response to treatment is permitted by the revised composite Index (Table 4), which is completely deprived of subjective elements. This composite index should, therefore, represent the primary CRO. Changes in the composite index, while providing a reliable overview of the general effectiveness of a given treatment, do not unveil the effects of treatment on the individual components of GO. For this reason, we propose that details on the individual features of the disease be provided as secondary outcomes, because this is helpful to orientate subsequent medical and/or surgical interventions.
If objective assessment is essential, we feel that subjective evaluation by the patient himself/herself is even more important. We physicians can tell the patient that exophthalmos has decreased by 2–3 mm, eye motility has improved by 8–10°, or the CAS has decreased by 2 points, and we consider this a success. But, from the patient’s point of view, this may still be a failure, if it does not translate into a substantial improvement in the quality of life [33, 90]. Accordingly, we believe that, much more than in the past, assessment of outcome of treatment for active, moderate-to-severe GO should be patient-centered. Therefore, we propose, as illustrated in Figure 2, that primary outcomes should include both PRO (GO-QoL changes) and CRO (changes in the revised composite index). Secondary outcomes may include changes in individual objective features, safety (information on adverse events), and information on relapses after treatment (durability) and on the need of additional medical or surgical treatments. Changes in the 7-item CAS remain an important secondary outcome to facilitate the shared decision on the need of further medical or surgical treatments.
Proposal for assessment of treatment outcome in randomized clinical trials for active, moderate-to-severe Graves’ orbitopathy.
Citation: European Thyroid Journal 9, 1_Suppl; 10.1159/000510700
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The authors did not receive any funding.
Author Contributions
Both authors equally contributed to design the study, to search literature, to write the paper, and to revise it, and are fully responsible for its content.
Footnotes
verified
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