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Eur J Ophthalmol 2014; 00 (00): 000-000 DOI: 10.5301/ejo.5000463 ORIGINAL ARTICLE
Safety and efficacy of combined immunosuppression and orbital radiotherapy in thyroid-related restrictive myopathy: two-center experience Nikolaos T. Chalvatzis1,2, Argyrios K. Tzamalis1, Georgios K. Kalantzis2,3, Nabil El-Hindy3, Stavros A. Dimitrakos1, Michael J. Potts2 1 2nd Department of Ophthalmology, Aristotle University of Thessaloniki - Greece2 Bristol Eye Hospital, Bristol - UK3 Ophthalmology Department, St James Hospital, Leeds - UK Purpose: To evaluate the safety and efficacy of oral steroids when combined with long-term oral
azathioprine (AZA) and orbital radiotherapy in patients with active thyroid-related restrictive myopathy.
Methods: A total of 88 patients from adnexal outpatient clinics of Bristol Eye Hospital, UK, and
2nd Department of Ophthalmology at Aristotle University of Thessaloniki, Greece, were enrolled in
a retrospective, twin-center study. All patients were diagnosed with active thyroid eye disease and
concomitant restrictive myopathy. Treatment included oral AZA, low-dose steroids, and orbital radio-
therapy (20 Gy). Clinical activity scores as well as orthoptic assessments were consistently evaluated.
Clinical activity scores, improved levels of diplopia, and single muscle excursions were considered
major criteria for treatment success.
Results: Clinical success was achieved in 54 (61.4%), 57 (64.8%), and 61 (69.3%) patients at 3-, 6-,
and 12-month time points, respectively, after the initiation of the combined treatment. At 18 months
following initiation of treatment, the percentage of treatment success reached 73.9% (n = 65). Nine
patients developed AZA-related side effects. In 4 patients the drug had to be discontinued.
Conclusions: Combined immunosuppression with orbital radiotherapy appears to reduce morbidity
in patients with marked restrictive myopathy by improving major motility parameters such as diplopia
and duction amplitude.
Keywords: Azathioprine, Diplopia, Immunosuppression, Orbital radiotherapy, Thyroid eye disease
Accepted: February 27, 2014 edema and enlargement of extraocular muscles (3-6). There are several classifications of severity and activity. The re- Thyroid eye disease (TED) is an autoimmune disorder cently revised consensus of the European Group on Graves' strongly related to Graves disease. Thyroid-derived anti- Orbitopathy (EUGOGO) (7-10) seems to ensure an accurate gens are found in orbital tissues and trigger a cell-mediated and reproducible assessment of TED patients.
immune response. Orbital lymphocyte infiltration as well as Ocular restrictive myopathy is considered one of the severe fibroblast proliferation and adipogenesis seems to play a morbidities that patients may experience during the course major part in pathogenesis and clinical severity of TED (1, 2). of the disease. It is either due to inflammatory involvement Locally produced cytokines amplify the immune response and enlargement of extraocular muscles in the active phase while high glycosaminoglycan levels contribute to interstitial of TED or to fibrosis, usually observed during the burnt-out 2014 Wichtig Editore - ISSN 1120-6721 Immunosuppression and radiotherapy in thyroid-related restrictive myopathy phase of TED. Inferior rectus is most frequently affected, TABLE I - INCLUSION CRITERIA FOR STUDY CANDIDATES
with medial and superior rectus following (10, 11). As a result, this group of patients complains predominantly of Definitive criteria for •   Recently diagnosed marked TED (the time  intermittent or, less frequently, constant diplopia in either of first TED diagnosis should not exceed 2 months from presentation) primary or extreme positions of gaze.
Steroids represent the mainstay in management of TED higher on 2 clinical visits 8 weeks apart (1-2, 8). Other therapeutic options such as orbital radio- therapy and second-line immunosuppressants (12, 13) muscle confirmed by MRI-STIR sequences such as azathioprine (AZA) and cyclosporine, nonste- Relative criteria for •  Diplopia in primary position of gaze roidal anti-inflammatory drugs, and, more recently, bio- logical agents (14, 15) have been proposed with success of normal thyroid function tests for a rates that vary according to different studies. Combined minimum 3-month period regimens have often been tried aiming to achieve better All definite criteria represented prerequisites for patient selection.
efficacy while reducing steroid-related adverse effects EUGOGO = European Group on Graves' Orbitopathy; STIR = short T1 inversion (16, 17). We have routinely used combined treatment pro- recovery; TED = thyroid eye disease.
tocols for 10 consecutive years in patients with severe, active, noncompressive TED using the onset of motility restriction as indication for treatment. Anecdotal evidence TABLE II - EXCLUSION CRITERIA FOR STUDY CANDIDATES
has risen over this period of time that such patients may benefit significantly by using oral steroids when combined with orbital radiotherapy and AZA. This study investigates Thiopurine methyltransferase enzyme deficiency this hypothesis by analyzing essential parameters con- Known malignancies cerning ocular motility and clinical activity scores.
Age younger than 20 yearsDiabetic retinopathy or other retinal vasculopathies (potential exacerbation during radiotherapy) MATERIALS AND METHODS Drugs with known interaction with azathioprine (e.g., allopurinol)Burnt-out diseaseHistory of strabismus or other ocular conditions that may interfere This is a retrospective, record-based study conduct- with ocular motility variables ed by 2 tertiary centers specializing in management of Previous steroid treatment was an exclusion criterion TED. Bristol Eye Hospital, Bristol, UK (center 1), and 2nd Department of Ophthalmology at Aristotle University of Thessaloniki, Greece (center 2), shared therapeutic lone 0.5 mg/kg/day, for at least 2 weeks, tapered gradually protocols for patients with marked disease and thyroid- to 0.2 mg/kg/day and discontinued when clinical activity related restrictive myopathy. Both centers facilitate joined score (CAS) was ≤3 for more than 4 weeks. The AZA was TED outpatient clinics run by expert ophthalmologists and also administered from week 1 after initial diagnosis, at endocrinologists. Data collected from both centers came doses of 200 mg/day reduced gradually to 50 mg/day and from patients treated between 2000 and 2011.
discontinued at 6 months after withdrawal of steroids (stable The medical records of 88 patients were studied in total. CAS ≤3). Standard guidelines and precautions regarding ad- This series was extracted from a total of 142 patients treat- ministration of steroids were also followed (i.e., blood pres- ed for TED in the same period. Fifty-four patients were not sure measurements, glucose levels, body weight). Patients found eligible for the study, with decisions based on inclu- were advised to take AZA at night, before sleep, to avoid sion and/or exclusion criteria outlined in Tables I and II. A any drug-related sickness. All patients underwent focused total of 65 were seen in center 1 in 2000-2009 and 23 in orbital radiotherapy of 20 Gy in total (6 MV photons from center 2 in 2005-2011.
a linear accelerator; Mevatron MD2 and Primus, Siemens The therapeutic treatment protocol consisted of an initial in- Medical Solutions, Erlangen, Germany). Radiotherapy was travenous pulse of methylprednisolone 10 mg/kg no later started within the first 2 weeks after the initial visit given in than 7 days from the diagnosis followed by oral predniso- 10 fractions of 200 cGy for 10 consecutive days.
2014 Wichtig Editore - ISSN 1120-6721 Chalvatzis et al Hematologic tests was requested at every follow-up and were 2-sided, and considered statistically significant when included full blood count, liver function parameters (SGOT, less than 0.05.
SGPT, γGT, bilirubin, albumin), urea and electrolytes, and blood glucose.
Azathioprine-related side effects were closely monitored and considered to be a strict indication for drug discontin-uation in cases where abnormal hepatic enzymes (SGOT Demographic and clinical characteristics of the study are and/or SGPT >80 IU/L and/or γGT >60 IU/L), leukopenia presented in Table III. A total of 88 patients (61 female and (<4000/mL), low mononuclear count (<1%), pancreatitis, or 19 male), mean age 52.3 years, were found eligible for the persistent vomiting were apparent.
study. Signs and symptoms of TED were recognized and Clinical assessment and orthoptic examination based on recorded bilaterally in 30 subjects, while 58 patients were Hess chart, field binocular single vision (BSV test), as well as unilaterally affected (27 right eyes and 31 left eyes) at the uniocular fields of fixation (UFF) were performed at baseline beginning of treatment. Total duration of follow-up ranged and on regular follow-up usually arranged bimonthly, and between 24 and 77 weeks.
at 6 months following withdrawal of treatment. The BSV and Mean duration of combined treatment was 44.8 ± 4.25 Hess chart interpretation was mainly based on 3 restriction weeks. Azathioprine administration ranged from 1 to 55 zones assessment: inside the central 30° zone (zone 1: weeks (38.4 ± 2.6). Nine patients (10.2%) developed AZA- severe restriction) or outside the central 30° zone (zone 2: related side effects during treatment. Of the above patients, moderate/mild restriction) and no detectable restriction 4 experienced nausea to a variable degree, 2 had mildly (zone 3). Uniocular fields of fixation has been suggested as elevated SGOT (55-70 IU), and 3 patients developed leuko- a more accurate test in quantification of muscle restriction penia (leukocytes <3500 cells/mcL and monocytes <1%). in TED patients (18). Although less than 5° changes may In 4 cases the drug had to be discontinued due to leuko- be recognizable with this technique, we decided to apply penia (n = 3) and persistent nausea (n = 1). Prednisolone a simpler evaluation that conforms to our BSV and Hess tapering ranged from 4 to 25 weeks (11.4 ± 2.3). Exacerba- chart measurements. Thus, restriction of at least one single tion of TED was diagnosed in 11 patients over the taper- muscle excursion within the central 30° was considered ing phase of immunosuppression and treated with higher to be severe impairment, while restriction outside 30° was doses until reduced activity was diagnosed.
considered as moderate to mild. However, changes of 5° in motility were still applicable for CAS assessment purposes.
Parameters for treatment success were defined as CAS TABLE III - MAIN DEMOGRAPHIC AND CLINICAL CHARAC-
≤3 and concomitant improvement in diplopia and muscle TERISTICS DATA OF STUDY POPULATION excursions by at least one zone of restriction, as stated above.
Signal intensity ratio (SIR) in short T1 inversion recovery (STIR)–MRI sequences was also assessed in all patients prior to and after therapy. Signal intensity ratio represents the ratio of signal brightness between the examined ex- administration, wk traocular muscle and the ipsilateral temporalis muscle. As Mayer and colleagues (19) proposed, the higher the ratio, the more active the disease.
administration, wk Statistical analysis was performed by the use of Medcalc statistical software (version 9.3.0.0, Medcalc, Mariaker- ke, Belgium) and SPSS (v. 17.0 for Windows, SPSS Inc., Chicago, Illinois, USA). The data are given as mean ± stan- dard deviation. Both parametric and nonparametric sta- tistical tests were used for the analysis according to the T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; existence of normal distributed data per case. All p values TSI = thyroid-stimulating immunoglobulin; SRR = specimen-to-reference ratio.
2014 Wichtig Editore - ISSN 1120-6721 Immunosuppression and radiotherapy in thyroid-related restrictive myopathy Forty patients (45.5%) had previously undergone radio- TABLE IV -
DIPLOPIA, CLINICAL ACTIVITY SCORE, AND active iodine ablation for hyperthyroidism and developed SIGNAL INTENSITY RATIO AT BASELINE AND 6 MONTHS POSTTREATMENT WITH RESPEC- flare-up shortly thereafter. On initial examination, 29 pa- tients (33%) experienced diplopia in primary position of gaze, within the central 30° of field, confirmed by BSV test, while 59 patients (67%) were diagnosed with diplopia on extremes of gaze outside the central 30° of field. Hess charts and UFF tests showed severe restriction in single ductions, of at least one muscle, in 35 patients (39.8%) and mild to moderate restriction in 53 patients (60.2%) outside Primary position central 30° of excursion.
CAS, median (range) and Orthoptic assessment at the end of treatment revealed an overall improvement in both diplopia and single muscle ductions. More specifically, 10 patients (11.4%) had re- sidual diplopia in primary position. A total of 39 patients (44.3%) experienced diplopia only in extreme gaze, while 39 patients (44.3%) experienced complete relief from dou- p Values using Mann-Whitney nonparametric test for median comparison in cli- ble vision (p<0.001, chi-square test). With respect to duc- nical activity score (CAS), Student t test for mean comparison in signal intensity ratio (SIR), chi-square test for frequencies comparison of diplopia and CAS, and tions, only patients with severe restriction of at least one Fisher exact test for frequencies comparison of SIR.
muscle benefited significantly from the regimen (p = 0.023, McNemar test for paired proportions).
Mean CAS, calculated at final follow-up, was 1.91 ± 1.02 at 3-, 6-, and 12-month time points, respectively, after (median 2, range 0-6), and had significantly improved com- the initiation of the combined treatment. All patients were pared to mean CAS before treatment, which was 5.97 ± evaluated 6 months following withdrawal of treatment. At 0.78 (median 6, range 4-7, p<0.001, Mann-Whitney test).
18 months following initiation of treatment, the percentage Further subgroup analysis of the study population (n = 88) of treatment success reached 73.9% (n = 65).
was undertaken according to CAS score after completion With respect to surgical procedures required during the of treatment. This is detailed in Table IV.
course of treatment or following remission of disease, 8 pa- Group A (CAS 0-3) included 64 patients (72.7%), group B tients underwent strabismus surgery for correction of persis- (CAS 4-5) 23 patients (26.1%), and group C (CAS ≥6) 1 pa- tent diplopia. Three patients underwent orbital decompres- tient (1.2%). The latter patient was reported to show poor sion for cosmetic reasons and 10 patients had correction of compliance to treatment. Compared to baseline data, a eyelid malposition in the burnt-out phase of TED.
clinical improvement was noted in diplopia, CAS, and SIR (p<0.001, chi-square test).
Signal intensity ratio comparison before and after treatment The concept of 2-agent medical immunosuppression com-bined with orbital radiotherapy derived from the notion that A total of 35 patients had shown a ratio less than 2 in at other combinations such as steroids and second-line im- least one muscle and 53 patients ≥2. At the last follow-up munosuppressant (AZA or cyclosporine) or steroids and review, 67 patients were found with ratio 1-2, while only orbital radiotherapy are more efficacious than use of ei- 21 patients had ratio of 2 or more (p<0.001, Fisher exact ther treatment alone (20). It is recommended that orbital test). The SIR indicated a statistically significant reduc- radiotherapy is avoided in ages younger than 35; however, tion from 2.16 ± 0.58 to 1.63 ± 0.53 (p<0.0001, paired there are studies comprising patients as young as 17 years t test).
who received irradiation of 20 Gy without showing higher Out of the study population of 88 cases, clinical success incidence of extraocular or radiation-related morbidities was achieved in 54 (61.4%), 57 (64.8%), and 61 (69.3%) compared to older age groups (21). We included one man 2014 Wichtig Editore - ISSN 1120-6721 Chalvatzis et al under the age of 35 (23 years old) in our study, who had se- improvement at 6 months was 61.4%, improving to 69.3% at vere, persistent diplopia in primary position of gaze, previ- 18 months. Our study shows a lesser degree of clinical im- ously unresponsive to steroid treatment alone. Long-term provement in TED in comparison to Kahaly et al. However, immunosuppression based on AZA and low-dose steroids when specifically looking at the motility deficit subgroup was subsequently administered in patients whose disease (constant diplopia), we note an improvement in 33.3% in remained active.
the oral glucocorticoid group and an improvement of 56.5% It is encouraging to observe that there was a sustained in the intravenous glucocorticoid subgroup at 12 weeks. In positive clinical improvement at 3-, 6-, and 12-month time this respect, our study shows a more favorable improve- points equating to 61.4%, 64.8%, and 69.3%, respec- ment in this subgroup of 65.5%.
tively, after the initiation of the combined treatment. At Although alterations in ocular motility were our primary 18 months following initiation of treatment, the percentage concern, CAS as well as SIR was also assessed in all pa- of treatment success reached 73.9% (n = 65).
tients pretreatment and posttreatment and this may rep- Diplopia, particularly in the primary position of gaze, repre- resent the first attempt in the literature to apply a modern sents one of the most disabling morbidities related to TED. assessment consensus in combined treatment regimens Driving, reading, and working, either in office or industry for TED. Overall improvement in CAS was found to be sta- environment, become difficult or impossible for affected tistically significant and positively comparable to recent patients. As shown in Table III, diplopia improved signifi- studies that involve pulse steroid treatment alone (17). Im- cantly with our combined treatment, resulting in complete provement in TED-related myopathy correlates to low CAS cure in almost half of the patients enrolled in the study scores after treatment in this series of patients.
(44.3%). Additionally, primary gaze diplopia improved in The use of AZA, as a steroid-sparing agent, significantly 65.5% of cases in this subgroup. It is also notable that only reduced the total prednisolone intake on a long-term basis 10 patients experienced persistent, posttreatment diplopia since the vast majority of patients did not exceed 25 mg/ and among those 8 (9.1%) required strabismus surgery day. Azathioprine-related adverse effects have been ex- while 2 were satisfied with prism prescription. As Prum- tensively studied because of its broad use in many other mel and colleagues (22) reported, squint or decompression autoimmune diseases such as rheumatoid arthritis, sys- surgery was required in over 70% of their series of patients temic lupus erythematosus, myasthenia gravis, and ocular following treatment with either orbital radiotherapy or stan- pemphigoid (24). In our series, 4 patients (4.5%) required dard dose steroids. However, patients with inactive and ir- withdrawal of AZA due to adverse effects. These effects reversible disease were not excluded from the above study were reversible after discontinuation of treatment.
and this might be related to high demand for rehabilitative Over the last 4-5 years, a multicenter prospective, controlled, randomized study between tertiary centers specializing in Direct comparison of TED studies is notoriously difficult management of TED, the Combined Immunosuppression due to differences in study designs and variable outcome and Radiotherapy in Thyroid Eye Disease (CIRTED) study, measures. The current consensus treatment for active TED has been undertaken (25). Patients enrolled in this study were remains high-dose intravenous steroids. However, in our initially put on oral steroids and subsequently randomized to study, we tried to combine an initial intravenous pulse with 4 groups including possible combinations with radiotherapy, lower oral dosages since at the time the particular treat- sham radiotherapy, AZA and placebo, and AZA. Results are ment protocol was conducted no prospective random- expected shortly.
ized studies were available comparing intravenous to oral In conclusion, combined immunosuppression with orbital steroids in TED. A regimen commonly used is outlined in radiotherapy appears to reduce morbidity in patients with Kahaly et al (23). In this study, patients received either once active disease and specifically the subgroup with marked weekly intravenous methylprednisolone (0.5 g, then 0.25 g, restrictive myopathy by improving major motility parame- 6 weeks each) or oral prednisolone starting with 0.1 g/day, ters such as diplopia and duction amplitude and decreases then tapering the dose by 0.01 g/wk. At 6 months follow-up, the need for rehabilitative surgery. In this study, AZA ap- there was a positive clinical improvement in TED in 77% peared to be well-tolerated. Azathioprine used as a ste- of the intravenous glucocorticoid group compared to 51% roid-sparing agent may reduce the total cumulative steroid in the oral glucocorticoid group. In our study, the overall dose and the related adverse effects. Although the present 2014 Wichtig Editore - ISSN 1120-6721 Immunosuppression and radiotherapy in thyroid-related restrictive myopathy study has some limitations due to its retrospective nature tion in management of the above series of patients and for and the difficulty in distinguishing cases whose improve- ment was a result of the natural course of the disease, it provides useful clinical evidence to support the efficacy Financial Support: No financial support was received for this
of combined regimens in management of active thyroid- related myopathy.
Conflict of Interest Statement: None of the authors has conflict of
interest with this submission.
Address for correspondence: The authors thank the Medical Records Department of Argyrios Tzamalis, MD, PhD, FEBO2nd Department of Ophthalmology Bristol Eye Hospital, UK, for help in data collection; Ann Aristotle University of Thessaloniki Starbuck, Senior Orthoptist at Bristol Eye Hospital, UK, and Faculty of Medicine the orthoptic staff for patient assessment and care; and the "Papageorgiou" General HospitalGR-56429, Thessaloniki staff of the Radiotherapy Department at the Papageorgiou General Hospital, Thessaloniki, Greece, for their collabora- 10. Rundle FF, Wilson CW. Development and course of exoph- thalmos and ophthalmoplegia in Graves' disease with spe- 1. Perros P, Krassas GE. Graves orbitopathy: a perspective. cial reference to the effect of thyroidectomy. Clin Sci 1945;5: Nat Rev Endocrinol 2009;5:312-8.
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