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Original Investigation Adalimumab as Steroid-Sparing Treatment of Inflammatory-Stage Thyroid Eye Disease Reed Ayabe, B.A.*, Dan B. Rootman, M.D.†, Catherine J. Hwang, M.D.†, Ami Ben-Artzi, M.D.‡, and Robert Goldberg, M.D.† *Division of Orbital and Ophthalmic Plastic Surgery, Jules Stein Eye Institute; †David Geffen School of Medicine; and ‡Department of Medicine, Division of Rheumatology, University of California, Los Angeles, U.S.A. Purpose: Steroids are often used as medical therapy for active thyroid eye disease (TED). While high-dose steroids have been shown to be effective in reducing the severity of TED symptoms, the side effects of steroids can be severe. As the pathogenesis of TED is thought to involve the upregulation of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), it has been postulated that anti-TNF agents may be used as steroid-sparing agents in the treatment of TED. This retrospective study was conducted to examine the efficacy of adalimumab, a subcutaneously administered TNF-α antagonist, in treating the inflammatory symptoms of active TED. Methods: All patients in the inflammatory phase of TED who were treated with adalimumab at the Jules Stein Eye Institute over a 2-year period were reviewed. Data concerning visual acuity, optic nerve function, extraocular motility restriction, binocular visual fields, and proptosis were extracted from patient charts. Clinical photographs from baseline and 3-month follow-up visits were reviewed by masked orbital specialists. Each photograph was graded on the severity of conjunctival injection, chemosis, eyelid erythema, and eyelid edema on a scale from 1 to 4. An inflammatory score was calculated as the sum of these 4 elements. Groups were compared using paired t tests. Results: Six of 10 patients showed a decrease in inflammatory score while on adalimumab, whereas 3 showed an increase and 1 stayed the same. One patient experienced a significant complication (hospital admission for sepsis). Eight patients received concomitant tapering steroids during the first 6 weeks of therapy as the adalimumab reached maximum efficacy. When data from all 10 subjects were analyzed together, there was no significant change in inflammatory index after 3 months of treatment with adalimumab. However, when the 5 patients with a high baseline inflammatory index (>4) were considered separately, there was a significant improvement (mean decrease of 5.2 ± 2.7; p < 0.01) after adalimumab treatment. Four of 5 patients also reported a subjective improvement in symptoms while on adalimumab. Conclusions: This study suggests that adalimumab may have a role in the treatment of active TED with prominent inflammatory symptoms. The use of adalimumab and other immunosuppressive agents in the treatment of TED may help to mitigate some of the metabolic and psychiatric side effects of pulsed steroid treatment. A future randomized controlled study Accepted for publication March 28, 2014. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Daniel B. Rootman, M.Sc., M.D., University of California Los Angeles, CA 12159. E-mail: dan. [email protected] DOI: 10.1097/IOP.0000000000000211 Ophthal Plast Reconstr Surg, Vol. 30, No. 5, 2014 will be necessary to determine the efficacy of adalimumab as a primary therapy for TED. (Ophthal Plast Reconstr Surg 2014;30:415–419) S teroids are the current mainstay of medical therapy for inflammatory-stage thyroid eye disease (TED).1 While highdose steroids can effectively reduce the severity of inflammatory TED symptoms, the side effects of steroids can be severe and include diabetes, cardiovascular disease, infection, hepatotoxicity, major depression, and psychosis.1 The rate of steroid-related morbidity in the treatment of TED is reported to be as high as 6.5% and appears to correlate directly with steroid dosage.1,2 Potential targets for steroid-sparing agents have come to light as more is learned about the complex pathogenesis of TED. A 2003 study using reverse transcriptase– polymerase chain reaction to quantify the expression of inflammatory cytokines in orbital tissue specimens from patients with TED found that TNF-α, interleukin-1β, interferon-γ, interleukin-6, interleukin-8, and interleukin-10 transcription was increased.3 One of these cytokines, TNF-α, has garnered much attention because of the use of anti-TNF-α agents in the treatment of rheumatoid arthritis. The effectiveness of anti-TNF-α agents in treating rheumatoid arthritis has led to their application in other autoimmune diseases, including TED. A 2005 case report demonstrated that a patient with steroid-refractory TED responded favorably to the anti-TNF-α agent infliximab, and a pilot study the same year showed an overall reduction in inflammatory symptoms using the recombinant anti-TNF-α agent etanercept in 10 patients with new-onset TED.4,5 The newest of the commonly prescribed TNF-α inhibitors, adalimumab (Humira), is a fully human monoclonal antibody whose main advantage is that it can be taken as a subcutaneous injection administered every other week (etanercept is typically given twice per week and infliximab must be given as an intravenous infusion). The Anti-TNF Research Study Program of the Monoclonal Antibody Adalimumab trial in 2003 found that patients with rheumatoid arthritis treated with adalimumab plus methotrexate were more likely to experience a reduction in disease severity compared with patients treated with methotrexate alone (67% vs. 14%).6 Further studies comparing adalimumab with etanercept and infliximab in patients with rheumatoid arthritis have found no significant difference in efficacy or adverse effect rates among the 3 agents.7–10 A 2011 study showed that the in vitro treatment of orbital fat in patients with TED with adalimumab resulted in a decreased expression of proinflammatory cytokines.11 However, to the best of the authors’ knowledge, no study examining the clinical efficacy of adalimumab in the treatment of TED has been reported. 415 Ophthal Plast Reconstr Surg, Vol. 30, No. 5, 2014 R. Ayabe et al. Here, the authors retrospectively examine the efficacy of adalimumab in 10 patients with active inflammatory TED. MATERIALS AND METHODS Subject Selection. Institutional approval for this review was obtained from the University of California Los Angeles Institutional Review Board, and all procedures were performed in accordance with the 1964 Declaration of Helsinki. Patients at the Jules Stein Eye Institute’s TED clinic who were treated with adalimumab within the past 2 years were selected from the clinic’s electronic database. Criteria for inclusion included 1) diagnosis of TED within 9 months of starting adalimumab therapy; 2) the presence of at least 1 inflammatory symptom including chemosis, conjunctival injection, eyelid erythema, and eyelid edema (Table 1); 3) treatment with adalimumab for at least 10 weeks at a standard dosing of one 80 mg injection followed by biweekly 40 mg injections; and 4) age from 18 to 75 years. All injections were self-administered by patients after an instructional session. Patients who received decompression surgery or orbital radiation during the treatment period were excluded. Patients on other biologic agents, including certolizumab, rituximab, and ustekinumab, were also excluded. Patients who were pregnant or lactating were also excluded. Measures of Treatment Efficacy: Inflammatory Composite Score. Photographs of 10 subjects, taken from 6 standard angles at baseline and after 3 months of adalimumab therapy, were graded in a randomized fashion by masked oculoplastics specialists at the Jules Stein Eye Institute. A score of 0 to 4 was assigned for each of 4 visible signs of inflammation: chemosis, conjunctival injection, eyelid erythema, and eyelid edema. An inflammatory composite score (0 to 16) was calculated by summation. Extraocular Movement Restriction. Horizontal and vertical extraocular movement restriction was recorded as a score from 0 to −4 at each clinic visit. These values were summed across the horizontal and vertical axes, respectively, to provide 2 composite restricting scores. Values at baseline and after 3 months of adalimumab therapy were calculated. Proptosis. The degree of proptosis at baseline and 3 months was graded by Hertel exophthalmometry. Subjective Improvement. Patients at each visit were prompted with an open-ended question concerning their perception of improvement. Statements of improved pain, diplopia, or swelling from each patient’s 3-month visit were recorded as subjective improvement. TABLE 1. Criteria for active TED and signs of TED severity Criteria for active TED Criteria for severity of inflammation Hyper- or hypothyroidism associated with 1 or more of the following inflammatory signs with onset under 9 months prior to presentation: Chemosis Conjunctival injection Eyelid edema Eyelid erythema Progressive restriction of extraocular movement Progressive proptosis Inflammatory composite score, each graded on scale from 0 (absent) to 4 (severe) and the score summed: Chemosis Conjunctival injection Eyelid erythema Eyelid edema TED, thyroid eye disease. 416 Data Analysis. A paired samples t test was performed to compare composite inflammatory scores, extraocular movement restriction, and proptosis at baseline and 3 months. A subgroup of 5 patients with baseline inflammatory composite score >4 was also analyzed separately using a paired samples t test. RESULTS Subject Baseline Characteristics. Of 10 patients who satisfied the inclusion criteria, 5 were men and 5 were women. The average age was 56.3 years. The average number of weeks subjects received concurrent intravenous steroid treatment was 5. Most of these subjects had been receiving steroids prior to starting treatment with adalimumab. None of the patients were current smokers, and 1 had a distant history of smoking. Three of the patients had previous radioactive iodine ablation, 2 had a previous thyroidectomy, and 3 were on concurrent antithyroid medications (Table 2). Treatment Effect. After 3 months of adalimumab therapy, the inflammatory composite score was decreased for 6 patients, increased for 3 patients, and the same for 1 patient. Four patients reported a subjective improvement in pain, swelling, or diplopia. The average reduction in inflammatory composite score was 2.2, but this reduction did not achieve statistical significance (p = 0.09; Table 3). However, when the subset of patients with a baseline inflammatory composite score >4 were analyzed separately, there was a significant decrease in inflammatory composite score after 3 months of adalimumab treatment (5.2 ± 2.7; p < 0.01; Table 3). All the 4 patients with documented subjective improvement were part of this subset. Pre- and post-treatment photographs of the subset of patients with high baseline inflammatory scores are shown in Figure. There was no significant change in proptosis or extraocular movement restriction between baseline and 3 months of treatment for all 10 patients taken together, or for the subgroup of patients with high baseline inflammatory composite score (Table 3). Complications. One patient was admitted to the hospital for diarrhea and sepsis while on adalimumab and intravenous steroids. All immunosuppressive therapy was held for a 3-week period until the patient had fully recovered. Adalimumab therapy was then restarted and continued at the standard dose as the patient was clinically stable and had reported subjective improvement while on adalimumab. No other adverse events including infusion-related reactions were reported by any of the patients. DISCUSSION To the authors’ knowledge, this is the first study of the clinical efficacy of adalimumab in treating active-stage TED. After 3 months of treatment with biweekly adalimumab injections, the subset of patients with more severe baseline inflammation had a significant reduction in inflammatory composite score, while patients with less severe baseline inflammation did not experience a significant change in their inflammatory status. This suggests that patients with TED with severe inflammation may benefit most from adalimumab therapy. These findings are in agreement with those of a pilot study examining the efficacy of etanercept treating active TED. In that study, patients’ clinical activity scores12 decreased by an average of 60% after 6 weeks of treatment.5 In this study, the average decrease in inflammatory composite score was 44% overall and 66% in the subset with higher baseline inflammation. A calculation of clinical activity scores for each patient in this study may have allowed for a more direct comparison to the etanercept pilot study.5 However, they used an inflammatory composite score comprising the objective components of the clinical activity scores in lieu of the actual clinical activity scores, because these patients were not routinely screened for gaze-evoked orbital pain and they find that caruncular edema can be a deceiving and late sign of congestion in general. © 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Ophthal Plast Reconstr Surg, Vol. 30, No. 5, 2014 Steroid-Sparing Treatment of Thyroid Eye Disease TABLE 2. Subjects’ baseline characteristics Patient Sex Age Duration of Graves disease (months) 1 M 54 15 3 5 2 3 M F 54 62 18 147 9 9 0 8 4 F 53 1 1 6 5 F 32 27 4 3 6 F 42 7 6 6 7 M 66 22 9 10 8 9 F M 73 65 3 14 3 4 0 9 10 M 62 8 6 6 56 26.4 5 5 Average Duration of TED (months) Weeks on concurrent steroids Dose and route of steroids Methylprednisone 500 mg intravenous weekly —* Methylprednisone 500 mg intravenous weekly Prednisone 50 mg per os daily tapering by 10 mg each week and 5 mg for sixth week Methylprednisone 500 mg intravenous weekly Methylprednisone 400 mg per os weekly Methylprednisone 400 mg per os weekly —* Methylprednisone 320 mg per os weekly Methylprednisone 500 mg intravenous weekly — Smoking Prior RAI Prior thyroidectomy Concurrent antithyroid medication No No No Yes No No No‡ Yes† No Yes No No No No No No§ No Yes† No No No No No Yes No No Yes No Hx No No Yes† No No Yes No No No No No Of note, the subjects who received prior RAI or thyroidectomy either did not experience significant improvement in eye symptoms after the procedure or developed TED after the procedure. Hx, history of smoking; RAI, radioactive iodine; TED, thyroid eye disease. *Did not receive prior steroid therapy due to steroid intolerance (patient 2, previous psychosis; patient 8, personal preference). †RAI therapy did not affect the course of disease in these patients. ‡Received RAI shortly after the completion of adalimumab course. §Patient with subclinical hyperthyroidism. Patients receiving TNF-α inhibitors have been shown to be at increased risk of infection, particularly when first beginning the therapy.10 Only 1 subject in this study experienced a severe infection while on adalimumab, and it is possible that other factors contributed to this, including concomitant steroid treatment and multiple comorbidities. The treatment was otherwise tolerated well, even in patients who received an extended course of adalimumab. Studies of adalimumab and other TNF-α inhibitors in patients with rheumatoid arthritis suggest that they are generally safe, and serious complications such as infection, lupus-like reactions, immunogenicity, and demyelinating disorders are extremely rare.7–10 The greatest limitation of this study was lack of a control group. For this reason, there was no way to definitively determine whether any of the subjects’ improvement was due to steroids, adalimumab, or a natural history of the disease. However, the improvement for patients with inflammatory disease was seen with tapering doses of steroids, suggesting an adalimumab effect. Further, these patients were either unresponsive or intolerant of steroids, pointing toward a complementary role for adalimumab in certain cases. A larger sample of active patients with high inflammatory scores would have enabled the pairing of these subjects to age- and gender-matched historical controls. Unfortunately, patients often present late to this quaternary care center and can be concurrently on steroid therapy, thus reducing their overall inflammatory presentation. The retrospective study design also made it difficult to control for therapies used to treat hyperthyroidism, including antithyroid medication, 134I ablation, and total thyroidectomy. Studies have shown that these measures may shorten the course of TED.13,14 The authors were also unable to control for concomitant steroid dosages, although most of the subjects were treated by pulsed methylprednisone at 300 to 500 mg weekly. One subject who was not treated with steroids due to a past episode of steroid-induced depression experienced significant improvement in inflammation and subjective symptoms while on adalimumab. Finally, the authors were not Patient photograph prior to (left) and after (right) 3 months of adalimumab treatment. © 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. 417 Ophthal Plast Reconstr Surg, Vol. 30, No. 5, 2014 R. Ayabe et al. TABLE 3. Treatment effect Individual patients Baseline Patient 1 1 Patient 2 1 Patient 3 4 Patient 4 3 Patient 5 5 Patient 6 7 Patient 7 7 Patient 8 11 Patient 9 9 Patient 10 4 All patients (n = 10) Mean inflammatory 5.2 composite score Mean horizontal EOM −3.1 restriction Mean vertical EOM −3.6 restriction Mean Hertel OD 23.5 Mean Hertel OS 23.9 Subset with baseline inflammatory score >4 (n = 5) Mean inflammatory 7.8 composite score Mean horizontal EOM −4 restriction Mean vertical EOM −4 restriction Mean Hertel OD 23.7 Mean Hertel OS 24.8 3 months Change (3-month baseline) Subjective improvement? 4 2 4 4 2 3 0 3 5 3 +3 +1 0 +1 −3 −4 −7 −8 −4 −1 3 −2.2 (−4.8–0.4) No No No No Yes Yes No Yes Yes No p 0.09 −3 +0.1 (−1.1–1.39) 0.85 −4.6 −1 (−2.9–0.9) 0.27 23.7 23.9 +0.2 (−0.6–0.0) +0.1 (−3.7–3.9) 2.6 −5.2 (−7.9–−2.5) 0.60 0.96 p <0.01 −3.4 +0.6 (−2.1–3.3) 0.57 −3.6 +0.4 (−3.8–4.6) 0.83 23.8 24.8 +0.1 (−5.9–6.1) 0.0 (−4.8–4.8) 0.97 1.00 Subjects’ inflammatory scores were compared at baseline and after 3 months of adalimumab treatment using a paired samples t test. A statistically significant decrease was noted in patients whose initial inflammatory composite score was >4. EOM, extraocular muscle. able to quantify subjective improvement, which may have been useful in this analysis. Steroids are known to be effective in reducing the inflammatory symptoms of active TED, with an average response rate to intravenous steroids of 80% across numerous studies.1 However, the relatively high dose of steroids required to reduce the symptoms of active TED is associated with significant morbidity.15 A 2012 trial of 3 doses of methylprednisolone sodium succinate found that the highest dose (7.47 g weekly) was most effective, but was also associated with the highest rate of major adverse events, including diabetes, sepsis, psychosis, and major depression.2 There is ample evidence that patients with active inflammatory TED benefit more from steroid therapy than those with less active or fibrotic disease.1 As this appears to be the same group of patients that benefits most from adalimumab thearpy, the authors believe that adalimumab may have a role as a steroidsparing agent for patients with TED. In conclusion, this retrospective study suggests that adalimumab is of greatest benefit to patients with active TED associated with severe inflammatory signs. A randomized controlled trial is necessary to more accurately determine the efficacy and adverse effects of adalimumab and whether it can reduce the steroid requirements for patients with active TED. REFERENCES 1. Zang S, Ponto KA, Kahaly GJ. Clinical review: intravenous glucocorticoids for Graves’ orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab 2011;96:320–32. 2. Bartalena L, Krassas GE, Wiersinga W, et al.; European Group on Graves’ Orbitopathy. Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to 418 severe and active Graves’ orbitopathy. J Clin Endocrinol Metab 2012;97:4454–63. 3.Kumar S, Bahn RS. Relative overexpression of macrophage-derived cytokines in orbital adipose tissue from patients with graves’ ophthalmopathy. 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