The Cost-Effectiveness of Tocilizumab (Actemra) Therapy in Giant Cell Arteritis

Background: Tocilizumab (Actemra) is a humanized anti-interleukin-6 receptor antibody that has been used as a steroid-sparing agent in giant cell arteritis (GCA). Although the clinical effects are well described in GCA, the cost-effectiveness of the use of tocilizumab in GCA is ill defined. The purpose of this study was to determine the cost-effectiveness of tocilizumab in GCA compared with prednisone alone. Methods: A retrospective study of 32 patients with biopsy-proven GCA comparing prednisone alone (16 patients) and prednisone with tocilizumab (16 patients) was performed. The cost for tocilizumab therapy for 26 weeks with mild and severe side effects (Groups 1 and 2, respectively) and for 52 weeks with mild and severe side effects (Group 3 and 4, respectively) was compared with estimated costs of mild and severe steroid-induced side effects (Groups 5 and 6, respectively). Statistical analysis between groups was conducted using independent sample t tests. Results: Three out of the 4 group combinations of tocilizumab with prednisone demonstrated a statistically significant (P < 0.05) difference in cost compared with prednisone alone for GCA. Group 2 (26-week tocilizumab therapy with severe steroid-induced side effects), with no statically significant difference in price when compared with steroid therapy alone and far fewer side effects, demonstrated the potential use of tocilizumab in GCA therapy. As expected, longer treatment duration with tocilizumab was associated with greater cost. With respect to side effect severity, the number of side effects of steroid therapy was inversely associated with difference in cost between tocilizumab therapy and steroid side effect treatment. Conclusion: This study demonstrates that combination therapy of tocilizumab and prednisone is significantly more expensive than steroids alone with or without accounting for the cost of steroid-induced side effects in treated GC. The difference in cost between the 2 therapy types is directly related to tocilizumab therapy duration and inversely related to the number or severity of steroid side effects. Patients with GCA who require a shorter duration of steroid therapy and are at risk for a high number of side effects from steroid use may be potential candidates for tocilizumab therapy, from an economic perspective.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD The Cost-Effectiveness of Tocilizumab (Actemra) Therapy in Giant Cell Arteritis Arjun V. Jogimahanti, BS, Ashwini T. Kini, MD, Lauren E. Irwin, PhD, Andrew G. Lee, MD Background: Tocilizumab (Actemra) is a humanized anti– interleukin-6 receptor antibody that has been used as a steroid-sparing agent in giant cell arteritis (GCA). Although the clinical effects are well described in GCA, the costeffectiveness of the use of tocilizumab in GCA is ill defined. The purpose of this study was to determine the cost-effectiveness of tocilizumab in GCA compared with prednisone alone. Methods: A retrospective study of 32 patients with biopsyproven GCA comparing prednisone alone (16 patients) and prednisone with tocilizumab (16 patients) was performed. The cost for tocilizumab therapy for 26 weeks with mild and severe side effects (Groups 1 and 2, respectively) and for 52 weeks with mild and severe side effects (Group 3 and 4, respectively) was compared with estimated costs of mild and severe steroid-induced side effects (Groups 5 and 6, respectively). Statistical analysis between groups was conducted using independent sample t tests. Results: Three out of the 4 group combinations of tocilizumab with prednisone demonstrated a statistically significant (P , 0.05) difference in cost compared with prednisone alone for GCA. Group 2 (26-week tocilizumab therapy with severe steroid-induced side effects), with no statically significant difference in price when compared with steroid therapy alone and far fewer side effects, demonstrated the potential use of tocilizumab in GCA therapy. As expected, longer treatment duration with tocilizumab was associated with greater cost. With respect to side effect severity, the number of side effects of steroid therapy was inversely associated with difference in cost between tocilizumab therapy and steroid side effect treatment. University of Texas Medical School at Houston (AVJ), Houston, Texas; Department of Ophthalmology (AK), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Houston Methodist Hospital (LI), Houston, Texas; Department of Ophthalmology and Visual Sciences (AGL), University of Texas Medical Branch, Galveston, Texas; Department of Ophthalmology (AGL), Baylor College of Medicine, Houston, Texas; Departments of Ophthalmology, Neurology, and Neurosurgery (AGL), Weill Cornell Medicine, New York, New York; Section of Ophthalmology (AGL), University of Texas Maryland Anderson Cancer Center, Houston, Texas; and Department of Ophthalmology (AGL), the University of Iowa Hospitals and Clinics, Iowa City, Iowa. The authors report no conflicts of interest. Address correspondence to Arjun V. Jogimahanti, BS, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street Suite 450, Houston, TX 77030; E-mail: [e-mail] 342 Conclusion: This study demonstrates that combination therapy of tocilizumab and prednisone is significantly more expensive than steroids alone with or without accounting for the cost of steroid-induced side effects in treated GCA. The difference in cost between the 2 therapy types is directly related to tocilizumab therapy duration and inversely related to the number or severity of steroid side effects. Patients with GCA who require a shorter duration of steroid therapy and are at risk for a high number of side effects from steroid use may be potential candidates for tocilizumab therapy, from an economic perspective. Journal of Neuro-Ophthalmology 2021;41:342–350 doi: 10.1097/WNO.0000000000001220 © 2021 by North American Neuro-Ophthalmology Society G iant cell arteritis (GCA) is a medium to large vessel vasculitis of the elderly. Common clinical symptoms of GCA include bitemporal headache, jaw claudication, and scalp tenderness, but the most feared complication is loss of vision (1). The first-line treatment for GCA is immediate highdose corticosteroid therapy (1 mg–1.5 mg/kg body weight per day), but some doctors give intravenous steroids at the onset especially with severe visual loss in GCA. The mean duration of treatment with steroids is variable but can be up to 2 years after diagnosis (1). However, steroids are associated with a number of significant side effects, such as weight gain, diabetes, osteoporosis, hypertension, and systemic infections (2).Many patients with GCA have a relapse of symptoms during the prolonged steroid-tapering schedule (3). Tocilizumab (Actemra) is a steroid-sparing regimen in GCA and works by blocking the acute phase reactant interlukin-6 (IL-6). By blocking IL-6, several proinflammatory processes, such as B-cell activation and TH17 cell differentiation, are inhibited (4). Although the clinical effects of tocilizumab as a steroid-sparing agent are well known, the cost-effectiveness of the drug has not been as well studied (5).The standard dosing for tocilizumab is 1 injection per week or every other week over the course of 52 weeks. This retrospective study was performed to compare the costJogimahanti et al: J Neuro-Ophthalmol 2021; 41: 342-350 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution effectiveness of tocilizumab as a steroid-sparing drug in GCA when compared with prednisone alone. METHODS AND MATERIALS Study Design This was a retrospective study of patients with biopsy-proven GCA treated with either prednisone alone or in conjunction with tocilizumab. All patients were seen at the Blanton Eye Institute at Houston Methodist Hospital. Patients were extracted by diagnosis code (GCA) from Epic, an electronic medical record database. Patients were treated with prednisone or a combination of tocilizumab and prednisone, for GCA. Patient charts were extracted for steroid-related side effects, and coarse cost estimates were calculated. Patients were divided into 2 main groups: the treatment group and control group. Next, the treatment group patients were divided into 4 groups: projected costs based on tocilizumab for 26 week treatment plans with mild (Group 1) and severe (Group 2) prednisone side effects and projected costs based on tocilizumab for 52 week treatment plans with mild (Group 3) and severe (Group 4) prednisone side effects. The severity of steroid side effects is a predetermined cost of severity of steroid side effect treatment based on the literature review. The low-severity designation is the hypothetical cost for treatment of the least severe steroid side effects. The highseverity designation is the hypothetical cost for treatment of the most severe steroid side effects. Patients were assigned certain categories of side effects based on their actual preexisting conditions or actual documented side effect types. Cost was just extrapolated from these original conditions. Groups 1–4 represented the same patients, GCA patients who were actually treated with tocilizumab, chosen for treatment group (patients numbered 1–16), but the basis of variation in the groups was hypothetical length of tocilizumab therapy, hypothetical complication severity, or both. These patients are listed in Table 1. Finally, the control group patients were divided into 2 groups: Groups 5 and 6. Groups 5 and 6 consisted of patients who were treated with prednisone only and the cost of mild and severe prednisone side effects, respectively. The sample population of patients in Groups 5 and 6 were the same patients with the only difference between the 2 groups being the hypothetical severity of steroid side effects. There is no variation in length, like the treatment groups, because these patients, being the control, were chosen from a pool of GCA patients not being treated with tocilizumab. The patients in Groups 5 and 6 were randomly selected through a random number generator in Microsoft Excel. These patients are also listed in Table 1. Regarding study approval, Institutional Review Board approval at the Houston Methodist Research Institute was obtained through expedited review. Inclusion/Exclusion Criteria Patients were included in the current study if they had active or previously diagnosed biopsy-proven GCA, were treated for GCA with prednisone or corticosteroids, were treated with tocilizumab for steroid tapering, and had TABLE 1. Demographics of the patient population Treatment group (tocilizumab) Group 1 Patient number Age, yr Gender Group 2 Patient number Age, yr Gender Group 3 Patient number Age, yr Gender Group 4 Patient number Age, yr Gender Control group (non-tocilizumab) Groups 5 and 6 Patient number Age, yr Gender 1 83 F 2 72 M 3 67 M 4 62 F 5 68 M 6 82 F 7 83 F 8 66 F 9 70 F 10 62 M 11 87 F 12 64 F 13 83 F 14 70 F 15 72 F 16 86 F 1 83 F 2 72 M 3 67 M 4 62 F 5 68 M 6 82 F 7 83 F 8 66 F 9 70 F 10 62 M 11 87 F 12 64 F 13 83 F 14 70 F 15 72 F 16 86 F 1 83 F 2 72 M 3 67 M 4 62 F 5 68 M 6 82 F 7 83 F 8 66 F 9 70 F 10 62 M 11 87 F 12 64 F 13 83 F 14 70 F 15 72 F 16 86 F 1 83 F 2 72 M 3 67 M 4 62 F 5 68 M 6 82 F 7 83 F 8 66 F 9 70 F 10 62 M 11 87 F 12 64 F 13 83 F 14 70 F 15 72 F 16 86 F 17 81 F 18 93 F 19 65 M 20 74 F 21 63 F 22 73 F 23 78 F 24 83 M 25 82 F 26 69 F 27 71 F 28 68 F 29 67 F 30 70 F 31 68 F 32 80 M This table includes the gender and age of the selected patients for the treatment and control groups. Note that the patients in Groups 1–4, the treatment groups, are the same. M, male; F, female. Jogimahanti et al: J Neuro-Ophthalmol 2021; 41: 342-350 343 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution sufficient follow-up of 52 weeks or greater. Patients were included if all of the inclusion criteria were met. Patient were excluded from the study if they were not diagnosed with GCA, were not being treated with prednisone or steroids for GCA, were being treated with another immunosuppressive agent other than tocilizumab, or had less than 52 weeks of follow-up or with insufficient chart documentation. Patients were excluded if one of the exclusion criteria was met. The demographics of the patients chosen are represented in Table 1. The patients were chosen to reduce any variability between the treatment groups, Groups 1–4, and the control groups, Groups 5 and 6. The male to female ratio is 1:3 in the treatment groups, whereas the ratio is 1:4 in the control group. Furthermore, the average age in the treatment group is 73.6 vs 74.0. The similarity in the groups makes it unlikely that any variation in the results is due to differences in the demographics of the patients. Cost Evaluation Following data collection, a literature analysis on the types of conditions associated with each class of side effect was performed. For example, one of the major classes of side effects of steroid therapy is disease related to bone reabsorption. Table 2 demonstrates the spectrum of severity of bone-related side effects. A spectrum of severity was determined because side effects are not all uniform and different factors, such as length of prednisone therapy and patient preexisting conditions will affect the intensity of the side effects. This stratification allows for determination of the level and thus cost of side effects of steroids. Patients on tocilizumab therapy for more than the recommended initial prescription of 52 weeks were included in the treatment groups but only the cost of 1 year of therapy was used for the calculations. The literature analysis focused on the estimated cost of alleviation of specific steroid-related side effects. Cost alleviation includes all the medically relevant costs to treating that particular side effect but not factors, such as lost wages or extraneous transportation costs. The cost associated with each of the treatment Groups 1–4, thus, was calculated by determining the total of the tocilizumab drug cost for the indicated treatment duration and the average cost of treatment of steroid side effects based on the indicated complication severity level. The costs associated with the control groups, Groups 5 and 6, were determined by just the average cost of treatment of steroid side effects because the patient population of the control groups were not taking tocilizumab. These values are represented in Table 3. Microsoft Excel was used to organize costs and to calculate the differences in cost of tocilizumab therapy and cost of steroid side effect treatment. Statistical Analysis Following the determination of cost, a statistical analysis on the difference between the cost of the 4 treatment groups with their respective prednisone control group was performed. Two control groups of prednisone side effects were chosen to protect against the confounding variable of severity of side effects. Group 1 (tocilizumab 26-week treatment with mild side effects) and Group 3 (tocilizumab 52-week treatment with mild side effects) were compared against Group 5 (prednisone only treatment TABLE 2. Categories of side effects of steroids and varying degrees of severity Side Effect Type Sleep apnea (2) Depression (2) Bone defects (6) Gastric complications (6) Weight gain (2) Blood pressure (2) Infection (2) Myopathy (2) Class I Severity Mild Mild depression Bone weakness (osteoporosis) Gastritis-treat with steroid cessation Overweight Hypertension Outpatient treated Mild myopathy, cessation of steroid Glaucoma Early-stage disease Avascular necrosis of the hip Nonoperative stage: bisphosphonate (7) therapy DVT (8) Anticoagulation prophylaxis Ankylosing spondylitis (9) Outpatient management Sacroiliitis (10) Cessation of steroid Type II diabetes (11) Cost of insulin Class II Severity Severe Major depressive disorder Fracture Gastrointestinal hemorrhage Obese Hypertensive emergency Inpatient treated Cessation of steroid + physical therapy Physical therapy duration: 6 months (once a week) Late-stage disease Operative-hip decompression DVT event Management including hospital visits Cessation of steroid + physical therapy Insulin+ complications+ uncontrolled diabetes cost This table demonstrates the most common outcomes, both mild and severe, of the specific side effects of steroids and underlying patients’ conditions exacerbated by steroid use. These values were obtained from a literature search of previous data. The parenthesis in the data corresponds to the source the value was obtained from. 344 Jogimahanti et al: J Neuro-Ophthalmol 2021; 41: 342-350 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Associated costs of steroid side effects Side Effect Type Sleep apnea (12) Depression (13) Bone defects (14) Gastric complications Weight gain (17) Hypertension (18) Infection (19) Myopathy (20) Glaucoma (21) Avascular necrosis of hip DVT Novolin (insulin for diabetes) Ankylosing spondylitis (9) Sacroiliitis (9) Annual Class I Severity Cost (U.S. Dollars) Annual Class II Severity Cost (U.S. Dollars) 1,950.00 1,098.00 500.00 0.00 (15) 266.00 459.54 2,495.00 2 2,997.00 (7-day cost) Avg: 2,746 0 3,889.00 2,390.00 8,600.00 31,633.00 (16) 1,723.00 1,248.89 15,071.00 (7-day cost) 623 500 (14) Warfarin annual cost (23): 90 tablets: $35.30 35.30 · 4= 141.20 Eliquis annual cost (24): 60 tablets price: $566.66 730 tablets: $566.66 · 12= $6,799.92 500.97 per month · 12= 6,011.64 (26) 11,981.00 0.00 50 2 125 (·52) Avg: 4,550 (87.5 · 52) 2,511 27,498 (22) 18,000–23,000 (25) Average: 20,500.00 6,011.64 + 937 + 648 = 7,596.64 (11,26) 17,764.00 50 2 125 (·52) (20) Avg: 4,550 (87.5 · 52) This table demonstrates the associated costs of steroid-therapy side effects and underlying conditions exacerbated by steroid use. These values represent the total medical cost of disease. These values were obtained from a literature search of previous data. The parenthesis in the data corresponds to the source the value was obtained from. Values in bold indicate that a calculation was performed to obtain the cost for the category. The entry in bold is the amount used for statistical determination. with mild side effects). Additionally, Group 2 (tocilizumab 26-week treatment with severe side effects) and Group 4 (tocilizumab 52-week treatment with severe side effects) were compared against Group 6 (prednisone only treatment with severe side effects). Statistical significance was calculated using a Student independent sample t test for comparison of 2 types of quantitative data sets. For the t test, the null hypothesis (Ho) was defined as there being no difference in cost between patients treated with tocilizumab therapy and the control group not treated with tocilizumab. The alternative hypothesis (Ha) was defined as there is a difference in cost between patients treated with tocilizumab therapy and the control group not treated with tocilizumab. The outcome was measured against a 5% overall significance level (alpha level of 0.05) against 2-sided alternatives. Statistical significance, consequently, was determined as having a P value of less than 0.05. For statistical determination, the IBM program SPSS Software was employed. RESULTS In the study, 106 total charts were reviewed; of which, 16 patients met inclusion criteria and 90 were excluded from the treatment group. Table 1 shows the demographics of the patients included in the study. Jogimahanti et al: J Neuro-Ophthalmol 2021; 41: 342-350 Tables 4 and 5 show the side effects exhibited by the patients in the study and the long-term effects of each. The effects were determined through a literature search of peerreviewed journals. For severity, a Class I severity is a milder version of the category of side effect. A Class II severity is the most severe possible effect of the side effect or condition. Table 3 represents the cost of disease of the side effects listed in Table 2. Unless specified in the Table 2, the value represents the cost of disease. If the treatment was specified in Table 2, then the value represents the cost of treatment in Table 2. Previously conducted studies have demonstrated the therapeutic efficacy of tocilizumab as a steroid-sparing therapy for GCA (5). For our cost estimates, the annual public domain high- and low-end pricing of 26-week and 52-week prescriptions was used. The cost of 9 prefilled syringes of tocilizumab, with a dose of 162 mg/0.9 mL, is $2,363.32 (27). At this rate, the annual estimated cost to fulfill the standard 26-week subscription would be $7,089.96. Alternatively, at a dose of 162 mg/0.9 mL at $1,153.00 and assuming a once weekly prescription for 26 weeks, this cost would amount to $29,978 (28). Thus, the range of price for a standard prescription of tocilizumab every other week is $7,089.96– $29,978.00 with an average of $18,533.98. This average is the price that will be used to compare across the individual side effects for the 26-week tocilizumab prescription. 345 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 4. Side effects and underlying conditions of patients treated with prednisone and tocilizumab Patient Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Steroid-Induced Side Effect(s) Steroid-Related Underlying Condition(s) — Gastric AVM Chest pain HTN, HLD — HTN, chronic back pain — Post-menopausal, hyperparathyroidism Weight gain (12 lbs), sleep apnea Ehlers-Danlos syndrome Back pain Recurrent infections Cushingoid fat distribution, steroid-induced myopathy — — HTN Weight gain (10 lbs) Sleep apnea, back pain, HTN Steroid-induced osteoporosis, HTN — Cushingoid fat distribution, shaking from steroids, sleep apnea, memoryDepression, type II diabetes, HTN loss HTN Back pain — HTN, HLD — Osteoporosis — HTN Moon facies — This table includes the results of the EPIC Chart patient search for the side effects of the patients taking tocilizumab and prednisone for giant cell arteritis treatment. AVM, arteriovenous malformation; HLD, hyperlipidemia; HTN, hypertension. At the low end, the annual estimated cost to fulfill the standard 52-week subscription, assuming a set of 9 syringes per purchase, would be $14,179.92. The high end, with a dose of 162 mg/0.9 mL costing $1,153, would amount to $59,956. Thus, the range of price for a standard 52-week prescription of tocilizumab is $14,179.92–$59,956 with an average of 37,067.96. This average is the price that will be used for the 52-week tocilizumab simulation. TABLE 5. Side effects and underlying conditions of patients treated with prednisone ONLY Patient Number Steroid-Induced Side Effect(s) Steroid-Related Underlying Condition(s) — HTN, HLD HTN HTN, ankylosing spondylitis HTN, DVT (warfarin: 1 tablet, 7.5 mg daily) HTN, osteoporosis Decreased range of motion of back, sacroiliitis Osteoporosis, DVT (eliquis treatment: 5 mg, 2 times a day) HTN HTN Osteoporosis, HTN Low back pain/osteoporosis, HTN 17 18 19 20 21 22 — Flu-like symptoms, dizziness, light-headedness, edema Weight gain, cushingoid, sleep apnea Gastritis, headache, dizziness 23 Diabetes (novolin treatment), glaucoma, HTN 24 25 26 27 Dizziness, weakness, cushingoid, glaucoma Weight gain (10 lbs), mental decompensation Weight gain (10 lbs), sleep apnea, myopathy Elevated blood sugar, weight gain, cushingoid fat distribution, superimposed infection Avascular necrosis of the hip, ecchymosis, osteoporosis (fracture), HTN superimposed infection Superimposed infection Osteoporosis, HTN Hyperglycemia, sleep apnea, weight gain Peptic ulcer disease, HTN Painful skin nodules, hair loss, weight gain HTN Mood changes, weight gain, easy bruising, oral thrush of the mouthHTN 28 29 30 31 32 Osteoporosis This table includes the results of the EPIC chart patient search for the side effects of the patients taking prednisone only for giant cell arteritis treatment. AVM, arteriovenous malformation; HLD, hyperlipidemia; HTN, hypertension. 346 Jogimahanti et al: J Neuro-Ophthalmol 2021; 41: 342-350 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 6. Cost of side effects in patients treated with prednisone and tocilizumab Patient Number Cost of Class I Severity Cost of Class II Severity (US Dollars) (US Dollars) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 0.00 0.00 209.09 436.59 227.50 2,216.00 1,749.43 0.00 209.09 1,589.84 959.54 5,393.98 687.04 209.09 227.50 209.09 0.00 14,393.02 568.24 4,481.24 3,913.00 5,612.00 15,457.31 4,550.00 568.24 7,973.74 9,848.89 9,001.17 5,161.89 568.24 3,913.00 568.24 This table represents the calculated cost of side effects that each patient would have to pay based on the side effects listed in Table 4. For the cost adjustment with tocilizumab therapy, the predicted cost of treatment of exacerbation of underlying steroid-related side effects was multiplied by 0.455. This value was obtained from the average percentage of tocilizumab users who obtained remission in previous trials of tocilizumab use in GCA (5). With the 2 tocilizumab trials obtaining a remission rate of 53% and 56%, the average rate was 54.5%. This adjustment reflects the likely outcome of decreased side effect rate of GCA patients taking tocili- zumab for steroid-sparing therapy. The cost of steroidinduced side effects for those taking tocilizumab was unaltered. Cost Tables 6–8 represent the calculated values for each patient in the study. The cost of steroid side effects and steroidrelated underlying conditions for both groups, patients treated with tocilizumab and prednisone and those treated only with prednisone, was calculated. A graphical display of the results is demonstrated in Figures 1 and 2. Statistical Analysis The results of the 4 independent t sample tests, comparing the costs of patients treated with tocilizumab for 26 weeks (Groups 1 and 2) or patients treated with tocilizumab for 52 weeks (Groups 3 and 4) against the prednisone control groups (Groups 5 and 6) revealed statistically significant differences or no statistically significant cost savings, in price between tocilizumab with prednisone patients and prednisone-only patients for 3 of the 4 combinations of therapy. For the tocilizumab 26week therapy with mild prednisone side effects (Group 1) in comparison to Class I prednisone side effects (Group 5), there was a statistically significant difference of t(17.656) = 12.652 (P , 0.5). For the tocilizumab 52week therapy with mild prednisone side effects (Group 3) in comparison to Class I prednisone side effects (Group 5), there was a statistically significant difference of t(17.655) = 28.009 (P , 0.5). The last statistically significant group was the tocilizumab 52-week therapy with TABLE 7. Total cost of patients treated with tocilizumab and prednisone Group 1: Tocilizumab 26 WeekGroup 2: Tocilizumab 26 WeekGroup 3: Tocilizumab 52 WeekGroup 4: Tocilizumab 52 Week Cost With Class I Side effects Cost With Class II Side Effects Cost With Class I Side Effects Cost With Class II Side Effects (US Dollars) (US Dollars) (US Dollars) (US Dollars) 18,533.98 18,533.98 18,743.07 18,970.57 18,761.48 20,749.98 20,283.41 18,533.98 18,743.07 20,123.82 19,493.52 23,927.96 19,221.02 18,743.07 18,761.48 18,743.07 18,533.98 32,927.00 19,102.22 23,015.22 22,446.98 24,145.98 33,991.29 23,083.98 19,102.22 26,507.72 28,382.87 27,535.15 23,695.87 19,102.22 22,446.98 19,102.22 37,067.96 37,067.96 37,277.05 37,504.55 37,295.46 39,283.96 38,817.39 37,067.96 37,277.05 38,657.80 38,027.50 42,461.94 37,755.00 37,277.05 37,295.46 37,277.05 37,067.96 51,460.98 37,636.20 41,549.20 40,980.96 42,679.96 52,525.27 41,617.96 37,636.20 45,041.70 46,916.85 46,069.13 42,229.85 37,636.20 40,980.96 37,636.20 This table represents the calculated cost of side effects that each patient would have to pay based on the side effects listed in Table 4 plus the total cost of Tocilizumab therapy. Jogimahanti et al: J Neuro-Ophthalmol 2021; 41: 342-350 347 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 8. Cost of steroid side effects of patients treated with prednisone only Patient Number 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Cost of Class I Severity Cost of Class II Severity (US Dollars) (US Dollars) 459.54 959.54 12,440.54 600.74 3,175.54 500.00 14,394.10 1,082.54 1,823.54 3,175.54 3,971.54 12,305.54 3,705.54 2,675.54 725.54 4,569.54 1,248.89 9,848.89 19,012.89 21,748.89 15,460.89 44,783.00 40,456.53 3,759.89 5,361.89 20,010.89 26,642.89 52,417.89 24,919.89 38,493.89 2,971.89 20,432.89 This table represents the calculated cost of side effects that each patient would have to pay based on the side effects listed in Table 5. No “total cost” table was included for the prednisone therapy only group because there was no additional drug, such as tocilizumab. severe prednisone side effects (Group 4) in comparison to Class II prednisone side effects (Group 6), demonstrating a statistical significance in cost of t(17.818) = 5.056 (P , 0.5). The one statistically insignificant result was the difference in price of Group 2 patients (patients treated with tocilizumab for 26 weeks with Class II prednisone side effects) and patients with Class II prednisone side effects (Group 6), demonstrating values of t(17.82) = 0.54 (P . 0.05). DISCUSSION Our results suggest that combination therapy of tocilizumab (Actemra) with prednisone is significantly more expensive than therapy with prednisone alone for GCA in most cases. However, GCA patients treated with tocilizumab for 26 weeks had less cost overall (accounting for steroid-related side effects) than those treated with tocilizumab for 52 weeks when compared with the cost of patients experiencing severe prednisone side effects. The difference in price of Group 2 patients (patients treated with tocilizumab for 26 weeks with Class II prednisone side effects) was not statistically significant with patients with Class II prednisone side effects (t(17.82) = 0.54; P . 0.05). This demonstrates promise due to the fact that the tocilizumab patients experience fewer side effects for a treatment plan that is at worst the same price as prednisone therapy (5). This suggests that the potential use of tocilizumab in GCA patients is at low drug frequencies and high steroid-related side effects. We recognize the limitations of this study including purposefully short length of the study duration (26 weeks and 52 weeks), relatively small sample size, and the ability to estimate true costs of disease and side effect in a retrospective design. A longer study duration with a larger sample size prospectively might be useful to confirm our initial findings. The high cost of tocilizumab is a barrier to obtaining a larger sample size because only 15.09% of the patient population with biopsy-proven GCA was using the IL-6 inhibitor. In addition, we did not include all of the potential costs of tocilizumab vs prednisone and focused only on specific steroid-related side effects. Omitted from our study were other cost considerations such as medically related loss of economic productivity and transportation. Additional limitations of the study include the FIG. 1. Graph of total cost of patients treated with tocilizumab and prednisone. This figure is a graphical representation of the data in Table 7. 348 Jogimahanti et al: J Neuro-Ophthalmol 2021; 41: 342-350 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Graph of total cost of patients treated with prednisone only. This figure is a graphical representation of the data in Table 8. demographics of the population due to the fact that the average age for the treatment groups and control group was in the 70s. In summary, although tocilizumab is an expensive drug, the efficacy as a steroid-sparing regimen is well known, and we believe that the reduction in steroid-related side effects may be cost-effective especially in higher-risk patients treated with 26-week duration of tocilizumab. Further work is necessary to determine if our findings are generalizable. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. V. Jogimahanti, A. Kini, L. Irwin, and A. G. Lee; b. Acquisition of data: A. V. Jogimahanti, A. Kini, L. Irwin, and A. G. Lee; c. Analysis and interpretation of data: A. V. Jogimahanti, A. Kini, L. Irwin, and A. G. Lee. Category 2: a. Drafting the manuscript: A. V. Jogimahanti, A. Kini, L. Irwin, and A. G. Lee; b. Revising it for intellectual content: A. V. Jogimahanti, A. Kini, L. Irwin, A. G. Lee. Category 3: a. Final approval of the completed manuscript: A. V. Jogimahanti, A. Kini, L. Irwin, and A. G. Lee. 6. 7. 8. 9. 10. 11. 12. 13. REFERENCES 1. Ness T, Bley TA, Schmidt WA, Lamprecht P. The diagnosis and treatment of giant cell arteritis. Deutsches Arzteblatt Int. 2013;110:376–386. 2. Stanbury RM, Graham EM. Systemic corticosteroid therapy— side effects and their management. Br J Ophthalmol. 1998;82:704–708. 3. Ponte C, Rodrigues AF, O’Neill L, Luqmani RA. Giant cell arteritis: current treatment and management. World J Clin Cases. 2015;3:484–494. 4. Samson M, Audia S, Janikashvili N, CiudadM, TradM, FraszczakJ, OrnettiP, MaillefertJF, MiossecP, BonnotteB, et al. Brief report: inhibition of interleukin-6 function corrects Th17/ Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64:2499–2503. 5. Stone J, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid M, Dasgupta B, Rech J, Salvarani Jogimahanti et al: J Neuro-Ophthalmol 2021; 41: 342-350 14. 15. 16. 17. C, Schett G. Trial of tocilizumab in giant cell arteritis. New Engl J Med. 2017;377:317–328. Moghadam-Kia S, Werth VP. Prevention and treatment of systemic glucocorticoid side effects. Int J Dermatol. 2010;49:239–248. Hsu H, Nallamothu SV. Hip Osteonecrosis StatPearls [Internet]. 2020. Available at: https://www.ncbi.nlm.nih.gov/books/ NBK499954/. Accessed June 8, 2020. Adriance SM, Murphy CV. Prophylaxis and treatment of venous thromboembolism in the critically ill. Int J Crit Illn Inj Sci. 2013;3:143–151. Greenberg J, Palmer J, Li Y, Herrera V, Tsang Y, Liao M. Healthcare resource use and direct costs in patients with ankylosing spondylitis and psoriatic arthritis in a large US cohort. J Rheumatol. 2015;43:88–96. Buchanan BK, Varacallo M. Sacroiliitis StatPearls [Internet]. 2020. Available at: https://www.ncbi.nlm.nih.gov/books/ NBK448141/. Accessed June 8, 2020. GoodRx. The Staggering Cost of Controlled and Uncontrolled Diabetes. 2020. Available at: https://www.goodrx.com/ diabetes/annual-cost-of-managing-diabetes-and-treatinguncontrolled-diabetes. Accessed June 8, 2020. Knauert M, Naik S, Gillespie MB, Kryger M. Clinical consequences and economic costs of untreated obstructive sleep apnea syndrome. World J Otorhinolaryngol Head Neck Surg. 2015;1:17–27. Simon G, Ormel J, VonKorff M, Barlow W. Health care costs associated with depressive and anxiety disorders in primary care. Am J Psychiatry. 1995;152:352–357. Blume SW, Curtis JR. Medical costs of osteoporosis in the elderly medicare population. Osteoporos Int. 2011;22:1835– 1844. Fakheri R. Corticosteroids and Prophylaxis. What Complications Should You Try to Prevent in Patients on Chronic Corticosteroids? Clinical Correlations. 2013. Available at: https://www.clinicalcorrelations.org/2013/10/ 30/corticosteroids-and-prophylaxis-what-complicationsshould-you-try-to-prevent-in-patients-on-chroniccorticosteroids/. Cryer BL, Wilcox CM, Henk HJ, Zlateva G, Chen L, Zarotsky V. The economics of upper gastrointestinal bleeding in a US managed-care setting: a retrospective, claims-based analysis. J Med Econ. 2010;13:70–77. Tsai AG, Williamson DF, Glick HA. Direct medical cost of overweight and obesity in the USA: a quantitative systematic review. Obes Rev. 2011;12:50–61. 349 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 18. Nuckols TK, Aledort JE, Adams J, Lai J, Go MH, Keesey J, McGlynn E. Cost implications of improving blood pressure management among U.S. adults. Health Serv Res. 2010;46:1124–1157. 19. Ektare V, Khachatryan A, Xue M, Dunne M, Johnson K, Stephens J. Assessing the economic value of avoiding hospital admissions by shifting the management of gram + acute bacterial skin and skin-structure infections to an outpatient care setting. J Med Econ. 2015;18:1092–1101. 20. Thevro. How Much Does Physical Therapy Cost? 2020. Available at: https://thervo.com/costs/physical-therapy-cost. Accessed June 8, 2020. 21. Lee PP, Walt JG,, Doyle JJ. A multicenter, retrospective pilot study of resource use and costs associated with severity of disease in glaucoma. Arch Ophthalmol. 2006;124:12–19. 22. SooHoo N, Vyas S, Manunga J, Sharif H, Kominski G, Lieberman J. Cost-effectiveness analysis of core decompression. J Arthroplasty. 2008;21:670–681. 350 23. GoodRx. Warfarin. 2020. Available at: https://www.goodrx. com/warfarin?dosage=5mg&form=tablet&label_ override=warfarin&quantity=90. Accessed June 8, 2020. 24. GoodRx. Eliquis. 2020. Available at: https://www.goodrx. com/eliquis. Accessed June 8, 2020. 25. Grosse SD, Nelson RE, Nyarko KA, Richardson LC, Raskob GE. The economic burden of incident venous thromboembolism in the: a review of estimated attributable healthcare costs. Thromb Res. 2016;137:3–10. 26. The Checkup. Insulin Prices: How Much Does Insulin Cost? 2020. Available at: https://www.singlecare.com/blog/insulinprices/. Accessed June 8, 2020. 27. Epocrates. Actemra. 2020. Available at: https://online. epocrates.com/u/1065615/Actemra/Pricing+Manufacturer. Accessed June 8, 2020. 28. GoodRx. Tocilizumab. 2020. Available at: https://www.goodrx. com/actemra?dosage=162mg-0.9ml&form=syringe&label_ override=Actemra&quantity=1. Accessed June 8, 2020. Jogimahanti et al: J Neuro-Ophthalmol 2021; 41: 342-350 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.