The Role of Tocilizumab in Glucocorticoid Resistant Giant Cell Arteritis: A Case Series and Literature Review

Glucocorticoid-resistant giant cell arteritis (GCA) describes a subgroup of patients whose visual acuity further declines despite immediate administration of highdose intravenous glucocorticoids. Tocilizumab, a recombinant humanized anti-interleukin-6 receptor monoclonal antibody may be used as "rescue" therapy in these cases but requires more research.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD The Role of Tocilizumab in Glucocorticoid Resistant Giant Cell Arteritis: A Case Series and Literature Review Brandon Stretton, MBBS, Yiran Tan, MBBS, M.Med (ClinEpi), Mark Hassall, MBBS, BMedSci [Hons], D.Phil, Sumu Simon, MBBS, MS G Background: Glucocorticoid-resistant giant cell arteritis (GCA) describes a subgroup of patients whose visual acuity further declines despite immediate administration of highdose intravenous glucocorticoids. Tocilizumab, a recombinant humanized anti-interleukin-6 receptor monoclonal antibody may be used as “rescue” therapy in these cases but requires more research. Methods: We present a literature review on tocilizumab as rescue therapy and a retrospective case series of 5 consecutive glucocorticoid (GC) resistant, temporal artery biopsy (TAB) negative patients. Results: The use of tocilizumab as rescue therapy for GCresistant GCA is limited to 3 case reports. Two cases saw visual acuity improvement in the newly affected contralateral eye after 8 mg/kg of intravenous tocilizumab (from 6/60 to 6/ 15 in one case and hand motion to 6/6 in another). The third described stabilization and prevention of further best-corrected visual acuity (BCVA) decline. All 5 of our patients presented with acute monocular vision loss. BCVA ranged from 6/12 to light perception (LP). All patients were promptly commenced on 1 g intravenous methylprednisolone daily. Weekly 162 mg of subcutaneous tocilizumab was commenced once contralateral eye involvement was noted. Tocilizumab resulted in bilateral BCVA gains in 2 cases, recovery of the contralateral eye in one, and no effect in the remaining 2 cases. BCVA recovery was no light perception to 6/6 after 6 weeks of tocilizumab. Tocilizumab had no effect in cases with severe vision loss and high C-reactive protein on presentation. Conclusions: We agree with existing hypothesis that tocilizumab likely prevents a “pending” central retinal artery occlusion by maintaining retinal vasculature perfusion. Our case series suggests that there is a role for tocilizumab as “rescue” therapy for GC-resistant GCA, where vision loss would otherwise be imminent. iant cell arteritis (GCA) is the most common form of primary systemic vasculitis (1). The disease is characterized by chronic, granulomatous inflammation that affects the aorta and its branches. Risk factors for GCA include advanced age, smoking, female gender, and Caucasian race (2). The most serious ocular complication of GCA is acute vision loss secondary to anterior ischemic optic neuropathy (AION), which can affect up to 20% of patients. Mainstay treatment of GCA involves the use of high-dose glucocorticoids (GC). Deterioration in spite of steroids generally occurs within 5 days of treatment and although corticosteroids may take several days to demonstrate disease modifying activity within the arterial wall, the fact that visual deterioration despite corticosteroid treatment occurs in a minority (up to w30%) and generally results in profound visual loss to some or nil light perception, its commonly referred to as GC-resistant GCA (3). Therefore, GC-resistant GCA describes a subgroup of the disease where patients progress to partial or complete vision loss despite immediate administration of high-dose intravenous GC (3). There is emerging evidence to suggest that tocilizumab, a recombinant humanized anti-interleukin (IL)-6 receptor monoclonal antibody, is effective in treating both newonset and relapsing GCA. The role of tocilizumab as “rescue” therapy in sight-threatening GCA remains controversial. Herein, we describe 5 cases of GC-resistant GCA treated with tocilizumab and present a review of the current literature. Journal of Neuro-Ophthalmology 2023;43:91–95 doi: 10.1097/WNO.0000000000001645 © 2022 by North American Neuro-Ophthalmology Society METHODS Adelaide Medical School (BS), Adelaide, South Australia, Australia; and Department of Ophthalmology (YT, MH, SS), Royal Adelaide Hospital, Adelaide, South Australia, Australia. The authors report no conflicts of interest. Address correspondence to Sumu Simon, MBBS, MS, Department of Ophthalmology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia; E-mail: [e-mail] Stretton et al: J Neuro-Ophthalmol 2023; 43: 91-95 We conducted a retrospective case series of 5 consecutive patients with temporal artery biopsy–proven GC-resistant GCA treated with tocilizumab at the Royal Adelaide Hospital, Australia between June 1, 2019, to March 1, 2021. GCresistant GCA was defined by the clinical progression of optic nerve compromise or persistently elevated inflammatory markers despite intravenous (IV) glucocorticoid therapy in temporal artery biopsy (TAB)–positive patients. 91 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution RESULTS Case Reports Case 1 An 80-year-old man presented with sudden-onset vision loss in the left eye on the background of a 2-day history of ipsilateral amaurosis fugax. On examination, Snellen bestcorrected visual acuity (BCVA) was 6/18 in the right eye (RE) and no light perception (NPL) in the left eye (LE). A relative afferent pupillary defect (RAPD) was present in the LE. Fundus examination showed left pallid disc swelling with cilioretinal artery occlusion. Initial erythrocyte sedimentation rate (ESR) was 59 mm/hour, and C-reactive protein (CRP) was 13.2 mg/dL. Diagnosis of GCA was suspected and later confirmed with a TAB. The patient was admitted and treated with 1 g of intravenous methylprednisolone (IVMP) daily for 3 days. VA remained stable initially on treatment but deteriorated to counting fingers (CF) in the contralateral eye following the completion of 3 days of IVMP. Examination confirmed new pallid disc swelling and cotton wool spots in the RE (Fig. 1). In view of imminent vision loss in both eyes, we extended the duration of IVMP to 5 days and trialed tocilizumab as “rescue” therapy. The patient received 162 mg of subcutaneous (SC) tocilizumab after 3 doses of IVMP and did not experience further deterioration in VA afterward. He was discharged on weekly SC tocilizumab injections in combination with a tapering course of GC. Remarkably, at 6 weeks of follow-up, BCVA had improved to 6/6 in the RE and CF in the LE. Examination showed the resolution of disc pallor and cotton wool spots in the RE but persistent pallid disc swelling in the LE. VA and ophthalmic examination findings remained stable at 6-month follow-up. His baseline RE visual field (VF) from before contralateral spread demonstrated similar results to the VF conducted at the 6month follow-up. Case 2 An 85-year-old woman with a medical history significant for bilateral dry age-related macular degeneration, atrial fibrillation, and hypertension presented with left monocular vision loss. This is on a background of 2-week history of intermittent visual disturbance in the LE accompanied by malaise, jaw claudication, headaches, scalp tenderness, and subjective fevers. On examination, BCVA was 6/9 in the RE and 6/12 in the LE. There was no RAPD. Funduscopy revealed bilateral pallid disc swelling and cilioretinal artery occlusions (Fig. 2). Inflammatory markers were elevated with an ESR of 120 mm/hour and a CRP of 75.6 mg/dL. GCA was suspected and later confirmed with a TAB. The patient was promptly treated with 1 g IVMP but experienced a bilateral decline in BCVA to 6/12 in the RE 92 FIG. 1. Retinal photograph showing new pallid disc swelling and cotton wool spots despite IVMP and 6/60 in the LE on day 3 of treatment. IVMP course was prolonged to 5 days, and we commenced tocilizumab “rescue” therapy to good effect. VA improved to 6/9 in the RE and 6/15 in the LE within 24 hours following tocilizumab treatment and continued to improve throughout admission. The patient was discharged on tapering oral GC in combination with weekly tocilizumab injection. At 1-month follow-up, BCVA was 6/9 in the RE and 6/12 in the LE; however, visual fields were not repeated. Case 3 A 73-year-old man with no significant medical history presented with acute monocular vision loss over 6 hours. He also reported 6 weeks of headache, scalp tenderness, jaw claudication, and generalized myalgia. Initial ophthalmic examination revealed BCVA of LP in the RE and 6/7.5 in the LE. A RAPD and mild optic disc edema were noted in the RE. Inflammatory markers were elevated with an ESR of 94 mm/hr and a CRP of 128.5 mg/dL. GCA was suspected and later confirmed with a TAB. The patient reported rapid resolution of systemic symptoms and downtrending inflammatory makers following initiation of IVMP. However, after the second dose of IVMP, BCVA had decreased to 6/12 in the contralateral eye with a new altitudinal inferior field loss on examination. IVMP course was extended to 5 days in the setting of disease progression. Following the third dose of IVMP, examination showed pallid disc swelling affecting both eyes with a central retinal artery occlusion (CRAO) in the RE and a cilioretinal artery occlusion in the LE (Fig. 3). In view of rapid progression to bilateral vision loss, we initiated urgent SC tocilizumab treatment. Unfortunately, the patient progressed to hand movements (HM) vision in both eyes with persistently elevated inflammatory markers after 5 days of IVMP. At 1-month follow-up, inflammatory markers had normalized, but VA had deteriorated further to NPL in both eyes despite ongoing treatment consisting Stretton et al: J Neuro-Ophthalmol 2023; 43: 91-95 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Bilateral pallid disc swelling and cilioretinal artery occlusions found on presentation of 1 mg/kg of oral GC and weekly tocilizumab injections. Unfortunately, no visual fields were conducted in this case. Case 4 A 68-year-old man with a medical history significant for Type-2 diabetes mellitus presented with sudden-onset monocular vision loss in the RE. This is on the background of an ipsilateral, prodromal, 10-minute, transient visual obscuration the night before. The patient also reported systemic symptoms of neck pain, temporal headache, and tenderness for 2 weeks before presentation. Initial BCVA was HM in the RE and 6/6 in the LE. Examination showed a RAPD in the RE, associated with dyschromatopsia and CRAO. Optical coherence tomography (OCT) and fluorescein angiogram (FFA) demonstrated severely decreased arterial filing and nondistinct retinal layers in both eyes. CRP was 29.8, ESR was 59, and platelets was 362 on presentation. GCA was suspected and later confirmed with a TAB. The patient was promptly treated with 1 g IVMP daily for 3 days. After 2 doses of IVMP, BCVA had declined to LP in the RE and CF in the LE. Examination showed a development of a new CRAO in the LE despite appropriate medical therapy. In view of contralateral GCA involvement and refractory inflammatory markers, we prolonged IVMP course to 5 days and initiated salvage tocilizumab treatment. SC tocilizumab was delivered following 3 doses of IVMP. BCVA improved to HM in RE and 6/12 in LE within 48 hours of tocilizumab treatment. At 4-month follow-up, BCVA had improved further to 6/9 in the LE and remained stable at HM in the RE. Additionally, her visual field index had improved by 9%. Case 5 An 83-year-old woman with metabolic syndrome, hypothyroidism, mild cognitive impairment, and left eye amblyopia, presented to emergency with blurred vision in her RE on waking 2 days ago, intermittent bitemporal headaches, and scalp tenderness. This is on the background of 3 months of jaw pain, which was investigated by GP with CT (reportedly normal) and left-sided myalgia. BCVA on presentation was HM in RE and 6/7.5 in LE with a RAPD and 0/15 on Ishihara in her RE. Her temporal, radial, and tibial pulses palpable bilaterally. Funduscopic examination revealed a chalky pale swollen disc (AAION) with superior BRAO in the RE and normal in the LE. CRP was 216, ESR .120, platelets 526. She was admitted under general medicine due to complicating cognition difficulties and commenced on 50mg prednisone by mouth, quickly resolving her temporal headache and scalp tenderness. The following day a temporal artery biopsy as performed (later positive for GCA) and commenced on daily 1 g IVMP. After 4 days of corticosteroids (1 oral, 3 IVMP), she awoke to a visual acuity reduction in her left eye. On review, her RVA = LP, LVA = HM, and RNFL = 219 and 242 in her right and left eyes, respectively, increasing from 102 to 163 the day prior. Her left eye now demonstrated an AAION. She was subsequently commenced on 162 mg of subcutaneous tocilizumab. Unfortunately, despite 5 days of IVMP and tocilizumab initiation, on review 2 weeks post discharge, her BCVA had not improved, with NPL and CF in right and left eyes, respectively, with no VF performed on followup. FIG. 3. Bilateral pallid disc swelling with right eye CRAO and left eye cilioretinal artery occlusion despite IVMP Stretton et al: J Neuro-Ophthalmol 2023; 43: 91-95 93 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution CONCLUSIONS High-dose glucocorticoid (GC) remains the gold-standard treatment of GCA. Symptomatic improvement and normalization of biochemical targets are typically observed within 4 weeks of initiating GC therapy, at which stage tapering is recommended (4,5). Long-term management of GCA is complicated by high rates of relapse in up to 62% of cases when GC is tapered (6). Tocilizumab is a recombinant humanized anti–IL-6 receptor monoclonal antibody, which has demonstrated efficacy in achieving sustained remission of GCA when used in combination with a prednisolone taper regimen. Tocilizumab inhibits IL-6 signal transduction and works on the basis that elevated serum IL-6 increases the concentration of acute phase reactants such as CRP, which correlate with increased disease severity. Existing evidence supports the use of tocilizumab in GCA as an augmenting steroidsparing agent. Notably, the GiACTA trial demonstrated remission rates of up to 56% in patients receiving tocilizumab and GC combination therapy, compared with 18% in patients treated with GC monotherapy (7). There is limited evidence on the early use of immunomodulatory therapy to improve visual outcomes when corticosteroid monotherapy has failed. The use of tocilizumab as “rescue” therapy for GCresistant GCA is limited to case reports. A meta-analysis was not performed due to the significant heterogenicity between study groups and the variations in subgroups of GCA. Our literature review identified 3 cases where the acute use of tocilizumab, together with high-dose GC therapy, rescued vision. The cases involved TAB-proven recalcitrant GCA with the progression of visual symptoms despite appropriate and timely GC intervention. Kherani et al described a case of GCA where the patient’s contralateral eye developed an arteritic AION despite being on prednisolone with consequent VA decline from 6/15 to 6/60. With IV 8 mg/kg 4 weekly tocilizumab, BCVA had improved from 6/60 to 6/15 at a 4-month follow-up (8). Svasti-Salee et al reported a case of biopsy-proven GCA complicated by decline in VA from 6/ 9 to HM with an ischemic optic neuropathy and central retinal artery occlusion in the RE despite treatment, 3 IVMP doses and 13 days of oral prednisolone. IV tocilizumab (8 mg/kg) was administered within 48 hours of vision loss and resulted in improvement of BCVA to 6/6 on review 5 days later (9). The third case by Vionnet et al described progression of involvement into the contralateral eye despite 5 days of IVMP but IV tocilizumab stabilized and prevented further bilateral BCVA decline (10). It is important to note that these case reports did not correlate BCVA changes with pre and post visual fields. Our study is the largest consecutive case series of GCresistant GCA with severe ocular complications treated with tocilizumab. Three of the 5 patients (60%) in our group experienced improvement in vision in at least one eye 94 following initiation of tocilizumab therapy for GC-resistant GCA. It is possible that the observed visual recovery may represent a delayed effect of GC treatment. However, the aforementioned reports (8–10) and our case series describing rapid improvement of GCA symptoms following tocilizumab alongside how steroids only stabilize, not acutely improve, visual acuity and prior consensus concluding steroids uncommonly improve VA support a cause–effect relationship (3). The exact mechanism of how tocilizumab leads to recovery of vision is not known. We agree with existing hypothesis that tocilizumab likely prevents a “pending” central retinal artery occlusion by maintaining sufficient retinal vascular perfusion. Two patients in our case series unfortunately experienced loss of vision in both eyes despite appropriate GC and tocilizumab intervention. These patients had severe vision loss at presentation and the highest CRP in our case series. These cases are consistent with the natural history of GCA, where a small group of patients with severe and recalcitrant disease will still progress to vision loss irrespective of treatment. The case reports from our literature review all utilized IV tocilizumab while our case reports used subcutaneous tocilizumab. Intravenous tocilizumab does have a shorter time to maximum serum concentration and so theoretically should be the modality of choice for the acute visual salvage therapy (11). Findings from our study however suggest that subcutaneous delivery can also achieve good efficacy in the acute setting if IV is unavailable and is consistent with prior demonstrations of weekly subcutaneous tocilizumab’s noninferiority to 4 weekly intravenous tocilizumab in rheumatoid arthritis (12). Danesh-Meyer et al (3) has demonstrated that visual gains of $2 lines on Snellen chart can be expected in 15% of eyes managed with IVMP and prednisone monotherapy; however, the mean time of this documented recovery is one month and does not correlate with visual field improvements. This suggests that the visual improvement may be a function of learnt eccentric fixation as opposed to real visual improvement. This lack of pre and post tocilizumab visual fields was a limitation in our study. We found it difficult in this emergency setting to acquire repeat visual field testing. However, we did manage to correlate objective visual field finding with clinically significant BCVA gain of up to 6 lines in Case 4 and return to baseline visual field in Case 1. Our case series serves to demonstrate that there is a role of the use of tocilizumab as “rescue” therapy for GCresistant GCA, where severe vision loss would otherwise be imminent. Our case series is limited by a small sample size, lack of randomization, and visual field testing; therefore, there is insufficient evidence to determine what proportion of visual recovery is due to tocilizumab alone. Our clinical observation in this study however is that patients who report acute worsening of visual acuity and who would otherwise progress from functional individuals to legally blind, tocilizumab may rescue these patients and therefore feel our case series worth highlighting to promote further Stretton et al: J Neuro-Ophthalmol 2023; 43: 91-95 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution research. This case series adds to the literature and promotes the early use of tocilizumab in treatment recalcitrant GCA. Further research should endeavor to assess visual fields, take serial fundoscopy photographs, consider randomization of tocilizumab use, and account for eccentric fixation in order to affirm our current suspicions of tocilizumab resulting in true visual recovery. STATEMENT OF AUTHORSHIP Conception and design: B. Stretton, S. Simon; acquisition of data: B. Stretton, Y. Tan; analysis and interpretation of data: B.Stretton, Y. Tan, M. Hassall, S. Simon; drafting the manuscript: B. Stretton, Y. Tan, M. Hassall, S. Simon; revising the manuscript for intellectual content: B. Stretton, Y. Tan, M. Hassall, S. Simon; final approval of the completed manuscript: B. Stretton, Y. Tan, M. Hassall, S. Simon. 5. 6. 7. 8. 9. REFERENCES 1. Crowson CS, Matteson EL, Myasoedova E, Michet CJ, Ernste FC, Warrington KJ, Davis JM, Hunder GG, Therneau TM, Gabriel SE. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 2011;63:633–639. 2. David Carmona F, Mackie SL, Martin J-E, Taylor JC, Vaglio A, et al. A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility. Am J Hum Genet. 2015;96:565–580. 3. Danesh-Meyer H, Savino PJ, Gamble GG. Poor prognosis of visual outcome after visual loss from giant cell arteritis. Ophthalmology. 2005;112:1098–1103. 4. Dasgupta B, Borg FA, Hassan N, Alexander L, Barraclough K, Bourke B, Fulcher J, Hollywood J, Hutchings A, James P, Kyle V, Nott J, Power M, Samanta A. BSR and BHPR guidelines for the Stretton et al: J Neuro-Ophthalmol 2023; 43: 91-95 10. 11. 12. management of giant cell arteritis. Rheumatology (Oxford). 2010;49:1594–1597. Mukhtyar C, Guillevin L, Cid MC, Dasgupta B, De Groot K, Gross W, Hauser T, Hellmich B, Jayne D, Kallenberg CG, Merkel PA, Raspe H, Salvarani C, Scott DG, Stegeman C, Watts R, Westman K, Witter J, Yazici H, Luqmani R. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2009;68:318–323. Dejaco C, Brouwer E, Mason JC, Buttgereit F, Matteson EL, Dasgupta B. Giant cell arteritis and polymyalgia rheumatica: current challenges and opportunities. Nat Rev Rheumatol. 2017;13:578–592. Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, Salvarani C, Schett G, Schulze-Koops H, Spiera R, Unizony SH, Collinson N. Trial of tocilizumab in giant-cell arteritis. N Engl J Med. 2017;377:317–328. Kherani I, Chin C, Kherani RB, Kherani F. Refractory giant cell arteritis on prednisone and tocilizumab: improvement with subsequent tuberculosis reactivation. Can J Ophthalmol. 2019;54:e192–e194. Svasti-Salee CR, Mollan SP, Morgan AW, Quick V. Rapid visual recovery following intravenous tocilizumab in glucocorticoid resistant refractory giant cell arteritis. BMJ Case Rep. 2019;12:e229236. Vionnet J, Buss G, Mayer C, Sokolov AA, Borruat FX, Spertini F. Tocilizumab for giant cell arteritis with corticosteroid-resistant progressive anterior ischemic optic neuropathy. Joint Bone Spine. 2017;84:615–619. Burmester GR, Rubbert-Roth A, Cantagrel A, Hall S, Leszczynski P, Feldman D, Rangaraj MJ, Roane G, Ludivico C, Bao M, Rowell L, Davies C, Mysler EF. Efficacy and safety of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at week 97 (SUMMACTA). Ann Rheum Dis. 2016;75:68–74. Abdallah H, Hsu JC, Lu P, Fettner S, Zhang X, Douglass W, Bao M, Rowell L, Burmester GR, Kivitz A. Pharmacokinetic and pharmacodynamic analysis of subcutaneous tocilizumab in patients with rheumatoid arthritis from 2 randomized, controlled trials: SUMMACTA and BREVACTA. J Clin Pharmacol. 2017;57:459–468. 95 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.