Alpa, Mirella

Cecchi, Irene

Naretto, Carla

Roccatello, Dario

Rossi, Daniela

Sciascia, Savino

English

Institutional Research Information System University of Turin

S-125Clinical and Experimental Rheumatology 2021CMID-Nephrology and Dialysis Unit (ERK-net Member) Center of Research of Nephrology, Rheumatology, and Rare Diseases, Interregional Coordinating Centre of the Network of Rare Diseases, G. Bosco Hospital and University of Turin, Italy.Daniela Rossi, MDIrene Cecchi, MDSavino Sciascia, MD, PhDCarla Naretto, MDMirella Alpa, MDDario Roccatello, MDPlease address correspondence to:Dario Roccatello,CMID, Centro di Coordinamento Rete Interregionale Malattie Rare, Ospedale G. Bosco,P.zza del Donatore di Sangue 3,10154 Torino, Italy.E-mail: dario.roccatello@unito.itReceived on August 23, 2020; accepted in revised form on November 9, 2020.Clin Exp Rheumatol 2021; 39 (Suppl. 129): S125-S128.© Copyright CliniCal and ExpErimEntal rhEumatology 2021.Key words: tocilizumab, abatacept, giant cell arteritisCompeting interests: none declared.ABSTRACTObjective. The present study aimed at evaluating the efficacy of abatacept (ABA) compared to tocilizumab (TCZ), assumed as a gold standard biologic treatment in the management of pa-tients with giant cell arteritis (GCA).Methods. Thirty-three biospy-proven GCA consecutive patients were pro-spectively collected. Odd patients (from 1 to 33) were assigned to TCZ, given ei-ther intravenously (IV 8 mg/kg/month), #8 cases, or subcutaneously (SC 162 mg/week) #9, based on patient’s prefer-ence. ABA was administered subcuta-neously at the dose of 125 mg/week in 16 even patients (from 2 to 32). Biologi-cal therapies were prescribed in addi-tion to oral prednisone. Results. A single biologic agent was administered in 28 patients out of 33 (85%) (8 TCZ IV, 9 TCZ SC and 16 ABA). Five patients (15%) needed a therapeutic switch (one patient from TCZ to ABA, and 4 patients from ABA to TCZ). Among the TCZ IV group, all patients experienced a response (57% complete response and 43% partial re-sponse). Among the TCZ SC group, 7 ex-perienced a clinical response (complete in 67% and partial in 16%). Among the ABA group, 10 patients (62%) achieved either complete (5 patients) or partial (5) response, respectively. After 12 months of therapy, 100% of patients in TCZ groups, both IV and SC, and 7 (43%) of ABA group were receiving doses of oral prednisone not exceeding 7.5 mg/day as maintenance. Conclusion. Both TCZ and ABA can be proposed as an effective therapeutic option in GCA with relevant inflamma-tory symptoms. ABA can be considered in the patient with absolute or relative or contraindications to TCZ.IntroductionGiant cell arteritis (GCA) belongs to a group of immune-mediated diseases af-fecting vessels of large size. It is con-sidered a rare disease, but among the primary systemic vasculitis is the most prevalent (1, 2), and is characterised by high morbidity and mortality. In 1932, Horton et al. described the picture of a patient suffering from blindness, necro-sis of the tongue, and mandibular clau-dication that they referred to a new clin-ical entity (3), the characteristic vessel wall infiltration by T lymphocytes and macrophages, with giant cells. It is his-tologically characterised by intimal hy-perplasia, granulomatous lesions, and the disruption of of the elastic fibres (4). GCA mainly affects people over 50 years. The prevalence is greater in Scandinavia and North American than in South Europe, and black people are only occasionally affected. Geographi-cal differences and occasional fam-ily clustering suggest a role for either environmental or infectious or genetic factors (2). A genetic predisposition in subjects with the HLA-DRB1*04 allele is recognised (5).The histologic changes of GCA are especially relevant in temporal artery, a traditional milestone of diagnosis. However, there is a marked heterogene-ity in histopathology findings in biopsy samples from different patients. Only half of the positive biopsies show mult-inucleated giant cells associated with granulomatous infiltrates, including CD41 T-cells and macrophages detected at the intima-media junction. In the oth-er cases, the histopatology findings are characterised by lympho-mononuclear-infiltrates with panarteritis features, oc-casionally including granulocytes in the absencee of giant cells. A minority of the cases present with periadventitial vessels and/or vasa vasorum inflamma-tion (6). Of special clinical importance, arterial wall thickening with partial or complete occlusion of the lumen (with ischaemic sequaele) can lead to anterior ischaemic optic neuropathy (7).An agent-to-agent real life comparison study of tocilizumab versus abatacept in giant cell arteritisD. Rossi, I. Cecchi, S. Sciascia, C. Naretto, M. Alpa, D. RoccatelloS-126 Clinical and Experimental Rheumatology 2021Tocilizumab versus abatacept in GCA / D. Rossi et al.Therapy has rapidly progressed in these years, achieving prolonged survival and, occasionally, definitive healings. Therapy of CGA has been centered on the use of glucocorticoids (GCs) (8) with immunosuppressive agents, e.g. methotrexate (MTX), considered as GCs-sparing therapy or in cases of refractory/resistant cases. Neverthe-less, results in terms of efficacy have not been well established (8). While numerous biologic agents have been proposed over the last decades to con-trol GCA, the recombinant humanised anti-IL-6 receptor antibody, tocilizum-ab (TCZ), is the sole avaialbe biologic agent currently approved for this indi-cation. It proved to be effective in im-proving clinical manifestations, having a GCs-sparing effect and reducing the rate of relapses both in clinical trials and in real-life studies (9-11). Some data suggest a possible role for abatacept (ABA), a fusion protein composed of the Fc region of the im-munoglobulin IgG1 and the extracel-lular domain of CTLA-4. Some data showed that inappropriate activation, development, and overexpression of antigen-presenting adventitial dendrit-ic cells (11) are involved in the early stages of the pathogenis of GCA. These cells create an ideal environment for microbial pathogens via the action of toll-like receptors (TLRs). Due to their vessel-specifcity, TLR profiles might justify the typical vessel involment charaterising GCA (12).In order to activate T cell, the antigen-presenting cell must present two sig-nals: the MHC complexed with the antigen, and the co-signaling of CD80 or CD86 molecule. Binding the CD80 and CD86 molecule, ABA inihibits the second signal. In randomised controlled trials (RCT), ABA proved to be signifi-cantly more effective compared to pla-cebo for the management of GCA. In the intent-to-treat analysis of the 41 pa-tients randomised to receive ABA (20 patients) or placebo (20 patients) the relapse-free survival at 12 months was higher for ABA than placebo, and the median duration of remission signifi-cantly prolonged (13).The present study aimed at evaluating the efficacy of ABA compared to TCZ, assumed as a gold standard biologic treatment.MethodsData from 33 GCA consecutive patients recruited at the San Giovanni Bosco Hub Hospital in Turin (north-west Italy) between 2016 and 2018 were prospectively collected. Diagnosis was based on clinical and histological ground, each patient having a temporal artery biopsy-proven diagnosis (Figs. Fig. 1. Simplifying histological findings in temporal artery biopsy from one patient involved in the study. A: vessel lumen; B: lymphocyte and monocyte infiltrates; C: granulomatous lesion; D: intimal hyperplasia.Fig. 2. Magnification of the granulomatous lesion. A: giant cell; B: eosinophils; C: lymphocyte and monocyte infiltration.S-127Clinical and Experimental Rheumatology 2021Tocilizumab versus abatacept in GCA / D. Rossi et al.1 and 2). Odd patients (from 1 to 33) were assigned to TCZ, given either intravenously (IV) (8 mg/kg/month), #8 cases, or subcutaneously (SC) (162 mg/week), #9, based on the patient’s preference. ABA was administered SC at the dose of 125 mg/week in 16 even patients (from 2 to 32). Biological therapies were prescribed in addition to oral prednisone 50 mg/day for 2 weeks (tapered to 20 mg/day by the end of the 3rd month and then slowly tapered un-til discontinuation within 6 months). In patients who were receiving mycophe-nolate mofetil (MMF) or MTX (Table I), biological agents were started after conventional synthetic disease-modify-ing antirheumatic drugs (csDMARDs) discontinuation.Table I summarises the patients’ main characteristics.Complete response to treatment after 12 months of therapy was defined, based on clinical (disappearance of symp-toms), imaging (ultrasound reversal of abnormalities) and serological [nor-malisation of erythrocyte sedimenta-tion rate (ESR) and C reactive protein (CRP)] ground. Partial response was defined as a substantial amelioration of clinical manifestations and serological parameters with persistent ultrasound abnormalities at one-year.Efficacy and safety outcomes were as-sessed every three months or in case of clinical changes.Eleven out of 16 cases treated wit ABA could be examined for the presence of CD80 staining. Statistical analysisFor the comparison of variables at baseline and follow-up, Student’s t-test was used for normally distributed parameters and the non-parametric Mann-Whitney test for non-normally distributed parameters. For these anal-yses, the SPSS (IBM Corporation, NY, USA) software was used. p<0.05 was considered statistically significant.ResultsThis prospective study included 33 GCA patients [mean age 74 (range 85-57), females 63%, mean follow-up from GCA diagnosis 44.4±33.5 months)].A single biologic agent was admin-istered in 28 patients out of 33 (85%) (8 TCZ IV, 9 TCZ SC, and 16 ABA). Five patients (15%) needed a thera-peutic switch (one patient from TCZ to ABA for referred general malaise the day after the drug administration, and 4 patients from ABA to TCZ for lack of efficacy).No difference was observed in terms of baseline disease symptoms, vessel in-volvement, sex, age, comorbidities when comparing the TCZ and ABA groups. In 17 patients, biological treatment (8 TCZ and 9 with ABA) was started be-cause of a disease relapse despite on-going therapy.Among the TCZ IV group, all patients experienced a response (57% complete response and 43% partial response). Among the TCZ SC group, 7 experi-enced a clinical response (complete in 67% and partial in 16%). Among the ABA group, 10 patients (62%) achieved either complete (5 patients) or partial (5 patients) response, respectively. After 12 months of therapy, 100% of patients in TCZ groups, both IV and SC, and 7 (43%) of ABA group were receiving doses of oral prednisone not exceeding 7.5 mg/day as maintenance (Table II). A significant reduction in in-flammatory parameters (CRP and ESR) Table I. Characteristics of GCA patients included in the study. Total number of patients (33) %Demographic characteristics  Female/male 21/12 Age (years) (mean, SD) 73.6 ± 8.7 Clinical characteristics at the onset of GCA  Fever (n) 12 36.4Fatigue (n) 18 54.5Headache (n) 28 84.8Scalp tenderness (n) 8 24.2Jaw claudication (n) 15 45.4Vision loss (n) 16 48.5Polymyalgia rheumatica (n) 11 33.3Diagnosis  Biopsy-proven 27/32 84.4Positron emission tomography positivity 12/29 41.4Eco-colour-Doppler positivity 30/31 97.0GC therapy  Previous methylprednisolone pulses (n) 7 21.2Oral prednisone (n) 33 100.0Dose of oral prednisone (mg/day) (mean, SD) 49.7 ± 15.1 Previous immunosuppressive therapies  Methotrexate (n) 11 33.3          mean dose (mg/week) (mean, SD) 15.6 ± 1.7 Mycophenolate (n) 11 33.3          mean dose (mg/day) (mean, SD) 2.2 ± 0.4 Table II. Dose of GCs at baseline, 6 months, and 12 months as well as the number of switches due to lack of efficacy. TCZ=17 ABA=16 pMean GCs dose at baseline 50 mg/day 50 mg/day NS  Mean GCs dose at 6 months 0 mg/day 2.5 mg/day NS  (min 0-max 10)N° of patients on PDN >7.5 mg/day 0 4 0.0445  Mean GCs dose at 12 months 0.8 mg/day 5.6 mg/day NS  (min 0-max 10)N° of patients on PDN >7.5 mg/day 0 9 0.0003  N° of switch for lack of efficacy 0 4 0.0445TCZ: tocilizumab; ABA: abatacept; GCs: glucocorticoids; PDN: prednisone.S-128 Clinical and Experimental Rheumatology 2021Tocilizumab versus abatacept in GCA / D. Rossi et al.was observed after 12 months of ther-apy with TCZ: TCZ IV group: mean baseline CRP (mg/dl) 3.9±2.3, mean CRP after 12 months of therapy 0.3±0.2 (p<0.01); mean baseline ESR (mm/h) 58.1± 25.6, mean ESR after 12 months 9.5±4.2 (p<0.01); TCZ SC group: mean baseline CRP 4.5±3.8, mean CRP af-ter 12 months 0.2±0.2 (p<0.01); mean baseline ESR 51.9±27, mean ESR after 12 months 6.5±6, p<0.01].With regard to ABA, mean baseline ESR and CRP were 57.8±35.8 and 3.8±3.1, respectively, and 8.7±7.1 and 0.3±0.2 at 12 months (p<0.01 for both parameters).Of the 11 cases treated with ABA that could be examined for CD80 staining, 10 were positive. Three of them showed complete remission, 5 had partial remis-sion and 2 were non-responders. The negative case had a complete response. One out of the 5 remaining cases who could not be analysed for CD80 stain-ing had a complete remission.When compared to standard GCs regi-men (8), in patients treated with TCZ, we estimated a median steroid-sparing effect of 30 mg daily in the first month and an overall steroid-sparing effect of 15 mg daily when assessed in 12 months.No significant difference in outcomes was observed when comparing relaps-ing patients with newly diagnosed CGA. No significant side effect related to biological administration was re-corded.DiscussionGCA is considered the most prevalent vasculitis in elderly people, especially in western countries. It is characterised by severe mortality and morbility, in-cluding permanent visual loss.The therapy for GCA has been cen-tered on GCs. While the use of GCs has been associated to an excellent rate of response, yet relapses are frequent when GCs are tapered and their pro-longed use is associated to metabolic and infective complications (14), pav-ing the way for the search of alternative options for the management of GCA. Among the conventional immunosup-pressant agents, MTX has been the most commonly reported, especially in cases of refractory GCA, albeit with only modest results.The positive results of RCTs showing the efficacy of TCZ in both newly di-agnosed and in relapsing cases of GCA (9-11) led to the approval of its use for the management of GCA. Results for RCTs were mirrored by those coming from real-life experience, further sup-porting the inclusion of TCZ in the therapeutic harmamentarium for the management of GCA, especially in re-fractory cases. ABA was proven to be more effective than placebo in treating GCA patients (13).This is the first study that has compared the effectiveness of these two biologic agents in treating GCA.In our experience, both TCZ and ABA (though at a lesser extent) showed sig-nificant sparing effects on steroid dose, and proved to limit the risk of disease re-exacerbation. Compared to ABA, TCZ showed to be more effective both in inducing a clinical response and sparing steroids.CD80 staining revealed to be almost in-variably positive in biopsies of tempo-ral artery. A positive staining cannot be used as a predictor of clinical response to ABA. A negative staining does not affect response to ABA. However, we acknowledge that our study is limited by the lack of randomi-sation and the relatively small sample size. Larger randomised trials are need-ed to address this topic in a definite way. Similarly, some degree of heterogeneity in previous treatment exists when refer-ring to the use of steroids. Both TCZ and ABA can be proposed as an effective therapeutic option in cases of GCA with relevant inflammatory symptoms. Although significant, in this study the effect of ABA seemed to be moderate and arose concerns about its position as a first- or second-line therapeutic ap-proach.While further studies are still needed for including ABA in the standard treatment of severe cases of GCA, a putative role can be envisaged in the patients with absolute or relative or contraindications to TCZ, such as those with diverticulitis, hepatopathies, and hypercolesterolaemia.References  1. HUNDER GG: Epidemiology of giant-cell arteriitis. Cleve Clin J Med 2002; 69 (Suppl. 2): SII79-82.  2. GONZALEZ-GAY MA, VAZQUEZ-RODRIGUEZ TR, LOPEZ-DIAZ MJ et al.: Epidemiology of giant cell arteriitis and polymyalgia rheu-matica. Arthritis Rheum 2009; 61: 1454-61.  3. HORTON BT MT, BROWN GE: An undescribed form of arteriitis of the temporal vessels. Proc Staff Meet Mayo Clin 1932; 7: 700.  4. BJÖRNSSON J: Histopathology of primary vasculitic disorders. In: HOFFMAN GS WC, (Ed.) Inflam Marcel Dekker; 2002: 255-65.  5. MACKIE SL, TAYLOR JC, HAROON-RASHID L et al.: Association of HLA-DRB1 amino acid residues with giant cell arteritis: genetic as-sociation study, meta-analysis and geo-epide-miological investigation. Arthritis Res Ther 2015; 17: 195.  6. DENG J, YOUNGE BR, OLSHEN RA, GORONZY JJ, WEYAND CM: Th17 and Th1 T-cell re-sponses in giant cell arteriitis. Circulation 2010; 121: 906-15.  7. YOUNGER D: Vasculitis and the nervous sys-tem, an issue of neurologic clinics. Elsevier, 2019.  8. SEO P, STONE JH: Large-vessel vasculitis. Arthritis Rheum 2004; 51: 128-39.  9. VILLIGER PM, ADLER S, KUCHEN S et al.: Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-con-trolled trial. Lancet 2016; 387: 1921-7.10. STONE JH, TUCKWELL K, DIMONACO S et al.: Trial of tocilizumab in giant-cell arteritis. 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An agent-to-agent real life comparison study of tocilizumab versus abatacept in giant cell arteritis

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An agent-to-agent real life comparison study of tocilizumab versus abatacept in giant cell arteritis

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