Four months of treatment with anakinra combined with glucocorticoids for giant cell arteritis: a multicenter, randomized, double-blind, placebo-controlled trial

doi:10.21203/rs.3.rs-5231536/v1

Background

Efficacy and tolerance of anakinra (ANK) in the treatment of giant cell arteritis (GCA) need to be assessed.

Methods

This phase 3 study (NCT02902731) was a prospective multicenter, randomized, double-blind, placebo-controlled trial conducted over a 52-week period. GCA patients were randomized 1:1. From inclusion to week 16 (W16), patients in the anakinra (ANK) group received a daily subcutaneous injection of 100 mg of anakinra, whereas patients in the other group received placebo (PBO). In both arms, glucocorticoid (GC) discontinuation was planned at week 52 (W52). The endpoints were the relapse rates at W16, W26, and W52 and the completion of GC tapering. Given the emergence of the SARS-CoV-2 pandemic, the study was stopped prematurely.

Results

Thirty patients with new GCA diagnoses from 5 centers were randomized as follows: 17 in the ANK group and 13 in the PBO group. During the first 16 weeks, the relapse rates were 12% (n = 2) and 23% (n = 3) in the ANK and PBO groups, respectively (p = 0.63). At week 26, 12 (40%) patients had relapsed: 8 (47%) in the ANK group and 4 (31%) in the PBO group (p = 0.47). At W52, the relapse rate (overall, 50%) did not differ between the ANK group (53%; 9/17 patients) and the PBO group (46%; 6/13 patients) (p = 1). Two patients in each group discontinued GCs (p = 0.87). Seven serious AEs were reported in five patients, including 4 in patients receiving ANK.

Conclusions

Although prematurely discontinued, this study does not support the use of 4 months of treatment with anakinra combined with GCs to reduce the risk of relapse or GC exposure.

Trial registration:

ClinicalTrials.gov NCT02902731

giant cell arteritis

anakinra

glucocorticoids

interleukin-1

quality of life

Giant cell arteritis (GCA) is the most common systemic vasculitis in patients over 50 years of age. The involvement of cranial vessels, especially branches of the external carotid, explains the cephalic symptoms or signs, especially headaches, scalp tenderness, or jaw claudication. Involvement of the ophthalmologic arteries can lead to bilateral blindness if left untreated [1]. Since the 1950s, glucocorticoids (GCs) have been the cornerstone of treatment and the best therapeutics for rapidly inducing disease remission [2–4]. However, during GC tapering, relapses are common and affect nearly half of patients [5]. Increasing the GC dose is often sufficient to control disease activity, but this leads to a subsequent increase in the duration of GC treatment. During the last two decades, many studies have indicated that important GC-related adverse events are observed in > 80% of patients, especially dependent on cumulative doses [6–8]. Therefore, many efforts have been made to identify new therapeutic options that may help better control disease activity and reduce GC exposure. The increase in knowledge about the GCA pathophysiology allows a better understanding of the central roles of inflammatory cytokines such as IL-1, IL-6, IL-17 or interferon-gamma, suggesting the possibility of targeted treatment [9]. Historically, methotrexate (MTX) has been used for a long time in GCA treatment, but studies have failed to demonstrate a sufficient GC-sparing effect, and recent studies have questioned the use of biologics to spare GCs [10]. Since the 2017 trial of tocilizumab demonstrated the possibility of reducing GC exposure by combining GCs with an anti-interleukin (IL)-6 receptor [11], the paradigm of GC-sparing strategies has become a priority in GCA treatment. In addition to Il-6, IL-1, especially IL-1beta, also appears to be a central inflammatory cytokine in the mechanism underlying GCA. High levels of IL-1beta were observed in the sera of GCA patients, as well as in the vessel wall of temporal artery biopsies (TAB). IL-1 secretion by monocytes/macrophages is an early occurrence in GCA pathogenesis and participates in the induction of the inflammatory cascade, leading to vascular damage [12, 13]. Thus, there is a rationale for specifically inhibiting this cytokine.

Anakinra (ANK) is an inhibitor of the IL-1 receptor (IL-1Ri) that is approved for the treatment of autoinflammatory diseases and Still’s disease. A previous small case series reported the efficacy of ANK in treating patients with relapsing GCA receiving reduced GC doses [14, 15]. Thus, in this study (NCT02902731), we investigated whether the administration of anakinra for 4 months in combination with GCs would reduce the relapse rate compared with standard-of-care treatment with GCs alone. Owing to the SARS-CoV-2 pandemic, the study was prematurely discontinued by the sponsor because of initial uncertainties about patient outcomes under both conditions. However, we analyzed the available data for the 30 included patients.

Study design and population

This phase 3 study (NCT02902731) was a multicenter, randomized, double-blind, placebo-controlled trial conducted over a 52-week period. Each included patient approved the study and provided written consent.

Patients with a new GCA diagnosis or with relapsing GCA lasting more than 6 months after discontinuation of any GCA-related treatment were eligible. To be included in this study, patients had to satisfy the three following criteria: 1) over 50 years of age; 2) demonstrated vasculitis on a TAB or on large-vessel imaging (PET/CT, aortic CT angiography or aortic MRA); and 3) started GC treatment less than 14 days before inclusion.

Patients who previously received another immunosuppressant (e.g., methotrexate) or biologic were not included.

Study protocol and endpoints

The study protocol is shown in Figure 1. Patients who met the inclusion criteria and who provided written consent were randomized in a double-blinded manner into two groups. Patients in the anakinra group (ANK patients) received a daily subcutaneous injection of 100 mg of anakinra from inclusion to week 16 (W16). Patients in the placebo group (PBO patients) received a daily injection of placebo from inclusion to W16.

In both arms, the GC protocol was similar. GC doses were calculated according to body weight (in mg/kg). Briefly, each included patient started on 0.7 mg/kg prednisone equivalent. Eventually, patients with ischemic complications might have received methylprednisolone pulses and a 1 mg/kg dose within the 14 days preceding inclusion. Week 0 was defined as inclusion in the study. According to the protocol schedule, the dose of prednisone in both arms was planned as follows: 0.5 mg/kg at W4, 0.3 at W8, 0.2 at W12, and 0.1 at W24. At W28, a 1 mg decrease every 4 weeks until discontinuation was planned.

The study ended at W52.

The primary endpoints were the relapse rate at W26 and the completion of protocolary GC tapering. At W26, patients should receive 0.1 mg/kg prednisone equivalent according to the study protocol.

The secondary endpoints were as follows:

- Analyze the relapse rates in both groups at different timeframes: between W0 and W16 (while receiving ANK or PBO injections), between W17 and W26, and between W27 and W52.

- Compare the rate of first relapse in the two groups over the 52-week duration

- Compare the GC doses in the two groups over the 52-week duration

- Assess treatment tolerance in the two groups over the 52-week duration

- Analyze the quality of life (QoL) of the patients via the 36-item short-form health survey questionnaire (SF-36) at W0, W16 and W52 and the health assessment questionnaire (HAQ) at different medical visits (W0, W4, W8, W12, W16, W26, W42 and W52).

Relapse was defined as the reoccurrence of GCA or polymyalgia rheumatica (PMR) symptoms along with increased acute phase reactants in a patient who was previously in remission and who required a treatment increase.

Before W26, relapses were treated with a 4-week increase in the GC dose at the previous threshold and then decreased following protocolary tapering. For patients with severe relapse (e.g., ischemic events), relapses occurring after W26 or relapses that did not respond to the 4-week increase in the GC dose at the previous threshold, treatment was allowed at the discretion of the responsible physician.

Safety was assessed throughout the study, and adverse events (AEs) observed during each follow-up visit were retrieved. Serious AEs were defined as any undesirable medical occurrence that met any of the following criteria: resulted in death; was life-threatening; required an inpatient hospitalization (or a prolonged existing hospitalization); or resulted in significant disability.

Sample size determination

We initially hypothesized that the GCA relapse rate may decrease to 10% in ANK patients and remain at 40% in PBO patients. With a 5% bilateral alpha risk and an overall power of 80%, we estimated that 31 subjects in each group might be needed. In anticipation of patients with ANK discontinuation due to adverse events and patients lost to follow-up, we ultimately aimed to include 35 patients in each arm (i.e., a total of 70 patients).

Premature study discontinuation

The study started in April 2017, and the last patients were included in April 2021. Given the SARS-CoV-2 pandemic, the study was stopped prematurely, and 30 patients were included. We herein present the results of the intent-to-treat population of 30 patients.

Statistical analyses

Categorial variables are expressed as numbers (%), and quantitative variables are expressed as medians [interquartils 25–75]. Given the small sample size in both groups, Fisher’s exact test was used to compare categorical variables. Quantitative variables were analyzed via the Wilcoxon rank-sum test.

Statistical analyses were computed with JMP 9.0.1 (SAS Institute Inc., Cary, NC). p<0.05 was considered to indicate a statistically significant difference.

Study population

Between 2017 and 2021, a total of 31 patients from 5 different centers were screened and randomized. One patient was prematurely excluded after randomization and did not receive treatment. The other 30 patients were randomized as follows: 17 in the ANK group and 13 in the PBO group. All the patients were included at GCA diagnosis, and none were included at relapse. Their characteristics are described and compared in Table 1. At baseline, no significant difference in those characteristics was observed between the two groups.

Table 1. Characteristics at baseline of GCA patients who received anakinra or placebo

	Anakinra (n=17)	Placebo (n=13)	P
Demographics
Female	11 (65)	10 (77)	0.69
Age	70 [65–80]	77 [67–81]	0.44
Medical History
Hypertension	11 (65)	8 (62)	1
Tobacco use	7 (41)	4 (31)	0.71
Hypercholesterolemia	5 (29)	4 (31)	1
Diabetes mellitus	3 (18)	0	0.24
Previous coronary disease or stroke	2 (12)	0	0.49
Clinical manifestations
Body mass index, kg/m²	24.9 [22.24–30.58]	24.1 [21.36–26.51]	0.38
Fever	7 (41)	3 (23)	0.44
Headaches	14 (82)	10 (77)	1
Scalp tenderness	9 (53)	8 (62)	0.72
Jaw claudication	9 (53)	7 (54)	1
Abnormal temporal artery	7 (41)	5 (38)	1
Ophthalmologic signs	6 (35)	5 (38)	1
AION	2/6 (33)	1/5 (20)	1
CRAO	1/6 (17)	1/5 (20)	1
Blindness	0	3 (23)	0.07
Polymyalgia rheumatica	3 (18)	4 (31)	0.67
Vascular work-up
Positive temporal artery biopsy	14/16 (88)	10/12 (83)	1
Positive ultrasonography	13/15 (87)	6/12 (50)	0.09
LVV on imaging	5/10 (50)	3/10 (30)	0.65
Laboratory tests
C-reactive protein, mg/l	22 [6–61]	19 [6–42]	0.75
Fibrinogen, g/l	5.45 [4.1–7.6]	4.6 [3.6–6.9]	0.31
Erythrocyte sedimentation rate, mm	49 [26–85]	50 [32–86]	0.81
Hemoglobin, g/dl	10.6 [10.1–12.82]	11.7 [11.1–13.38]	0.26
Platelets, G/l	367 [288–489]	401 [335–453]	0.46
LDL-cholesterol, g/l	2.49 [2–3.2]	3.26 [2.1–4.1]	0.20
Total cholesterol, mmol/l	4.6 [3.99–5.18]	4.45 [3.84–6.35]	0.53
Triglycerid, g/l	1.29 [0.88–1.68]	1.15 [1.01–1.46]	0.71
Glucocorticoids starting dose, mg/day	50 [41–57]	52 [40—67]	0.93
Intravenous boli	4 (24)	1 (8)	0.35

The values are presented as numbers (%) or medians [IQRs 25–75]. AION: acute anterior ischemic optic neuropathy; CRAO: central retinal artery occlusion; LVV: large vessel vasculitis; LDL: low-density lipoprotein

Among the 30 patients, 26 completed the protocolary visit at W52. Among the four other patients, one in the ANK arm was last observed at W42 and did not experience any relapse during follow-up. Two other patients, one each in the ANK and PBO arms, left the study at W20 after they experienced two relapses. The last patient in the ANK arm stopped the study at W16 after he experienced two relapses.

Among the 17 patients who received ANK, one patient stopped treatment at W12 after he experienced serious AEs. He did not relapse before discontinuation.

Efficacy endpoints

Glucocorticoid management and outcomes are indicated in Table 2.

Table 2. Glucocorticoid management and outcomes in GCA patients who received anakinra or placebo

	Anakinra (n=17)	Placebo (n=13)	p
Glucocorticoid doses
At inclusion	50 [41.5–57.5]	52.5 [40–67.5]	0.93
At W4	35 [28–41]	30 [25–40]	0.21
At W8	22 [17–25]	18 [15.5–24.5]	0.22
At W12	15 [12–16]	12 [10–14]	0.17
At W16	11 [9–13]	9.5 [8–11.5]	0.18
At W20	10 [7.5–12]	8 [7–11.5]	0.33
At W26	9 [6–15]	6.5 [5–9]	0.09
At W36	6 [4.5–10]	5 [3.5–11]	0.42
At W42	5 [2.5–7.5]	3 [1–5]	0.13
At W52	2 [1.5–7]	2 [1–5]	0.69
Glucocorticoids discontinuation at W52	2 (14)	2 (17)	0.87
Protocolary GC decrease deviation at W52	12 (71)	8 (62)	0.71
Relapses
W0-W52	9 (53)	6 (46)	1
< W16	2 (12)	3 (23)	0.63
W17-W26	6 (35)	1 (8)	0.10
>W27	1 (7)	2 (15)	0.55
>1 relapse	3/9 (33)	2/6 (33)	1

The values are presented as numbers (%) or medians [IQRs 25–75].

At week 26, 12 (40%) patients had relapsed: 8 (47%) in the ANK group and 4 (31%) in the PBO group (p=0.47). No ischemic complications occurred at the time of relapse. The GC dose at W26 was 0.105 [0.08–0.32] mg/kg in the ANK group, whereas it was 0.098 [0.08–0.25] mg/kg in the PBO group (p=0.10). Deviation of protocolary GC tapering was observed in 13 (43%) patients, 7 (41%) in the ANK group and 6 (46%) in the PBO group (p=0.99). In 10 of these 13 patients, the GC dose was increased to control disease relapse. In the other 3 patients, GC tapering was slowed by the treating physician, although there was no clear evidence of relapse.

At week 52, a total of 15 (50%) patients had relapsed: 9 (53%) in the ANK group and 6 (46%) in the PBO group (p=0.99). The relapse-free survival data are shown in Figure 2. Seven of the nine relapsing patients who received ANK experienced a disease flare after ANK discontinuation.

The distribution of first relapses at the different timepoints was as follows:

- Between W0 and W16, 2 (12%) patients relapsed in the ANK group, and 3 (23%) in the PBO group (p=0.63)

- Between W17 and W26, 6 (35%) patients relapsed in the ANK group (including the one who stopped ANK at W12 for serious AEs) and 1 (8%) patient relapsed in the PBO group (p=0.10)

- Between W27 and W52, 1 (7%) patient relapsed in the ANK group and 2 (15%) patients relapsed in the PBO group (p=0.55)

The GC doses used in both groups at the different follow-up visits are shown in Table 2 and Figure 3 and were not different. At W52, GCs were discontinued in 2 (14%) patients in the ANK group and in 2 (17%) in the PBO group (p=0.87).

Safety

The adverse events observed during the study are noted in Table 3. No patient died during the follow-up. One patient stopped ANK prematurely at W12 because of a serious AE.

Table 3. Adverse events observed in GCA patients who received anakinra or placebo

	Anakinra (n=17)	Placebo (n=13)	p
Any serious adverse event	4 (24)	1 (8)	0.35
Muscular and skeletal	4 (24)	8 (62)	0.06
Cramp	0	3 (23)	0.07
Myopathy	2 (12)	2 (15)	1
Osteopenia	2 (12)	4 (31)	0.36
Fracture	1 (6)	2 (15)	0.56
Gastro-intestinal	5 (29)	4 (31)	1
Gastro-esophageal reflux	3 (18)	2 (15)	1
Epigastralgy	3 (18)	1 (8)	0.61
Constipation	1 (6)	1 (8)	1
Diarrhea	0	1 (8)	0.43
Neuropsychiatric	7 (41)	10 (77)	0.07
Asthenia	2 (12)	4 (31)	0.36
Psychiatric troubles	5 (29)	2 (15)	0.43
Anxiety	2 (12)	0	0.49
Insomnia	4 (24)	6 (46)	0.26
Infections	10 (59)	8 (62)	1
>1 infection	6 (35)	4 (31)	1
Bronchitis	5 (29)	4 (31)	1
Erysipelas	1 (6)	1 (8)	1
Sinusitis	0	1 (8)	0.43
Cystitis	4 (24)	0	0.11
Dental infections	1 (6)	3 (23)	0.29
Pharyngitis	2 (12)	2 (15)	1
Zoster reactivation	1 (6)	1 (8)	1
Cutaneous mycosis	1 (6)	0	1
Prostatitis	1 (6)	0	1
Pyelonephritis	1 (6)	0	1
Angina	1 (6)	0	0
Flu-like syndrome	1 (6)	1 (8)	1
SARS-CoV-2 infection	2 (12)	0	0.49
Decreased visual acuity	4 (24)	4 (31)	0.70
Headaches	4 (24)	5 (39)	0.44
Local cutaneous reaction	5 (29)	1 (8)	0.20
Weight gain	4 (24)	3 (23)	1
Hypercholesterolemia	1 (6)	0	1
Cytopenia	3 (18)	1 (8)	0.61
Thrombopenia	1 (6)	0	1
Anemia	2 (12)	0	0.49
Lymphopenia	1 (6)	0	1
Agranulocytosis	0	1 (8)	0.43
Increased gamma-GT	2 (12)	0	0.49
Cancer	1 (6)	1(8)	1
Epistaxis	2 (12)	1 (8)	1
Cardiovascular	2 (12)	3 (23)	0.63
Atrial fibrillation	0	2 (15)	0.18
Hypertension	2 (12)	1 (8)	1
Cutaneous	2 (12)	3 (23)	0.63
Frailty	0	1 (8)	0.43
Pruritis	2 (12)	0	0.49
Ecchymosis	0	2 (15)	0.18

Values are numbers (%)

All the 30 patients experienced at least one AE. Seven serious AEs were reported by five patients, including 4 receiving ANK. The first patient in the ANK arm required two hospitalizations, one for hematemesis favored by thrombocytopenia and a second for arm erysipelas. He stopped ANK treatment at W12. The second patient received ANK and was hospitalized for a fall with a fracture. The third patient experienced two complicated urinary infections, one involving obstructive pyelonephritis and one involving nosocomial cystitis with multiresistant bacteria. ANK was stopped at the time of the second infection. The fourth patient was hospitalized due to COVID-19 infection, and ANK was stopped for several weeks. Finally, the fifth patient experienced agranulocytosis while receiving PBO.

Infections were observed in 59% of the patients who received ANK and 62% of those who received PBO (p=0.99).

Five (29%) patients receiving ANK experienced a cutaneous reaction after the injection.

Assessment of quality of life

The detailed SF-36 assessment results at baseline, at W16 and W52 are reported in Table 4.

Table 4. SF-36 analysis in GCA patients who received anakinra or placebo

		Baseline	Week 16	Week 52	P1	P2
SF-36
Physical functioning	Anakinra	59.7 (30.3)	66.1 (31.2)	66.3 (19.8)	0.24	0.91
	Placebo	54.2 (24.9)	54.6 (33.2)	53.1 (27.1)	0.97	0.74
Physical limitations	Anakinra	32.4 (42.2)	71.4 (43.7)	39.6 (40.5)	0.02	0.15
	Placebo	29.5 (40.0)	39.6 (39.1)	47.5 (46.3)	0.70	0.62
Emotional limitations	Anakinra	50.98 (47.31)	66.67 (43.36)	47.22 (48.11)	0.07	0.65
	Placebo	30.56 (43.71)	50 (43.81)	63.30 (48.30)	0.046	0.45
Energy	Anakinra	46.47 (23.44)	50 (19.55)	47.92 (20.32)	0.79	0.90
	Placebo	43.33 (16.0)	47.00 (15.13)	50 (14.34)	0.86	0.58
Emotional wellbeing	Anakinra	61.88 (13.05)	69.50 (13.88)	65.67 (18.09)	0.04	0.89
	Placebo	56.67 (18.09)	57.0 (16.72)	55.80 (18.24)	0.63	0.53
Social functioning	Anakinra	69.85 (30.32)	76.25 (18.26)	68.54 (20.85)	0.55	0.98
	Placebo	61.46 (20.96)	63.75 (17.30)	66.75 (12.25)	0.76	0.047
Pain	Anakinra	50.88 (35.94)	66.79 (23.75)	67.29 (25.99)	0.30	0.95
	Placebo	43.75 (31.34)	57.92 (24.79)	45.75 (16.07)	0.32	0.12
General health	Anakinra	56.99 (11.67)	58.04 (11.35)	57.81 (11.96)	0.82	0.78
	Placebo	61.98 (14.46)	62.50 (11.31)	61.88 (10.40)	0.87	0.68

The data are presented as means ± SD; bold, significant after Bonferroni correction.

Paired t tests: P1: W16 compared to baseline, P2: W52 compared to W16.

During the first 16 weeks, patients receiving ANK experienced significant improvements in terms of physical limitations and well-being. However, no significant difference in the general health assessment was observed among patients receiving ANK between W0 and W16.

The HAQ score assessed at each medical visit did not significantly differ between the two treatment arms (Supplemental Table 1).

Recent advances in understanding GCA pathophysiology have suggested that targeting the IL-1 pathway may be an interesting therapeutic option for this disease. In addition, preliminary observations reported the possible efficacy of ANK in GCA [14, 15]. Although prematurely discontinued, the present study did not show that adding four months of anakinra treatment to GCs at GCA onset reduced the risk of relapse. In both groups, half of the patients experienced at least one relapse. However, in patients who received ANK, most relapses (7/9) occurred after ANK discontinuation, which may indicate a suspensive effect. A deviation of the GC protocolary decrease was observed in two-thirds of the patients in both groups. Although patients receiving ANK described a significant improvement in the physical limitations and well-being components, a serious adverse event occurred in one quarter of them.

Although the results of this study are negative, some important points should be discussed.

First, since the study was prematurely discontinued, no definitive conclusion can be drawn. The small sample size did not allow us to show any differences between the two groups, and the data are shown only for descriptive purposes.

Second, this therapeutic trial was designed before 2017, i.e before the GiACTA trial was published [11]. GC-sparing strategies were less established, and at that time, the standard-of-care treatment in France was to maintain GCs for at least 18 months. The present study aimed to analyze whether a 4-month prescription of ANK resulted in a reduction in the relapse rate and the discontinuation of GCs at W52, which was a significant endpoint.

Therapeutic trials of new treatments for GCA are now designed differently to analyze the GC-sparing effects, especially with shorter GCs durations [16–18]. Unfortunately, the present study was not designed to assess the GC-sparing effect of ANK, and we cannot draw any strong conclusions regarding this point. However, 86% of the patients in the ANK arm were still receiving GCs at W52 and did not stop GCs.

Third, although the relapse rate at W52 was not different between the groups, most relapses in the ANK group occurred after discontinuation of the biologic. This suspensive effect raises questions about the beneficial effect of prolonged use. In recent studies, the biologic has often been maintained for 12 months. Our study design may thus have contributed to the negative results observed.

Finally, tolerance issues should be discussed. Only one patient receiving ANK stopped treatment because of an SAE that was probably directly linked to the treatment. All the other SAEs in the ANK group occurred after the treatment was stopped or lacked direct imputability. The most frequent adverse events in both groups were infections, the frequencies of which did not differ. This finding highlights the probable imputability of GCs. ANK injections are often painful or lead to local reactions, which were observed in 29% of involved patients.

This multicenter, randomized, double-blind, placebo-controlled trial of anakinra in the treatment of giant cell arteritis was prematurely discontinued. However, the intent-to-treat analysis of the 30 included patients failed to demonstrate a beneficial effect of anakinra in reducing the risk of relapse or GC exposure. The present study does not support the use of anakinra for 4 months at the time of diagnosis in GCA patients.

AEs: adverse events

ANK: anakinra

CT: computed tomography

GCs: glucocorticoids

GCA: giant cell arteritis

HAQ: health assessment questionnaire

IL: interleukin

MRA: magnetic resonance angiography

MTX: methotrexate

PBO: placebo

PET/CT: positron emission tomography coupled with computed tomography

PMR: polymyalgia rheumatica

QoL: quality of life

SF36: short form

Ethics approval and consent to participate

Written informed consent was obtained from all participating patients.

Consent for publication

Not applicable

Availability of data and materials

The data are available upon reasonable request to the corresponding author.

Competing interests

Hubert de Boysson reports receiving fees for serving on advisory boards from Roche-Chugai and Novartis and lecture fees from Roche-Chugai, Novartis, Fresenius Kabi, GlaxoSmithKline, Amicus therapeutics, and Sanofi.

Funding

This study was funded by the French PHRC (Protocole Hospitalier de Recherche Clinique) program.

Authors' contributions

HdB, KHL, LG, TQ, EL, HB, NLG, AlA, AD, SD, JB, GM, NMS, AS, BLM, GP, JJP and AcA acquired the data and were involved in the interpretation of the results and in the review of the manuscript. HdB, AS, JJP and AcA designed the study. HdB and AcA wrote the first draft of the manuscript, which was read, corrected and approved by all the authors.

Acknowledgements

Not applicable

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Competing interest reported. Hubert de Boysson reports receiving fees for serving on advisory boards from Roche-Chugai and Novartis and lecture fees from Roche-Chugai, Novartis, Fresenius Kabi, GlaxoSmithKline, Amicus therapeutics, and Sanofi.

Four months of treatment with anakinra combined with glucocorticoids for giant cell arteritis: a multicenter, randomized, double-blind, placebo-controlled trial

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Abstract

Background

Methods

Results

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INTRODUCTION

METHODS

RESULTS

DISCUSSION

CONCLUSIONS

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Version 1