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Vasculitis
Baricitinib for relapsing giant cell arteritis: a prospective open-label 52-week pilot study
  1. Matthew J Koster1,
  2. Cynthia S Crowson2,
  3. Rachel E Giblon2,
  4. Jane M Jaquith1,
  5. Ali Duarte-García1,
  6. Eric L Matteson1,
  7. Cornelia M Weyand1,
  8. Kenneth J Warrington1
  1. 1 Department of Internal Medicine, Division of Rheumatology, Mayo Clinic, Rochester, Minnesota, USA
  2. 2 Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Matthew J Koster, Department of Internal Medicine, Division of Rheumatology, Mayo Clinic, Rochester, USA; koster.matthew{at}mayo.edu

Abstract

Background/purpose Preclinical vascular inflammation models have demonstrated effective suppression of arterial wall lesional T cells through inhibition of Janus kinase 3 and JAK1. However, JAK inhibition in patients with giant cell arteritis (GCA) has not been prospectively investigated.

Methods We performed a prospective, open-label, pilot study of baricitinib (4 mg/day) with a tiered glucocorticoid (GC) entry and accelerated taper in patients with relapsing GCA.

Results 15 patients were enrolled (11, 73% female) with a mean age at entry of 72.4 (SD 7.2) years, median duration of GCA of 9 (IQR 7–21) months and median of 1 (1–2) prior relapse. Four (27%) patients entered the study on prednisone 30 mg/day, 6 (40%) at 20 mg/day and 5 (33%) at 10 mg/day. Fourteen patients completed 52 weeks of baricitinib. At week 52, 14/15 (93%) patients had ≥1 adverse event (AE) with the most frequent events, including infection not requiring antibiotics (n=8), infection requiring antibiotics (n=5), nausea (n=6), leg swelling (n=2), fatigue (n=2) and diarrhoea (n=1). One subject required baricitinib discontinuation due to AE. One serious adverse event was recorded. Only 1 of 14 (7%) patients relapsed during the study. The remaining 13 patients achieved steroid discontinuation and remained in disease remission during the 52-week study duration.

Conclusion In this proof-of-concept study, baricitinib at 4 mg/day was well tolerated and discontinuation of GC was allowed in most patients with relapsing GCA. Larger randomised clinical trials are needed to determine the utility of JAK inhibition in GCA.

Trial registration number NCT03026504.

  • giant cell arteritis
  • systemic vasculitis
  • therapeutics

Data availability statement

All data relevant to the study are included in the article.

https://doi.org/10.1136/annrheumdis-2021-221961

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    Key messages

    What is already known about this subject?

    • Giant cell arteritis (GCA) is a chronic rheumatic disease with a high frequency of relapse during glucocorticoid tapering.

    • Tocilizumab has been proven effective in the management of GCA; however, there was 15%–26% flare while receiving tocilizumab and approximately 50% flare following discontinuation, highlighting an unmet need for additional therapeutics.

    What does this study add?

    • Baricitinib at a dose of 4 mg was well tolerated and showed preliminary efficacy in patients with relapsing GCA.

    How might this impact on clinical practice or future developments?

    • Larger clinical trials are needed to assess the utility of Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibition in the management of GCA.

    Introduction

    Giant cell arteritis (GCA) is the most common primary systemic vasculitides in patients ≥50 years of age.1 Glucocorticoids (GCs) have been the primary therapeutic intervention in GCA since their earliest use in the 1950s.2 Relapse is common, occurring in 43%–79% of patients with GC tapering or discontinuation.3–5 Though GCs have shown efficacy, ongoing use is often required with over 40% of patients still on GCs at 5 years.4 Unfortunately, long-term use of GCs is associated with significant side effects and between 50% and 100% of patients have at least one GC-associated adverse event (AE).3–6 Clinical trials evaluating disease-modifying agents and tumour necrosis factor (TNF)-alpha inhibitors have not demonstrated significant benefit.7–12

    Thus far, only tocilizumab, an interleukin (IL)-6 inhibitor, has shown safety and efficacy in relapse reduction and decrease in GC requirements.13 14 Given tocilizumab is the only currently approved treatment for GCA by the US Food and Drug Administration (FDA) and the European Commission, it has been quickly incorporated in clinical practice and included in recently updated consensus management guidelines.15 16 While markedly improved compared with GC monotherapy, patients with GCA treated with tocilizumab still have flare rates of 15%–26%.13 14 In addition, clinical trial and observational data have shown that at 12 months of tocilizumab therapy, 30%–47% of patients have still not achieved sustained clinical remission.13 17 Furthermore, the length of treatment required for tocilizumab in GCA remains unknown. In the first clinical trial evaluating intravenous tocilizumab by Villiger and colleagues, 17/20 patients randomised to the treatment arm were in remission at the end of the 52-week study, of which 8 patients (47%) relapsed after a mean of 6.3 months from tocilizumab discontinuation.14 18 The 2-year open-label extension phase of the Giant Cell Arteritis Actemra (GiACTA) trial showed similar findings. Of patients who were in remission following 1 year of weekly subcutaneous tocilizumab, only 42% remained in tocilizumab-free and GC-free remission over the subsequent 2 years of observation.19 Even though tocilizumab has dramatically improved the treatment of GCA, additional agents are needed to increase the therapeutic options, specifically among those for whom tocilizumab is not tolerated or who have not achieved sustained remission.

    Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibition with tofacitinib (JAK1/Janus kinase 3 (JAK3) inhibitor) in patients with refractory Takayasu arteritis have shown promise in several case reports and small series.20–25 A preclinical vascular inflammation model has demonstrated that JAK inhibition with tofacitinib suppressed innate and adaptive immunity in the arterial wall, particularly through suppression of tissue-resident memory T cells, and additionally further reduced inflammation by inhibition of vasculogenic effector pathways.26 In addition, interferon-gamma stimulation of the JAK1/JAK2 pathway has been observed to promote macrophage recruitment to ex vivo cultured arteries from patients with GCA.27 Evaluation of JAK inhibition in the clinical management of GCA, on the other hand, is sparse. Among the limited information available, baricitinib (JAK1/JAK2 inhibitor) has been used in two cases of recalcitrant GCA with beneficial outcome.28 29 The preclinical findings and preliminary case report responses demonstrate the biological plausibility that agents selectively targeting JAK1/JAK2 hold potential promise in GCA. Although a large phase III randomised, placebo-controlled trial evaluating upadacitinib (JAK1 selective inhibitor) is ongoing (ClinicalTrials.gov identifier NCT03725202), to date, there has been no formal evaluation of safety or efficacy of JAK1/JAK2 inhibition in GCA. The purpose of this study was to evaluate the prospective safety and preliminary efficacy of baricitinib, an oral selective JAK1/JAK2 inhibitor in patients with relapsing GCA.

    Methods

    Study design and patient population

    This was a prospective, open-label interventional study of patients with relapsing GCA. Patients were recruited from the division of rheumatology at Mayo Clinic in Rochester, Minnesota, USA. The study was approved by the Mayo Clinic Institutional Review Board (16–0 08 993) and registered in Clinicaltrials.gov. Study definitions, which were adapted from similar GCA clinical trials, are listed in table 1.13 30 31 All patients were required to have a prior confirmed diagnosis of GCA by either temporal artery biopsy and/or confirmatory radiographic evidence of large-vessel vasculitis (table 1). Patients were required to have a physician-confirmed relapse of GCA within 6 weeks of study entry with evidence of active disease. Relapsing patients with severe vascular symptoms, such as active visual ischaemia, aortic dissection, critical limb ischaemia, myocardial infarction or cerebrovascular event attributable to GCA were excluded. Treatment with the following agents were required to be held prior to baseline study entry: methotrexate (2 weeks), leflunomide (12 weeks), anti-IL-6 agent (4 weeks if infusible, 2 weeks if subcutaneous), rituximab (12 months), TNF-alpha inhibitor (etanercept 4 weeks, remainder of class 8 weeks) and abatacept (8 weeks). Pulse dose methylprednisolone (>100 mg/day) within 8 weeks of baseline was exclusionary as was any prior treatment of tofacitinib or other JAK-STAT inhibitor.

    View this table:
    Table 1

    Study definitions

    Study medications

    During the screening phase (minimum of 2 weeks and maximum of 6 weeks), prednisone was increased to achieve symptom control prior to initiation of the study drug and subsequent accelerated GC taper. Three tiers of prednisone dose were allowed for study entry: 10, 20 or 30 mg/day. The prednisone dose of study entry was commensurate with the prednisone level at which the relapse occurred. For example, patients with a relapse with prednisone doses of ≥20 mg but <30 mg/day were allowed to have prednisone increase to at least 30 mg/day, but not to exceed 40 mg/day for symptom control. Similarly, patients with relapse that occurred with prednisone of ≥10 mg/day but <20 mg/day had an increase to at least 20 mg/day but not to exceed 30 mg/day, and patients with relapse occurring with prednisone dose of 0 to <10 mg/day were allowed a reinstitution or increase in prednisone to at least 10 mg/day but not exceeding 20 mg/day. All patients were required to have a minimum of 2 weeks of clinical stability at their entry-level prednisone dose before study drug initiation and accelerated GC tapering. The accelerated GC taper is outlined in online supplemental table S1. GC discontinuation was at weeks 22, 19 and 15 for tiered entry of 30, 20 and 10 mg, respectively. On study entry, all participants received baricitinib 4 mg/day. Baricitinib was dispensed from a central pharmacy. Pill counts were completed at each visit to assess compliance.

    Data collection and outcome measures

    Laboratory parameters (complete blood count with differential, alanine aminotransferase, creatinine with estimated glomerular filtration rate (eGFR), erythrocyte sedimentation rate (ESR) and C reactive protein (CRP)), physical examination and disease activity assessment were performed at each visit (weeks 0, 4, 8, 16, 24, 32, 40 and 52). Fasting lipid profile was checked at baseline and week 16. The primary outcome was the frequency of AEs and serious adverse events (SAEs) at week 52. Definitions of AE and SAE are listed in online supplemental table S2. Parameters used for temporary hold and permanent discontinuation of baricitinib are outlined in online supplemental table S3.

    Secondary outcomes included relapse (table 1) at week 24, relapse at week 52, change in pre-enrolment ESR and CRP compared with week 24 and week 52, comparison of GC dose at enrollment to week 24 and week 52. The Birmingham Vasculitis Activity Score (BVAS) V.3 was assessed at weeks 0, 24 and 52.32 A patient global assessment was obtained at baseline and each study visit using a visual analogue scale of 100 mm length with perceived level of symptoms attributable to GCA from ranging from 0 (none) to 100 (maximum).

    Statistical analysis

    Descriptive statistics (eg, means, median and percentages) were used to summarise the data. Paired comparisons of measures at different timepoints were performed using paired t-tests. Measures that were not normally distributed and did not have symmetric differences were compared using sign tests. Analyses were performed using SAS V.9.4.

    Results

    Patient characteristics

    Nineteen patients were screened for this study, all of which met the initial inclusion criteria. During the screening phase, four patients were excluded: one developed active infection requiring antibiotics; one had two consecutive indeterminate tuberculosis tests; and two patients subsequently declined participation due to travel difficulty. No patients were excluded during the screening phase due to lack of clinical stability prior to study entry. Fifteen patients (100% white, 73% female) were enrolled in the study with a mean±SD age at entry of 72.4±SD 7.2 years), a median duration of GCA of 9 (IQR 7–21) months, and a median of 1 (IQR 1–2) prior relapse before study entry. Mean±SD body mass index at study entry was 26.3±3.4 kg/m2. Thirteen (87%) patients had received historical herpes zoster (HZ) live-attenuated viral vaccine prior to screening; 1 patient received recombinant, adjuvanted HZ vaccine after study entry; and 1 patient remained unvaccinated. Characteristics at GCA diagnosis and at relapse prior to study entry are listed in table 2.

    View this table:
    Table 2

    Characteristics of patients at GCA diagnosis and at relapse prior to study entry

    All patients had received GC for initial treatment at GCA diagnosis with only one (patient 5) off of prednisone at the time of relapse prior to study entry. Other previous agents included methotrexate (2, 13%); cyclophosphamide (1, 7%); and sirukumab (1, 7%). No patient had previously received tocilizumab. Four (27%) patients entered the study on prednisone 30 mg/day, 6 (40%) at 20 mg/day and 5 (33%) at 10 mg/day (table 2).

    Safety

    One patient (patient 1) with baseline chronic kidney disease (entry eGFR 51 mL/min/1.73 m2) had a decline in renal function at week 4 to a level below study threshold for continuation (eGFR 40 mL/min/1.73 m2), and though improvement in renal function occurred with temporary hold (eGFR 48 mL/min/1.73 m2), the patient did not have an increase to a level allowing resumption after 4 weeks of holding and therefore was prematurely withdrawn at week 8. The remaining 14 patients completed all 52 weeks of baricitinib treatment.

    At week 52, 14/15 (93%) patients had at least one AE recorded with the most frequent events, including infection not requiring antibiotics (n=8), infection requiring antibiotics (n=5), nausea (n=6), leg swelling (n=2), fatigue (n=2), diarrhoea (n=1) and abdominal pain (n=1). One patient developed symptomatic HZ, which resolved within 2 weeks of holding the study drug and treatment with antiviral, allowing for subsequent reinitiation. Two patients contracted COVID-19 during the study, both with mild symptoms; neither required hospitalisation.

    Only one patient had an SAE during the study (transient thrombocytopenia <75×109/L attributed to concomitant use of antiviral). No patients had any of the following during the study: gastrointestinal perforation, major cardiovascular event (MACE), venous thromboembolism (VTE) or severe vascular symptom.

    Changes in laboratory parameters at weeks 24 and 52 compared with baseline are outlined in table 3. Compared with week 0, haemoglobin, leucocytes, neutrophils and lymphocytes were lower at weeks 24 and 52. At baseline, nine patients were already receiving statin medications for non-GCA indications. Alterations in the cholesterol profile were observed at week 16 with a statistically significant increase in low-density lipoprotein (LDL) and decrease in high-density lipoprotein (HDL), but triglycerides and total cholesterol were not significantly different (table 4).

    View this table:
    Table 3

    Laboratory parameter changes comparing weeks 0, 24 and 52 for 14 patients

    View this table:
    Table 4

    Lipid profile changes comparing baseline (week 0) to week 16 for 14 patients

    Efficacy

    Only 1 of 14 (7%) patients relapsed during the study (same patient at weeks 24 and 52). The subject (patient 10) relapsed at week 24 while on 0 mg/day prednisone with recurrent headache, scalp tenderness, PMR and increased inflammatory markers. Baricitinib was continued and prednisone increased to a dose of 20 mg/day, which resulted in symptom and laboratory control. Prednisone was then tapered down to 7.5 mg/day by week 52, at which time the second relapse occurred with recurrent headache, fatigue, weight loss and increased inflammatory markers. The remaining 13 patients were able to follow the accelerated GC taper, achieve GC discontinuation and remained in disease remission during the duration of the 52-week study. No vision loss or severe vascular symptoms were present as a relapse while receiving baricitinib. Additional study outcomes are highlighted in table 5. ESR and CRP were both significantly lower at weeks 24 and 52 compared with pre-enrolment values. Patient global assessment at week 0 (median 20, IQR 0–50) was also significantly improved at both week 24 (median 0, IQR 0–10, p=0.022) and week 52 (median 5, IQR 0–10, p=0.039). Among patients completing the study, 4/14 (29%) flared during the 12-week follow-up period after baricitinib discontinuation.

    View this table:
    Table 5

    Study outcomes

    Discussion

    This report constitutes the first prospective trial using an oral JAK1/JAK2 inhibitor in the management of GCA. The results of this open-label pilot study demonstrate baricitinib at a dose of 4 mg/day appeared both safe and potentially effective in the treatment of patients with relapsing GCA.

    Baricitinib at a dose of 4 mg/day appeared to have sufficient control over subsequent relapse both during accelerated GC tapering and also following GC discontinuation, with only one patient (7%) having a flare while receiving the study drug. Formal clinical trials in GCA have had varying endpoints and approaches to GC tapering. Among trials with defined, accelerated, GC-tapering regimens completing at or before 28 weeks, the frequency of relapse in the placebo arms has ranged between 68% and 78%.8 9 12 13 30 With tiered entry stratification of prednisone dosing, patients starting on 30, 20 and 10 mg discontinued prednisone at weeks 22, 19 and 15, respectively. As such, the current study constitutes the first trial where all patients were tapered off GCs earlier than 24 weeks, resulting in a prolonged time of observation off of concomitant GC therapy. The only other study with discontinuation of planned prednisone dosing at 22–24 weeks was Hoffman et al, evaluating adjunct infliximab in patients with newly diagnosed GCA, which resulted in observed relapse rates of 82% in the study drug arm and 75% in the placebo group.9 Compared with patients without a prior relapse, patients with a history of relapse are more likely to have a subsequent relapse.33 Therefore, the low observed rate of subsequent relapse among patients with known relapsing GCA, combined with the accelerated prednisone taper, indicates a perceived benefit of baricitinib in control of disease activity and warrant study in a larger clinical setting.

    At least one AE was recorded in all but one patient (93%). This frequency is similar to other clinical trials performed in patients with GCA, regardless of treatment or placebo arm.9 11–13 Specifically, the AE frequency in the tocilizumab GiACTA study was 96%–98% in treatment arms and 92%–96% in placebo arms, highlighting the high frequency of AEs in patients, in part attributable to GCs.13 The rates of AEs in this study are similar to those observed in patients receiving baricitinib for rheumatoid arthritis (RA), despite the average age of patients in the current study being 20 years older than patients treated in the RA trials.34–40 No new forms of treatment-emergent AEs were identified among this population.

    A reduction in eGFR precluded the study completion in one patient. Alteration in renal function with slight increase in creatinine and reduction in eGFR has been observed at all dosing levels of baricitinib evaluated (ie, 1, 2, 4 and 8 mg/day).35 Discontinuation due to renal insufficiency has occurred in 5%–6% of patients receiving 4 mg/day baricitinib in RA studies, similar to the current report.38 The overall mean difference in creatinine observed in our study was 0.02 mg/dL at both weeks 24 and 52. This mean difference was lower than studies in RA which have shown mean changes of 0.05–0.07 mg/dL at week 24 and 0.086 mg/dL at week 52 in patients receiving 4 mg/day baricitinib.35–37 Therefore, use of baricitinib in patients with GCA with impaired renal function should be monitored closely.

    HZ occurred in one patient (7%) during study drug treatment. Rates of HZ in RA studies evaluating baricitinib at doses between 2 and 8 mg/day range between 1% and 8%, similar to the frequency observed in our cohort.36–38 40 HZ in patients with GCA is not unique to treatment with baricitinib. Among clinical trials providing sufficient detail regarding frequency of HZ, 1/20 (5%) patients receiving abatacept, 3/34 (8%) receiving adalimumab and 2/12 (17%) receiving methotrexate developed infections.11 30 41 JAK3 inhibition appears to have greater risk of HZ than JAK2 or selective JAK1 inhibition.42 For patients with RA, it is conditionally recommended to vaccinate prior to initiation of tofacitinib (JAK3/JAK1 inhibitor), but guidance on other es is limited.43 The European Alliance of Associations for Rheumatology recommendations considers vaccination against HZ in high-risk patients but does not require vaccination prior to initiation of targeted synthetic disease-modifying antirheumatic drugs.44 In the current study, the patient developing HZ had received a live-attenuated zoster vaccination after the age of 60 years but had not received a recombinant, adjuvanted zoster vaccine prior to study entry. Larger trials are necessary to assess the relative risk of HZ in the GCA population receiving JAK inhibition and to delineate the appropriate vaccination mitigation strategies among these patients.

    In RA cohorts, use of baricitinib has been associated with lipid profile alterations including a rise in both HDL and LDL.35–38 40 In the current study, the LDL increased, but the HDL decreased from weeks 0 to 16; however, there was no significant change in the overall total cholesterol. It is possible that higher-dose GCs used in the current study, in comparison to lower doses used in the management of patients with RA, may have resulted in higher baseline lipid concentrations, thus attenuating the perceived effect of baricitinib on the cholesterol profile during follow-up. Evaluation in larger cohorts is needed to better understand the impact of baricitinib on cholesterol metabolism in this patient population. Of note, no patient required initiation of lipid-lowering agent during the study based on lipid profile alteration.

    Use of JAK inhibition has gained scrutiny among older adults due to concern of possible increased risk of MACE and VTE. Initial trial safety data in patients with RA >50 years of age with at least one cardiovascular risk factor comparing use of tofacitinib to those receiving a TNF inhibitor have led the US FDA to include a boxed warning for tofacitinib indicating a higher risk of MACE and VTE among patients with RA.45 Although these preliminary data are specific to tofacitinib, the boxed warning has been extended to include upadacitinib and baricitinib. Data pooled from nine RA studies (3492 patients with 7860 patient-years of exposure), however, showed a VTE risk of only 0.5 per 100 patient-years and no increased risk of MACE in patients with RA receiving 2 or 4 mg baricitinib per day.46 While no VTE or MACE occurred during treatment with baricitinib in the current study, the sample size is too small extrapolate overall safety in this patient population, and thus exploration of JAK1/JAK2 inhibition in this elderly population will require appropriate caution.

    SAEs were notably rare in our study, only occurring in one patient with the development of significant thrombocytopenia. This particular SAE was most likely attributable to concomitant antiviral as it occurred temporally after initiation of acyclovir and recovered following cessation. In addition, the patient restarted baricitinib after a 2-week hold and continued for another 32 weeks without further thrombocytopenia developing. Furthermore, thrombocytopenia is uncommon in the use of baricitinib as a dose-dependent increase in platelets has been observed in patients with RA receiving this therapy.34–37

    This study must be interpreted in the context of its limitations. First, the results require external validation, given the single-centre nature of this report. Second, this was an uncontrolled, open-label study without blinded clinical assessment, and therefore the lack of blinding and a control arm raises the possibility of assessment bias. Objective assessments (laboratory parameters and physical examination findings) and subjective measures (patient and physician global assessments) were used to assess response in this study as is in keeping with clinical care and current trial formats. Given improvement was noted among all evaluated domains, the likelihood of results being from assessment bias alone is unlikely. Although BVAS was incorporated as an outcome parameter, the utility of BVAS in measuring disease activity in GCA is admittedly limited.47 Nevertheless, it is noteworthy that, to date, there remains no validated disease activity score for GCA, which consequently limits comprehensive objective clinical assessment in this condition. Third, patients evaluated in this study all had relapsing GCA, and thus the effect of this treatment on patients with new-onset disease will require formal evaluation. Fourth, patients with severe vascular manifestations present at the time of relapse were excluded, and therefore the utility of baricitinib in this subgroup remains yet unknown. Fifth, this study was designed prior to the approval of baricitinib by the US FDA, which only approved the 2 mg/day dose for RA. The use of the 4 mg/day dose in this study was based on initial preapproval studies highlighting the 4 mg/day dosing as the optimal dosing for treatment of RA.35 Therefore, it is not certain whether a 2 mg/day dose provides a similar treatment response. Lastly, none of the patients in this study had received or failed tocilizumab prior to study entry. The utility of baricitinib in patients refractory to tocilizumab is unknown and needs to be evaluated.

    In conclusion, this single-centre, open-label study of 4 mg/day baricitinib in patients with relapsing GCA demonstrated preliminary evidence of both safety and efficacy. Larger, double-blind, placebo-controlled studies are warranted to assess the utility of baricitinib in the management of patients with GCA.

    Data availability statement

    All data relevant to the study are included in the article.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by the Mayo Clinic Institutional Review Board (16-008993) and registered in Clinicaltrials.gov. Participants gave informed consent to participate in the study before taking part.

    References

    1. ↵
      2. Crowson CS ,
      3. Matteson EL ,
      4. Myasoedova E , et al
      . The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum 2011;63:633–9.doi:10.1002/art.30155 pmid:http://www.ncbi.nlm.nih.gov/pubmed/21360492
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      2. Hunder GG
      . The early history of giant cell arteritis and polymyalgia rheumatica: first descriptions to 1970. Mayo Clin Proc 2006;81:1071–83.doi:10.4065/81.8.1071 pmid:http://www.ncbi.nlm.nih.gov/pubmed/16901030
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      2. Proven A ,
      3. Gabriel SE ,
      4. Orces C , et al
      . Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis Rheum 2003;49:703–8.doi:10.1002/art.11388 pmid:http://www.ncbi.nlm.nih.gov/pubmed/14558057
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      2. Labarca C ,
      3. Koster MJ ,
      4. Crowson CS , et al
      . Predictors of relapse and treatment outcomes in biopsy-proven giant cell arteritis: a retrospective cohort study. Rheumatology 2016;55:347–56.doi:10.1093/rheumatology/kev348 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26385368
      OpenUrlCrossRefPubMed
    5. ↵
      2. Alba MA ,
      3. García-Martínez A ,
      4. Prieto-González S , et al
      . Relapses in patients with giant cell arteritis: prevalence, characteristics, and associated clinical findings in a longitudinally followed cohort of 106 patients. Medicine 2014;93:194–201.doi:10.1097/MD.0000000000000033 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25181312
      OpenUrlCrossRefPubMed
    6. ↵
      2. Nesher G ,
      3. Sonnenblick M ,
      4. Friedlander Y
      . Analysis of steroid related complications and mortality in temporal arteritis: a 15-year survey of 43 patients. J Rheumatol 1994;21:1283–6.pmid:http://www.ncbi.nlm.nih.gov/pubmed/7966070
      OpenUrlPubMedWeb of Science
    7. ↵
      2. Jover JA ,
      3. Hernández-García C ,
      4. Morado IC , et al
      . Combined treatment of giant-cell arteritis with methotrexate and prednisone. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;134:106–14.doi:10.7326/0003-4819-134-2-200101160-00010 pmid:http://www.ncbi.nlm.nih.gov/pubmed/11177313
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      2. Hoffman GS ,
      3. Cid MC ,
      4. Hellmann DB , et al
      . A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002;46:1309–18.doi:10.1002/art.10262 pmid:http://www.ncbi.nlm.nih.gov/pubmed/12115238
      OpenUrlCrossRefPubMedWeb of Science
    9. ↵
      2. Hoffman GS ,
      3. Cid MC ,
      4. Rendt-Zagar KE , et al
      . Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med 2007;146:621–30.doi:10.7326/0003-4819-146-9-200705010-00004 pmid:http://www.ncbi.nlm.nih.gov/pubmed/17470830
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      2. Mahr AD ,
      3. Jover JA ,
      4. Spiera RF , et al
      . Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis. Arthritis Rheum 2007;56:2789–97.doi:10.1002/art.22754 pmid:http://www.ncbi.nlm.nih.gov/pubmed/17665429
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      2. Seror R ,
      3. Baron G ,
      4. Hachulla E , et al
      . Adalimumab for steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised controlled trial. Ann Rheum Dis 2014;73:2074–81.doi:10.1136/annrheumdis-2013-203586 pmid:http://www.ncbi.nlm.nih.gov/pubmed/23897775
      OpenUrlAbstract/FREE Full Text
    12. ↵
      2. Martínez-Taboada VM ,
      3. Rodríguez-Valverde V ,
      4. Carreño L , et al
      . A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects. Ann Rheum Dis 2008;67:625–30.doi:10.1136/ard.2007.082115 pmid:http://www.ncbi.nlm.nih.gov/pubmed/18086726
      OpenUrlAbstract/FREE Full Text
    13. ↵
      2. Stone JH ,
      3. Tuckwell K ,
      4. Dimonaco S , et al
      . Trial of tocilizumab in giant-cell arteritis. N Engl J Med 2017;377:317–28.doi:10.1056/NEJMoa1613849 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28745999
      OpenUrlCrossRefPubMed
    14. ↵
      2. Villiger PM ,
      3. Adler S ,
      4. Kuchen S , et al
      . Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2016;387:1921–7.doi:10.1016/S0140-6736(16)00560-2 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26952547
      OpenUrlCrossRefPubMed
    15. ↵
      2. Hellmich B ,
      3. Agueda A ,
      4. Monti S , et al
      . 2018 update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2020;79:19–30.doi:10.1136/annrheumdis-2019-215672 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31270110
      OpenUrlAbstract/FREE Full Text
    16. ↵
      2. Maz M ,
      3. Chung SA ,
      4. Abril A , et al
      . 2021 American College of Rheumatology/Vasculitis Foundation guideline for the management of giant cell arteritis and Takayasu arteritis. Arthritis Rheumatol 2021;73:1349–65.doi:10.1002/art.41774 pmid:http://www.ncbi.nlm.nih.gov/pubmed/34235884
      OpenUrlPubMed
    17. ↵
      2. Calderón-Goercke M ,
      3. Loricera J ,
      4. Aldasoro V , et al
      . Tocilizumab in giant cell arteritis. observational, open-label multicenter study of 134 patients in clinical practice. Semin Arthritis Rheum 2019;49:126–35.doi:10.1016/j.semarthrit.2019.01.003 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30655091
      OpenUrlPubMed
    18. ↵
      2. Adler S ,
      3. Reichenbach S ,
      4. Gloor A , et al
      . Risk of relapse after discontinuation of tocilizumab therapy in giant cell arteritis. Rheumatology 2019;58:1639–43.doi:10.1093/rheumatology/kez091 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30915462
      OpenUrlPubMed
    19. ↵
      2. Stone JH ,
      3. Han J ,
      4. Aringer M , et al
      . Long-Term effect of tocilizumab in patients with giant cell arteritis: open-label extension phase of the giant cell arteritis Actemra (GiACTA) trial. Lancet Rheumatol 2021;3:e328–36.doi:10.1016/S2665-9913(21)00038-2
      OpenUrl
    20. ↵
      2. Li J ,
      3. Li M ,
      4. Tian X , et al
      . Tofacitinib in patients with refractory Takayasu's arteritis. Rheumatology 2020;59:e95–8.doi:10.1093/rheumatology/keaa281 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32591815
      OpenUrlPubMed
    21. ↵
      2. Kuwabara S ,
      3. Tanimura S ,
      4. Matsumoto S , et al
      . Successful remission with tofacitinib in a patient with refractory Takayasu arteritis complicated by ulcerative colitis. Ann Rheum Dis 2020;79:1125–6.doi:10.1136/annrheumdis-2019-216606 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32213500
      OpenUrlFREE Full Text
    22. ↵
      2. Sato S ,
      3. Matsumoto H ,
      4. Temmoku J , et al
      . A case of Takayasu arteritis complicated by refractory ulcerative colitis successfully treated with tofacitinib. Rheumatology 2020;59:1773–5.doi:10.1093/rheumatology/kez580 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31776552
      OpenUrlPubMed
    23. ↵
      2. Wang C-R ,
      3. Tsai Y-S ,
      4. Liu Y-W , et al
      . Extended-Release tofacitinib improves refractory Takayasu's arteritis. Scand J Rheumatol 2022;51:72–5.doi:10.1080/03009742.2021.1911054 pmid:http://www.ncbi.nlm.nih.gov/pubmed/34106042
      OpenUrlPubMed
    24. ↵
      2. Kong X ,
      3. Sun Y ,
      4. Dai X , et al
      . Treatment efficacy and safety of tofacitinib versus methotrexate in Takayasu arteritis: a prospective observational study. Ann Rheum Dis 2022;81:117–23.doi:10.1136/annrheumdis-2021-220832 pmid:http://www.ncbi.nlm.nih.gov/pubmed/34362744
      OpenUrlAbstract/FREE Full Text
    25. ↵
      2. Rathore U ,
      3. Thakare DR ,
      4. Patro P , et al
      . A systematic review of clinical and preclinical evidences for Janus kinase inhibitors in large vessel vasculitis. Clin Rheumatol 2022;41:33–44.doi:10.1007/s10067-021-05973-4 pmid:http://www.ncbi.nlm.nih.gov/pubmed/34729652
      OpenUrlPubMed
    26. ↵
      2. Zhang H ,
      3. Watanabe R ,
      4. Berry GJ , et al
      . Inhibition of JAK-STAT signaling suppresses pathogenic immune responses in medium and large vessel vasculitis. Circulation 2018;137:1934–48.doi:10.1161/CIRCULATIONAHA.117.030423 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29254929
      OpenUrlAbstract/FREE Full Text
    27. ↵
      2. Corbera-Bellalta M ,
      3. Planas-Rigol E ,
      4. Lozano E , et al
      . Blocking interferon γ reduces expression of chemokines CXCL9, CXCL10 and CXCL11 and decreases macrophage infiltration in ex vivo cultured arteries from patients with giant cell arteritis. Ann Rheum Dis 2016;75:1177–86.doi:10.1136/annrheumdis-2015-208371 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26698852
      OpenUrlAbstract/FREE Full Text
    28. ↵
      2. Régent A ,
      3. Terrier B ,
      4. Legendre P , et al
      . Efficacy of baricitinib for refractory large-vessel vasculitis. Rheumatology 2021;60:e389–91.doi:10.1093/rheumatology/keab541 pmid:http://www.ncbi.nlm.nih.gov/pubmed/34247230
      OpenUrlPubMed
    29. ↵
      2. Prigent K ,
      3. Aouba A ,
      4. Aide N , et al
      . Jak inhibitor effectiveness in giant-cell arteritis with large-vessel involvement assessed by 18F-FDG PET-CT. Clin Nucl Med 2022;47:234–5.doi:10.1097/RLU.0000000000003913 pmid:http://www.ncbi.nlm.nih.gov/pubmed/34653043
      OpenUrlPubMed
    30. ↵
      2. Langford CA ,
      3. Cuthbertson D ,
      4. Ytterberg SR , et al
      . A randomized, double-blind trial of abatacept (CTLA-4Ig) for the treatment of giant cell arteritis. Arthritis Rheumatol 2017;69:837–45.doi:10.1002/art.40044 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28133925
      OpenUrlPubMed
    31. ↵
      2. Cid MC ,
      3. Unizony S ,
      4. Pupim L , et al
      . OP0059 MAVRILIMUMAB (ANTI GM-CSF RECEPTOR Α MONOCLONAL ANTIBODY) REDUCES RISK OF FLARE AND INCREASES SUSTAINED REMISSION IN A PHASE 2 TRIAL OF PATIENTS WITH GIANT CELL ARTERITIS. Ann Rheum Dis 2021;80:31.1–2.doi:10.1136/annrheumdis-2021-eular.1915
      OpenUrl
    32. ↵
      2. Mukhtyar C ,
      3. Lee R ,
      4. Brown D , et al
      . Modification and validation of the Birmingham vasculitis activity score (version 3). Ann Rheum Dis 2009;68:1827–32.doi:10.1136/ard.2008.101279 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19054820
      OpenUrlAbstract/FREE Full Text
    33. ↵
      2. Kermani TA ,
      3. Warrington KJ ,
      4. Cuthbertson D , et al
      . Disease relapses among patients with giant cell arteritis: a prospective, longitudinal cohort study. J Rheumatol 2015;42:1213–7.doi:10.3899/jrheum.141347 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25877501
      OpenUrlAbstract/FREE Full Text
    34. ↵
      2. Keystone EC ,
      3. Genovese MC ,
      4. Schlichting DE , et al
      . Safety and efficacy of Baricitinib through 128 weeks in an open-label, longterm extension study in patients with rheumatoid arthritis. J Rheumatol 2018;45:14–21.doi:10.3899/jrheum.161161 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28811354
      OpenUrlAbstract/FREE Full Text
    35. ↵
      2. Keystone EC ,
      3. Taylor PC ,
      4. Drescher E , et al
      . Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis 2015;74:333–40.doi:10.1136/annrheumdis-2014-206478 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25431052
      OpenUrlAbstract/FREE Full Text
    36. ↵
      2. Taylor PC ,
      3. Keystone EC ,
      4. van der Heijde D , et al
      . Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 2017;376:652–62.doi:10.1056/NEJMoa1608345 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28199814
      OpenUrlCrossRefPubMed
    37. ↵
      2. Genovese MC ,
      3. Kremer J ,
      4. Zamani O , et al
      . Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med 2016;374:1243–52.doi:10.1056/NEJMoa1507247 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27028914
      OpenUrlCrossRefPubMed
    38. ↵
      2. Fleischmann R ,
      3. Schiff M ,
      4. van der Heijde D , et al
      . Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol 2017;69:506–17.doi:10.1002/art.39953 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27723271
      OpenUrlPubMed
    39. ↵
      2. Fleischmann R ,
      3. Takeuchi T ,
      4. Schiff M , et al
      . Efficacy and safety of long-term Baricitinib with and without methotrexate for the treatment of rheumatoid arthritis: experience with Baricitinib monotherapy continuation or after switching from methotrexate monotherapy or Baricitinib plus methotrexate. Arthritis Care Res 2020;72:1112–21.doi:10.1002/acr.24007 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31233281
      OpenUrlPubMed
    40. ↵
      2. Tanaka Y ,
      3. Ishii T ,
      4. Cai Z , et al
      . Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis: a 52-week, randomized, single-blind, extension study. Mod Rheumatol 2018;28:20–9.doi:10.1080/14397595.2017.1307899 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28440680
      OpenUrlCrossRefPubMed
    41. ↵
      2. Spiera RF ,
      3. Paget S ,
      4. Spiera H
      . Methotrexate in giant-cell arteritis. Ann Intern Med 2001;135:1006–7.doi:10.7326/0003-4819-135-11-200112040-00018 pmid:http://www.ncbi.nlm.nih.gov/pubmed/11730407
      OpenUrlPubMed
    42. ↵
      2. Sunzini F ,
      3. McInnes I ,
      4. Siebert S
      . Jak inhibitors and infections risk: focus on herpes zoster. Ther Adv Musculoskelet Dis 2020;12:1759720X20936059.doi:10.1177/1759720X20936059 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32655703
      OpenUrlPubMed
    43. ↵
      2. Singh JA ,
      3. Saag KG ,
      4. Bridges SL , et al
      . 2015 American College of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 2016;68:1–26.doi:10.1002/art.39480 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26545940
      OpenUrlPubMed
    44. ↵
      2. Smolen JS ,
      3. Landewé RBM ,
      4. Bijlsma JWJ , et al
      . EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020;79:685–99.doi:10.1136/annrheumdis-2019-216655 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31969328
      OpenUrlAbstract/FREE Full Text
    45. ↵
      1. Administration USFaD
      . FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions, 2021. Available: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death
    46. ↵
      2. Taylor PC ,
      3. Weinblatt ME ,
      4. Burmester GR , et al
      . Cardiovascular safety during treatment with Baricitinib in rheumatoid arthritis. Arthritis Rheumatol 2019;71:1042–55.doi:10.1002/art.40841 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30663869
      OpenUrlPubMed
    47. ↵
      2. Kermani TA ,
      3. Cuthbertson D ,
      4. Carette S , et al
      . The Birmingham vasculitis activity score as a measure of disease activity in patients with giant cell arteritis. J Rheumatol 2016;43:1078–84.doi:10.3899/jrheum.151063 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27036388
      OpenUrlAbstract/FREE Full Text

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    Footnotes

    • Handling editor Josef S Smolen

    • Contributors All authors were involved in drafting the article or revising it critically for important intellectual content, and approved the final version to be submitted for publication. MJK and KJW had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Guarantor of study: MJK. Study conception and design: MJK and KJW; acquisition of data: MJK, KJW and JMJ; analysis and interpretation of data: REG, CSC, MJK, KJW, ELM, AD-G and CMW.

    • Funding Eli Lilly and Company provided funding to support the completion of this investigator-initiated study.

    • Competing interests KJW (principal investigator) and JMJ (study coordinator) received support through funds paid to Mayo Clinic, from Eli Lilly, to assist in the completion of this study.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.