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Abstract
Objective To investigate the treatment efficacy and safety of baricitinib in patients with refractory Takayasu arteritis (TAK).
Methods We performed a prospective cohort study in which baricitinib 4 mg daily was prescribed to patients with refractory TAK, combined with oral glucocorticoids (GCs).
Results 10 patients with refractory TAK were enrolled with a median age of 28 (IQR=22–37) years, median disease duration of 50 (IQR=24–65) months. The median dose of GCs was 10 (IQR=8.1–22.5) mg prednisone or equivalence dosage at baseline. At 6 months of baricitinib treatment, 6/10 (60%) patients had an overall treatment response. During an average follow-up of 15.3 (range 4–31) months, 4/10 (40%) patients maintained overall treatment response. 8/10 (80%) patients tapered or maintained the same dose of GCs with no change of the combined classical synthetic disease-modifying antirheumatic drugs. Two patients discontinued GCs at 18 and 24 months and were in continuous remission till the end of the study. One patient withdrew baricitinib due to liver dysfunction.
Conclusion Baricitinib 4 mg daily is effective for refractory TAK and is well tolerated.
- Vasculitis
- Therapeutics
- Antirheumatic Agents
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information. All data relevant to the study are included in the article.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Takayasu’s arteritis (TAK) often manifests relapsing disease courses and requires glucocorticoid and classical synthetic disease-modifying antirheumatic drugs to maintain disease remission, but some patients are resistant to the conventional therapy.
Janus kinase (JAK)-signal transducer and activator of the transcription pathway is involved in the pathogenesis of TAK. Tofacitinib, a JAK inhibitor, has been recently recommended for treating refractory TAK.
WHAT THIS STUDY ADDS
In patients with refractory TAK, baricitinib 4 mg daily reached an overall treatment response in 60% of the patients with no severe adverse events.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Baricitinib is effective for refractory TAK and is well tolerated, therefore, it may be a treatment alternative for refractory TAK.
Introduction
Takayasu’s arteritis (TAK) is a chronic systemic large-vessel vasculitis typically affecting the aorta and its major branches. TAK mainly occurs in young women. Chronic granulomatous inflammation of the arterial walls can cause structural changes of the involved arteries and finally leads to stenosis, occlusion and aneurysm formation. Relapsing is the characteristic theme of the majority of patients with TAK.1 Maintaining the disease in long-term remission and reducing relapses are the goals of the management and are also the most challenging part. Glucocorticoids (GCs) are the foundation of TAK treatment, but two-thirds of the TAK patients present a relapsing course when tapering GCs.2 Therefore, according to current guidelines, classical synthetic disease-modifying antirheumatic drugs (csDMARDs) are applied to aid GCs tapering while maintaining the disease in remission.3 In clinical practice, conventional synthetic csDMARDs (azathioprine, methotrexate, leflunomide, mycophenolate mofetil, tacrolimus) are the options for induction and maintain remission in the treatment of TAK. However, some patients still have relapses even being treated with GCs combined with conventional csDMARDs when GCs were tapered. These patients are regarded as refractory. Biological csDMARDs (bDMARDs) (of tumour necrosis factor inhibitors, tocilizumab or secukinumab) were reported to be effective in the treatment of refractory TAK. However, some patients are resistant to these csDMARDs and bDMARD csDMARDs. Therefore, unmet clinical needs for novel drugs remain for TAK.
Cumulating evidence discovered the promising effect of Janus kinase (JAK) inhibitors in controlling TAK. JAK inhibitors are synthetic small molecule compounds that inhibit the JAK- signal transducer and activator of the transcription (STAT) pathway and can be given orally. JAK inhibitors have shown efficacy in multiple autoimmune diseases and autoinflammatory diseases.4 They suppress the activation of multiple immune cells (effector T cells, macrophage, NK cells) and reduce the release of type I proinflammatory cytokines.5 In vitro studies also showed that JAK inhibitors could suppress the activation of aortic adventitial fibroblasts and reduce ECM production, potentially halting the progression of arterial fibrosis.6 Tofacitinib, a JAK1/JAK3 inhibitor, can induce TAK remission and prevent relapses in observational studies and was recommended by the most recent European Alliance of Associations for Rheumatology (EULAR) recommendations.3 7–9 One study showed that interleukin (IL)-12 and IL-23 are central to the TAK pathogenesis. These cytokines activate downstream JAK2.10 Therefore, targeting the JAK2 may achieve equal or better efficacy in refractory TAK patients. Baricitinib, an oral and reversible JAK1/JAK2 inhibitor, is commercially available and has been approved for treating rheumatoid arthritis and COVID-19 disease due to its immunomodulatory effects.11 Recently, a pilot study has shown the efficacy and safety of baricitinib in treating giant cell arteritis, another large-vessel vasculitis.12 However, there is limited research that assessed the efficacy and safety of baricitinib in treating refractory TAK in the literature.
In this study, we conducted a prospective cohort study to evaluate the efficacy and safety of baricitinib in patients with refractory TAK.
Methods
Study design and patient recruitment
This is a single-centre prospective study conducted in Peking Union Medical College Hospital (PUMCH), a national tertiary referral centre for TAK in China. We consecutively enrolled patients with refractory TAK from 1 November 2021 to 31 August 2022. All the patients fulfilled the modified 1990 American College of Rheumatology classification criteria for TAK.13 All patients had active disease at baseline and were refractory to at least two csDMARDs. Patients were considered as refractory if they had persistently active disease under the csDMARD therapy or had relapse on the maintenance therapy despite they had ever reached remission.3 Patients were excluded from the study if they had any of the following: active infections, thrombosis, liver dysfunction, renal insufficiency and malignancy.
Data collection
All the patients enrolled were registered in the Chinese Registry for Systemic Vasculitis (CRSV).14The baseline data and the related data during each follow-up visits were obtained from this registry database, including demographic data, disease duration, clinical manifestations and medication history (dosage of GC and prior treatment history of csDMARDs) as well as adverse events at each follow-up visit. Active disease was defined by the National Institutes of Health criteria15 or the 2018 EULAR recommendations for large vessel vasculitis3 or the general assessment of physician. All the enrolled patients met the definition of refractory TAK and were prescribed baricitinib 4 mg per day orally, which was added to the current treatment regimen csDMARDs (methotrexate, leflunomide and/or hydroxychloroquine, see details in table 1). So there is no wash-out period. Other JAK inhibitors such as tofacitinib were stopped thereafter without washout period. Patients were followed up at clinics 1 month after the initiation of baricitinib and then every 3–6 months until the cessation of baricitinib or until the end of this study. Laboratory tests and imaging of the arteries involved were repeated at predefined intervals by CRSV during the study period, that is, Doppler ultrasonography for the involved vessels every 3–6 months and CTA (CT angiogram) every 1 or 2 years. The laboratory tests including the complete blood count, serum liver and kidney function tests, acute phase reactants, serum IL-6 and tumour necrosis factor (TNF) were performed at each follow-up visit. At baseline, multiple imaging techniques, including CTA, contrast-enhanced ultrasound and conventional ultrasonography of all the accessible arteries, were applied to comprehensively assess the pattern of the arteries involved and were classified according to the Numano classification criteria.16 Serial vascular Doppler ultrasonography was performed to measure the mural thickness and the lumen diameter of the common carotid arteries (CCA) and subclavian arteries (SCA). The ultrasonography was conducted by two experienced physicians who are specialised for vascular ultrasound.
Baseline characteristics of the recruited patients
Baricitinib would be discontinued when considered as ineffective if the patient presents with any of the following: (1) no decrease in both erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) levels measured at two consecutive visits; (2) the mural thickness of CCA or SCA increased over 2 mm or vascular stenosis deteriorated at two consecutive measurements; (3) disease relapses defined by EULAR criteria or (4) when adverse events occurred.
Outcomes
Efficacy and safety of baricitinib were assessed in this study. The primary endpoint of this study was the overall response rate of baricitinib treatment at 6 months. The treatment response was defined as previously described.17 A complete response (CR) was defined as no evidence of active disease: (1) ESR<20 mm/hour and CRP<10 mg/L, (2) no progression of vessel damage and (3) the dose of GC<15 mg/day prednisone (or equivalence). A partial response (PR) was defined as (1) ESR<40 mm/hour or decrease over 50% compared with baseline, (2) CRP<20 mg/L or decrease over 50% compared with baseline and (3) not fulfilling the other two criteria of CR. Patients who did not meet the partial treatment response criteria were considered as having no response (NR) to baricitinib. Relapses was defined according to 2018 EULAR recommendations3: the presence of typical signs or symptoms of TAK with at least one of the following: (1) current activity on imaging or biopsy; (2) ischaemic complications attributed to TAK or (3) Persistently elevated inflammatory markers excluding other causes. Among the patients with disease relapses, those who had clinical features of ischaemia or evidence of active aortic inflammation resulting in progressive aortic or large vessel dilatation, stenosis or dissection were classified as major relapse, while those without the above features were defined as minor relapse.
Adverse events were recorded at each visit. Liver dysfunction was defined as the elevation of ALT or AST over the upper normal limit. Adverse events of special interest included infections, venous thrombosis, malignancy, cardiovascular events, renal dysfunction and liver dysfunction related to baricitinib.
Statistical analysis
Continuous variables were evaluated using a non-normal distribution and were expressed as the median and IQRs. Categorical data were expressed as numbers and percentages. Normal continuous data were analysed using t-test, while non-normal continuous and categorical data were analysed using the two-sided Mann-Whitney U test. Values of p<0.05 were considered as statistically significant. All the statistical analyses were conducted by R software (V.4.1.2, R Foundation for Statistical Computing). All figures were generated using the R package ggplot2 (V.3.3.5).
Results
Patient characteristics
10 patients with refractory TAK were consecutively enrolled in the study. The detailed baseline characteristics are shown in table 1. Nine patients were female and only one patient was male. The median age at enrolment was 28 (IQR=22–37) years, and the TAK disease duration at the initiation of baricitinib treatment was 50 (IQR=24–65) months. Most of the included patients were classified to Numano type V (n=5, 50%) and type I (n=4, 40%), while only one patient was type II (10%). At baseline, five (50%) patients experienced major relapse, the other five (50%) patients experienced minor relapse according to the EULAR criteria. Seven patients (70%) had active symptoms related to TAK at baseline, among whom five patients (50%) had active ischaemic symptoms and two (20%) patients had the constitutional symptoms alone. The median dose of GC was 10 (IQR=8.1–22.5) mg prednisone or equivalence, and two patients received methylprednisolone pulse therapy prior to baricitinib treatment. All patients were treated with at least two immunosuppressants before the baricitinib initiation.
Efficacy of baricitinib
Patients were followed up for a median of 15.3 (range 4–31) months. At 6 months of baricitinib treatment, six (6/10, 60%) patients had an overall treatment response to baricitinib, among whom four (4/10, 40%) patients reached CR and two (2/10, 20%) patients achieved PR. Of note, three (3/10, 30%) patients withdrew baricitinib at 4 months due to inadequate treatment responses and persistently active disease. At 12 months of baricitinib treatment, all but one patient maintained the same treatment response as 6 months. The patient had a CR at 6 months but developed lesions in a new artery territory and subsequently stopped baricitinib at 12 months. At the end of the study follow-up, four (4/10, 40%) patients maintained overall treatment response, of whom three (3/10, 30%) patients maintained CR throughout the follow-up duration and one (1/10, 10%) patient maintained PR to baricitinib.
All patients experienced normalisation of CRP and ESR and had decreased levels of IL-6 and TNF at 1-month postbaricitinib initiation. Compared with baseline, although not significantly, the median ESR at 6 months of baricitinib treatment decreased from 20.5 (IQR=12.5–24) mm/hour to 8 (IQR=6.0–15.0) mm/hour (p=0.10), CRP decreased from 14.5 (IQR=9.4–20.7) mg/L to 0.66 (IQR=0.4–12.6) mg/L (p=0.23), IL-6 decreased from 12.0 (IQR=5.9–20.4) pg/L to 2.8 (IQR=2.2–12.5) pg/L (p=0.18) and TNF decreased from 7.7 (IQR=5.1–52.9) pg/L to 5.8 (IQR=4.4–10.7) pg/L (p=0.30). The patients who maintained CR throughout the follow-up period had normal inflammatory parameters (figure 1A–D). Three patients who discontinued the treatment had elevated levels of CRP, ESR and IL-6.
Changes in the levels of inflammatory parameters and ultrasonography during the baricitinib treatment: erythrocyte sedimentation rate (ESR) (A), C reactive protein (CRP) (B), interleukin-6 (IL-6) (C), tumour necrosis factor (TNF) (D), mural thickness of common carotid artery (CCA) (E), lumen diameter of CCA (F), the mural thickness of subclavian artery (SCA) (G), and lumen diameter of SCA (H). Of note, only the stenosed arteries were measured for lumen diameter and plotted in the figure.
Eight (8/10, 80%) patients showed improvement and stabilisation of arterial lesions in CTA and improvement or stabilisation of mural thickness and lumen diameter of the carotid and SCA, as measured by serial Doppler ultrasonography during the follow-up visits (table 2, figure 1E–H). At 6 months or the end of baricitinib treatment (for patients who stopped baricitinib before 6 months), the median mural thickness decreased from 1.90 (IQR=1.50–2.30) mm to 1.55 (IQR=1.50–1.83) mm (p=0.20) in the CCAs, and 2.00 (IQR=1.88–2.60) mm to 1.90 (IQR=1.60–2.27) mm (p=0.17) in the SCA, as measured at the thickest site by ultrasound. Two (2/10, 20%) patients had worsening lesions: Patient three developed a novel lesion in the left SCA at month 12 and required revascularisation at month 16 due to the persistent occlusion of the right CCA; Patient 10 had recurrent in-stent stenosis in the coronary artery (left anterior descending artery) at month 4, and she received percutaneous transluminal coronary angioplasty thereafter.
Treatment response of baricitinib
Throughout the study period, eight (8/10, 80%) patients tapered or maintained the same dose of GCs, while two (2/10, 20%) patients required increased GCs dose at month 4 due to the inadequate responses to baricitinib and persistent active disease and these patients discontinued baricitinib treatment. Seven (7/10, 70%) patients gradually tapered to or maintained GCs dose at ≤10 mg prednisone daily. For the patients who reached CR or PR to baricitinib therapy, the median GCs dose decreased from 10 mg (IQR=10–20) prednisone or equivalence daily at baseline to 7.5 mg (IQR=7.5–10) daily at 6 months (p=0.058). Two patients (20%, patient 1 and 6) discontinued GCs at 18 and 24 months, respectively, with continuous remission till the end of the follow-up (figure 2). All the patients received one or two csDMARDs in combination with baricitinib, and no dose or type adjustment was made during the study period (figure 2).
Glucocorticoid and conventional synthetic csDMARDs dosage in the follow-up of the study. No change in csDMARDs dosage was made in the study follow-up period. csDMARDs, classical synthetic disease-modifying antirheumatic drugs; GCs, glucocorticoids; HCQ, hydroxychloroquine; LEF, Leflunomide; MTX, methotrexate.
Safety of baricitinib
No severe adverse events occurred during the study period. One patient (1/10, 10%, patient 1) experienced elevated aminotransferase at 18 months after the initiation of baricitinib. Baricitinib was then discontinued, and her liver enzymes gradually returned to the normal range. One patient (patient 10) had persistent angina and recurrent in-stent stenosis in the involved coronary artery, which was found to be caused by active TAK disease. No severe infection requiring antibiotics or deep venous thrombosis, malignancy, cardiovascular events occurred during the study period.
Discussion
Managing refractory TAK patients is challenging in clinical practice and the evidence is scarce. The most updated guidelines recommended tocilizumab or TNF inhibitors for TAK patients who do not respond to standard therapy or repeatedly experience relapses.3 However, the recommendations were based on small-size randomised controlled trials (RCTs) with borderline significance or uncontrolled open-label studies.3 To our knowledge, this is the first prospective study to investigate the efficacy and safety of baricitinib in refractory TAK patients. We observed that baricitinib administered at 4 mg per day reached an overall treatment response in 60% of the refractory TAK patients with no severe safety concerns, indicating that baricitinib was well tolerated and potentially effective.
Very recently, JAK inhibitors have emerged as promising drugs in controlling TAK. Basic science research has shown that both TAK patients and mouse model engrafted with human inflamed arteries from TAK patients had aberrantly activated JAK/STAT signalling pathway.18 19 In vitro treatment with JAK inhibitors inhibits the activation of circulating T cells and decrease polarisation to Th1 and Th17 cells.19 Therefore, targeting JAK-STAT pathway was theoretically effective in controlling TAK. Baricitinib and tofacitinib are both JAK inhibitors that are widely used in the treatment of rheumatic diseases in which inflammation is the most prominent feature of the disease, such as rheumatoid arthritis and spondyloarthritis. Baricitinib has stronger inhibition on JAK2 compared with tofacitinib, this may translate to better efficacy in treating refractory TAK. Theoretically, baricitinib alleviates TAK through the following mechanisms: (1) inhibition of the granulocyte-macrophage colony-stimulating factor, which was highly expressed in TAK patients20 21 and (2) blocking the aberrant IL-12/IL-23-JAK2 pathway10 22 23 and thereby reduce the production of inflammatory cytokines, including IL-6 and IL-17A.24 25 In this study, we demonstrated the potential efficacy of baricitinib in treating refractory TAK although a head-to-head comparison is needed to investigate the superiority of baricitinib to tofacitinib.
There is very limited evidence for the efficacy or safety of JAK inhibitors in the treatment of refractory TAK. In the literature, two cohort studies and several case series assessed the efficacy and safety of tofacitinib in TAK patients. The reported overall response rate ranged between 60.0% and 87.0%.7–9 26 The response rate of patients with refractory TAK to tofacitinib was 60.87%–78.9% at 12 months.7 Only one published case study reported successful disease control by baricitinib in overlapping TAK and GCA refractory to methotrexate, cyclophosphamide, tocilizumab and infliximab.27 In this study, we investigated the efficacy of baricitinib in TAK patients who were refractory to at least two csDMARDs. 60% of the refractory TAK patients responded to baricitinib, with decreased inflammatory parameters and improved or stable artery lesions. The baseline disease courses, ESR, CRP, TNF and IL-6 did not differ between the responders and non-responders. At 6 months of baricitinib treatment, the levels of inflammatory parameters, mural thickness of the involved arteries (CCA and SCA) and the dosage of GCs used decreased compared with baseline, although not statistically significant, probably due to the small sample size. Of note, two of the included patients who had ever failed to respond IL-17A inhibitors had overall responses to baricitinib and they maintained the responses throughout the study periods. Therefore, baricitinib may induce long-term disease control for patients who failed csDMARDs and bDMARDs. However, for the patients who failed TNF inhibitors or tocilizumab, they did not respond to baricitinib treatment. The difference in responses to baricitinib may reflect distinct underlying mechanisms related to the disease heterogeneity, which requires further exploration. Our study demonstrated that baricitinib was effective for TAK patients.
No severe adverse events were observed in this study. One patient had transient hepatocellular injury related to baricitinib but remitted after the drug cessation. As previously reported, liver dysfunction is a common adverse event related to baricitinib use but was generally asymptomatic, transient and rarely led to severe or life-threatening conditions.28 29 Prior RCTs had reported cases of herpes zoster, venous thrombosis and increased risks of cardiovascular diseases and malignancies with the use of JAK inhibitors.30 31 No such event was observed during the study period, this may partially because of the follow-up time was relatively short and the sample size was small. In our study, baricitinib is generally safe and well tolerated.
The results should be interpreted considering the following limitations: first, this study had a small sample size and no control arm, which potentially increased the risk of bias. Of note, all patients in this study had refractory TAK. The comparations in the treatment efficacy of baricitinib vs other csDMARDs will need further evaluation. Second, the follow-up time is relatively short, so some adverse events or relapses could not be observed. Third, we serially assessed the mural thickness and lumen diameter of the CCA and SCA to reflect treatment responses because these arteries were superficial and could be accurately assessed by noninvasive methods. Other involved arteries were not included in the analysis.
In conclusion, baricitinib 4 mg per day is effective for refractory TAK and is well tolerated. Baricitinib may be a treatment alternative for refractory TAK. Double-blinded randomised clinical trials are required to validate the efficacy and safety of baricitinib in treating refractory TAK and comparison with other csDMARDs should be carried out in the future.
Supplemental material
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information. 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 this study was approved by the ethics committee of PUMCH (No. S-478). Informed consents were obtained from each patient in compliance with the Declaration of Helsinki. Participants gave informed consent to participate in the study before taking part.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
ZZ and CF contributed equally.
Contributors XT and XZ designed and supervised the study; XT, JL, YY, LZ and SJ recruited and followed the patients. ZZ, CF and LW collected clinical information and performed the statistical analysis. ZZ, CF, JL and XT drafted and revised the manuscript. All the authors read and approved for the manuscript. XT was the guarantor of this study.
Funding This study was supported by the Chinese National Key Technology R&D Program, Ministry of Science and Technology (2021YFC2501300); Beijing Municipal Science and Technology Commission (Z201100005520022,23, 25-27); CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-005); National High Level Hospital Clinical Research Funding (2022-PUMCH-B-013, D-009).
Competing interests None declared.
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.