JAK Inhibitors for the Treatment of Axial Spondyloarthritis Текст научной статьи по специальности «Фундаментальная медицина»

34 2

2023

G2022 The Author(s).

This work is licensed under a Creative Commons Attribution 4.0 International L

REVIEW

JAK Inhibitors for the Treatment of Axial Spondylarthritis

Kalliopi Klavdianou12 , Charalampos Papagoras3 , Xenofon Baraliakos1

1Rheumazentrum Ruhrgebiet Herne, Ruhr-University Bochum, Germany, 2Department of Rheumatology, 'Asklepieion' General Hospital, Athens, Greece, 3 First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece

Axial spondylarthritis (axSpA) is a chronic disease characterized by inflammation and new bone formation that causes pain and results in functional impairment and long-term disability. Biologic agents targeting TNFa or IL-17 have been the mainstay of treatment for patients with axSpA and an inadequate response to nonsteroidal anti-inflammatory drugs. However, a proportion of axSpA patients do not respond adequately to those drugs either, creating the need to target alternative disease pathways. Janus kinase (JAK) inhibitors (JAKis) are a group of targeted synthetic disease-modifying antirheumatic drugs that block the intracellular signalling pathway of several proinflammatory cytokines. Given their efficacy in the management of rheumatoid arthritis and that JAKs mediate the signalling of cytokines involved in the pathogenesis of axSpA as well, JAKis have been successfully tested in a number of clinical trials in axSpA, which has led to the approval of two compounds, tofacitinib and upadacitinib for the treatment of the disease. Data from new clinical trials, long-term extensions of completed trials, and real-life observational studies that continuously emerge will shape the efficacy and safety profile and ultimately the place of JAKis in the treatment of AxSpA.

Mediterr J Rheumatol 2023;34(2):129-8 https://doi.org/10.31138/mjr.34.2.129

Article Submitted: 11 Nov 2022; Revised Form: 30 Nov 2022; Article Accepted: 30 Nov 2022; Available Online: 30 Jun 2023

Keywords: JAK inhibitors, axial spondylarthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis

INTRODUCTION

Janus kinases (JAKs) are a group of intracellular tyrosine kinases with four members in humans [JAK1, JAK2, JAK3, and Tyrosine kinase2 (Tyk2)], involved in the signalling of plenty of cytokines and growth factors.1 Upon binding of a cytokine molecule to its cell membrane

receptor, a specific combination of JAKs Corresponding Author: associate with the

Xenofon Baraliakos cytoplasmic domain of

Rheumazentrum Ruhrgebiet Herne the receptor leading

Ruhr-University Bochum, Germany both to JAK and to the

E-mail: Xenofon.Baraliakos@ receptor phosphoryla-

elisabethgruppe.de tion. This enables the

recruitment of transcription factors of the signal transducer and activator of transcription (STAT) family. Each receptor/JAK complex associates with specific STATs which are subsequently activated via phosphorylation by JAKs. Following this step STATs translocate to the nucleus and regulate target gene expression.JAK inhibitors (JAKis) are a relatively new class of drugs that bind and inhibit the enzymatic activity of JAKs. Several JAKis have been developed for a broad array of clinical applications, including immunology and hematology.2 Among them, at least 5 compounds have already been licensed for rheumatologic indications across the globe forming the first members of the so-called targeted synthetic disease modifying antirheumatic drugs (tsDMARDs): tofacitinib,

Cite this article as: Klavdianou K, Papagoras C, Baraliakos X. JAK Inhibitors for the Treatment of Axial Spondyloarthritis. Mediterr J Rheumatol 129 2023;34(2):129-8.

baricitinib, upadacitinib, filgotinib, and peficitinib. They are small molecules which can be taken up orally in contrast to the traditional biological DMARDs (bDMARDs). Most literature regarding their mode of action and clinical effects in inflammatory arthritis derive from studies in rheumatoid arthritis (RA), which is the first rheumatic condition those drugs have been approved for. Indeed, in RA JAKis modulate the intracellular signalling of plenty of cytokines within a multi-level and intertwined cytokine network resulting in high levels of disease response, often surpassing TNFa inhibitors.3,4 They have also an acceptable safety profile, with some common features across the class, such as an increased risk for herpes zoster.5

The pathogenesis of axial spondylarthritis (axSpA) is multifactorial involving various immune cells and cytokines. Innate immune cells such as dendritic cells, macrophages, mast cells, innate-like lymphocytes (ILCs) and mucosal-associated invariant T cells (MAITs) are activated often at extra-skeletal sites, such as the gut, and release cytokines or migrate themselves to musculoskeletal structures, primarily the entheses.6,7 A number of cytokines such as ifny, IL-6, IL-12, IL-23, IL-17, and TNFa are involved in this process.8,9 Enhanced myelo-poiesis and neutrophil priming through GM-CSF also appear to contribute to the SpA-related inflammation.10,11 Several of those cytokines including ifny, IL-6, IL-12, IL-23 and GM-CSF signal directly through JAKs. On the other hand, although the "signature cytokines" of AxSpA, i.e. IL-17 and TNFa, do not depend on JAK-STAT activation, they are either downstream of JAK-dependent cytokines, such as IL-23, or their effects on target cells are modulated by other cytokines signalling via JAK.12-15 Indeed, data from animal models suggest a link connecting JAKis and the IL-23/IL-17 axis and therefore could at least partially explain the efficacy of this drug class in psoriatic arthritis (PsA) and SpA.16,17 Despite the progress in the treatment of axSpA, a significant proportion of patients do not respond adequately or are intolerant to TNFa and/or IL17 inhibitors.18,19 Therefore, drugs with alternative mechanisms of action are needed for the management of those patients. The lack of response to a single anti-cytokine therapy in SpA could be overcome by targeting a combination of cytokines. Given the paradigm of RA, targeting JAKs could be an effective approach for SpA, as well.14 Data from clinical studies reveal that JAK inhibition offers clinically significant improvements in skeletal and extra-skeletal SpA manifestations with an acceptable safety profile. In the following lines, clinical data on the use of JAK inhibitors in axSpA will be presented and the prospects created by their introduction in axSpA therapeutics will be discussed.

EFFICACY OF JAK INHIBITORS IN AXSPA

Ankylosing Spondylitis Tofacitinib

Tofacitinib is a non-selective inhibitor that inhibits JAK1, JAK3 and JAK2 in order of potency.20 Following a successful phase 2 study, a phase 3 clinical trial randomized patients with ankylosing spondylitis (AS) who were either naive to bDMARDs (77%) or TNFa inhibitor inadequate responders (TNFi-IR, 22%) to tofacitinib 5 mg twice per day or placebo. At 16 weeks, tofacitinib-treated patients achieved Assessment of SpondyloArthritis International Society 20% improvement (ASAS 20), the study primary endpoint, at a significantly higher proportion than those treated with placebo (56.4% us 29.4%, p<0.0001) (Figure 1).21 Higher levels of clinical response, such as ASAS 40 and ASAS partial remission, were also achieved more frequently with tofacitinib and sustained in the long term during the study open label extension (Table 1 ). Regarding other efficacy endpoints, tofacitinib was associated with a rapid alleviation of pain and improvements across several patient-reported outcomes including fatigue, health-related quality of life and work productivity in both its phase 2 and 3 studies.22,23 Magnetic resonance imaging (MRI) data collected during the phase 2 study revealed that approximately one third of tofacitinib-treat-ed patients achieved minimally important changes in the SPondyloArthritis Research Consortium of Canada (SPARCC) spinal and sacroiliac joint score.24 These data led to the Food and Drug Administration (FDA) approval of tofacitinib as a treatment for patients with active AS with previous failure or intolerance to at least one TNFa blocker25 and the recent European Medicines Agency (EMA) approval for the treatment of adult patients with active AS who have responded inadequately to conventional therapy.26

Filgotinib

A phase 2 study of the selective JAK1 inhibitor filgotinib in patients with active AS and inadequate response or intolerance to at least two NSAIDs or having previously received no more than one TNFa inhibitor (TORTUGA trial) was successful across a wide range of disease parameters (Table 1, Figure 1).27 Filgotinib at a daily dose of 200mg led to a significantly higher reduction from baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at week 12, compared to placebo (-1.47 vs -0.57, p<0.0001). Significant improvements in disease activity with filgotinib were observed as early as 1 week. Bath Ankylosing Spondylitis Metrology Index (BASMI) also improved significantly with filgotinib compared to placebo by week 12 (-0.75 us -0.39, p=0.0093). Regarding imaging, significant improvements in SPARCC MRI spine and sacroiliac joint scores at week 12 were seen in the filgotinib group compared with the placebo group (-5.7 us 0.52, p=0.0066 and -3.52 us 0.06, p=0.015, respec-

ASAS20 ASAS40 ASAS20 ASAS40 ASAS20 ASAS40 ASAS20 ASAS40 ASAS20 ASAS40

Deodhar, 2021 TORTUGA SELECT-AXIS-1 SELECT-AXIS-2 SELECT-AXIS-2

NSAID-IR bDMARD-IR

■> - R-axSpA ---Nr-axSpA

J Tofacitinib Filgotinib Upadacitinib Placebo

Figure 1. Efficacy of JAK inhibitors in latest clinical trials in axial spondyloarthritis: ASAS20 and ASAS40 responses are shown for filgotinib at 12 weeks, for upadacitinib at 14 weeks and for tofacitinib at 16 weeks in the respective trials. The data do not represent a head-to-head comparison, as they are taken from different studies.

*ASAS: Assessment of SpondyloArthritis international Society; R-axSpA: radiographic axial spondyloarthritis; Nr-axSpA: non-radiographic axial spondyloarthritis

tively). In a post-hoc analysis of TORTUGA, spine MRIs were assessed using the Canada-Denmark (CANDEN) MRI scoring system. Changes from baseline to week 12 in total spine score and subscores for inflammation, fat, erosion, and new bone formation at various anatomical locations were evaluated.28 Filgotinib significantly reduced spinal inflammation, particularly in the facet joints and posterolateral elements . Another post-hoc analysis of the trial revealed that SPARCC MRI sacroiliac joint erosion significantly decreased and backfill increased with filgotinib compared to placebo (p=0.02 and p=0.005, respectively) by week 12, suggesting that tissue repair starts early after treatment initiation.29

Upadacitinib

Upadacitinib, a selective JAK1 inhibitor, was investigated for the treatment of AS patients who had an inadequate response or intolerance to NSAIDs in the randomized, placebo-controlled phase 2/3 SELECT-AXIS 1 study.30 The study met its primary endpoint with 52% of patients in the 15mg once daily upadacitinib group achieving ASAS40 at week 14 compared to 26% in the placebo group (p=0.0003) (Table 1, Figure 1). Upadacitinib additionally

led to a significantly greater change of the mean ASDAS compared to placebo (-1.45 vs -0.54 respectively at week 14, p<0.0001). Moreover, Bath Ankylosing Spondylitis Disease Activity Index 50 (BASDAI50) response rates were significantly higher for upadacitinib than placebo (45% vs 23% at week 14%, p=0.0016), as well as the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES). Consistent significant improvements were also seen for mobility (BASMI), as well as AS quality of life score (ASQol) and AS Health Index. MRI assessment at week 14 also favoured upadacitinib over placebo with a treatment difference for SPARCC MRI spine score -6.71 [95% confidence interval (CI) -9.01 to -4.41, p<0.0001] and for SPARCC MRI sacroiliac joint score -3.91 (95% CI -5.05 to -2.77, p<0.0001). The one year open-label extension revealed sustained efficacy both for the patients initially randomized to upadacitinib and those who switched from placebo.31 Moreover, a post hoc analysis of SELECT-AXIS 1 showed a rapid (as early as week 2) and sustained -over 1 year- improvement in multiple pain-related outcomes including spine-specific ones, such as total and nocturnal back spinal.32 At 2 years, radiographic progression was minimal with 89.7% of patients showing an mSASSS

34 2

2023

Table 1. ASAS responses with JAK inhibitors in Phase 3 clinical trials in axSpA.

Disease Study tsDMARD* Population studied Primary endpoint ASAS 20 response to tsDMARD at week 12/14/16** (%) ASAS 20 response to PBO at week 12/14/16** (%) ASAS40 response to tsDMARD at week 12/14/16** (%) ASAS40 response to PBO at week 12/14/16** (%) ASAS20 response to tsDMARD at OLE (%) ASAS40 response to tsDMARD at OLE (%)

Deodhar A, 202121 Tofacitinib IR/intolerance to >2 NSAIDs or IR to <2 TNFi or prior bDMARD (TNFi or non-TNFi) use without IR (23%) ASAS20 at week 16 56.4 29.4 40.6 12.5 at week 48a 65.4 at week 48a 50.4

AS TORTUGA27* Filgotinib IR/intolerance to >2 NSAIDs or previous use of <1 TNFi (9.5%) Change of ASDAS from BL to week 12 76 40 38 19 n/a n/a

SELECT-AXIS 1 30t Upadacitinib IR/intolerance to >2 NSAIDs/ contraindication to NSAIDs ASAS40 at week 14 65 40 52 (NRI) 54 (observed) 26 at week 6431 b 79.6 (NRI) 93.7 (observed) at week 6431 b 72 (NRI) 84.8 (observed)

SELECT-AXIS 234 Upadacitinib IR/intolerance to <2 bDMARDs (TNFi or non-TNFi) ASAS40 at week 14 65.4 38.3 45 18 n/a n/a

nrAxSpA SELECT-AXIS 237 Upadacitinib IR/intolerance to >2 NSAIDs/ contraindication to NSAIDs or IR/intolerance to 1 bDMARD (TNFi or IL17i) (33%) ASAS40 at week 14 67 44 45 23 n/a n/a

*ln approved dosing regimen when applicable; **based on the primary endpoint; fphase 2/3 study; *phase 2 study; Continuous tofacitinib; Continuous Upadacitinib; axSpA: axial spondyloarthritis; ASAS: Assessment of SpondyloArthritis international Society; ASAS20: ASAS >20% improvement; ASAS40: ASAS >40% improvement; ASDAS: Ankylosing Spondylitis Disease Activity Score; bDMARD: biologic disease-modifying antirheumatic drug; BL: baseline; IL17i: IL-17 inhibitor; IR: inadequate response; n/a: not available; NRI: non responder imputation; NSAIDs: non-steroidal anti-inflammatory drugs; OLE: open-label extension; PBO: placebo; TNFi: TNFa inhibitor; tsDMARD: targeted synthetic disease-modifying antirheumatic drug.

increase <2 and 76.5% no mSASSS increase at all, respectively.33 SELECT-AXIS 2 (NCT04169373) was a clinical trial program which tested upadacitinib in two different axSpA populations: patients with active AS despite treatment with up to two bDMARDs (82% had been exposed to TNFi only) and patients with non-radiographic

axSpA (nr-axSpA, see below). Concerning AS refractory to bDMARDs, the trial achieved its primary outcome, that is significantly more upadacitinib-treated patients attained ASAS40 at week 14 compared to patients receiving placebo (45% vs 18%, p<0.0001)(Figure 1).34 Similar to SELECT-AXIS 1, upadacitinib was significantly better

than placebo in an array of outcomes, including ASDAS, total and nocturnal back pain, MASES, BASMI, ASQol, AS Health Index and SPARCC MRI spine and sacroiliac joint scores. Based on the above trial data upadacitinib has been approved by EMA for the treatment of active AS with inadequate response to conventional therapy35 and by FDA for patients with active AS and an insufficient response or intolerance to at least one TNFi.36

NON-RADIOGRAPHIC AXSPA

As mentioned above, the SELECT-AXIS 2 protocol included the only study of JAKis in patients with nr-axSpA and objective evidence of inflammation as shown by increased serum C-reactive protein or a positive sacroiliac joint MRI. Included patients had failed NSAIDs or a bDMARD (33%). Significantly more nr-axSpA patients on upad-acitinib 15mg daily achieved the trial primary endpoint, ASAS40 at week 14 compared to placebo (45% versus 23%, p<0.0001) (Table 1, Figure 1). Patients receiving upadacitinib showed significantly greater improvements in ASDAS, total and nocturnal back pain, MASES, ASQol, AS Health Index and SPARCC MRI spine and sacroiliac joint scores at 14 weeks of treatment.37 Based on these results, upadacitinib is the first JAKi approved for nr-axSpA by both EMA and FDA on the same conditions as in AS.38

EFFICACY OF JAK INHIBITORS IN AXIAL PSORIATIC ARTHRITIS

Although it is still unclear whether AS and PsA with axial involvement are two distinct entities with overlapping features or parts of the same disease spectrum, in clinical practice they share several common therapeutic modalities.39,40 The trials of JAKis for PsA included patients with peripheral involvement.41-46 While both tofacitinib and upadacitinib are already approved for the treatment of PsA, the efficacy of JAKis in axial PsA largely remains unknown. It was recently reported that 23.1% and 27.5% of the patients with active PsA included in SELECT-PsA 144 and SELECT-PsA 243 trials of upadacitinib in PsA had axial involvement, defined by both investigator assessment and patient reported outcome- (BASDAI >4 and BASDAI Question 2 >4 at baseline) based criteria.47 These patients demonstrated statistically greater clinical responses related to their axial involvement with upad-acitinib 15 mg compared to placebo, and consistently numerically higher responses compared to adalimumab at week 24. A retrospective analysis of pooled data from clinical studies assessed the performance of JAK inhibitors in PsA in comparison with AS.48 Five publications in PsA were included (4 with tofacitinib and 1 with filgotinib). The tofacitinib studies showed that the drug significantly improved ASQol in PsA patients, although other AxSpA-specific measures were not available to analyse. Currently, there is a single ongoing phase 2 randomised double-blind, placebo-controlled study,

PASTOR, which will assess the efficacy of tofacitinib in reducing MRI inflammation of the sacroiliac joints and the spine in patients with active axial PsA.49

SAFETY

Since JAKis may be associated with effects in normal immune pathways beyond those targeted in disease, their safety is under continuous surveillance. The overall safety profile of JAKis in clinical trials has mainly been assessed in patients with RA and seems to be comparable to that of biologic cytokine inhibitors, except for an almost 2-fold higher risk for herpes zoster.50,51 The main safety issue of JAKis, however, concerns cardiovascular (CV) adverse events (AEs) and first emerged during the approval process of baricitinib for RA.52 As a result, the regulatory authorities requested additional studies enrolling RA patients with high CV risk, in order to compare the safety of tofacitinib (ORAL surveillance trial) and baricitinib (NCT03915964) with TNFa blockers. The publication of the results of ORAL surveillance showed that the combined dosages of tofacitinib (ie, 5mg twice daily and 1 0mg twice daily) failed to meet the study endpoint of non-inferiority regarding major adverse cardiovascular events (MACE) and cancers compared to TNFi.53 Subsequently, authorities in the USA and Europe noted this risk in tofacitinib's Summary of Product Characteristics. Moreover, the FDA issued a black-box warning for increased risk for MACE, cancers and mortality, which was also extended to baricitinib and upadacitinib, and limited the prescription of all 3 drugs to patients having failed at least 1 TNFi. Recently, EMA's safety committee also recommended that JAKis be prescribed to patients at increased risk for CV events, thromboembolic events or cancer (including but not limited to those at least 65 years old and smokers) only in the absence of suitable alternatives and that reduced doses be used in those patients.54 On the other hand, a post-hoc analysis of ORAL Surveillance comparing RA patients with and without a history of atherosclerotic CV disease, suggested that in the latter group the absolute excess risk might be quite low, despite the presence CV risk factors.55 Moreover, no statistically increased risk of CV events or malignancies with tofacitinib were identified in patients with RA treated in the real-world cohort of the more recent STAR-RA study.5657 Concerns regarding gastrointestinal perforation in patients treated with JAKis have been expressed, as such a risk has been shown to be numerically, but not statistically, higher in patients treated with tofacitinib than those treated with bDMARDs.58 However, more data are needed. Laboratory abnormalities, such as anaemia, elevated transaminase and creatine phosphokinase (CPK) levels, alterations in the lipid profile, and infections, such as herpes zoster, are often seen in patients treated with JAKis, especially in those aged >65years and are

mentioned in the EULAR points-to-consider for the use of JAKis.59

As axSpA has an earlier onset in life than RA, axSpA patients are usually younger suggesting a lower CV risk and fewer comorbidities. Moreover, the concomitant use of glucocorticoids and csDMARDs is less common in ax-SpA compared to RA. However, the CV risk is known to be increased in axSpA as well60,61 while AxSpA patients may still use NSAIDs, which raise the risk for MACE and gastrointestinal AEs. An outline of safety data from JAKi trials in AxSpA follows below.

Tofacitinib

In the phase 2 trial of tofacitinib in AS, AEs with tofacitinib 5mg or 1 0mg twice daily were similar between the 2 dosing regimens, (53.8% and 51.9% versus 43.1% with placebo), with nasopharyngitis and upper respiratory tract infection being the most frequently reported.62 Two serious AEs (SAEs) led to drug discontinuation: peripheral swelling and one herpes zoster infection for 5mg twice daily and 10mg twice daily, respectively. Over the 16-week double blind period of the phase 3 trial of tofacitinib 5mg twice daily in AS, AEs were reported in 54.9% of patients receiving tofacitinib and 51.5% of patients on placebo.21 During 48 weeks of the study, no deaths, MACE, opportunistic infections or thromboembolic events were reported. Five cases (1.9% of tofacitinib-treated patients) of herpes zoster infections were reported.

Filgotinib

In the TORTUGA trial, the filgotinib and placebo group had the same total AE and infection rates. Nasopharyngitis was the most common AE.27 One case of serious lower respiratory tract infection and another of deep vein thrombosis were reported in the filgotinib arm. No malignancies or deaths were reported through 12 weeks of the study.

Upadacitinib

In SELECT AXIS 1 trial, 62% of upadacitinib- and 55% of placebo-treated patients had AEs with CPK elevation being the most common.30 Through week 14, the upadacitinib and placebo group had one serious AE each (not classified as of special interest). At one year, no serious infections, MACE, venous thromboembolic events or deaths were reported. There were 5 cases of herpes zoster corresponding to 2.1 events per 100 patient- years.31 A similar safety profile for upadacitinib was shown throughout the 14-week double blind period of the SELECT AXIS 2 studies, except for in the bDMARD-refractory group a higher incidence of serious infections (mostly COVID-19) was noted.34,37 Meta-analyses of safety data from phase 2 and 3 studies of JAKis in AS concluded that the incidence of AEs, serious AEs and treatment discontinuations did not differ

between JAK inhibitors and placebo.63,64 Furthermore, no new safety signals, such as inflammatory bowel disease (IBD), new-onset uveitis or psoriasis, have been identified so far. Importantly, more safety data on the use of JAKis in patients with AxSpA are needed from long-term extensions of randomized trials and real-world observational studies to inform the safety profile of JAKis in patients with axSpA.

DISCUSSION

Over the last decade, JAK inhibitors have emerged as a new class of drugs for the management of immune-mediated diseases and have received approval for a number of indications.65 The pathogenesis of axSpA unfolds through a complex network of inflammatory processes, some of which involve signalling through the JAK-STAT pathway, that makes axSpA a disease amenable to JAK inhibition.66 Given the previous experience with JAKis in RA, the need for new treatments for axSpA led to clinical trials of three compounds, tofacitinib, upadacitinib and filgotinib to assess their efficacy and safety in axSpA. The patient population most studied were those with radiographic axSpA who had failed NSAIDs, although most trials also included a small proportion of inadequate responders to bDMARDs. These trials yielded favourable results across several clinical domains of radiographic axSpA, including axial symptoms, enthesitis and a large set of patient-reported outcomes. Among them, the early and sustained pain relief stands out, as has been noted with JAKis in RA as well, and merits further inves-tigation.67 The recent publication of the SELECT AXIS 2 trials of upadacitinib in patients refractory to bDMARDs and patients with nr-axSpA, completed the picture by demonstrating efficacy over the whole spectrum of axSpA.

Although JAK-STAT signalling may interfere with the IL-23/IL-17 axis and perhaps with other pathways governing bone turnover,68 the effects of JAKis on ax-SpA structural progression remains to be investigated. Although early MRI data support a positive role,24,28-30 the question remains as how clinically relevant these findings on MRI are, particularly regarding the long-term radiographic outcome.

The safety profile of JAKis in axSpA, as shaped by randomised clinical trials, appears acceptable. However, as JAKis are a relatively new drug class, long-term safety data still accumulate deriving mainly from the RA population. Although the ORAL Surveillance study in RA yielded a safety signal regarding malignancies and MACE,53 several meta-analyses of JAKi clinical trials did not reveal increased risks for thrombotic events compared to placebo,50,69,70 except for a baricitinib dose-dependent effect.69 Since axSpA patients are generally younger, with fewer comorbidities and less exposure to concomitant glucocorticoids and csDMARDs, they may be at less risk

than their RA counterparts. However, awaiting more clinical trial and real-world data, a careful assessment of the cardiovascular risk profile of every axSpA patient should be made before a JAKi is prescribed. Accordingly, established cancer prevention strategies should be followed and a raised awareness for early signs of cancer should be demonstrated when dealing with patients on JAKi. A safety advantage of JAKi over biologics is the short halflife (usually spanning a few hours) which allows for the drug to be eliminated from the body within a few days in case of an adverse event, particularly infectious.71 No new safety signals were identified in the RCTs in AS, including cases of IBD, new onset uveitis or psoriasis. This is particularly relevant for patients with axSpA and co-existent IBD, since the treatment options for this patient group is limited to monoclonal anti-TNFa antibodies.72 Moreover, tofacitinib and upadacitinib are efficacious in ulcerative colitis and are already approved in this indication.73,74 Furthermore, upadacitinib and filgo-tinib have shown favorable results in Crohn's disease in phase 2 studies,75-77 while the results of a phase 3 study of upadacitinib in Crohn's disease are awaited. Therefore, tofacitinib and upadacitinib may represent alternative treatment options for patients with active axSpA despite anti-TNFa treatment and concomitant IBD. Apparently, such a decision should be discussed and agreed with a gastroenterologist, as well.

Choosing the best JAKi based merely on pharmacological terms is a challenging and likely misleading task. Indeed, predicting the efficacy of a JAK inhibitor in any disease is difficult considering the diversity of inflammatory and parenchymal cells which are involved in a vast array of pro-inflammatory and anti-inflammatory interactions, as well as differences among compounds regarding pharmacodynamics at the level of cytokine/re-ceptor/cell, JAK selectivity and pharmacokinetics due to renal/hepatic factors, active metabolites etc.3 Therefore, pharmacologic properties should be assessed along with clinical efficacy, safety data and the patient profile, so as to choose the most suitable -if possible- JAKi. Regarding their position in the treatment of axSpA, clinical trial data support the use of tofacitinib and upadacitinib both after NSAID failure, as well as after inadequate response to bDMARDs. The 2019 ACR recommendations for the treatment of axSpA designated tofacitinib as an advanced-line therapy after TNFa and IL-17 inhibitors, with the reservation that the part regarding JAKis may change, since results from large clinical trials were still pending by then.78 In the updated ASAS-EULAR recommendations for the management of axSpA, TNFa, IL-17 and JAK inhibitors were equally included as a second-line treatment after NSAID failure, noting though that current practice are TNFa and IL-17 inhibitors.79 Finally, in the most recent GRAPPA recommendations JAKis may be considered for psoriatic axial disease as a second line

after NSAIDs , along with TNFa and IL-17 inhibitors.80 In conclusion, JAK inhibitors have formally entered the therapeutics of axSpA. They are effective over a broad spectrum of disease manifestations, both skeletal and extra-skeletal. They have a fast onset and sustained action, including pain relief, they are easily taken via the oral route and have a safety profile compatible with what has already been observed in RA. Therefore, they represent a useful treatment option for axSpA patients, while, conversely, their clinical application will likely help further elucidate the pathophysiology of the disease. More research is needed to identify the best patient candidates for JAKi treatment and to establish the long-term safety and efficacy profile, including the effects in structural progression.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

REFERENCES

1. Clark JD, Flanagan ME, Telliez J-B. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem 2014;57(12):5023-5038. doi:10.1021/jm401490p

2. Bertsias G. Therapeutic targeting of JAKs: from hematology to rheumatology and from the first to the second generation of JAK inhibitors. Mediterr J Rheumatol 2020;31(Suppl 1):105-111. doi:10.31138/mjr.31.1.105

3. Traves PG, Murray B, Campigotto F, Galien R, Meng A, Di Paolo JA. JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib. Ann Rheum Dis 2021 ;80(7):865-875. doi:10.1136/annrheumdis-2020-219012

4. Chatzidionysiou K. Beyond Methotrexate and Biologics in RA -Efficacy of JAK Inhibitors and their Place in the Current Treatment Armamentarium. Mediterr J Rheumatol 2020;31(Suppl 1):120-128. doi:10.31138/mjr.31.1.120

5. Thomas K, Vassilopoulos D. Infections in Patients with Rheumatoid Arthritis in the Era of Targeted Synthetic Therapies. Mediterr J Rheumatol 2020;31(Suppl 1):129-36. doi:10.31138/mjr.31.1.129

6. Mauro D, Nakamura A, Haroon N, Ciccia F. The gut-enthesis axis and the pathogenesis of Spondyloarthritis. Semin Immunol 2022 Jul:101607. doi:10.1016/j.smim.2022.101607

7. Mauro D, Simone D, Bucci L, Ciccia F. Novel immune cell phenotypes in spondyloarthritis pathogenesis. Semin Immunopathol 2021;43(2):265-77. doi:10.1007/s00281-021-00837-0

8. Sieper J, Poddubnyy D, Miossec P. The IL-23-IL-17 pathway as a therapeutic target in axial spondyloarthritis. Nat Rev Rheumatol 2019;15(12):747-57. doi:10.1038/s41584-019-0294-7

9. Schett G, Lories RJ, D'Agostino M-A, Elewaut D, Kirkham B, Soriano ER, et al. Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol 2017;13(12):731-41. doi:10.1038/nrrheum.2017.188

10. Regan-Komito D, Swann JW, Demetriou P, Cohen ES, Horwood NJ, Sansom SN, et al. GM-CSF drives dysregulated hematopoietic stem cell activity and pathogenic extramedullar/ myelopoiesis in experimental spondyloarthritis. Nat Commun 2020;11 (1 ):155. doi:10.1038/s41467-019-13853-4

11. Papagoras C, Tsiami S, Chrysanthopoulou A, Mitroulis I, Baraliakos X. Serum granulocyte-macrophage colony-stimulating factor (GM-CSF) is increased in patients with active radiographic axial spondyloarthritis and persists despite anti-TNF treatment. Arthritis Res Ther 2022;24(1):195. doi:10.1186/s13075-022-02888-6

12. Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 2009;9(8):556-567. doi:10.1038/nri2586

13. Raychaudhuri SK, Abria C, Raychaudhuri SP. Regulatory role of the

JAK STAT kinase signalling system on the IL-23/IL-17 cytokine axis in psoriatic arthritis. Ann Rheum Dis 2017;76(10):e36. doi:10.1136/ annrheumdis-2016-211046

14. Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs 2017;77(5):521-46. doi:10.1007/s40265-017-0701-9

15. Yarilina A, Xu K, Chan C, Ivashkiv LB. Regulation of inflammatory responses in tumor necrosis factor-activated and rheumatoid arthritis synovial macrophages by JAK inhibitors. Arthritis Rheum 2012;64(12):3856-66. doi:10.1002/art.37691

16. Ghoreschi K, Gadina M. Jakpot! New small molecules in autoimmune and inflammatory diseases. Exp Dermatol 2014;23(1):7-11. doi:10.1111/exd.12265

17. Raychaudhuri SK, Raychaudhuri SP. Janus kinase/signal transducer and activator of transcription pathways in spondyloarthritis. Curr Opin Rheumatol 2017;29(4):311-6. doi:10.1097/B0R.0000000000000399

18. Deodhar A, Yu D. Switching tumor necrosis factor inhibitors in the treatment of axial spondyloarthritis. Semin Arthritis Rheum 2017;47(3):343-50. doi:10.1016/j.semarthrit.2017.04.005

1 9. Sieper J, Deodhar A, Marzo-Ortega H, Aelion JA, Blanco R, Jui-Cheng T, et al. Secukinumab efficacy in anti-TNF-naive and anti-TNF-experienced subjects with active ankylosing spondylitis: results from the MEASURE 2 Study. Ann Rheum Dis 2017;76(3):571-92. doi:10.1136/annrheumdis-2016-210023

20. Hodge JA, Kawabata TT, Krishnaswami S, Clark JD, Telliez JB, Dowty ME, et al. The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin Exp Rheumatol 2016;34(2):318-28.

21. Deodhar A, Sliwinska-Stanczyk P, Xu H, Baraliakos X, Gensler LS, Fleishaker D, et al. Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study. Ann Rheum Dis 2021 Apr. doi:10.1136/ annrheumdis-2020-219601

22. Ogdie A, de Vlam K, McInnes IB, Mease PJ, Baer P, Lukic T, et al. Efficacy of tofacitinib in reducing pain in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis. RMD Open 2020;6(1). doi:10.1136/rmdopen-2019-001042

23. Navarro-Compán V, Wei JC-C, Van den Bosch F, Magrey M, Wang L, Fleishaker D, et al. Effect of tofacitinib on pain, fatigue, health-related quality of life and work productivity in patients with active ankylosing spondylitis: results from a phase III, randomised, double-blind, placebo-controlled trial. RMD Open 2022;8(2). doi:10.1136/rmdopen-2022-002253

24. Maksymowych WP, van der Heijde D, Baraliakos X, Deodhar A, Sherlock SP, Li D, et al. Tofacitinib is associated with attainment of the minimally important reduction in axial magnetic resonance imaging inflammation in ankylosing spondylitis patients. Rheumatology (Oxford) 2018;57(8):1390-1399. doi:10.1093/ rheumatology/key104

25. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2021/203214s028, 208246s013 213082s003lbl.pdf.

26. Https://www.ema.europa.eu/en/medicines/human/ summaries-opinion/xeljanz-3.

27. van der Heijde D, Baraliakos X, Gensler LS, Maksymowych WP, Tseluyko V, Nadashkevich O, et al. Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial. Lancet (London, England) 2018;392(10162):2378-87. doi:10.1016/S0140-6736(18)32463-2

28. Maksymowych WP, 0stergaard M, Landewé R, Barchuk W, Liu K, Gilles L, et al. Filgotinib decreases both vertebral body and posterolateral spine inflammation in ankylosing spondylitis: results from the TORTUGA trial. Rheumatology (Oxford) Published online October 2021. doi:10.1093/rheumatology/keab758

29. Maksymowych WP, 0stergaard M, Landewé R, Barchuk W, Liu K, Tasset C, et al. Impact of filgotinib on sacroiliac joint magnetic resonance imaging structural lesions at 12 weeks in patients with

active ankylosing spondylitis (TORTUGA trial). Rheumatology (Oxford) 2022;61(5):2063-71. doi:10.1093/rheumatology/keab543

30. van der Heijde D, Song I-H, Pangan AL, Deodhar A, van den Bosch F, Maksymowych WP, et al. Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial. Lancet (London, England) 2019;394(10214):2108-2117. doi:10.1016/S0140-6736(19)32534-6

31. Deodhar A, van der Heijde D, Sieper J, Van den Bosch F, Maksymowych WP, Kim TH, et al. Safety and Efficacy of Upadacitinib in Patients With Active Ankylosing Spondylitis and an Inadequate Response to Nonsteroidal Antiinflammatory Drug Therapy: One-Year Results of a Double-Blind, Placebo-Controlled Study and Open-Label Extension. Arthritis Rheumatol (Hoboken, NJ) 2022;74(1):70-80. doi:10.1002/art.41911

32. McInnes IB, Ostor AJK, Mease PJ, Tillett W, Baraliakos X, de Vlam K, et al. Effect of upadacitinib on reducing pain in patients with active psoriatic arthritis or ankylosing spondylitis: post hoc analysis of three randomised clinical trials. RMD Open 2022;8(1) doi:10.1136/rmdopen-2021-002049

33. van der Heijde D, Deodhar A, Maksymowych WP, Sieper J, Van den Bosch F, Kim TH, et al. Upadacitinib in active ankylosing spondylitis: results of the 2-year, double-blind, placebo-controlled SELECT-AXIS 1 study and open-label extension. RMD Open 2022;8(2). doi:10.1136/rmdopen-2022-002280

34. van der Heijde D, Baraliakos X, Sieper J, Sieper J, Deodhar A, Inman RD, et al. Efficacy and safety of upadacitinib for active ankylosing spondylitis refractory to biological therapy: a doubleblind, randomised, placebo-controlled phase 3 trial. Ann Rheum Dis, Published online July 2022. doi:10.1136/ard-2022-222608

35. European Medicines Agency. Rinvoq (upadacitinib). 2019;1(May):1-3.

36. Https://www.accessdata.fda.gov/drugsatfda_docs/ label/2022/211675s003lbl.pdf.

37. Deodhar A, Van den Bosch F, Poddubnyy D, Maksymowych WP, van der Heijde D, Kim TH, et al. Upadacitinib for the treatment of active non-radiographic axial spondyloarthritis (SELECT-AXIS 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England) 2022;400(10349):369-79. doi:10.1016/ S0140-6736(22)01212-0

38. https://www.ema.europa.eu/en/documents/product-information/ rinvoq-epar-product-information_en.pdf.

39. Feld J, Chandran V, Haroon N, Inman R, Gladman D. Axial disease in psoriatic arthritis and ankylosing spondylitis: a critical comparison. Nat Rev Rheumatol 2018;14(6):363-71. doi:10.1038/ s41584-018-0006-8

40. Lopez-Medina C, Ziade N. Axial Disease in Psoriatic Arthritis: how can we Define it, and does it have an Impact on Treatment? Mediterr J Rheumatol 2022;33(Suppl 1):142-9. doi:10.31138/ mjr.33.1.142

41. Mease P, Hall S, FitzGerald O, van der Heijde D, Merola JF, Avila-Zapata F, et al. Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis. N Engl J Med 2017;377(16):1537-50. doi:10.1056/NEJMoa1615975

42. Gladman D, Rigby W, Azevedo VF, Behrens F, Blanco R, Kaszuba A, et al. Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors. N Engl J Med 2017;377(16):1525-36. doi:10.1056/NEJMoa1615977

43. Mease PJ, Lertratanakul A, Anderson JK, Papp K, Van den Bosch F, Tsuji S, et al. Upadacitinib for psoriatic arthritis refractory to biologics: SELECT-PsA 2. Ann Rheum Dis 2020;80(3):312-20. doi:10.1136/annrheumdis-2020-218870

44. McInnes IB, Anderson JK, Magrey M, Merola JF, Liu Y, Kishimoto M, et al. Trial of Upadacitinib and Adalimumab for Psoriatic Arthritis. N Engl J Med 2021;384(13):1227-39. doi:10.1056/NEJMoa2022516

45. Mease P, Coates LC, Helliwell PS, Stanislavchuk M, Rychlewska-Hanczewska A, Dudek A, et al. Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active psoriatic arthritis (EQUATOR): results from a randomised, placebo-controlled,

phase 2 trial. Lancet (London, England) 2018;392(10162):2367-77. doi:10.1016/S0140-6736(18)32483-8

46. Mease PJ, Deodhar AA, van der Heijde D, Behrens F, Kivitz AJ, Neal J, et al. Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis. Ann Rheum Dis 2022;81(6):815-22. doi:10.1136/annrheumdis-2021-221664

47. Baraliakos X, Ranza R, Ostor A, Ciccia F, Coates L, Rednic S, et al. P0S0934 EFFICACY OF UPADACITINIB ON PSORIATIC ARTHRITIS WITH AXIAL INVOLVEMENT DEFINED BY INVESTIGATOR ASSESSMENT AND PRO-BASED CRITERIA: RESULTS FROM TWO PHASE 3 STUDIES. Ann Rheum Dis 2022;81(Suppl 1):768 LP - 768. doi:10.1136/annrheumdis-2022-eular.722

48. Wang L, Ping X, Chen W, Xing W. Performance of Janus kinase inhibitors in psoriatic arthritis with axial involvement in indirect comparison with ankylosing spondylitis: a retrospective analysis from pooled data. Clin Rheumatol 2021 ;40(5):1725-1737. doi:10.1007/s10067-020-05442-4

49. Proft F, Torgutalp M, Muche B, Rios Rodriguez V, Verba M, Poddubnyy D. Efficacy of tofacitinib in reduction of inflammation detected on MRI in patients with Psoriatic ArthritiS presenTing with axial involvement (PASTOR): protocol of a randomised, double-blind, placebo-controlled, multicentre trial. BMJ Open 2021;11(11):e048647. doi:10.1136/bmjopen-2021-048647

50. Olivera PA, Lasa JS, Bonovas S, Danese S, Peyrin-Biroulet L. Safety of Janus Kinase Inhibitors in Patients With Inflammatory Bowel Diseases or Other Immune-mediated Diseases: A Systematic Review and Meta-Analysis. Gastroenterology 2020;158(6):1554-1573.e12. doi:10.1053/j.gastro.2020.01.001

51. Vieira M-C, Zwillich SH, Jansen JP, Smiechowski B, Spurden D, Wallenstein GV. Tofacitinib Versus Biologic Treatments in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Tumor Necrosis Factor Inhibitors: Results From a Network Meta-analysis. Clin Ther 2016;38(12):2628-2641 .e5. doi:10.1016/j.clinthera.2016.11.004

52. Scott IC, Hider SL, Scott DL. Thromboembolism with Janus Kinase (JAK) Inhibitors for Rheumatoid Arthritis: How Real is the Risk? Drug Saf 2018;41(7):645-653. doi:10.1007/s40264-018-0651-5

53. Ytterberg SR, Bhatt DL, Mikuls TR, Koch GG, Fleischmann R, Rivas JL, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med 2022;386(4):316-326. doi:10.1056/NEJMoa2109927

54. https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-24-27-october-2022.

55. Charles-Schoeman C, Buch MH, Dougados M, Bhatt DL, Giles JT, Ytterberg SR, et al. Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance. Ann Rheum Dis. Published online September 2022. doi:10.1136/ard-2022-222259

56. Khosrow-Khavar F, Desai RJ, Lee H, Lee SB, Kim SC. Tofacitinib and Risk of Malignancy: Results From the Safety of Tofacitinib in Routine Care Patients With Rheumatoid Arthritis (STAR-RA) Study. Arthritis Rheumatol (Hoboken, NJ) Published online May 2022. doi:10.1002/art.42250

57. Khosrow-Khavar F, Kim SC, Lee H, Lee SB, Desai RJ. Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study. Ann Rheum Dis 2022;81(6):798-804. doi:10.1136/ annrheumdis-2021-221915

58. Xie F, Yun H, Bernatsky S, Curtis JR. Brief Report: Risk of Gastrointestinal Perforation Among Rheumatoid Arthritis Patients Receiving Tofacitinib, Tocilizumab, or Other Biologic Treatments. Arthritis Rheumatol (Hoboken, NJ) 2016;68(11):2612-2617. doi:10.1002/art.39761

59. Nash P, Kerschbaumer A, Dörner T, Dougados M, Fleischmann RM, Geissler K, et al. Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase

Inhibitors: a consensus statement. Ann Rheum Dis 2021;80(1):71-87. doi:10.1136/annrheumdis-2020-218398

60. Papagoras C, Voulgari P V, Drosos AA. Cardiovascular Disease In Spondyloarthritides. Curr Vasc Pharmacol 2020;18(5):473-87. doi: 10.2174/1570161117666190426164306

61. Toussirot E. The Risk of Cardiovascular Diseases in Axial Spondyloarthritis. Current Insights. Front Med 2021 ;8:782150. doi:10.3389/fmed.2021.782150

62. van der Heijde D, Deodhar A, Wei JC, Drescher E, Fleishaker D, Hendrikx T, et al. Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, doseranging study. Ann Rheum Dis 2017;76(8):1340-7. doi:10.1136/ annrheumdis-2016-210322

63. Lee YH, Song GG. Janus kinase inhibitors for treating active ankylosing spondylitis: a meta-analysis of randomized controlled trials. Z Rheumatol. Published online December 2020. doi:10.1007/ s00393-020-00948-3

64. Li S, Li F, Mao N, Wang J, Xie X. Efficacy and safety of Janus kinase inhibitors in patients with ankylosing spondylitis: A systematic review and meta-analysis. Eur J Intern Med. Published online April 2022. doi:10.1016/j.ejim.2022.04.007

65. McLornan DP, Pope JE, Gotlib J, Harrison CN. Current and future status of JAK inhibitors. Lancet (London, England) 2021;398(10302):803-16. doi:10.1016/S0140-6736(21)00438-4

66. Veale DJ, McGonagle D, McInnes IB, Krueger JG, Ritchlin CT, Elewaut D, et al. The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis. Rheumatology (Oxford) 2019;58(2):197-205. doi:10.1093/rheumatology/key070

67. Mehta P, Taylor PC. Pain in Rheumatoid Arthritis: Could JAK Inhibition be the Answer? Mediterr J Rheumatol 2020;31 (Suppl 1):112-119. doi:10.31138/mjr.31.1.112

68. Klavdianou K, Kanellou A, Daoussis D. Molecular Mechanisms of New Bone Formation in Axial Spondyloarthritis. Mediterr J Rheumatol 2022;33(Suppl 1):115-125. doi:10.31138/mjr.33.1.115

69. Xie W, Huang Y, Xiao S, Sun X, Fan Y, Zhang Z. Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials. Ann Rheum Dis 2019;78(8):1048-1054. doi:10.1136/annrheumdis-2018-214846

70. Yates M, Mootoo A, Adas M, Bechman K, Rampes S, Patel V, et al. Venous Thromboembolism Risk With JAK Inhibitors: A Meta-Analysis. Arthritis Rheumatol (Hoboken, NJ) 2021;73(5):779-788. doi:10.1002/art.41580

71. Macaluso FS, Rodríguez-Lago I. JAK Inhibition as a Therapeutic Strategy for Inflammatory Bowel Disease. Curr Drug Metab 2020;21(4):247-55. doi:10.2174/1389200221666200310111409

72. Zioga N, Kogias D, Lampropoulou V, Kafalis N, Papagoras C. Inflammatory Bowel Disease-related Spondyloarthritis: The Last Unexplored Territory of Rheumatology. Mediterr J Rheumatol 2022;33(Suppl 1):126-36. doi:10.31138/mjr.33.1.126

73. Sandborn WJ, Su C, Sands BE, D'Haens GR, Vermeire S, Schreiber S, et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med 2017;376(18):1723-36. doi:10.1056/NEJMoa1606910

74. Danese S, Vermeire S, Zhou W, Pangan AL, Siffledeen J, Greenbloom S, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet (London, England) 2022;399(10341 ):2113-28. doi:10.1016/S0140-6736(22)00581-5

75. Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, et al. Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet (London, England) 2017;389(10066):266-275. doi:10.1016/S0140-6736(16)32537-5

76. Sandborn WJ, Feagan BG, Loftus EVJ, Peyrin-Biroulet L, Van Assche G, D'Haens G, et al. Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease.

Gastroenterology 2020;158(8):2123-2138.e8. doi:10.1053/j. gastro.2020.01.047

77. Rogler G. Efficacy of JAK inhibitors in Crohn's Disease. J Crohns Colitis 2020;14(Supplement_2):S746-S754. doi:10.1093/ ecco-jcc/jjz186

78. Ward MM, Deodhar A, Gensler LS, Dubreuil M, Yu D, Khan MA, et al. 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol (Hoboken, NJ) 2019;71(10):1599-613. doi:10.1002/ art.41042

79. Ramiro S, Nikiphorou E, Sepriano A, Ortolan A, Webers C, Baraliakos X, et al. ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update. Ann Rheum Dis. Published online October 2022. doi:10.1136/ard-2022-223296

80. Coates LC, Soriano ER, Corp N, Bertheussen H, Callis Duffin K, et al. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA): updated treatment recommendations for psoriatic arthritis 2021. Nat Rev Rheumatol 2022;18(8):465-479. doi:10.1038/s41584-022-00798-0