# Consensus statement on the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: 2023 Update

Peter Nash, Andreas Kerschbaumer, Victoria Konzett, Daniel Aletaha, Thomas Dörner, Roy Fleischmann, Iain Mcinnes, Jette Primdahl, Naveed Sattar, Yoshiya Tanaka, et al.

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## To cite this version:

Peter Nash, Andreas Kerschbaumer, Victoria Konzett, Daniel Aletaha, Thomas Dörner, et al. Consensus statement on the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: 2023 Update. Annals of the Rheumatic Diseases, 2025, 84 (5), pp.664-679. 10.1016/j.ard.2025.01.032. hal-05441052

HAL Id: hal-05441052

https://hal.science/hal-05441052v1

Submitted on 5 Jan 2026

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# Consensus statement on the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: 2023 Update

Peter Nash, Andreas Kerschbaumer, Victoria Konzett, Daniel Aletaha, Thomas Dörner, Roy Fleischmann, Iain McInnes, Jette Primdahl, Naveed Sattar, Yoshiya Tanaka, Michael Trauner, Kevin Winthrop, Maarten de Wit, Johan Askling, Xenofon Baraliakos, Wolf-Henning Boehncke, Paul Emery, Laure Gossec, John D. Isaacs, Maria Krauth, Eun Bong Lee, Walter Maksymowych, Janet Pope, Marieke Scholte, Karen Schreiber, Stefan Schreiber, Tanja Stamm, Peter Taylor, Tsutomu Takeuchi, Lai-Shan Tam, Filip van den Bosch, Rene Westhovens, Markus Zeitlinger

## Abstract

In light of the introduction of new JAK inhibitors (JAKi), new indications for JAKi and recent safety considerations which arose since the preceding consensus statement on JAKi therapy, a multidisciplinary taskforce was assembled, encompassing patients, health care professionals and clinicians with expertise in JAKi therapy across specialties. This taskforce, informed by a comprehensive systematic literature review, undertook the objective to update the previous points to consider developed in 2019. The taskforce deliberated on overarching principles, indications, dosage and co-medication strategies, warnings and contraindications, screening protocols, monitoring recommendations and adverse effect profiles. These elements were voted upon in accordance with the EULAR standard operating procedures. Furthermore, an updated research agenda was proposed. This update aims to equip clinicians with the necessary knowledge and guidance for the efficient and safe administration of this expanding and significant class of drugs, once the decision has been made to use them.

## Keywords

JAKi, IMID, efficacy, safety, monitoring, screening

## Introduction

Immune-mediated inflammatory diseases (IMIDs) comprise a variety of diseases, a list that includes rheumatoid arthritis (RA), psoriatic arthritis (PsA); axial spondyloarthritis/ankylosing spondylitis (AxSpA/AS); connective tissue diseases (CTDs), also called systemic autoimmune rheumatic diseases (SARDs), such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc); but also autoimmune skin diseases like psoriasis (PsO); atopic dermatitis (AD) and autoimmune alopecia (AA); inflammatory bowel diseases such as Crohn's disease (CD) and ulcerative colitis (UC); and others, including multiple sclerosis (MS). Each of these represents a distinct, organ specific or systemic
clinical entity with a genetic predisposition mostly linked to the presence of certain immune
response genes which under specific environmental conditions allows tolerance to be broken. ¹² For
some we may have a clue on this breaking point,³ and for others there are indications for viral
involvement. ⁴⁵ All of them share the pathogenesis of an immune mediated inflammatory response
involving a variety of common and disparate cytokines, among them those related to the polarization
of T-cells, various lymphokines as well as pro-inflammatory cytokines. ⁶⁷

Cytokines, after binding to their cell-membrane-associated cognate receptors, activate a variety of
intracellular signal transduction mechanisms. Important pro-inflammatory cytokines use mitogen-
activated protein kinases (MAPK) and/or nuclear factor kappa B (NFκB) for this purpose⁸ whereas the
majority of cytokines involved in immune cell activation and various pro-inflammatory messenger
molecules act via the Janus kinase (JAK) pathway.⁹ Interestingly, neither inhibitors of MAPK nor NFκB
have been found successful in interfering with IMIDs.¹⁰ ¹¹ In contrast, JAK-inhibitors (JAKi) have been
approved for a variety of IMIDs over the last decade and continue to be studied in others.

In order to account for the complexity of using JAKi in various diseases, a large taskforce has
developed a consensus statement on the use of JAKi in IMIDs a few years ago. ¹² However, since its
publication, JAKi have been approved for a variety of new indications and, even more importantly,
safety issues when compared to TNFi have arisen. ¹³ Therefore it was deemed important to revisit the
efficacy and safety of JAKi and develop an update of the consensus statement. The result of the
taskforce's deliberations and decisions are presented here.

Methods

The consensus statement was developed in line with the general methodology provided by the
European Alliance of Associations for Rheumatology (EULAR) in its standard operating procedures
(SOPs) for the development of recommendations. ¹⁴ First a steering committee was formed to
address all necessary aspects for a systematic literature research (SLR) in a face-to-face meeting on
April 16, 2023; the SLR focused on efficacy and safety of all JAKi across indications. The results of the
SLR were presented to the steering group on November 10, 2023 in another face-to-face meeting.
The steering group then prepared proposals for changes of the consensus statement that were to be
presented to the full taskforce. Levels of evidence (LoE) were assessed according to the Oxford
Centre for Evidence-Based Medicine. ¹⁵ On January 10, 2024, the taskforce met at two different times
to discuss the SLR results, review the steering group's proposals, and update the points to consider.
The morning session (CET) was designated to accommodate mainly participants from Asia, while the
afternoon session was set to enable experts from the Americas to contribute. Patients and non-
physician health care professionals were also present. The voting rules adhered to the EULAR SOPs,
which stipulate to accept a proposal if a 75% majority is reached; if a 75% majority is not reached, the discussion continues and an amendment is presented which is again voted for, with a >66% majority of participants necessary for acceptance; again, if this next proposal is not approved, another round of discussions is taking place, after which the new proposal has to be voted on by >50% of the members present in the room. The deliberations and changes were noted and recorded to allow their presentation in this report. After the meeting, all taskforce members received the ultimately approved version of the recommendations together with information on the LoE for each item to allow for a final vote on the level of agreement (LoA) with each of the items. Of note, an individual item which includes more than one aspect may have more than one LoE assigned, as will be seen in the individual items.

The last results of the LoA voting were received in February and the manuscript was subsequently written.

## Results

In the prior consensus statement, published in 2019,¹² the process leading to the overarching principles (OAPs) and recommendations outlined below was explained in detail¹² and in an abbreviated form in the methods' section above. The OAPs and individual recommendations all address issues related to JAKi treatment of patients diagnosed with IMIDs, once the decision has been made to commence this therapy. Of note, the taskforce did not discuss when to initiate JAKi therapy, as this should be covered by the respective disease specific management recommendations. The taskforce focused on assessing if the items previously established were still valid based on the information accrued over the past four years and, consequently, on changes from the prior published points to consider if deemed pertinent. As before, the recommendations were divided into a number of elements judged to be important in clinical practice and for the use of these points of guidance.
(Table 1)

These elements include: 4 overarching principles (4 in 2019), 2 points on indications (2 in 2019), 4 items on treatment dose and co-medications in different IMIDs (4 in 2019), 6 entries related to contra-indications (5 in 2019), 7 items on pre-screening and risks (7 in 2019), 3 entries regarding laboratory and clinical monitoring (3 in 2019) and 5 points on adverse effects (5 in 2019). While the number of bullet points has remained the same for most elements, many of these underwent changes based on the most recent insights. Further, each recommendation is accompanied by its associated level of evidence (LoE), strength of recommendation (SoR), vote (% final approval) and the
taskforce's levels of agreement with the final wording (LoA). Please note that for some recommendations the LoE, and thus SoRs, are low despite a strong vote and agreement by the task force members. Such results generally reflect the absence of a specific study investigating the point(s) raised specifically have been performed, even if secondary indications are present. Therein we rely on expert opinion, although often supported by some underlying data.

For the OAPs, the voting results and levels of agreement are presented, since they are general, explanatory statements mostly related to good clinical practice that do not require specific assessment of evidence.

**General Principles.**

Of the 4 overarching principles, 2 were unchanged and for 1, a slight wording change was applied to maintain uniformity with other principles. Key points of the discussions, taskforce voting results and levels of agreement are addressed below.

A. Initiation of JAK-inhibitor therapy and the treatment target to be achieved should be based on a shared decision between the patient and the clinician, fully informing the patient on the potential benefit and risks of this therapy. (Vote 100%, LOA 9.94)

The term “medical specialist” in the previous version was altered to “clinician” to keep uniformity with the term used in OAP 3 and 4. It acknowledges that a variety of specialties and health professionals are involved in the management of patients taking JAKi. The importance of shared decision making between clinician and patient was again emphasized as was the necessity to provide the patient with full and adequate information on the risk and benefit of JAKi therapy. However, there was a slight amendment from the prior “which requires full information of the patient” to the new “fully informing the patient” to streamline the wording. The SLR provided the latest evidence on efficacy and safety, building upon the 2019 SLR to guide the taskforce. Clinicians interested in the details are referred to the separate publications. /REF 77-78) Long term safety data with a number of JAK inhibitors now extends to over a decade particularly in rheumatologic and dermatologic diseases.¹⁶⁻²⁰
B. Therapeutic approaches to treating patients with chronic inflammatory conditions should be in line with international/national recommendations (algorithms) for the management of the respective disease. (Vote 100%, LOA 9.72)

The taskforce continues to recommend general management principles for individual diseases in line with international and national guidelines. The minor change made was to eliminate "and" between "international" and "national" to simply read "international/national", since these are not always fully aligned. Thus, when international or national recommendations differ, the clinician should choose the most appropriate recommendations considering individual country and access limitations.

C. The points-to-consider when initiating JAK-inhibitor therapy do not provide information on when JAK-inhibitors should be used in the treatment algorithm, but rather attempt to assist the clinician once the decision to prescribe a JAK-inhibitor has been made. (Vote 100%, LOA 9.72)

The usage of "consensus statement" or "recommendations" or "points-to-consider" and not "guidelines" throughout was regarded an important distinction when opinion and low LoE is utilised and for medico-legal implications, since a decision to use a given drug in a specific patient is always one that relates to that individual in a patient-clinician relationship and does not require strict guidelines but rather general considerations related to safety and efficacy in each specific circumstance. No guideline can address all circumstances that may be pertinent in a particular patient with a particular diagnosis, unique comorbidities, a personal disease history as well as treatment history and concomitant medications etc. (see also item D).

D. These points-to-consider address specific (but not all) aspects related to the application of JAK-inhibitor therapy and the clinician should additionally refer to the disease-specific product information. (Vote 100% LOA 9.81)

The importance of disease specific product information should be carefully considered. As new data emerge, updates to recommendations is necessary over time. A large number of clinical trials investigating JAKi is currently being conducted, with 487 trials involving JAKi therapy registered on clinicaltrials.gov at the time of writing this manuscript.

## I. Indications.

1. Patients with immune mediated inflammatory diseases (IMIDs). As of 2024, depending on the specific drug, these include rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis,
ulcerative colitis, Crohn's disease, psoriasis, atopic dermatitis, vitiligo and alopecia areata. (Level of evidence (LOE) 1A, Strength of recommendation(SOR) A, Vote 100%, LOA 9.91)

Since 2019 different JAKi were approved for several additional IMIDs. The taskforce noted that treatment dose and co-medications are important considerations in different IMIDs, and the status quo (2024) is mentioned. This list may soon be expanded. For example, whilst clinical trial evidence of efficacy of JAKi for patients with hidradenitis suppurativa exists, this is not an approved indication yet.²¹ Deucravacitinib has been investigated in a phase 2 trial of SLE and demonstrated significant efficacy at 3 mg twice daily.²² Also, JAKi are under active investigation in other IMIDs including interferonopathies, dermatomyositis, vasculitis, polymyalgia rheumatica and giant cell arteritis amongst many others. Of note, axial spondyloarthropathy includes both radiographic and non-radiographic spondyloarthropathy. Further, baricitinib has received regulatory approval in combination with remdesivir for the treatment of suspected or laboratory confirmed COVID-19 infection in hospitalised patients requiring supplemental oxygen, mechanical ventilation or extracorporeal membrane oxygenation. However, similar to other non IMID indications as e.g. hematologic malignancies, COVID-19 is also not considered an IMID nor was it included in the SLR, which is the reason why it has been excluded from the present indication list.²³ The different JAKi and their approved indications are listed in Table 2, while the different disease for which JAKi are approved and the respective JAKi are shown in Table 3.

2. Currently there is no direct evidence from head-to-head comparisons to show efficacy or safety superiority of one JAK-inhibitor over another one. (LOE 5, SOR D, Vote 94% 1 abstention, LOA 9.91)

The taskforce debated if this recommendation should be a note in the text, but agreed that it should be included to assuage attempts to claim superior efficacy between JAK inhibitors, as there is no evidence at the present time from multi-national, multi-center RCTs that one JAKi is more efficacious clinically, structurally or functionally than any other JAKi. There remain no clinical trials of JAK inhibitor after intolerance or lack of efficacy of another JAKi. This item has been minimally adjusted compared with the previous statement to make clear that any potential difference would have to be shown in trials directly comparing two or more drugs ("from head-to-head comparisons to show efficacy or safety superiority" now replaces "of superiority regarding efficacy or safety", see also Table 1).

## II. Treatment dose and co-medications in different diseases
1. Use the dose recommended for the specific disease. (LOE 1a, SOR A, Vote 100% LOA 9.84)

This recommendation (unchanged) highlights dose adjustments per disease indication; for example, in the treatment of inflammatory bowel disease differing induction and maintenance dosing are clearly defined.

2. Consider dose adjustments in patients with higher age, significant renal or hepatic impairment, other co-morbidities and/or at risk of drug interactions. (LOE 2b/5, SOR C/D, Vote 100% LOA 9.61)

JAKi metabolism is summarized in Table 2. As previously described in the 2019 consensus paper, JAKi that are metabolised by the hepatic cytochrome P (CYP) 450 pathway lead to drug interactions with other inhibitors of this pathway, such as ketoconazole, and promoters, such as rifampicin, necessitating dosage adjustments. Baricitinib is 70% renally excreted, so dosage should be reduced in patients with kidney disease and reduced GFR. Filgotinib is metabolised by hepatic carboxylesterases and its less potent major metabolite GS-829845 (by a factor of 10) is a pharmacologically active, selective inhibitor of JAK1. Upadacitinib undergoes hepatic oxidation with minor CYP metabolism, and peficitinib undergoes hepatic conjugation. Organic anion transporter 3 inhibitors, such as probenecid, interact with baricitinib requiring a dose reduction to 2 mg per day. Rifampicin, when used in latent tuberculosis (TB) prophylaxis or therapy for active TB, increases hepatic metabolism of tofacitinib and upadacitinib, so that a dose increase needs to be considered. Ketoconazole has the opposite effect, inhibiting tofacitinib and upadacitinib metabolism, so a dose reduction is suggested.

The general meaning of this item remains unchanged, but some details have been amended. Higher age is no longer specified as ">70 years" as age is relative to co-morbidities, frailty, and re-definition of meaningful age groups.²⁴ The taskforce debated the designation "impaired hepatic function" as this was considered to be not meaningfully measurable; for example, transaminase monitoring does not adequately measure hepatic function. The term "advanced chronic liver disease" would be the preferred term,²⁵ but it is less well recognised (10-11) and, therefore, it was agreed to keep the previous terminology. Co-morbidities include those relevant to JAKi therapy, such as reduced renal function, necessitating dose reduction; cardiovascular disease; or high thrombosis risk. It is noted that some haematological abnormalities that may affect the JAKi dose, such as neutropenia and lymphopenia may be drug-induced rather than a co-morbidity.

3. Regarding co-medication, follow specific recommendations for the respective disease. (LOE 1a, SOR B, Vote 100%, LOA 9,79)
This bullet which included only a statement about RA in 2019, was shortened so as to not single out a specific disease, since co-medication will depend on the specific disease and this was felt to be sufficiently covered in the new formulation of this item. Of note, for many indications combination with methotrexate shows superior efficacy to JAKi monotherapy; examples include RA<sup>26-28</sup> (13,14) and Crohn's disease.<sup>29</sup> Immunogenicity, which is an important issue for combining biological agents with MTX,<sup>30</sup> is not an issue with oral small molecules. Since data on the added efficacy of co-medication are not available for all diseases for which JAKi are approved, the LoE is mixed.

4. Consider dose reduction of the JAK inhibitor in patients in sustained remission according to established assessment instruments (regarding use of such instruments see recommendation V/3) (LOE 1b, SOR B, Vote 94% 1 abstention, LOA 9.12)

This bullet point previously focused on RA, but since this is relevant also in other diseases, such as UC, this part of the previous item I/4 was deleted and text about respective assessment instruments added to be more general. In a large randomised phase 3 trial, whilst maintenance of RA control following induction of sustained low disease activity/remission (LDA/REM) was greater with continued baricitinib 4 mg daily compared with taper to 2 mg. Nevertheless a large proportion of patients receiving the reduced dosing could maintain LDA/REM and recapture these treatment targets in case of disease flares when re-initiating the 4 mg dosage.<sup>31</sup> Patients with ulcerative colitis who are in tofacitinib induced stable remission could de-escalate the dose and maintain remission especially in those in deep endoscopic remission and those without prior TNF inhibitor failure. (18)

### III. Warnings and Contra-indications.

The heading was altered to "Warnings or Contraindications" as "contra-indications" are not always absolute and depend upon the patient journey and co-morbidities,

1. Severe active (or recurrent) infections, including tuberculosis and opportunistic infections. (LoE 2b/5, SoR B/D, Vote 94% 1 Abstention, LOA 9.73)

JAKi therapy may still be appropriate, taking safety issues into consideration. "Chronic" infection was changed to "recurrent" infection as a warning that also active infections may recur without being chronic (i.e. chronic infections are always also "active"). The risk of infections is similar among the currently approved JAK inhibitors, with filgotinib having a lower risk of Herpes Zoster on systematic review of RA trials, which was however not confirmed by sensitivity analyses.<sup>32 33</sup> Asian patient populations are more prone to develop Herpes zoster than non-Asian patients.<sup>34 35</sup> Tuberculosis and
opportunistic infections were observed during JAKi therapy, with higher rates at increased doses and in older patients.<sup>17 35 36</sup>

## 2. Current (or history of) malignancies. (LoE 5, SoR D, Vote 94% 1 Abstention LOA 9.15)

Different from the 2019 version (describing “current malignancies”), and given the ORAL Surveillance results<sup>13</sup> with a numerical imbalance in rates of some malignancies when compared with TNF inhibitors, the term “or history of” malignancies was added to this recommendation, until long term registry follow-up data provide more reassurance. This is important as patients with prior malignancies (typically within the last 5 years before study inclusion) are usually excluded from clinical trials. Registries including patients with co-morbidities and concomitant medications that would exclude them from clinical trials however, show no signal that JAK inhibitor therapy increases lymphoproliferative or solid tissue malignancy apart from an increase in non-melanoma skin cancer when compared to methotrexate and placebo.<sup>37</sup> However, in the ORAL Surveillance trial, a population particularly prone to develop major cardiovascular events was studied and an imbalance in lung cancer incidence was seen. Many of these patients had a history of current or past smoking with an imbalance in baseline smoking rates compared with the group treated with TNFi. Also, it is currently unknown, if JAKi could be used to treat checkpoint inhibitor associated side effects (e.g. checkpoint inhibitor induced arthritis, inflammatory bowel disease, etc.).

## 3. Severe organ dysfunction such as decompensated advanced chronic liver disease and severe renal disease (Cr Cl < 30 ml/min). (LoE 5, SoR D, Vote 100% LOA 9.67)

The term “severe hepatic disease” was now replaced by “decompensated advanced chronic liver disease” (ACLD), the designation preferred by hepatologists over the older term “liver cirrhosis” since this is defined by non-invasive criteria such as liver stiffness.<sup>25</sup> In this respect, JAKi should not be used in patients with a Child score ≥ 9 points, or a history or presence of hepatic decompensation (e.g., ascites, hepatic encephalopathy grade ≥ 2, variceal bleeding); and for those with creatinine clearance <30 ml/minute dose adjustments should be made.

## 4. Pregnancy and Lactation. (LoE 5, SoR D, Vote 100% LOA 9.76)

No change was made to this point compared with the prior consensus statement. Women of child-bearing age should adhere to contraception while taking JAKi because of evidence of animal
teratogenicity. Further, evidence from animal models on lactational pharmacokinetics showed an excretion of JAKi in breast milk. Sufficient human data on inadvertent pregnancies during JAKi therapy are currently lacking. Previous concerns on spermatogenesis based on animal data for filgotinib have been refuted in the filgotinib spermatogenesis studies, MANTA and MANTA-RAY. Filgotinib at 200 mg daily for 13 weeks had no impact on semen variables or sex hormones in men with active IBD or inflammatory rheumatic disease.³⁸ Paternal fertility appears unaffected by other JAK inhibitors in animal studies, but again there is only limited human data available.

### 5. History of arterial and venous thrombo-embolic events. (LoE 2b, SoR B, Vote 100% LOA 9.45)

This recommendation was changed from "recurrent VTE" to "history of" arterial "or" venous thromboembolic events to emphasize that arterial as well as venous thromboembolism are increased in a dose dependent manner with JAKi compared to TNFi.³⁹ While it is notable that active inflammation is thrombogenic, the data on increased thromboembolic risk stem from placebo- and active-controlled trials, although this has not been studied as a primary outcome. Thus, careful risk/benefit assessment is needed in this clinical situation.

### 6. Vaccination with live vaccines. (LoE 5, SoR D, Vote 100%, LOA 9.55)

This recommendation was added given increased use of recombinant and live vaccination in particular as far as herpes zoster is concerned.

## IV. Pre-Treatment screening and risks.

### 1. Patient history and physical examination, with a focus on warnings and contraindications. (LoE 5, SoR D, Vote 100% LOA 9.91)

The second half of the recommendation was added for consistency. Risk factors for adverse events of interest such as MACE, VTE, TB, Hepatitis B and C, complicated diverticulitis and Herpes zoster history should be considered. Basic skin checks for non-melanoma skin cancer should be performed for those at risk.

2. Consider risk factors for venous thromboembolic events (VTE), especially a history of thromboembolism and whether this was provoked or non-provoked, as well as cardiovascular risk such as previous history of cardiovascular event and the risk for malignancy, including smoking history.
(LoE 2b/5, SOR B/D, Vote 100%, LOA 9.91)
This item was the last in this category in 2019. Based on the importance of thromboembolism considerations, it was moved up and expanded regarding other risk factors, including cardiovascular events and malignancy. The taskforce was aware that there is some redundancy with item 1 in this section, but this is deliberate and the repetition and expansion should prompt higher vigilance, given that sub analyses of the ORAL Surveillance trial showed that those with a previous cardiovascular event are at particular risk to develop MACE.<sup>40 41</sup>

3. Routine laboratory testing (full and differential blood counts, liver function tests, renal function; and lipid levels as a baseline). (LoE 5, SoR D, Vote 100% LOA 9.73)

This item, like that of other points with a low level of evidence, is solely based on expert opinion, since no study investigated, which laboratory tests are indispensable prior to starting JAKi therapy. The taskforce felt that, for example, CPK testing was not routinely needed, even though CPK increases may occur under JAKi treatment.<sup>42 43</sup> Of note in this respect, myalgia without rhabdomyolysis has been rarely reported, so CPK testing should be done if respective symptoms develop.<sup>17</sup>

4. Hepatitis B testing (Hepatitis B surface antigen, Hepatitis B surface antibody, Hepatitis B core antibody, with/without HBV DNA testing); hepatitis C testing (Hepatitis C antibody, with HCV RNA testing if antibody positive). (LoE 2b, SoR B, Vote 100%, LOA 9.88)

Hepatitis serology is recommended for all patients. While this recommendation has remained the same as in 2019, it has been newly added that hepatitis D (delta) should also be tested in all patients with hepatitis B infection. Patients with chronic hepatitis B infection should avoid JAKi or receive it only after consultation with a hepatologist to potentially combine them with anti-viral agents. Patients with positive HCV RNA, should have hepatitis C treated prior to JAKi therapy.

5. Human immunodeficiency virus testing in high-risk populations. (LoE 2b, SoR B, Vote 100%, LOA 9.58)

No new data exists since 2019 and the readers are referred to the previous deliberations for further details.<sup>12</sup>

6. Tuberculosis screening as per national recommendation. (LoE 2b, SoR B, Vote 100%, LOA 9.91)

Risk of reactivation or new infection is similar to TNFi,<sup>13 44 45</sup> so that screening according to national guidelines is recommended. Patients with latent TB should have initial concomitant anti-TB therapy, again as per national guidelines, but generally isoniazid for 8 weeks is recommended.
7. Assess and update vaccination status in accordance with national recommendations; consider vaccination against Herpes zoster. (LoE 5, SoR D, Vote 100%, LOA 9.73)

The EULAR vaccination recommendations may assist clinicians treating IMIDs.⁴⁶ As mentioned in the 2019 recommendations, virus reactivation has been documented with JAKi therapy particularly Herpes zoster (but also simplex and HPV), in a dose dependent manner. Herpes zoster vaccination is recommended, either using the live attenuated vaccine with 2-4 weeks cessation of JAKi therapy or with the recombinant vaccine. Studies suggest that pausing methotrexate for one to two weeks from the time of vaccination reduces blunting of vaccine response.⁴⁷ ⁴⁸

### V. Laboratory and Clinical Monitoring.

This section has been moved from its previous position as number VI to now become element V for reasons of logical flow. The taskforce simply felt that the laboratory portion would fit better immediately after the section on pre-treatment screening and before dealing with adverse events (now section VI).

1. Periodic minimal laboratory monitoring: full and differential blood counts, liver and renal tests, lipid levels. (LoE 2b/5, SoR B/D, Vote 100%, LOA 9.76)

In the prior version of the consensus statements, specific time points were recommended, but the taskforce felt that this was too prescriptive and this debate was resolved by simply stating “periodic”, as was previously done after specifying initial detailed time points. With regard to lipid levels, it was suggested to measure these periodically, preferably also at baseline, and if levels are increased to suggest lipid lowering therapy as per national guidelines. With testing of liver and renal function testing it was acknowledged that not all instruments (e.g. liver enzyme tests) are practically adequate to assess “function”.

2. Regular skin examination (for detection of skin cancer), as per national recommendations. (LoE 5, SoR D, Vote 94% - 1 abstention, LOA 8.88)

This bullet point was changed from the previous recommendation of “annual skin examinations”, since it was felt that this depended on local risks and, therefore, national recommendations should be adhered to.

3. Evaluate response using validated, disease-specific measures of disease activity; for evaluation and definition of response, be aware that CRP and ESR may be reduced by JAK inhibitors independently of reduction of disease activity and possibly even for infections. (LoE 2b/5, SoR B/D, Vote 100%, LOA 9.97)
Several instruments used to assess disease activity include C-reactive protein (CRP) as one of the components. Since JAKi inhibits IL-6 signaling and IL-6 is a direct (hepatic) activator of acute phase reactants (APR), APR- and CRP-decreases and even normalization can often occur in the absence of significant clinical changes, suggesting the presence of low disease activity or remission without respective clinical evidence. Therefore instruments should be used that do not include APRs to preclude such erroneous results.⁴⁹ For example, the American College of Rheumatology (ACR) and EULAR have recommended to not use the Disease Activity Score (DAS, original or using 28 joint counts) to determine remission but rather other measures, such as Boolean, SDAI or CDAI definitions of remission.⁵⁰ The same caveat may pertain to the use of ASDAS in axial spondyloarthritis⁵¹ or MDA, DAPSA (though not clinical DAPSA) and PASDAS in psoriatic arthritis.⁵² Indeed, claims that one drug may be better than another one could be (and are) made when using such measures,⁵³ without such superiority being necessarily reflected in other objective assessments of disease activity, such as swollen joint counts in RA; at the least, potential small and clinically irrelevant differences may be highly exaggerated when using such instruments.

## VI. Adverse Effects.

This element was moved from its previous position as section V to now become group VI of the recommendations (see above).

1. Serious infections (similar to bDMARDs), opportunistic infections including TB, and Herpes zoster (increased rates compared to bDMARDs) may occur; the risk of infectious events can be lowered with reduction or elimination of concomitant glucocorticoid use. (LoE 2b, SoR B, Vote: 100%, LOA 9.70)

This item remained essentially unchanged and simply reflects the currently available data regarding infections under JAKis. As mentioned before, Herpes zoster rates may be lower with filgotinib than the other JAKis, but this is an impression, albeit based on the data from placebo and active controlled trials, and not deducted from head-to-head comparisons of different JAKis. Dose dependent risks for serious infections were observed in several trials,¹³ ³⁵ ⁴⁴ ⁵⁴ ⁵⁵ with higher age being an important risk factor.¹⁸ ⁴⁵ ⁵⁶ ⁵⁷

2. Rates of malignancy may be higher with JAK-inhibition compared with TNF-inhibitors; the risk of NMSC is elevated. (LoE 2b, SoR B, vote 94% - 1 abstention; LOA 9.52)

This recommendation was reformulated to reflect data from the ORAL Surveillance trial.¹³ ⁵⁸ The wording “may” was used despite the fact that this was an RCT, but a confirmatory RCT may be
needed to change “may” to “is”, especially since data from registries, which have primarily been
implemented to find rare adverse events, do not show an increased malignancy risk with JAKis.⁵⁹ ⁶⁰ As
indicated above, the ORAL Surveillance trial focused on a particular group of patients at risk for
developing malignancies due to their smoking behaviour.

3. Lymphopenia, thrombocytopenia, neutropenia, anaemia may occur; anaemia especially occurring with JAK-inhibitors that inhibit JAK2. (LoE 1b, SoR B, vote 100%, LOA 9.52)

Since anaemia of chronic disease is improved at the group level with filgotinib,³³ ⁶¹ ⁶² the second half of this recommendation was added to reflect the fact that anaemia occurs primarily upon inhibition of JAK2, since erythropoietin signals via the JAK2 homodimer. Lymphocyte counts <0.5 x 10(9)/L are associated with increased risk of serious and opportunist infection. Neutropenia 0.5-1.0 x 10(9)/L is common with JAKi, but rarely associated with infections.⁴³ ⁶³ Only a few haematologic abnormalities were observed in deucravacitinib treated patients, however larger studies are still ongoing.⁶⁴⁻⁶⁶

4. There is a dose dependent risk of venous thromboembolic events, especially pulmonary embolism with JAK-inhibition, particularly in patients with risk factors for venous thromboembolic events. (LoE 2b, SoR B, vote 100%, LOA 9.67)

This point, which focused on high dose tofacitinib and on baricitinib in 2019,³⁹ ⁶⁷ ⁶⁸ was expanded to reflect that the increased VTE risk may pertain to all JAKis, as long as no opposing data from RCTs has become available. It remains unknown whether this is an effect of JAK2 inhibition or a JAK class effect, nor is the exact mechanism for this adverse effect understood.

5. Elevations of CPK are noted with JAK inhibitors but have usually not been associated with clinical events; elevations of creatinine have been noted with JAK inhibitors but have not been associated with renal failure or hypertension. (LoE 2b, SoR B, vote 100%, LOA 9.55)

This last recommendation remained essentially the same as in 2019. The data accrued since the last SLR further strengthen and confirm this conclusion.⁴² ⁴³

Finally, a research agenda was discussed during and after the meeting and is shown in Table 4.

Discussion

This update presents an amended version of the consensus statement for using JAKi in IMIDs,
developed in 2019. The update became necessary because despite the short time since the
development of the original document new JAKi have been approved and JAKi have been licensed for
several new indications. Most importantly, new safety issues have arisen. This statement differs from
disease management recommendations in two important ways: firstly, as already pointed out, it
does not deal with how a particular disease should be managed but rather with how JAKi should be
used once the respective decision has been made, and secondly, it does not address a specific
disease but rather the range of IMIDs for which JAKi have been approved. To this end, the taskforce
included experienced clinicians from relevant specialties, but also health care professionals and
patients across nations and continents who focused on changes since the previous publication. The
amendments were based on a systematic literature review (SLR) over the intervening period which
covered efficacy and safety aspects across IMIDs and will be published separately.⁶⁹ ⁷⁰

The taskforce discussions and decisions addressed general principles, indications and contra-
indications, screening, and monitoring as well as a research agenda for the usage of JAKi therapy in
patients with IMIDs. They cover the significant advances in JAK inhibitor therapy since 2019 regarding
the development of novel agents such as the Tyk2 inhibitors; new approvals for novel indications,
such as axial spondylarthropathies, atopic dermatitis, and inflammatory bowel disease; economic
aspects given the advent of generics with implications for effective affordable therapy for less
affluent countries; safety data from trial data focusing on safety to a decade from extensive long
term extensions of clinical trial programmes as well as long duration registry data including patients
with co-morbidities and concomitant medications that would preclude their enrolment in clinical
trials; as well as black box warnings from the FDA and EMA adding safety concerns and dictating the
place of JAK inhibition in therapy for a number of countries.

Since COVID-19 is not an IMID, it has not been addressed in this update, but it should be pointed out
that baricitinib, in combination with remdesivir, has been approved for COVID-19 and that EULAR has
published recommendations which include advice for the management using immunomodulatory
therapy such as JAKi therapy in the setting of acute COVID-19 infection.⁷¹

Baricitinib, filgotinib (in Europe and Japan), peficitinib (in Japan), tofacitinib, upadacitinib and deucravacitinib are licensed for one or more autoimmune inflammatory diseases. Integrated safety analyses of tofacitinib up to 9.5 years (22,875 patient years of exposure),¹⁸ ⁷² baricitinib up to 9.3 years (13,148 patient years of exposure),¹⁶ ⁷³⁻⁷⁵ filgotinib to 5.6 years (5,493 patient years of exposure)³³ ⁷⁶ and upadacitinib (4,020 patient years of exposure)¹⁷ ⁴⁴ have been published to complement the SLR safety analysis.⁷⁷

JAK selectivity has led to the development of novel molecules. Tyk2 inhibitors target signal
transduction by IL12,23,10 and type 1 interferons. Some of them, like deucravacitinib, bind
covalently to the pseudokinase domain rather than reversibly to the ATP pocket of the kinase domain.⁷⁸ Deucravacitinib has approvals for psoriasis, a comprehensive psoriatic arthritis clinical trial programme,⁷⁹ ⁸⁰ and currently under investigation in SLE.²² Also under development are Beprocitinib and SAR-20347 which are inhibitors of TyK2 and JAK 1, while Ropsacitinib inhibits TyK2 and JAK 2 and is under investigation in psoriasis and hidradenitis suppurativa.

Follow-up data from long term extensions of clinical trials and registry data has yet to demonstrate that “JAK 1 selectivity/preferred” convincingly shows advantages in efficacy or safety between JAK inhibitors - apart possibly from reduced zoster and possibly thromboembolic rates for Filgotinib.¹⁹ However, whether increased cardiovascular and thrombosis risk, as suggested by a head to head safety study (compared with TNF inhibition)¹³ is a JAK inhibitor class effect or rather a specific JAK 2 inhibition effect remains an unsettled question for the research agenda as does the possible mechanism for increased malignancy risk compared to TNFi. The safety and contra-indication statements outlined in the respective sections of this update have been crafted to manage that risk until more definitive data is available.

Since drugs should generally be used at the minimum effective dose, the recommendations also address dose reduction once the desired state has been achieved. As far as this has been studied, good outcomes are maintained in most patients upon dose reduction and in those in whom disease activity then increases the good disease state is usually recaptured by returning to the previously more effective dose. Also, as indicated in the monitoring section, for all JAKi which interfere with IL-6 signal transduction and thus directly with CRP-production, instruments that include CRP should not be used in clinical trials nor clinical practice to prevent potentially false trial results and erroneous continuation of an insufficiently efficacious JAKi. This is not an issue for TYK2-selective inhibition.

Generic JAKi are now available in a number of countries and the first clinical equivalence study of originator tofacitinib and a generic has been published.⁸¹ Generic small molecules have the potential to provide highly effective therapy at a more affordable price for countries where access due to cost is a major limitation, especially when long term therapy is required.

The current consensus statement is certainly not a final one. Many other indications and many other Jaki are currently being investigated, and some of these studies are listed in Figure 1.

In conclusion, this update acknowledges that a variety of specialists and health professionals are involved in the management of patients taking JAKi and emphasizes the need for adequate
information to provide informed consent. The update stresses the use of national and international guidelines and recommends dose adjustments in the setting of co-morbidities like renal impairment and concomitant medications like rifampicin. Evidence for JAKi tapering whilst maintaining efficacy and recapture on flare has been updated. Given the ORAL Surveillance trial as well as extensive registry data, when JAKi therapy is considered, safety considerations like thrombosis, MACE and malignancy should be taken into account, as well as individual risk and benefit, the patients disease journey, co-morbidities and concomitant medications. The research agenda remains important to answer questions of risk, mechanistic issues, safety in pregnancy and lactation, and adequacy of monitoring. Once these data or other new information become available, a further update of this consensus statement may be desirable.

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71. Alunno A, Najm A, Machado PM, et al. 2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19. *Ann Rheum Dis* 2022;81(1):34-40. doi: 10.1136/annrheumdis-2021-221366 [published Online First: 20211007]

72. Burmester GR, Nash P, Sands BE, et al. Adverse events of special interest in clinical trials of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and psoriasis with 37 066 patient-years of tofacitinib exposure. *RMD Open* 2021;7(2) doi: 10.1136/rmdopen-2021-001595
73. Bieber T, Katoh N, Simpson EL, et al. Safety of baricitinib for the treatment of atopic dermatitis over a median of 1.6 years and up to 3.9 years of treatment: an updated integrated analysis of eight clinical trials. *J Dermatolog Treat* 2023;34(1):2161812. doi: 10.1080/09546634.2022.2161812

74. King B, Mostaghimi A, Shimomura Y, et al. Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials. *Br J Dermatol* 2023;188(2):218-27. doi: 10.1093/bjd/ljac059

75. Guttman-Yassky E, Thyssen JP, Silverberg JI, et al. Safety of upadacitinib in moderate-to-severe atopic dermatitis: An integrated analysis of phase 3 studies. *J Allergy Clin Immunol* 2023;151(1):172-81. doi: 10.1016/j.jaci.2022.09.023 [published Online First: 20221001]

76. Winthrop K, Aletaha D, Caporali R, et al. POS0844 INTEGRATED SAFETY ANALYSIS OF FILGOTINIB IN PATIENTS WITH MODERATE TO SEVERE ACTIVE RHEUMATOID ARTHRITIS WITH A MAXIMUM EXPOSURE OF 8.3 YEARS. *Annals of the Rheumatic Diseases* 2023;82(Suppl 1):721-22. doi: 10.1136/annrheumdis-2023-eular.1553

77. Szekanecz Z, Buch MH, Charles-Schoeman C, et al. Efficacy and safety of JAK inhibitors in rheumatoid arthritis: update for the practising clinician. *Nat Rev Rheumatol* 2024;20(2):101-15. doi: 10.1038/s41584-023-01062-9 [published Online First: 20240112]

78. Jensen LT, Attfield KE, Feldmann M, et al. Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitors. *EBioMedicine* 2023;97:104840. doi: 10.1016/j.ebiom.2023.104840 [published Online First: 20231018]

79. Armstrong AW, Gooderham M, Warren RB, et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: Efficacy and safety results from the 52-week, randomized, double-blinded, placebo-controlled phase 3 POETYK PSO-1 trial. *J Am Acad Dermatol* 2023;88(1):29-39. doi: 10.1016/j.jaad.2022.07.002 [published Online First: 20220709]

80. Strober B, Thaci D, Sofen H, et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: Efficacy and safety results from the 52-week, randomized, double-blinded, phase 3 Program fOr Evaluation of TYK2 inhibitor psoriasis second trial. *J Am Acad Dermatol* 2023;88(1):40-51. doi: 10.1016/j.jaad.2022.08.061 [published Online First: 20220914]

81. Zhao J, Huang H, Wang Y, et al. Real-World Clinical Equivalence of Generic and Branded Tofacitinib: A Prospective Longitudinal Cohort Study in Patients With Rheumatoid Arthritis. *Mayo Clin Proc* 2024;99(1):26-38. doi: 10.1016/j.mayocp.2023.08.029
<table><caption>Table 1. Overarching principles and individual recommendations by different categories.</caption><thead><tr><th>Item</th><th>Recommendation</th><th>LoE/SoR</th><th>Last vote</th><th>LoA</th></tr></thead><tbody><tr><td colspan="5"><strong>Overarching Principles</strong></td></tr><tr><td>A-</td><td>Initiation of JAK-inhibitor therapy and the treatment target to be achieved should be based on a shared decision between the patient and the clinician, fully informing the patient on the potential benefit and risks of this therapy.</td><td>N/A</td><td>100%</td><td>9.9±0.4</td></tr><tr><td>B.</td><td>Therapeutic approaches to treating patients with chronic inflammatory conditions should be in line with international/national recommendations (algorithms) for the management of the respective disease.</td><td>N/A</td><td>100%</td><td>9.7±0.6</td></tr><tr><td>C.</td><td>The points-to-consider when initiating JAK-inhibitor therapy do not provide information on when JAK-inhibitors should be used in the treatment algorithm, but rather attempt to assist the clinician once the decision to prescribe a JAK-inhibitor has been made.</td><td>N/A</td><td>100%</td><td>9.7±0.5</td></tr><tr><td>D.</td><td>These points-to-consider address specific (but not all) aspects related to the application of JAK-inhibitor therapy and the clinician should additionally refer to the disease-specific product information.</td><td>N/A</td><td>100%</td><td>9.8±0.5</td></tr><tr><td colspan="5"><strong>I. Indications</strong></td></tr><tr><td>1.</td><td>Patients with immune mediated inflammatory diseases (IMIDs). As of 2024, depending on the specific drug, these include rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, ulcerative colitis, Crohn's disease, psoriasis, atopic dermatitis, vitiligo, alopecia areata.</td><td>1a/A</td><td>100%</td><td>9.9±0.3</td></tr><tr><td>2.</td><td>Currently there is no direct evidence from head-to-head comparisons to show efficacy or safety superiority of one JAK-inhibitor over another on.</td><td>5/D</td><td>94%</td><td>9.9±0.3</td></tr><tr><td colspan="5"><strong>II. Treatment dose and co-medication</strong></td></tr><tr><td>1.</td><td>Use the dose recommended for the specific disease.</td><td>1a/A</td><td>100%</td><td>9.8±0.5</td></tr><tr><td>2.</td><td>Consider dose adjustments in patients with higher age*, significant renal or hepatic impairment*, other co-morbidities and/or at risk of drug-interactions.</td><td>2b,*5/C,*D</td><td>100%</td><td>9.6±1.0</td></tr><tr><td>3.</td><td>Regarding co-medication, follow specific recommendations for</td><td>1a/B</td><td>100%</td><td>9.8±0.5</td></tr></tbody></table>
<table><tr><td></td><td>the respective disease.</td><td></td><td></td><td></td></tr><tr><td>4.</td><td>Consider dose reduction of the JAK inhibitor in patients in sustained remission according to established assessment instruments (regarding use of such instruments, see recommendation V/3).</td><td>1b/B</td><td>94%</td><td>9.1±1.3</td></tr></table>

### III. Warnings or contraindications

<table><tr><td>1.</td><td>Severe active (or recurrent*) infections, including tuberculosis and opportunistic infections.</td><td>2b, *4/B, *D</td><td>94%</td><td>9.7±0.6</td></tr><tr><td>2.</td><td>Current (or history of) malignancies.</td><td>5/D</td><td>94%</td><td>9.2±0.9</td></tr><tr><td>3.</td><td>Severe organ dysfunction such as advanced chronic liver disease and severe renal disease (Cr Cl &lt; 30 ml/min).</td><td>5/D</td><td>100%</td><td>9.7±0.6</td></tr><tr><td>4.</td><td>Pregnancy and lactation.</td><td>5/D</td><td>100%</td><td>9.8±0.6</td></tr><tr><td>5.</td><td>History of arterial and venous thrombo-embolic events.</td><td>2b/B</td><td>100%</td><td>9.5±0.8</td></tr><tr><td>6.</td><td>Vaccination with live vaccines.</td><td>5/D</td><td>100%</td><td>9.6±1.0</td></tr></table>

### IV. Pre-treatment screening and risks

<table><tr><td>1.</td><td>Patient history and physical examination, with a focus on warnings and contraindications.</td><td>5/D</td><td>100%</td><td>9.9±0.4</td></tr><tr><td>2.</td><td>Consider risk factors for venous thromboembolic events (VTE), especially a history of thrombo-embolism; cardiovascular risk such as previous history of cardiovascular event; risk for malignancy, such as smoking history.*</td><td>2b,*5/B/D</td><td>100%</td><td>9.9±0.3</td></tr><tr><td>3.</td><td>Routine laboratory testing (full and differential blood counts, liver function tests, renal function; and lipid levels as a baseline.</td><td>5/D</td><td>100%</td><td>9.7±0.6</td></tr><tr><td>4.</td><td>Hepatitis B testing (Hepatitis B surface antigen, Hepatitis B surface antibody, Hepatitis B core antibody, and with/without HBV DNA testing. Hepatitis C testing (Hepatitis C antibody, with HCV RNA testing if antibody positive).</td><td>2b/B</td><td>100%</td><td>9.9±0.3</td></tr><tr><td>5.</td><td>Human immunodeficiency virus testing in high risk populations.</td><td>2b/B</td><td>100%</td><td>9.6±1.0</td></tr><tr><td>6.</td><td>Tuberculosis screening as per national recommendations.</td><td>2b/B</td><td>100%</td><td>9.9±0.3</td></tr><tr><td>7.</td><td>Assess and update vaccination status in accordance with national recommendations; consider vaccination against H. zoster.</td><td>5/D</td><td>100%</td><td>9.7±0.5</td></tr></table>

### V. Laboratory and clinical monitoring

<table><tr><td>1,</td><td>Periodic minimal laboratory monitoring: full and differential blood counts, liver and renal function tests, lipid levels.</td><td>2b,*5/B,*D</td><td>100%</td><td>9.8±0.5</td></tr></table>
<table><tr><td>2.</td><td>Regular skin examination (for detection of skin cancer), as per national recommendations.</td><td>5/D</td><td>94%</td><td>8.9±1.5</td></tr><tr><td>3.</td><td>Evaluate response using validated, disease-specific measures of disease activity; for evaluation and definition of response, be aware that CRP and ESR may be reduced by JAK inhibitors independently of reduction of disease activity and possibly even in infections*.</td><td>2b,*5/B,*D</td><td>100%</td><td>9.9±0.7</td></tr></table>

VI. Adverse effects

<table><tr><td>1.</td><td>Serious infections (similar to bDMARDs), opportunistic infections including TB, Herpes zoster (increased rates compared to bDMARDs) may occur; the risk of infectious events can be lowered with reduction or elimination of concomitant glucocorticoid use.</td><td>2b/B</td><td>100%</td><td>9.7±0.7</td></tr><tr><td>2.</td><td>Rates of malignancy may be higher with JAK-inhibition compared with TNF-inhibitors; the risk of NMSC is elevated.</td><td>2b/B</td><td>94%</td><td>9.5±0.7</td></tr><tr><td>3.</td><td>Lymphopenia, thrombocytopenia, neutropenia, anaemia may occur; anaemia especially occurring with JAK-inhibitors that inhibit JAK2.</td><td>1b/B</td><td>100%</td><td>9.5±1.1</td></tr><tr><td>4.</td><td>There is a dose dependent risk of venous thromboembolic events, especially pulmonary embolism with JAK-inhibition, particularly in patients with risk factors for venous thromboembolic events.</td><td>2b/B</td><td>100%</td><td>9.7±0.6</td></tr><tr><td>5.</td><td>Elevations of CPK are noted with JAK inhibitors but have usually not been associated with clinical events; elevations of creatinine have been noted with JAK inhibitors but have not been associated with renal failure or hypertension.</td><td>2b/B</td><td>100%</td><td>9.6±0.7</td></tr></table>
<table><caption>Table 2</caption><thead><tr><th>Drug</th><th>Target</th><th>Indications</th><th>Metabolism</th></tr></thead><tbody><tr><td>Tofacitinib</td><td>JAK1, JAK3, JAK2</td><td>RA, PsA, ulcerative colitis, JIA</td><td>CyP3A4, 30% renal excretion</td></tr><tr><td>Baricitinib</td><td>JAK1, JAK2</td><td>RA, AD, AA, JIA, COVID-19*</td><td>>66% renal excretion</td></tr><tr><td>Upadacitinib</td><td>JAK1, JAK2</td><td>RA, PsA, AD, UC, CD, axial SpA (incl. nr axSpA)</td><td>CyP3A4 20% renal excretion</td></tr><tr><td>Filgotinib</td><td>JAK1</td><td>RA</td><td>CES2, active metabolism</td></tr><tr><td>Ruxolitinib</td><td>JAK1, JAK2</td><td>Myelofibrosis, Polycythemia vera, GvHD, vitiligo (topical)</td><td></td></tr><tr><td>Fedratinib</td><td>JAK1-FLT3</td><td>Myelofibrosis</td><td></td></tr><tr><td>Peficitinib</td><td>Pan-JAK</td><td>RA**</td><td>NNMT, SULT2A1, 16S</td></tr><tr><td>Delgocitinib</td><td>Pan-JAK</td><td>AD**</td><td></td></tr><tr><td>Abrocitinib</td><td>JAK1,2</td><td>AD</td><td></td></tr><tr><td>Oclacitinib</td><td>JAK1, JAK2, JAK3</td><td>Canine AD</td><td></td></tr><tr><td>Ritlecitinib</td><td>JAK3, TEC</td><td>AA</td><td></td></tr><tr><td>Deucravacitinib</td><td>TYK2</td><td>PsO</td><td>CyP1A2 13% renal excretion, active metabolite BM</td></tr></tbody></table>

JAK inhibitors approved by EMA and/or FDA

* Approved by FDA in combination with remdesivir

** Approved in Japan.

AA, alopecia areaty; AD, atopic dermatitis; CD, Crohn's disease; CES2, carboxyesterase isoform 2; CypP cytochrome P; ER, extended release; JIA, juvenile idiopathic arthritis; NMNT, nicotinamide N-methyltransferase; nr, non-radiographic; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis; SULT2A1, sulfotransferase 2A1; UC, ulcerative colitis.

<table><caption>Table 3 Approved JAKi for specific IMID-indications.</caption><thead><tr><th>Indication</th><th>Approved Janus kinase inhibitor</th></tr></thead><tbody><tr><td>Rheumatoid arthritis</td><td>Baricitinib (JAK1, 2), filgotinib (JAK1), peficitinib (pan-JAK), tofacitinib (JAK 1, 3, 2), Upadacitinib (JAK1, 2)</td></tr></tbody></table>
<table><caption>**Table 4. Research Agenda.**</caption><tr><td>Psoriatic arthritis</td><td>Tofacitinib (JAK1,3,2), Upadacitinib (JAK1,2)</td></tr><tr><td>Psoriasis</td><td>Deucravacitinib (TYK2)</td></tr><tr><td rowspan="2">Atopic dermatitis</td><td>Abrocitinib (JAK1,2), baricitinib (JAK1,2)</td></tr><tr><td>Upadacitinib (JAK1,2)</td></tr><tr><td>Alopecia areata</td><td>Baricitinib (JAK1, 2), ritlecitinib (JAK3, TEC)</td></tr><tr><td>Axial spondyloarthritis</td><td>Tofacitinib (JAK1,3,2), upadacitinib (JAK1,2)</td></tr><tr><td>Juvenile idiopathic arthritis</td><td>Tofacitinib (JAK1,3,2), baricitinib (JAK1,2)</td></tr><tr><td>Crohn's disease</td><td>Upadacitinib (JAK1,2)</td></tr><tr><td>Ulcerative colitis</td><td>Tofacitinib (JAK1,3,2), upadacitinib (JAK1,2)</td></tr><tr><td>Vitiligo</td><td>Ruxolitinib (JAK1,2,) - topical</td></tr></table>

1. What is the efficacy and safety of switching between JAKi in non-responders or due to lack of tolerability?

2. What are the predictors of response to JAK-inhibitors as compared to other DMARDs used for RA?

3. Do JAKi reduce CV risk by interfering with inflammation, despite the ORAL-Surveillance study?

4. Is VTE a class effect or a JAK 2 inhibition effect and what is the mechanism of VTE? What is the actual risk of VTE when treating with a JAK-inhibitor?

5. What is the safety of JAK-inhibition in patients with prior or current malignancy or who develop a malignancy whilst on therapy?

6. Are JAK-inhibitors effective and safe as therapy for autoimmune diseases induced by checkpoint inhibitors in patients with malignancy?

7. How safe are JAK-inhibitors in Hepatitis B, C, infected patients and also other viral infections such as HPV? In case of active infections, esp COVID19, should JAKinibs be temporarily discontinued? If so for how long?

8. How safe are JAK-inhibitors in pregnancy and lactation? What should be recommended if a woman taking a JAK-inhibitor becomes pregnant?

9. Safety of JAK-inhibitors in elective surgery – should they be discontinued and if so for how long and when should they be restarted?

10. What is the efficacy of JAK-inhibitors in extra-articular(EA) RA manifestations including vasculitis, nodulosis, lung involvement, overlap syndromes, and also EA manifestations of axSpA, etc, IBD, etc
11. What is the efficacy and safety of combination therapies with JAK-inhibitors and other targeted therapies, especially bDMARDs in patients with severe RA or other diseases?

12. What are the distinct molecular *in vivo* down-stream effects of JAK-inhibition in the setting of individual diseases?

13. What are the differences between different JAKi (eg TYK2i) regarding efficacy and safety?

14. Are JAKi plus MTX more efficacious than MTX + GC in DMARD-naive RA? (at least in the short term)

15. Are JAKi plus GC more effective and as safe as MTX + GC in DMARD-naive patients

16. What is the mechanism for JAKi-induced acne?

17. Can the dose of all JAKi be tapered or discontinued in remission?

18. Do drug levels of JAKi correlate with adherence to drug?

19. What is the mechanism leading to JAKi induced creatinine and CPK elevations?

20. Will JAKi be efficacious in pre-RA or in preventing RA?

21. Can JAKi prevent radiographic progression in AxSpA?

22. What is the effect of JAKi on pain and fatigue and what is the mechanism?

23. How long should one interrupt JAKi therapy before and/or after vaccination?

24. Are there clinically meaningful efficacy and/or safety differences between the different JAKi (including deucravacitinib)?
<table><caption>Fig. 1. Status of using JAK inhibitors in IMIDs (green: approved, white: in trial).</caption><thead><tr><th></th><th>TOFA</th><th>BARI</th><th>UPA</th><th>FILGO</th><th>PEFI</th><th>DEUCRA</th><th>RITLE</th><th>ABRO</th><th>RUXO<br>(cream)</th></tr></thead><tbody><tr><td>Rheumatoid arthritis</td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td>phase 3<br>completed;<br>FDA (2mg) &amp;<br>EMA (4mg)<br>approved</td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td>phase 3<br>completed;<br>EMA<br>approved, FDA<br>pending</td><td>phase 2<br>multinational;<br>phase 3<br>completed in<br>Asia; approved<br>in Japan;<br>China/Taiwan/<br>South Korea<br>ongoing)</td><td></td><td></td><td></td><td></td></tr><tr><td>Psoriatic arthritis</td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td></td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td>phase 2<br>completed;<br>phase 3<br>terminated<br>early<br>(NCT04115748<br>;<br>NCT04115839;<br>Penguin 1&amp;2)</td><td></td><td>phase 2<br>completed;<br>phase 3<br>ongoing<br>(NCT04908202<br>NCT04908189)</td><td></td><td></td><td></td></tr><tr><td>Ankylosing spondylitis</td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td></td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td>phase 2<br>completed;<br>phase 3<br>withdrawn<br>(NCT04483687<br>;<br>SEALION-IR)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>non-radiographic axSpA</td><td></td><td></td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Systemic lupus</td><td></td><td>phase 3<br>completed<br>(SLE-BRAVE<br>I&amp;II)</td><td>phase 3<br>ongoing<br>(NCT05843643<br>;<br>SELECT-SLE)</td><td></td><td></td><td>phase 2<br>completed;<br>phase 3<br>ongoing<br>(NCT05620407;<br>NCT05617677;<br>POETYK SLE-<br>1&amp;2)</td><td></td><td></td><td></td></tr></tbody></table>

<table><tr><td>Cutaneous/ discoid lupus</td><td></td><td></td><td></td><td>phase 2<br>completed</td><td></td><td>phase 2<br>ongoing (NCT04857034)</td><td></td><td>single-arm<br>phase 2<br>ongoing<br>(NCT04414514<br>)</td></tr><tr><td>Lupus nephritis</td><td></td><td></td><td></td><td>phase 2<br>completed</td><td></td><td>phase 2<br>terminated early due to<br>low enrollment<br>(NCT03943147<br>;<br>PAISLEY-LN)</td><td></td><td></td></tr><tr><td>Sjogren's syndrome</td><td>phase 2<br>ongoing<br>(NCT04496960<br>)</td><td>phase 2<br>ongoing<br>(NCT05016297<br>;<br>China)</td><td></td><td>phase 2<br>completed</td><td></td><td>phase 3<br>ongoing (NCT05946941<br>(POETYK SJS-1))</td><td></td><td></td></tr><tr><td>Juvenile idiopathic arthritis</td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td>phase 3<br>completed;<br>EMA approved</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ulcerative colitis</td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td></td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td>phase 3<br>completed;<br>EMA approved</td><td>phase 2<br>completed</td><td>phase 2<br>completed</td><td>phase 2<br>completed</td><td></td></tr><tr><td>Crohn's disease</td><td>phase 2<br>completed</td><td></td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td></td><td></td><td>phase 2<br>ongoing<br>(NCT03599622<br>)</td><td></td><td></td></tr><tr><td>Psoriasis</td><td>phase 3<br>completed</td><td></td><td></td><td></td><td>phase 2<br>completed</td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td></td><td></td></tr><tr><td>Atopic dermatitis</td><td>phase 2<br>completed for<br>Topical TOFA</td><td>phase 3<br>completed;<br>EMA approved<br>(4mg)</td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td></td><td></td><td>phase 3<br>completed;<br>FDA&amp;EMA<br>approved</td><td>phase 3<br>completed<br>(TBJUE, AD1-3)</td><td></td></tr></table>
<table><tr><td>Alopecia areata</td><td>only phase 2 pilot study</td><td>phase 3 completed; FDA (2mg) &amp; EMA (4mg) approved</td><td>phase 3 ongoing (NCT06012240; UP-AA)</td><td></td><td>phase 2 ongoing (NCT05556265)</td><td>phase 3 completed; FDA&amp;EMA approved (also age≥12)</td><td>phase 2 completed</td></tr><tr><td>Vitiligo</td><td></td><td></td><td></td><td></td><td></td><td>phase 2 completed; phase 3 ongoing (NCT06072183; NCT05583526; Tranquillo &amp; Tranquillo2)</td><td>phase 3 completed; FDA&amp;EMA approved (also age≥12)</td></tr><tr><td>Hidradenitis suppurativa</td><td></td><td>phase 2 completed; phase 3 ongoing (NCT05889182; Step-Up HS)</td><td></td><td></td><td>single-center phase 2 ongoing (NCT05997277)</td><td></td><td>single-arm, single-center phase 2 ongoing (NCT05635838)</td></tr></table>