# JAK inhibitors (JAKi): Mechanisms of action and perspectives in systemic and autoimmune diseases.

Liticia Chikhoune, Claire Poggi, Julie Moreau, Sylvain Dubucquoi, Eric Hachulla, Aurore Collet, David Launay

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Liticia Chikhoune, Claire Poggi, Julie Moreau, Sylvain Dubucquoi, Eric Hachulla, et al.. JAK in-hibitors (JAKi): Mechanisms of action and perspectives in systemic and autoimmune diseases.. La Revue de Médecine Interne, 2024, La Revue de Médecine Interne, 10.1016/j.revmed.2024.10.452. hal-04844657

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Review article

# JAK inhibitors (JAKi): Mechanisms of action and perspectives in systemic and autoimmune diseases

## Inhibiteurs de JAK (JAKi) : mécanismes d'action et perspectives dans les maladies systémiques et auto-immunes

Liticia Chikhouneª, Claire Poggiª, Julie Moreauª, Sylvain Dubucquoib,c, Eric Hachullaa,c,d, Aurore Colletb,c, David Launaya,c,d,\*

## INFO ARTICLE

Disponible sur Internet le xxx

Keywords :

JAKi

Systemic disease

Autoimmune disease

Mots clés :

JAKi

Maladies systémiques

Maladies auto-immunes

## ABSTRACT

Janus kinase (JAK) molecules are involved in important cellular activation pathways. Over the past decade, many targeted therapies have emerged, including the increasingly promising role of JAK inhibitors (JAKi) in the treatment of inflammatory and autoimmune diseases. The spectrum of use of these small molecules is increasingly broader. JAKi have been approved in several autoimmune diseases. Currently, four molecules (tofacitinib, baricitinib, upadacitinib and filgotinib) have been labeled for moderate to severe rheumatoid arthritis (RA) with failure or poor tolerance of one or more conventional disease-modifying antirheumatic drug (csDMARDS), or biologics (bDMARDS). JAKi are now also commonly used in other diseases such as psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis. They have also shown promising results in clinical trials for the treatment of other autoimmune conditions. We present here their mechanisms of action, and the main data about JAKi use on systemic and autoimmune diseases.

© 2024 Les Auteurs. Published par Elsevier Masson SAS au nom de Société Nationale Française de Médecine Interne (SNFMI). Cet article est publié en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

## RÉSUMÉ

Les molécules Janus kinase (JAK) sont impliquées dans d'importantes voies d'activation cellulaire. Au cours de la dernière décennie, de nombreuses thérapies ciblées ont vu le jour, notamment le rôle de plus en plus prometteur des inhibiteurs de JAK (JAKi) dans le traitement des maladies inflammatoires et auto-immunes. Le spectre d'utilisation de ces petites molécules est de plus en plus large. Les JAKi ont été approuvés dans plusieurs maladies auto-immunes. Actuellement, quatre molécules (tofacitinib, baricitinib, upadacitinib et filgotinib) ont été étiquetées pour la polyarthrite rhumatoïde (PR) modérée à sévère avec échec ou mauvaise tolérance d'un ou plusieurs médicaments antirhumatismaux modificateurs de la maladie conventionnels (csDMARDS), ou biologiques (bDMARDS). Les JAKi sont désormais également couramment utilisés dans d'autres maladies telles que le rhumatisme psoriasique, la spondylarthrite ankylosante et la rectocolite hémorragique. Ils ont également montré des résultats prometteurs dans des essais cliniques pour le traitement d'autres maladies auto-immunes. Nous présentons ici leurs mécanismes d'action, ainsi que les principales données sur l'utilisation des JAKi dans les maladies systémiques et auto-immunes.

© 2024 Les Auteurs. Published par Elsevier Masson SAS au nom de Société Nationale Française de Médecine Interne (SNFMI). Cet article est publié en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

<footnote>ª CHU de Lille, Service de Médecine Interne et Immunologie Clinique, Centre de référence des Maladies Auto-Immunes et Auto-inflammatoires Systémiques rares de l'Adulte du Nord, Nord-Ouest, Méditerranée et Guadeloupe (CeRAINOM), 59000 Lille, France</footnote>

<footnote>ᵇ Institut d'Immunologie, Pôle de Biologie Pathologie Génétique Médicale, CHU de Lille, 59000 Lille, France</footnote>

<footnote>ᶜ U1286-INFINITE-Institute for Translational Research in Inflammation, Université de Lille, 59000 Lille, France</footnote>

<footnote>d Inserm, 59000 Lille, France</footnote>

<footnote>\* Corresponding author at: CHU de Lille, Centre de référence des Maladies Auto-Immunes et Auto-inflammatoires Systémiques rares de l'Adulte du Nord, Nord-Ouest, Méditerranée et Guadeloupe (CeRAINOM), 59000 Lille, France.</footnote>

<footnote>Adresse e-mail : david.launay@univ-lille.fr (D. Launay).</footnote>
# 1. Introduction

The Janus kinases (JAKs) are protein tyrosine kinases (TYKs) that bind to transmembrane type I and type II cytokine receptors and mediate cellular responses to numerous cytokines and growth factors; these mediators are important in immune defense and in immune-mediated disease. Several pharmacologic JAK inhibitors (JAKi) are commercially available for clinical use as oral and topical agents for immune-mediated and inflammatory diseases, although the availability of various JAKi varies among countries and regions. The spectrum of use of these small molecules is increasingly broader. JAKi have been approved in several autoimmune diseases and are considered for several other inflammatory and autoimmune diseases. Indeed, despite substantial advances, there is still a major need for novel therapeutic strategies for these conditions. If targeting specific cytokines outside the cell is insufficient to reliably achieve complete remission, an attractive alternative strategy is to target the action of different cytokines inside the cell, which is the hallmark of JAKi.

In this review, we will focus on the JAK STAT pathway, which is involved in the process of inflammation and autoimmune reactions. This pathway is key to target in the treatment of autoimmune diseases in order to block the inflammatory response. We will then present the various current approved indications of JAKi. Finally, we will discuss the available data and perspectives of JAKi in other autoimmune diseases.

# 2. Mechanisms of action

JAK STAT pathway is composed of a transmembrane receptor, which is coupled to an effector protein kinase called JAK, and a signaling intracellular protein called STAT [1]. The JAKs are intra-cytoplasmic protein TYK that bind to the cytoplasmic region of transmembrane cytokine receptors and promote signal transduc-

tion. JAK proteins share four components: the kinase domain, the pseudokinase domain, the four-point-one protein, ezrin, radixin, moesin (FERM) domain and the Src homology 2 (SH2)-like domain. Binding of the cytokine ligand to the receptor induces auto-phosphorylation and transphosphorylation of JAK proteins. These induce phosphorylation of STAT, which dimerizes. The dimer is translocated to the nucleus to act as transcriptional activator of the proteins synthesis involved in the inflammatory reaction [2] (Fig. 1).

Phosphorylation of JAKs induces recruitment of STAT proteins. There are 7 STAT proteins (STAT 1 to 4, 5a, 5b and 6). They contain many different domains, each with a different function. SH2 domain is the most conserved region. The docking of STAT proteins induces their phosphorylation, followed by homo-dimerization (STATx-STATx) or hetero-dimerization (STATx-STATy), leading to translocation of the dimer to the nucleus. The dimer, either alone or in association with other proteins (such as interferon response factor 9 [IRF9] in the type 1 interferon [IFN] signaling pathway), can then insert itself into a promoter region and induce the expression of genes specific to each inflammatory signal (IFN response genes, -activated sequences, etc.) or inducing cell proliferation (as with growth factor receptors). In addition, STAT can also be directly phosphorylated at their tyrosine residues by TYK present in the receptor (e.g. epidermal growth factor receptor [EGF]) or by c-src TYK. The JAK/STAT signalling pathway is regulated at several levels. Cellular phosphatases can remove phosphates from cytokine receptors and activated STATS. Recently identified suppressors of cytokine signaling (SOCS) proteins that inhibit STAT phosphorylation by binding to and blocking JAKs or by competing with STATS for binding sites of phosphotyrosine to cytokine receptors. STATS are also negatively regulated by activated STAT inhibitory proteins (PIAS) that act in the nucleus. Thus, PIAS1 and PIAS3 inhibit STAT1 and STAT3 mediated transcriptional activation by binding to them or blocking their access to sequences they recognize [4].

<figure><img src="image_2.png" /><figcaption>**Fig. 1.** Janus kinase (JAK)-STAT mechanism pathway [3]. 1. Cytokine ligand binding to the receptor. 2. JAK-autophosphorylation. 3. Receptors phosphorylation. 4. Recruitment of two STAT sub-units and binding to the receptors. 5. STAT phosphorylation. 6. Phosphorylated STAT detachment, dimerization and transit to the nucleus to modulate gene transcription.</figcaption></figure>
## 2.1. Ligands and receptors

The ligands of the receptors coupled to JAKs are mainly cytokines, chemokines, hormone-like cytokines, and growth factors. These receptors are classified into two categories according to their molecular structure and the ligands they can bind (type I or type II receptors) [2,3,5-8].

Within type I cytokines, subgroups could be distinguished according to the receptor subunit they share:

* γ chain cytokines: IL-2, IL-4, IL-7, IL-9, IL-13, IL-15 and IL-21;

* β chain cytokines: IL-3, IL-5, EPO, TPO and GM-CSF;

* cytokines with gp130 subunits: IL-6, IL-11, IL-27;

* dimeric cytokines: IL-12, IL-23 and IL-35;

* hormones: GH, Leptin, Prolactin.

Type II cytokines include:

* type I IFNs: IFNα (IFNα1, 2, 4, 5, 6, 7, 8, 10, 13, 14, 16, 17, 21), IFNβ, IFNε, IFNκ;

* type II IFNs: IFNγ;

* type III IFNs: IFNL1 (IL-29), IFNL2 (IL-28A), IFN3 (IL-28B), IFNL4, IFNω, and, IL-10 related cytokines: (IL-10, IL-19, IL-20, IL-22, IL-24 and IL-26).

## 2.2. JAK isoforms

Four isoforms of the JAK proteins have been described: JAK1, JAK2, JAK3 and TYK2, coupled as homodimer or heterodimer with the transmembrane receptor. Studies have shown that different cytokine receptors are associated with combinations of different JAK proteins. For example, growth factors receptors specifically use JAK2; cytokine receptors with the common γ chain, use JAK1 and JAK3 [7,9]. Furthermore, JAK3 expression is restricted to certain cell types. It is constitutively expressed in thymocytes and NK cells, and inducibly expressed in mature T cells, B cells and myeloid cells [7].

## 2.3. JAK inhibitors

The first therapeutics to reach the rheumatology market were intravenous antibody drugs targeting cytokines or cytokine receptors, such as anti-IL6 receptor and anti-TNF alpha. However, due to their lack of specificity, they also resulted in undesirable side effects. JAKi emerged from the need for more targeted approaches to specific signaling pathways, as well as the demand for oral medications from patients.

JAKi are small synthetic molecules that, for the majority, induce phosphorylation of JAK on the intracellular domain of the transmembrane receptor. These inhibitors act in a reversible manner. Signal blocking can be achieved either competitively by (i) binding to the ATP-binding site within the catalytic domain or (ii) allosterically by binding to another site to prevent receptor activation [3,10,11].

There are two generations of JAKi [11]:

* the first generation are non-selective molecules inhibiting several JAK (pan-JAKi), such as tofacitinib or baricitinib;

* the second generation is composed by molecules more specific to one isoform of JAK such as filgotinib.

JAKi available for clinical use differ in their selectivity for specific JAK isoforms. However, it is not clear how this apparent JAK selectivity in the laboratory and in experimental animal models extrapolates to meaningful differences among these agents in their clinical efficacy across the spectrum of chronic inflammatory diseases. At concentrations equivalent to clinically effective

doses, the JAKi overall appear to be less selective for particular JAK isoforms than when evaluated in cellular and biochemical assays. Tofacitinib, baricitinib, ruxolitinib and peficitinib are considered pan-JAK inhibitors, while upadacitinib is considered a highly selective JAK1 inhibitor. Filgotinib is a highly selective JAK1 inhibitor. Yet, there is not a perfect selectivity or specificity. For example, while upadacitinib is a highly selective inhibitor of JAK1, it also minimally inhibits JAK2 and TYK2.

## 2.4. Characteristics and indications of different JAKi

Tofacitinib inhibits JAK1 and JAK3, with partial inhibition of JAK2 and TYK2. JAK1 is involved in IFN signaling, so tofacitinib inhibits the Th1 response, while inhibition of JAK3 suppresses cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Additionally, by inhibiting JAK1, it blocks IL-6, type 1 interferons, and IFN-γ [11].

Tofacitinib is approved for rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, and polyarticular juvenile idiopathic arthritis.

Baricitinib is a JAK1 and JAK2 inhibitor and inhibits moderately TYK2, and very weakly JAK3. With JAK1 inhibition, IL-6 and type 1 IFNs and IFNγ are inhibited. With JAK2 inhibition, growth factors erythropoietin, thrombopoietin, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are inhibited. It is approved for use after conventional synthetic disease-modifying antirheumatic drug (csDMARDS) failure in patients with RA outside of the United States and for use after TNF inhibitor failure in patients with RA in the United States.

Ruxolitinib is a JAK2 inhibitor preferentially but is not isoform-specific. A topical form is available for the treatment of atopic dermatitis and vitiligo. It has been used primarily for the treatment of acute and chronic graft-versus-host disease, myelofibrosis, and polycythemia vera.

Filgotinib and upadacitinib are 2nd generation JAKi, and specifically inhibit JAK1. Filgotinib is approved for use in Europe and in Japan for the treatment of RA (only in women). Upadacitinib is approved for treatment of RA, psoriatic arthritis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, atopic dermatitis, crohn disease, and ulcerative colitis.

Decernotinib selectively inhibits JAK3.

Abrocitinib is a JAK1 inhibitor available for the treatment of atopic dermatitis in adults and adolescents.

Peficitinib is a pan-JAKi that binds irreversibly to JAK1, JAK2, JAK3, and TYK2. It is approved for the treatment of patients with RA with an inadequate response to DMARDs, including methotrexate. Peficitinib is approved for use in Japan and Korea.

Ritlecitinib selectively inhibits JAK3 and the TYK expressed in the hepatocellular carcinoma (TEC) kinase family. It is approved for the treatment of severe alopecia areata in adults and adolescents.

Itacitinib is a selective JAK1 inhibitor, which is studied in cytokine release syndrome induced by CAR T-cell therapy [11].

Deucravacitinib is a selective TYK2 inhibitor that is under investigation for the treatment of psoriatic arthritis and systemic lupus erythematosus, and is approved for the treatment of psoriasis.

These data are presented in the Fig. 2.

Understanding the cell signaling pathway, and more specifically the JAK STAT pathway, is a breakthrough in the era of biotherapies. JAKi are increasingly designed to target a single JAK isoform, to minimize collateral side effects. They are oral treatments to facilitate drug administration.

A better understanding of STAT protein isoforms could be a promising avenue for the design of new biotherapies for the treatment of autoimmune diseases, which inhibition could perhaps be combined with a JAKi for synergistic activity.
<figure><img src="image_3.png" /><figcaption>**Fig. 2.** Different cytokines and their receptors interacting with the different isoforms of Janus kinase (JAK).</figcaption></figure>

**3. Validated indications in systemic and autoimmune diseases**

All the ongoing or validated trials evaluating the efficacy and/or safety of JAKi in the various systemic and autoimmune diseases are summarized in Fig. 3.

**3.1. Rheumatoid arthritis**

Pathophysiologically, rheumatoid arthritis (RA) is characterized by a major infiltration of the synovium by immune cells with secretion of numerous soluble mediators and pro-inflammatory cytokines, such as IL-6, which is a cytokine dependent on the JAK STAT pathway. Thus, the use of JAKi would allow the restoration of a cytokine balance. Currently, 4 molecules (tofacitinib, baricitinib, upadacitinib and filgotinib [only in women]) are approved in moderate to severe RA with failure or poor tolerance of one or more CsDMARDS, or biotherapies, as monotherapy or in combination with methotrexate. Tofacitinib demonstrated faster efficacy than methotrexate with a satisfactory response as early as 2 to 4 weeks on the American College of Rheumatology (ACR) 20 [12-15]. Baricitinib, used in dual therapy with a CsDMARDS, showed superior efficacy to adalimumab [16]. The RA BEGIN study [17] also demonstrated the superiority of baricitinib monotherapy over methotrexate in active RA. Three phase III trial [18-20] showed efficacy of upadacitinib in moderate to severe RA after failure of CsDMARDS or biotherapies [21]. A phase III trial (DARWIN 1 study evaluating the combination of filgotinib and methotrexate versus placebo and DARWIN 2 studying filgotinib alone) showed the efficacy of filgotinib versus placebo [22]. Because of the occurrence of fertility problems in men on filgotinib, it has only been approved for use in women with moderate to severe RA who have failed or are intolerant of first-line therapy. Peficitinib is only available in Japan, not in the US or Europe, and is being studied or developed in

several other countries. However, the safety issues of a Phase 3b/4 clinical trial [23] demonstrating a dose-dependent increased risk of major adverse cardiovascular events, malignancy, opportunistic infection, venous thromboembolism, and overall mortality with tofacitinib compared with TNF inhibitors in RA patients with cardiovascular risk factors, the US Food and Drug Administration (FDA) has recommended the use of JAKi only after failure of TNF inhibitors, making it no longer an appropriate option for most patients.

**3.2. Psoriatic arthritis and spondyloarthropathy**

The cytokine secretion profile of spondyloarthropathy (SpA) highlights the production of pro-inflammatory cytokines such as IL12/IL23, dependent on the JAK/STAT pathway. Tofacitinib, at a dose of 5 mg twice daily, has been approved for use in active psoriatic arthritis with inadequate response (or intolerance to DMARDs). Its efficacy has been demonstrated in 2 clinical trials [24]. In the SELECT MONOTHERAPY trial [25] upadacitinib has been shown to be effective against methotrexate and an extension application has been made. The EQUATOR trial [26] evaluated the efficacy of filgotinib versus placebo in moderate to severe psoriatic arthritis after intolerance, contraindication or failure of at least one CsDMARD, with clinically relevant responses 16 weeks after the first dose favoring filgotinib (80% versus 33%).

For axial and peripheral SpA, a randomized phase III trial [27], evaluating the value of tofacitinib versus placebo, in cases of failure of at least 2 non-steroidal anti-inflammatory drugs, showed the superiority of tofacitinib versus placebo. A phase II/III trial [28] showed superiority of upadacitinib over placebo. The TOR-TUGA trial [29] showed the efficacy of filgotinib against placebo. An extension of the marketing authorization in SpA, after failure of 2 non-steroidal anti-inflammatory drugs, has been requested but its place remains uncodified.
<table><caption>**Fig. 3.** Summary of ongoing or validated trials evaluating the efficacy and/or safety of Janus kinase inhibitors (JAKi) in various systemic and autoimmune diseases. Other vasculitis*: ANCA-associated vasculitis, polyarteritis nodosa, cutaneous leukocytoclastic vasculitis. PE: primary endpoint.</caption><thead><tr><th rowspan="2">Disease with approval</th><th colspan="3">Non selective JAK inhibitors</th><th colspan="3">Selective JAK1 inhibitors</th><th rowspan="2">Selective TYK2 inhibitors<br>Deucravacitinib</th></tr><tr><th>Tofacitinib</th><th>Baricitinib</th><th>Ruxolitinib</th><th>Itacitinib</th><th>Filgotinib</th><th>Upadacitinib</th></tr></thead><tbody><tr><td>Rheumatoid arthritis (RA)</td><td>Approved</td><td>Approved</td><td></td><td></td><td>Approved</td><td>Approved</td><td></td></tr><tr><td>Ankylosing spondylitis/psoriatic arthritis</td><td>Approved</td><td>Approved</td><td></td><td></td><td></td><td>Approved</td><td></td></tr><tr><td>Ulcerative colitis (UC)</td><td>Approved</td><td>Approved</td><td></td><td></td><td></td><td>Approved</td><td></td></tr><tr><td>Atopic dermatitis (AD)</td><td>Approved</td><td>Approved</td><td></td><td></td><td></td><td>Approved</td><td></td></tr><tr><td>Systemic sclerosis (SSc)</td><td>Observational studies, phase 3<br>PE: modified Rodnan Skin Score<br>(mRSS) &gt;10 and &lt;45 cutaneous lesions, for 24 weeks</td><td>Non randomized, double blind controlled study<br>PE: change in mRSS at week 24</td><td>Observational study</td><td>Phase 2<br>PE: change in mRSS at 360 days</td><td></td><td></td><td>Phase 2<br>PE: SRI-4 response and steroid dose less than or equal to 10 mg prednisone equivalent once per day in patients with moderately to severely active SLE receiving standard lupus therapeutics</td></tr><tr><td>Systemic lupus erythematosus (SLE)</td><td>Randomized, double blind, placebo-controlled study, phase 1, 2<br>PE: CLASI at week 24</td><td>Phase 2<br>PE: SLEDAI-2K at week 24</td><td>Phase 3<br>PE: SRI-4 response at week 32</td><td>Interventional study</td><td>Phase 2</td><td></td><td>Phase 2<br>PE: SRI-4 response at week 32</td></tr><tr><td>Dermatomyositis (DM)</td><td>Prospective open label clinical trial<br>Case report</td><td>Prospective clinical trial<br>Case report</td><td>Phase 3<br>PE: to evaluate the efficacy of Baricitinib to obtain prednisone-free moderate improvement (ACR/EULAR ≥ 40) of DM as compared to placebo in addition to usual care, at 24 weeks</td><td>Case report</td><td></td><td></td><td></td></tr><tr><td>Primary Sjogren's syndrome (pSS)</td><td>Case report</td><td>Phase 1/2</td><td>Pilot non controlled study<br>Case report</td><td></td><td>Phase 2</td><td></td><td></td></tr><tr><td>Sarcoidosis</td><td>Phase 1</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Chronic atrophic polychondritis (PC)</td><td>Case report</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Giant cell arteritis (GCA)</td><td></td><td></td><td>Phase 2</td><td></td><td></td><td></td><td>Phase 3<br>PE: 46 percentage of participants achieving sustained remission (at week 52)</td></tr><tr><td>Takayasu's disease</td><td>Prospective observational trial</td><td></td><td></td><td></td><td></td><td></td><td>Phase 3</td></tr><tr><td>Behcet's disease</td><td>Retrospective study</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Other vasculitis*</td><td>Case report</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Auto inflammatory diseases (systemic juvenile idiopathic arteritis (sJIA))</td><td>Approved (sJIA)</td><td></td><td>Phase 3</td><td>Retrospective studies<br>(VEXAS)</td><td></td><td></td><td></td></tr><tr><td>Hemophagocytic lymphohistiocytosis (HLH)</td><td></td><td></td><td></td><td>Retrospective studies</td><td>Phase 2</td><td></td><td></td></tr><tr><td colspan="8">Approved and solid evidence for efficacy</td></tr><tr><td colspan="8">Positive studies showing suggesting the efficacy of JAKi</td></tr><tr><td colspan="8">No significant differences compared to placebo</td></tr><tr><td colspan="8">Clinical trials recruiting participants, results are pending</td></tr><tr><td colspan="8">Not evaluated/reported</td></tr></tbody></table>

### 3.3. Inflammatory bowel disease

Tofacitinib has received marketing approval (and upadacitinib has received FDA approval) for moderate to severe active ulcerative colitis (UC) after failure or poor tolerance to conventional therapy or a biologic agent. In the OCTAVE 1 and 2 trials [30], tofacitinib has been shown to be superior to placebo. An open-label extension study, OCTAVE Open (NCT01470612) will provide long-term efficacy and safety data regarding the use of tofacitinib in UC.

In Crohn's disease, two phase 2b studies have investigated the value of tofacitinib in this indication, but unlike in UC, the results did not show a significant difference between tofacitinib and placebo [31]. Selective inhibitors such as upadacitinib [32] and filgotinib [33] have shown encouraging clinical results and Phase II and III trials are underway.

### 3.4. JAKi use in dermatology

JAKi represent a promising class of drugs in dermatology, offering new therapeutic options for chronic and difficult to treat skin conditions. Their targeted mechanism allows for tailored treatments, potentially improving patient outcomes where traditional therapies have failed. The literature on effectiveness of JAKi in treatment of alopecia areata, vitiligo, atopic dermatitis, psoriasis and several other inflammatory and autoimmune diseases is growing. With the approval of the JAKi baricitinib, upadacitinib and abrocitinib, new systemic therapeutic agents are now available for moderate to severe atopic dermatitis (AD). Other diseases in which the effectiveness of these small molecules could be shown are psoriasis, vitiligo and alopecia areata.

#### 3.4.1. Atopic dermatitis

In atopic dermatitis, key cytokines in pathogenesis signaling via the JAK-STAT signaling pathway are IL-4, IL-13, and IL-31. With baricitinib (JAK1/2i), upadacitinib (JAK1i) and abrocitinib (JAK1i) as systemic therapeutics, moderate to severe atopic dermatitis is currently playing a pioneering role in dermatological approval of JAKi. In a completed phase 3 study (BREEZE-AD7), baricitinib in combination with topical corticosteroids showed significant effects compared to placebo at a dose of 4 mg for the primary endpoint [34]. Upadacitinib, a selective JAK1i, achieved its coprimary and secondary endpoints and improvement of pruritus [35]. In addition,
abrocitinib (JAK1i) showed significant efficacy compared to placebo After topical application for 24 weeks, delgocitinib (pan JAKi) and ruxolitinib (JAK1/2i) significantly improved pruritus and EASI in patients with moderate to severe atopic dermatitis [36,37].

### 3.4.2. Psoriasis

In Germany, tofacitinib (JAK1/3/2i) is the only JAKi currently approved for treatment of psoriatic arthritis. In several phase 3 studies, the agent was also efficient and effective in case of skin and nail involvement [38,39]. Another promising therapeutic approach in psoriasis is the inhibition of TYK2 with deucravacitinib, which was shown to be effective compared to placebo in a phase 2 study [40]. According to data from the manufacturer, a PASI75 response of 58.7% was achieved with deucravacitinib compared to 9.4% with placebo and 35.1% with apremilast in the phase 3 study POETYK PSO-1 [41]. Other JAKi (such as baricitinib) have been studied in psoriatic arthritis, but no additional benefit compared to tofacitinib has been shown as yet [42].

### 3.4.3. Alopecia and vitiligo

In a recently published meta-analysis of JAKi in alopecia areata, 72.4% of the patients showed a therapeutic response [43]; 45.7% with good (50-100% regrowth of hair) and 21.4% with partial response (5-50% regrowth of hair). In case of administration, however, a four times better response of oral JAKi (baricitinib, tofacitinib, ruxolitinib) compared to topical application was observed

In non-segmental vitiligo, two recent phase 3 studies (TRUE-V1) and (TRUE-V2) conducted in parallel in the USA and Europe showed a greater improvement in the primary endpoint, which was an improvement in F-VASI75 (reduction of at least 75% in the Facial-Vitiligo Area Scoring Index) at week 24 with the use of topical ruxolitinib 1.5% twice daily compared with the control group: TRUE-V1 29.8% vs. 7.4%, *P*<0.001, and TRUE-V2 30.9% vs 11.4%, *P*<0.001. The same results were obtained for the secondary endpoints, which focused in particular on extra-facial repigmentation.

## 4. Perspectives in systemic and autoimmune diseases

### 4.1. Systemic lupus erythematosus (SLE)

#### 4.1.1. In animal models

A study by Furumoto et al. [44] investigated the therapeutic potential of tofacitinib in a mouse model of SLE. The study found that tofacitinib treatment improved survival rates and decreased proteinuria in SLE mice. Tofacitinib treatment also decreased the number of activated T and B cells in the spleen and decreased the production of pro-inflammatory cytokines. MRL/lpr mice (Fas mutation mice) with active lupus nephritis show elevated levels of STAT1 and phospho-STAT1 within glomerular cells [45]. In addition, stimulation of mesangial cells with type 1 IFNs in vivo results in phosphorylation of STAT1. Treatment of MRL/lpr mice with a selective JAK2 inhibitor (AG490) resulted in a significant reduction in native anti-DNA antibody levels, proteinuria, and immune deposits within the glomerulus. In NZB/NZWF1 mice (a mouse model of lupus with nephropathy and predominantly female disease expression), identical results were demonstrated with tofacitinib [46,47]. Chan et al. [48] studied the effect of ruxolitinib on the development of cutaneous lupus in a mouse model with an improvement of the cutaneous T infiltrate in treated mice.

#### 4.1.2. In patients with SLE

The activation of plasmacytoid dendritic cells in response to defective clearance of apoptotic bodies induces secretion of cytokines such as IFNs type 1. The IFN type 1 receptor family includes cytokine receptors associated with JAKi. STAT4 polymorphisms have also been associated with more severe lupus disease [49]. The

use of JAKi is an increasingly promising therapeutic option under evaluation in this disease.

Observational studies and/or control trial are available for the following molecules.

#### 4.1.2.1. Tofacitinib
A recently published, randomized, double-blind, and placebo-controlled trial of tofacitinib (5 mg twice a day) in patients with SLE showed a satisfactorily safety profile, improved lipid profile disturbances, decreased IFN type I signature, and restored endothelial function. However, the authors failed to show any statistically significant changes in reduction of diseases activity, but it was clearly stated that the study was not designed to test the drug's efficacy [50]. The results of an open label phase 2 pilot study of oral tofacitinib in adult subjects with discoid lupus erythematosus are pending. Five patients were enrolled. The primary outcome measure is Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) at week 24. The study is not over yet, results are still coming in. Another phase 2, open label study of tofacitinib for moderate to severe skin involvement in young adults with SLE is ongoing. You et al. [51] reported their center's experience with improvement of rash and arthritis as assessed by SLEDAI-2K. Of the 10 patients in this series, 6 showed improvements in skin involvement and 4 in joint manifestations. Results from a phase I trial (tofacitinib versus placebo), started in 2015 and closed in 2018, are currently pending (NCT02535689). All these studies were carried out in the United States.

#### 4.1.2.2. Baricitinib
Baricitinib has shown efficacy in the control of lupus disease in a double-blind Phase II trial (conducted in United States) with remission assessed by SLEDAI-2K at a dose of 4 mg/day (74 of 104 [67%] responded at 24 weeks versus 53% in the placebo group with respect to skin and/or joint involvement) [52]. In this trial, the 2 mg/day dose was not associated with any clinical improvement. Serious adverse events occurred in 9.6% of patients in the baricitinib 4 mg group versus 4.8% in the placebo group. Yuan et al. [53,54] reported that the 4 mg dose of baricitinib was not approved by the FDA in RA due to the potential increased risk of infectious and thromboembolic events. Dörner et al. [55] conducted a randomized, double-blind, placebo-controlled phase II trial (conducted in United States) to assess the efficacy and safety of baricitinib in reducing anti-DNA antibody levels in SLE patients, who were randomized in a 1:1:1 ratio to receive either 2 mg or 4 mg of baricitinib or placebo once daily for 12 and 24 weeks. The primary endpoint was the percentage of patients who achieved a decrease in anti-DNA antibody levels of 25% or more at week 12 and 24. The results showed that a significantly higher proportion of patients in the baricitinib group achieved the primary endpoint compared to placebo. They did not show any effect on complement activation. This study provided evidence that baricitinib can decrease anti dsDNA antibody levels in patients with SLE, indicating its potential as a treatment option for this population.

In a multicenter, double-blind, randomized, placebo-controlled, parallel-group, phase 3 study, SLE-BRAVE-I (conducted in United States), patients (aged ≥ 18 years) with active SLE receiving stable background therapy were randomly assigned 1:1:1 to baricitinib 4 mg, 2 mg, or placebo once daily for 52 weeks with standard of care [56]. The primary endpoint was the proportion of patients reaching an SLE Responder Index (SRI)-4 response at week 52 in the baricitinib 4 mg treatment group compared with placebo. In total, 760 participants were randomly assigned and received at least one dose of baricitinib 4 mg (n=252), baricitinib 2 mg (n=255), or placebo (n=253). A significantly greater proportion of participants who received baricitinib 4 mg (P=0.016), but not baricitinib 2 mg (P=0.47), reached SRI-4 response compared with placebo. There were no significant differences between the proportions of participants in both baricitinib groups reaching any of the major
secondary endpoints compared with placebo, including glucocorticoid tapering and time to first severe flare. Twenty-six (10%) patients receiving baricitinib 4 mg had serious adverse events as compared to 24 (9%) patients receiving baricitinib 2 mg, and 18 (7%) patients receiving placebo. The safety profile of baricitinib in participants with SLE was consistent with the known baricitinib safety profile. In conclusion, the primary endpoint in this study was met for the 4 mg baricitinib group. However, key secondary endpoints were not. No new safety signals were observed.

In another phase 3 double-blind, randomized, placebo-controlled study, SLE-BRAVE-II (conducted in United States) [57], patients with active SLE receiving stable background therapy were randomly assigned 1:1:1 to baricitinib 4 mg, baricitinib 2 mg, or placebo once daily for 52 weeks. The primary endpoint was the proportion of patients with an SRI-4 response at week 52 in the baricitinib 4 mg treatment group compared with placebo. A total of 775 patients were randomly assigned and received at least one dose of baricitinib 4 mg (n = 258), baricitinib 2 mg (n = 261), or placebo (n = 256). There was no difference in the primary efficacy outcome of the proportion of SRI-4 responders at week 52 between participants who received baricitinib 4 mg, 2 mg and placebo. None of the major secondary endpoints, including glucocorticoid tapering and time to first severe flare, were met. Serious adverse events were observed in 29 (11%) participants in the baricitinib 4 mg group, 35 (13%) in the baricitinib 2 mg group, and 22 (9%) in the placebo group. The safety profile of baricitinib in patients with SLE was consistent with the known baricitinib safety profile. Although phase 2 data suggested baricitinib as a potential treatment for patients with SLE, which was supported in SLE-BRAVE-I, this result was not replicated in SLE-BRAVE-II, leading to a stop in baricitinib use in SLE.

#### 4.1.2.3. Ruxolitinib.
Ruxolitinib, a JAK1 and JAK2 approved by the FDA for the treatment of myelofibrosis, showed a potential to attenuate severe skin changes in a mouse model of SLE [58]. Following this promising result, the team from Rochester University started to recruit patients for a 12-week study with Ruxolitinib cream applied topically to areas with an active lupus skin lesion. The results from this study will be available soon. In 2016, Wenzel et al. [59] reported the improvement of a case of lupus engorgement on ruxolitinib that was prescribed in the setting of myelofibrosis.

#### 4.1.2.4. Filgotinib.
A randomized phase II trial (conducted in United States) evaluated the efficacy of filgotinib in lupus extramembranous glomerulonephritis in 9 patients. A > 50% reduction in 24-hour proteinuria at week 16 was observed with filgotinib [60]. But disappointing data come from a recently completed trial with filgotinib in patients with cutaneous lupus erythematosus. The study did not meet the primary endpoint as the patients treated with filgotinib did not significantly improve their CLASI [61].

#### 4.1.2.5. Upadacitinib.
A Phase 2 Study (conducted in United States) investigated the safety and efficacy of elsubrutinib (BTK inhibitor) and upadacitinib Given Alone or in Combination (ABBV-599 Combination) in subjects with moderately to severely Active SLE. At week 24, upadacitinib 30 mg given alone or as a combination therapy (ABBV-599 high dose [elsubrutinib 60 mg and upadacitinib 30 mg]) met the primary endpoint of SRI-4 response and steroid dose less than or equal to 10 mg prednisone equivalent once per day in patients with moderately to severely active SLE receiving standard lupus therapies. Upadacitinib maintained greater improvements in SLE disease activity at week 48 as measured by the British Isles Lupus Assessment Group-Based Composite Lupus Assessment (BICLA), SRI-4, Lupus Low Disease Activity State (LLDAS) and lupus flares compared with placebo. No new safety signals were observed beyond the known safety profile for upadacitinib. Types of adverse effects reported with ABBV-599 high dose were similar to those

reported for patients treated with upadacitinib alone. Study results were presented as an oral presentation at the European Congress of Rheumatology, EULAR 2023.

#### 4.1.2.6. Deucravacitinib.
Deucravacitinib is an oral selective, allogenic inhibitor of TYK2 that binds the regulatory domain and locks the enzyme in an inactive state, distinguishing it from inhibitors of JAK1, JAK2, and/or JAK3 that bind the highly conserved active domains [62]. Morand et al. [63] conducted a randomized, double-blind, placebo controlled phase 2 trial (conducted in United States) to evaluate the efficacy and safety of deucravacitinib, in patients with moderate-to-severe SLE. The study enrolled 363 patients who were randomized in a 1:1:1:1 ratio to receive deucravacitinib either 3 mg twice daily, 6 mg twice daily or 12 mg once daily or placebo. The primary endpoint was SRI-4 response at week 32. Secondary outcomes assessed at week 48 included SRI-4, British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response, CLASI-50, Lupus Low Disease Activity State (LLDAS), and improvements in active (swollen plus tender), swollen, and tender joint counts. The results showed that deucravacitinib 3 mg and 6 mg twice daily were associated with a significantly higher proportion of patients achieving the primary endpoint compared to placebo and deucravacitinib 12 mg (58% [P < 0.001]; 50% [P = 0.02], 34% and 45% [P = 0.08], respectively). The drug was also associated with improvements in multiple secondary endpoints. Rates of adverse events were similar across groups, except higher rates of infections and cutaneous events, including rash and acne, with deucravacitinib treatment. Rates of serious adverse events were comparable, with no deaths, opportunistic infections, tuberculosis infections, major adverse cardiovascular events, or thrombotic events reported. In conclusion, the study demonstrated that deucravacitinib was effective in reducing disease activity in patients with moderate to severe SLE. These findings suggest that deucravacitinib may represent a promising treatment option for SLE patients in the future.

#### 4.1.2.7. Other JAKi.
Since then, several randomized trials have been performed to evaluate JAK STAT pathway inhibition in this indication. A selective JAK2 inhibitor (CEP-33779) is currently in phase I trials. GSK2586184, a JAK1 inhibitor, was evaluated in a phase II trial that was prematurely terminated due to poor attenuation of the IFN signature in the first patients included. A topical JAK SYK inhibitor (R333) was evaluated in a phase II trial and failed to show surface regression of skin lesions in discoid lupus (NCT01597050). Pf-06700841, an oral JAK1 TYK2 inhibitor is currently being studied in patients with moderate to severe systemic lupus (NCT03845517).

Overall, the efficacy and use of JAKi in SLE is currently insufficient to draw firm conclusions. While several case series and phase I/II trials have demonstrated their efficacy in skin and joint involvement, results from some randomized trials are discordant. For example, the SLE-BRAVE-I trial supported baricitinib as a potential treatment for SLE patients, but this result was not replicated in SLE-BRAVE-II, leading to a halt in its use for SLE. However, other JAKi, such as Deucravacitinib, have shown promise; a randomized phase 2 trial found it effective in reducing disease activity in patients with moderate to severe SLE. Upadacitinib, alone or in combination with a BTK inhibitor, also appears promising. Currently, there is no proof of JAKi efficacy in treating the neurological or renal damage caused by lupus. The difficulty in assessing lupus therapy efficacy may stem from the disease's heterogeneity and the use of different classification criteria between trials. It is necessary to supplement these data with randomized phase 3 studies, some of which are currently underway.
## 4.2. Dermatomyositis

No preclinical studies are available. An IFN type 1 signature is also known in patients with inflammatory myositis [64]. Paudyal et al. [65] in a recently published review of the literature, identified more than 50 patients with refractory DM treated with JAKi (tofacitinib or ruxolitinib). Improvements in skin, muscle and general condition were observed with JAKi. A case of favorable evolution of diffuse interstitial lung disease (ILD) associated with anti-MDA5 positive DM refractory to rituximab, cyclophosphamide, cyclosporine A, and high dose corticosteroids has been reported. An important element to note is the potential interest of some JAKi in the efficacy of subcutaneous calcinosis found in some refractory DM, reported in case reports [66,67]. One hypothesis is that calcium storage and release is mediated by the STAT3 pathway.

Observational studies and/or control trial are available for the following molecules.

### 4.2.1. Tofacitinib

Some case reports have suggested that JAKi may be effective in treating DM [68-73]. Specifically, two studies addressed the role of tofacitinib for the treatment of the rapidly progressive-ILD in anti-MDA5-positive DM patients. Kurasawa et al. [69] included a case series of 5 patients who received tofacitinib at a dose of 10 mg/day after failed to respond to a triple therapy with high-dose glucocorticoids, cyclosporine, and cyclophosphamide. The authors compared the outcomes of these 5 patients with 6 historical patients who had been treated with triple therapy without tofacitinib. Both groups of patients were comparable regarding major factors of poor prognosis, including high serum ferritin levels, worsening pulmonary infiltrates, and generalized ground-glass opacities. Of note, three of the tofacitinib group had a favorable response, while the rest, including all patients from the historical cohort, died. Alternatively, cytomegalovirus reactivation was constant in patients who received triple therapy and tofacitinib. Chen et al. [71], from China, conducted an open-label clinical study from a single-center evaluating the efficacy of tofacitinib at the early stages of anti-MDA5 positive DM-associated ILD. From July 2017 to September 2018, a total of 18 consecutive patients were enrolled and received treatment mostly with glucocorticoids and tofacitinib (5 mg/12 h) and only occasionally with other immunosuppressants (2 patients received cyclosporine, and 1 mycophenolate mofetil). When compared with a historical control group of 25 patients treated with a step-wise immunosuppressive approach based on cyclosporine, mycophenolate mofetil, and/or cyclophosphamide, the survival at 6 months was significantly higher in the group treated with tofacitinib than in the historical control group. An issue to note in this study was that patients achieved a favorable outcome in the absence of severe immunosuppression, which helped to avoid infectious complications such as cytomegalovirus reactivation, or other fastidious opportunistic infections. In severe DM, Marchiset et al. [74] have described a case report including a patient recently diagnosed with rapidly progressive ILD associated, with anti-MDA-5 for whom no treatment showed efficacy, including glucocorticoids, cyclophosphamide, plasma exchanges, tofacitinib, and tacrolimus. She was placed under mechanical ventilation and venovenous extracorporeal membrane oxygenation 2 weeks after diagnosis in a bridge-to-transplant process. She was successfully transplanted 20 days later after having been registered on the French National Lung Transplant Waiting List with high priority. One year after surgery, her pulmonary function tests were good, and she showed no sign of relapse of anti-MDA-5 DM. The article emphasizes the importance of a rapid and thorough evaluation of patients with anti MDA-5 DM presenting respiratory symptoms, as lung transplantation can be a vital option for critically ill patients. However, this procedure emphasizes that this procedure carries risks and

should be approached with caution. Shirai et al. [75] have discussed a case report of a patient with severe anti-MDA5 antibody-positive DM who was treated with an intensive induction therapy regimen that combined tofacitinib, rituximab, and plasma exchange. The patient experienced significant improvement in both skin and muscle symptoms following the treatment, which was maintained for at least 6 months after completion. The authors suggest that this intensive induction therapy regimen may be a promising treatment option for severe cases of anti-MDA5 antibody-positive DM. Overall, the article highlights the potential of combining different treatments to manage severe cases of DM, particularly in those with specific autoantibodies such as anti-MDA5 antibody. Paik et al. [76] have conducted an open label pilot study of 10 patients to evaluate the efficacy and safety of Tofacitinib in active, treatment-refractory DM (STIR trial). Tofacitinib was given as 11 mg daily to 10 subjects. All subjects underwent complete washout of all steroid sparing agents. The primary outcome measure was the International Myositis Assessment and Clinical Studies (IMACS) definition of improvement. The response rate was measured by the 2016 ACR/EULAR Myositis Response Criteria using the total improvement score (TIS). The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), chemokine levels, skin STAT 1 expression by immunohistochemistry, RNA sequencing analysis, and safety were secondary outcome measures. All 10 subjects met the primary outcome at 12 weeks. Five of 10 (50%) had moderate improvement and the other half had minimal improvement on the TIS. The secondary outcome of the mean change in the CDASI activity score from baseline to 12 weeks was statistically significant (28 ± 15.4 vs. 9.5 ± 8.5, P=0.0005). This is the first prospective, open label, clinical trial, of Tofacitinib in DM that demonstrates strong clinical efficacy for a pan JAKi.

### 4.2.2. Baricitinib

Zhao et al. [77] presented a prospective open label study that evaluated the efficacy and safety of baricitinib in the treatment of cutaneous DM. A total of 12 patients with cutaneous DM received baricitinib (2 mg twice daily) for 12 weeks. Concomitant treatments, including prednisone (≤ 30 mg/day) and/or hydroxychloroquine, were maintained or tapered at the discretion of the clinicians. The primary outcome measure was the CDASI score. All 12 patients (mean age: 40.8 ± 10.4 years, 66.7% females) had active skin disease as defined by a CDASI score of at least 14 upon study enrollment. Clinically significant improvement was noted as early as week 4. Overall improvements in the CDASI score (P < 0.001) and Dermatology Life Quality Index score (P < 0.001) were observed from baseline to week 12. While this is a small and uncontrolled study, it supports baricitinib as a promising therapy for cutaneous DM. Further investigations are warranted to confirm these findings and to identify the patients most likely to benefit from JAKi. Delvino et al. [78] described a patient with refractory cutaneous DM who was successfully treated with baricitinib. The patient had previously failed treatment with multiple therapies, including glucocorticoids, hydroxychloroquine, mycophenolate mofetil, methotrexate, and intravenous immunoglobulin. Baricitinib was then initiated, and the patient experienced significant improvement in skin symptoms after 4 weeks of treatment. The patient's skin lesions continued to improve with continued treatment, and no significant adverse effects were observed. The case report suggests that baricitinib could be a promising treatment option for patients with refractory cutaneous DM who have failed previous therapies.

A prospective trial conducted by Allenbach's team (conducted in France, in Paris) baricitinib in patients with relapsing or naïve DM (BIRD) (NCT04972760), aim at studying the efficacy of baricitinib in refractory DM, and is underway. BIRD is a multicenter phase III double-blind randomized placebo-controlled trial
with two parallel arms (1:1). This is an add-on trial to usual care with rapid corticoid taper. Both groups (experimental and control groups) will receive corticosteroids and the conventional immunosuppressive drug (either azathioprine or methotrexate). They will be randomized in 1:1 ratio to receive baricitinib plus prednisone taper plus one immunosuppressive drug (either methotrexate or azathioprine) (experimental group) or placebo plus prednisone taper plus one immunosuppressive drug (either methotrexate or azathioprine) (control group) for a duration of 24 weeks. In both groups, corticosteroids are tapered following a predefined protocol. Their hypothesis is Baricitinib will permit to obtain DM improvement with a steroid sparing effect as compared to usual care. Their primary objective is to evaluate the efficacy of Baricitinib to obtain prednisone-free moderate improvement (ACR/EULAR ≥ 40) of DM as compared to placebo in addition to usual care, at 24 weeks. The results of this study are in progress.

### 4.2.3. Ruxolitinib

Some case reports have suggested that JAKi may be effective in severe juvenile DM [79-81]. We did not find much data regarding the efficacy of ruxolitinib in DM in adults. Hornung et al. [82] have described a case report of a patient with recalcitrant DM who achieved remission with treatment using ruxolitinib. The patient had previously failed multiple therapies, including glucocorticoids, methotrexate, mycophenolate mofetil, and intravenous immunoglobulin. Ruxolitinib was initiated, and the patient experienced significant improvement in both skin and muscle symptoms after 4 weeks of treatment. The patient's symptoms continued to improve with continued treatment, and no significant adverse effects were observed. The case report suggests that ruxolitinib may be a promising treatment option for recalcitrant DM, particularly in cases where other therapies have failed. Overall, the article highlights the potential of ruxolitinib as a treatment option for DM, particularly in patients who have failed previous therapies.

More recently, Paik et al. [83] have conducted a systematic literature review on use of JAKi in DM. A total of 48 publications reporting 145 unique patients (adult DM, n = 84; Juvenile DM [JDM], n = 61) were identified. Among cases of adult DM, 61 of 84 (73%) had refractory skin disease at baseline, and all (61 of 61) reported improvement in cutaneous symptoms. Of patients with adult DM, 16 of 84 (19%) had refractory muscle disease at baseline, and all (16 of 16) reported improvement in muscle symptoms. In patients with adult DM complicated by ILD (n = 33), 31 (94%) patients improved with JAKi treatment. Among cases of JDM with refractory skin disease at baseline (60 of 61), most patients (57 of 60; 95%) showed improvements in skin symptoms after JAKi treatment. Of patients with JDM with refractory muscle disease at baseline (36 of 61), most (30 of 36; 83%) reported improvement in muscle symptoms. Four patients with JDM and ILD experienced improvement in lung disease activity following treatment with a JAKi. Among both DM and JDM cases, all patients (17 with DM and 16 with JDM) who had elevated serum IFN and/or IFN-stimulated gene expression at baseline showed reduction in IFN or IFN gene expression. Although the conclusions that can be drawn from this analysis are limited because of the differences in assessments used across publications, overall treatment of patients with DM or JDM with a JAKi was associated with significant improvement of a wide range of DM manifestations, including skin lesions, muscle weakness, and ILD. This systematic literature review suggests that JAKi may be a viable treatment option for DM/JDM, and randomized controlled trials are necessary to confirm these findings.

Overall, the role of JAKi in the treatment of dermatomyositis seems to be promising, with initial results from randomized trials in favor of the treatment of cutaneous, articular and pulmonary involvement in rapidly progressive, refractory forms. Its place and the choice of molecule remain to be defined. We await the results of ongoing randomized trials.

## 4.3. Myocarditis induced by immune-checkpoint inhibitors

### 4.3.1. Ruxolitinib

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. Salem et al. [84] reported the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAKi ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis generating and need further evaluation.

## 4.4. Systemic sclerosis

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by fibrosis, vascular abnormalities, and immune dysfunction. Several arguments favor the possible use of JAKi in SSc.

### 4.4.1. In animal models

Bellamri et al. [85] investigated the therapeutic potential of the JAK1/2 inhibitor ruxolitinib in preclinical models of SSc. The study used two mouse models of SSc, one induced by bleomycin and the other by Tsk/+ mutation, and evaluated the effects of ruxolitinib treatment on skin fibrosis, lung fibrosis, and immune cell infiltration. The results showed that ruxolitinib treatment significantly reduced skin fibrosis and improved skin architecture in both mouse models of SSc. Ruxolitinib treatment also attenuated lung fibrosis in the bleomycin-induced model, but not in the Tsk/+ model. The study further demonstrated that ruxolitinib treatment decreased the number of infiltrating immune cells, including T cells, B cells, and macrophages, in the skin and lung of SSc mice. Aung et al. [86] investigated the effects of tofacitinib on immune dysfunction in a mouse model of bleomycin-induced SSc. The study found that tofacitinib treatment improved skin thickness and collagen content. Tofacitinib also decreased the number of immune cells infiltrating the skin and reduced the production of pro-inflammatory cytokines. In addition, the study demonstrated that tofacitinib treatment increased the number of regulatory T cells (Tregs) in the skin of SSc mice. Tregs play a crucial role in immune tolerance and can suppress the activity of other immune cells.

### 4.4.2. In patients with SSc

Transforming growth factor (TGFb) is the key cytokine in the profibrotic process. TGFb signals through both SMAD and non-SMAD pathways to elicit a wide array of biological effects. Tang et al. [87] showed that cooperation between the JAK1 STAT3 and SMAD pathways is essential for the role of TGFb in liver fibrosis. Additionally, similar to systemic lupus erythematosus and other connective tissue diseases, patients with SSc showed an overex-
pression of IFNα, suggesting a direct pathogenetic role in the disease's development [88]. Importantly, the IFN signature can be detected at very early stages of the disease and even years before a formal diagnosis can be established, suggesting that IFN upregulation is an early event and may contribute significantly to the disease pathogenesis [89]. Thus, blocking IFNs by blocking the JAK STAT pathway could be of interest. Another main players in the field of SSc pathogenesis are IL-6 and IL-6 cytokine family, which can be targeted by JAKi. IL-6 involved in the vasculopathy and in driving the fibrotic processes in SSc. IL-6 plasma levels correlates with disease activity and the extent of skin thickening [90]. This pathophysiological background favors the clinical trials aimed to block IL-6 activity [90,91]. Although promising, the results of the studies completed thus far have not achieved their primary endpoints [92] but tocilizumab is approved by the FDA in SSc patients with interstitial lung diseases. Wang et al. [93] discussed the activation of the JAK STAT signaling pathway in SSc, the authors conducted a series of experiments using skin and blood samples from SSc patients to evaluate the expression and activation of various components of the JAK STAT pathway. The results of the study showed that the JAK STAT pathway is significantly activated in SSc patients compared to healthy controls, and that this activation is associated with increased fibrosis and inflammation. The authors also demonstrated that tofacitinib effectively inhibits the JAK STAT pathway in SSc patient samples, reducing the expression of pro-fibrotic and pro-inflammatory markers. Based on these findings, the authors suggest that tofacitinib may have potential as a treatment option for SSc, based on its ability to inhibit the JAK STAT pathway and reduce fibrosis and inflammation. However, they note that further research is needed to establish the safety and efficacy of tofacitinib in SSc patients, and to evaluate the optimal dosing and administration of the drug.

Observational studies and/or control trial are available for the following molecules.

#### 4.4.2.1. Tofacitinib.
Moriana et al. [94] presents a systematic review of the literature on the use of JAKi in the treatment of SSc. The authors conducted a comprehensive search of multiple databases to identify relevant studies and included preclinical and clinical studies in their analysis. The review suggests that JAKi have the potential to be a treatment option for SSc, based on their ability to modulate immune function, reduce inflammation, and inhibit fibrosis. However, the authors note that the available evidence is limited to preclinical studies and a small number of clinical trials, and more research is needed to establish the safety and efficacy of JAKi in SSc patients. Nallapati et al. [95] reported on a case study of a patient with diffuse cutaneous systemic sclerosis (dcSSc) who experienced improvement in skin changes after treatment with tofacitinib. The patient had been experiencing progressively worsening skin changes, including thickening, tightening, and hyperpigmentation, despite previous treatment with other medications. After beginning treatment with tofacitinib, the patient experienced significant improvement in skin changes, with a reduction in both thickening and hyperpigmentation. Deverapalli et al. [96] discussed the potential use of JAKi as a treatment option for progressive SSc. The authors reviewed the current literature on the use of JAKi in SSc and evaluated the potential benefits and risks of this treatment approach. The authors highlighted the role of the JAK STAT pathway in the pathogenesis of SSc and suggested that JAKi may be effective in targeting the fibrotic and inflammatory processes involved in the disease. They also discussed the results of several clinical studies that have evaluated the safety and efficacy of JAKi in SSc patients, including tofacitinib and baricitinib. Based on their review of the literature, the authors conclude that JAKi may be a promising treatment option for progressive SSc, although further research is needed to establish the optimal dosing, duration, and

safety of these drugs in this patient population. They also highlighted the importance of carefully monitoring patients for potential adverse events, such as infections and thrombosis, when using JAKi. Overall, the article suggested that JAKi may represent a promising avenue for the treatment of progressive SSc, but further research is needed to fully evaluate their safety and efficacy in this patient population.

You et al. [97] discussed the potential use of tofacitinib, as a treatment option for skin thickening in dcSSc. The authors conducted a small pilot study in which five patients with dcSSc received tofacitinib for six months and were evaluated for changes in skin thickness and other clinical features. The results of the study showed a significant reduction in skin thickness in all patients, as well as improvements in other clinical features such as hand function and quality of life. The authors suggest that the mechanism of action of tofacitinib, which targets the JAK STAT pathway involved in fibrosis and inflammation, may be responsible for these improvements. However, the authors note that the study was small and lacked a control group, and further research is needed to establish the safety and efficacy of tofacitinib in dcSSc patients. They also highlight the need for larger clinical trials to evaluate the optimal dosing and administration of tofacitinib in this patient population. Overall, the study suggests that tofacitinib may have potential as a treatment option for skin thickening in dcSSc, but further research is needed to confirm these findings. The authors suggested that JAKi may have a therapeutic effect on the underlying mechanisms of SSc skin changes, including inflammation and fibrosis.

A Phase I/II TOFA SSc trial (NCT03274076, 2020) evaluated the safety, tolerability and efficacy of tofacitinib (5 mg twice a day) versus placebo in diffuse, early, modified Rodnan Skin Score (mRSS) > 10 and < 45 cutaneous forms, for 24 weeks. Fifteen participants were included. This study showed that tofacitinib was well tolerated with manageable adverse events, with no grade 3 or higher adverse events and there were trends in improvement of clinical outcome measures. The completed study from the USA did not show the superiority of Tofacitinib versus a placebo towards skin improvement mRSS, nor an improvement in Combined Response Index Systemic Sclerosis (CRISS). This is in contrast to previously published data, where in small observational studies Tofacitinib contributed to the reduction of skin thickness in SSc patients measured both clinically [98] as well as with ultrasound [98]. A prospective observational study showed improvement in skin involvement with tofacitinib in at least a similar manner as with standard immunosuppressant [95].

#### 4.4.2.2. Baricitinib.
Several cases were reported. Hou et al. [99] reported on a study investigating the potential of a baricitinib in treating skin fibrosis and digital ulcers in patients with SSc. The study was conducted on mice and human skin samples, as well as a small cohort of SSc patients. The results showed that treatment with baricitinib improved skin fibrosis and reduced the severity of digital ulcers in both mice and human skin samples. In addition, SSc patients treated with baricitinib showed improvements in skin fibrosis and a reduction in the frequency of digital ulcers. Fiorentini et al. [100] discussed the potential role of JAKi in the treatment of SSc-associated interstitial lung disease (SSc-ILD), a severe complication of SSc that can lead to lung fibrosis and respiratory failure. The authors provide a narrative review of the pathogenesis of SSc-ILD and the current treatment options, highlighting the limitations of current therapies. They then delve into the potential benefits of JAKi in treating SSc-ILD, citing preclinical and clinical data that suggest JAK inhibition can reduce inflammation and fibrosis in the lungs. The authors also discuss the safety and tolerability of JAKi in SSc-ILD patients, based on real-life data from clinical practice.

A study evaluating the efficacy and safety of baricitinib in SSc is underway (NCT05300932) (phase 3/4). This is 48 weeks, prospec-
tive, double-blind, controlled study. Sixty patients were included. The specific objectives are to determine whether baricitinib is effective and safe in the treatment of patients with dcSSc when compared to patients treated with cyclophosphamide and determine whether baricitinib is more effective than cyclophosphamide, as measured by change in CRISS. It incorporates change in the mRSS, Forced Vital Capacity (FVC) percent predicted, physician and patient global assessments, and Health Assessment Quality Disease Index (HAQ-DI). Additionally, hemoglobin corrected diffusion capacity (DLCO), Medsger Severity Scale (MSS), and by other physician and patient derived outcome measures will be used. The primary endpoint is the change in mRSS at week 24. The results are in progress.

4.4.2.3. Ruxolitinib. The SCLERO-JAK study is designed to evaluate the impact of ruxolitinib on monocyte-derived macrophage (MDM) activation states in patients with SSc (NCT04206644). The primary outcome will be the concentration of CCL18 evaluate by ELISA in the condition media of MDM from SSc patient's pretreated or not in vitro by ruxolitinib.

4.4.2.4. Itacitinib. A Phase II trial is ongoing to evaluate the effi-
cacy and safety of itacitinib in SSc (NCT04789850) (phase 2 study).
Seventy-four patients with diagnosis of dcSSc, as defined by the
American College of Rheumatology (ACR), with disease duration
of less than 36 months were included. They evaluated safety and
efficacy of Itacitinib in adults with SSc vs. placebo. The primary
endpoint is the change in mRSS at 360 days.

SCLEROJAKI study is a multicentric retrospective study, conduc-
ted in France, whose objective is to describe the use of JAKi in
real life SSc-ILD. The second objectives are to evaluate the efficacy
and safety of JAKi in SSc associated ILD. The primary endpoint is
relative change in FVC after 12 months of JAKi. The results are in
progress.

Overall, current data on JAKi in SSc are primarily derived
from case series or phase I/II studies, with conclusions that are
occasionally discordant, especially concerning efficacy on skin
involvement. Although some study results are promising, it
is thus mandatory to supplement these data with randomized
studies, some of which are currently underway.

4.5. Other systemic diseases

4.5.1. Primary Sjögren's syndrome

There are no many basic research data about JAKi in primary
Sjögren's syndrome (pSS). No preclinical studies are available. The
pathophysiology of pSS remains incompletely understood. Never-
theless, as in lupus, it seems that type I IFNs, and thus the JAK STAT
pathway, play a prominent role in the genesis and maintenance
of the autoimmune process [101]. Genomic studies have reported
polymorphisms in genes related to IFN signaling via JAK STAT (IRF5
and STAT4) [102]. The IL-12/23-Th17 pathway also seems to be
involved and polymorphisms in the IL-12A gene have also been
described [103].

Case report and observational studies and/or control trial are
available for the following molecules.

4.5.1.1. Tofacitinib. One case report describes the efficacy of topical tofacitinib in dry eye syndrome [104]. A Phase I/II trial evaluating the safety and tolerability of oral tofacitinib in pSS is ongoing (NCT04496960).

4.5.1.2. Baricitinib. A recent study demonstrated that baricitinib suppressed the destruction of acinar cells in the salivary gland of pSS patients by abrogating IFN-γ induced CXCL10 expression and CXCL10 dependent immune cell infiltration in human salivary gland ductal cells. CXCL10 is a chemokine induced by IFN-γ via JAK STAT during Th1 immune responses, released by peripheral blood mononuclear cells, fibroblasts, and endothelial cells. Aota et al. [105] demonstrated that baricitinib significantly inhibited IFN-γ-induced CXCL10 production in an immortalized human salivary gland ductal-cell clone and by a western blot analysis showed also its ability to strongly inhibit the phosphorylation of STAT1 and, to a less extent, of STAT3. These data suggested a possible role of Baricitinib in pSS treatment.

Very recently, the efficacy and safety of Baricitinib for active pSS patients have been explored in a pilot non-controlled trial [106]. This study enrolled 11 pSS patients, all fulfilling 2016 ACR/EULAR classification criteria for pSS, showing a ESSDAI of at least 5. The improvement of ESSDAI of at least 3 points has been considered as the minimal clinical improvement expected. Other measures, such as European pSS Patient Reported Index (ESSPRI), Physician Global Assessment Score (PGA), Immunoglobulin G (IgG), and remission/improvement of single-organ manifestations have been also collected and evaluated. Patients were treated with Baricitinib 2 mg per day and followed up at 3 months and 6 months after starting the therapy. Baricitinib treatment led to a significant ESSDAI reduction, as did with regard to the ESSPRI and PGA. At 6 months, 88.9% patients achieved minimal clinical improvement of ESSDAI [106]. A decreasing trend in IgG and ESR (Erythrocyte sedimentation rate) levels was also observed. Main clinical manifestations showing improvement compared with baseline were skin rash and arthritis, consistent with the study of baricitinib in active SLE patients [53] weight loss, anemia, and cytopenia. Two pSS patients with ILD and cough, short of breath, and dyspnea after exertion were relieved in symptoms, together with an improvement of lung involvement in follow-up High-resolution computed tomography (HRCT) scan. A flare of hepatitis B virus was the only adverse event reported [106]. Besides major limitations of the study, mainly the absence of a control group, the treatment with baricitinib appears promising in pSS, and high-quality randomized controlled clinical trials are needed to confirm these preliminary results.

4.5.1.3. Filgotinib. Results from a multicenter, double-blind placebo-controlled randomized phase II clinical trial including an arm with filgotinib, besides other agents (i.e., lanraplenib and tirabrutinib), in order to assess both safety and efficacy in patients with active pSS (ESSDAI ≥ 5), have been very recently published [107]. Patients randomized to the filgotinib arm received the dosage of 200 mg per day for 48 weeks. The primary endpoint was defined as the proportion of patients fulfilling at week 12 both protocol-specified improvement and no worsening criteria, based on C-reactive protein (CRP) and pSS-related symptoms, assessed by the visual analog scale (VAS) of global disease, pain, oral dryness, ocular dryness, and fatigue. Change in ESSPRI and ESSDAI was included as a secondary endpoint and assessed at week 12 and week 24. Exploratory efficacy endpoints included objective tests, such as Schirmer's test and salivary flow (unstimulated and stimulated), treatment response on specific ESSDAI domains, and ESSDAI score change from baseline in subgroups of patients. Exploratory biomarker-related endpoint was the change from baseline for selected peripheral biomarkers, e.g., IgA, IgG, IgM, rheumatoid factor (RF) and CRP, B cell and plasma cell subset, and IFN signature, for each patient at week 4, 12, and 24 [107].

At week 12, 43.3% of the filgotinib group achieved the primary endpoint, although no statistically significant difference was found compared with the placebo arm [107]. Neither secondary endpoint was met. However, some notable evidence emerged from the trial.
Change of ESSDAI appeared more pronounced after filgotinib treatment in the pSS subgroup of patients with baseline ESSDAI ≥ 14 or without disease-modifying antirheumatic drugs/corticosteroids. Moreover, by week 24, greater decreases in RF, IgM, IgG, and IgA were seen in the filgotinib group compared with placebo, and, very interestingly, the IFN activity was significantly reduced from baseline at week 4 and week 12. Cytosolic DNA sensing and chemokine signaling pathways were also reduced by filgotinib therapy. In exploratory analyses, the salivary rate and tear production resulted stabilized at similar levels compared with baseline during the treatment with filgotinib [107]. Finally, most adverse events were not severe, and overall safety and tolerability were consistent with the already known safety profile. In light of this, although primary and secondary endpoints were not met, these observations support post-hoc analyses in specific subgroups of pSS patients, possibly guided by peculiar biomarkers, which, together with a general deep revision of pSS outcome measures for clinical trials, already ongoing, might lead to target more accurately pSS patients and potentially to prove efficacy of promising novel therapeutic agents, such as filgotinib, for use in clinical practice [107].

Overall, current data on JAKi in pSS is currently insufficient. It is necessary to supplement the data with randomized phase 3 studies.

### 4.5.2. Sarcoidosis

In patients with sarcoidosis, the understanding of the pathophysiology has been modified by the demonstration of T lymphocytes secreting both IFN- and IL-17 in a so-called "Th17.1" environment. In addition, a transcriptomic analysis revealed an overexpression of RNA of genes related to JAK STAT signaling in a series of 17 patients [108].

No preclinical studies available. Observational studies and/or control trial are available for the following molecules.

#### 4.5.2.1. Tofacitinib.
Observational studies and two Phase I trials evaluating the efficacy of oral tofacitinib 5 mg twice daily in pulmonary (NCT03793439) and cutaneous (NCT03910543) sarcoidosis are ongoing [109]. In 2018, Damsky et al. [107] reported clearance of cutaneous sarcoidosis with oral tofacitinib 5 mg twice daily in a patient with refractory cutaneous sarcoidosis. The group subsequently published a report of a patient with a longstanding history of severe cutaneous and systemic sarcoidosis refractory to a multitude of treatments. The patient had clinical resolution of the cutaneous disease after 4 months of tofacitinib therapy, which initially started with 5 mg twice daily for 2 months followed by 10 mg twice daily thereafter. The systemic disease also cleared in this patient. At 6 and 9 months after initiating therapy with tofacitinib, positron emission tomography and computed tomography scans demonstrated that the systemic sarcoidosis had resolved. By abrogating the JAK/STAT signaling pathway, tofacitinib may lead to the improvement of sarcoidosis by altering the levels of key cytokines and factors involved in T-cell and macrophage activation as well as granuloma formation. Damsky et al. [109] demonstrated that lesional and plasma levels of IL-2 and tumor necrosis factor were decreased after treatment with tofacitinib.

#### 4.5.2.2. Baricitinib.
The literature review showed seven patients with uveitis and five with sarcoidosis treated with JAKi, with symptom improvement. An open-label, non-randomized, non-controlled, multicenter, interregional study (JAKUVEITE) is underway to evaluate the efficacy of Baricitinib in refractory, non-infectious uveitis.

#### 4.5.2.3. Ruxolitinib.
A case report by Valeyre et al. [110] describes a sarcoidosis associated with Vaquez disease with JAK2 V617F mutation. The patient showed improvement, particularly in pulmonary interstitial involvement, on ruxolitinib. Another case report improvement of cutaneous sarcoidosis on ruxolitinib in association with Vaquez disease [111]. A recent case report by Levraut et al. [112] described a systemic granulomatosis improved by ruxolitinib.

Overall, current data on JAKi in sarcoidosis are mainly based on case series. It is necessary to supplement the data with randomized studies.

### 4.5.3. Relapsing polychondritis

The etiology of relapsing polychondritis (RP) is unknown. In patients with RP, genetic susceptibility is suggested by the association between RPC and human leukocyte antigen (HLA) DR4 or other HLA class II alleles. There is evidence of autoimmunity, both antibody- and cell-mediated, to extracellular matrix components of cartilage, including types II, IX and XI collagen; matrilin-1; and proteoglycan constituents fractions. The immune response and subsequent release of cytokines may be responsible for cartilage destruction in RPC. Immune complexes, formed in situ and/or localized by affinity to polyanionic proteoglycans, bind to the surface of cartilage. Attempted removal by scavenger cells facilitates release of matrix degrading metalloproteinases, oxygen metabolites and/or cytokines. Cytokines such as IL-1 and tumor necrosis factor (TNF) induce chondrocyte production of matrix-degrading metalloproteinases, plasminogen activator and prostanoids [113,114]. There is a frequent association of RP with a diverse array of immune-mediated connective tissue, endocrine, and inflammatory bowel diseases, including systemic necrotizing forms of vasculitis, Graves' disease, and ulcerative colitis. A high proportion of patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome meet a clinical diagnosis of RP.

No preclinical studies available. Case report, observational studies and/or control trial are available for the following molecules.

#### 4.5.3.1. Tofacitinib.
The use of JAKi is still anecdotal [115]. Meshkov et al. [116] has described a case report of a 39-year-old female patient with a 6-year history of RP that manifested by progressive nasal chondritis with saddle nose deformity, recurrent arthritis and scleritis, involvement of laryngeal and tracheal cartilages low-grade fever and laboratory signs of inflammation (high erythrocyte sedimentation rate, C-reactive protein and rheumatoid factor). Treatment with medium-dose (30 mg/day) prednisone was initially effective. For steroid tapering, methotrexate, azathioprine, mycophenolate mofetil and dapsone were administered sequentially. However, all immunomodulators were discontinued within a relatively short period of time as a result of adverse drug reactions or persistent clinical and laboratory activity. Despite medium-dose to high-dose (up to 40 mg/day) corticosteroids, the disease showed a progressive course with recurrent episodes of acute respiratory distress and a persistent laboratory activity. The patient rejected treatment with any parenteral biologics. However, she gave an informed consent for an off-label oral tofacitinib administration. This agent was chosen given its action on the intracellular pathways responsible for triggering the inflammatory response. Treatment with tofacitinib 10 mg daily rapidly induced a clinical decrease in disease activity with corticosteroid tapering. At 12 months of treatment, she was in stable clinical remission and free from corticosteroids, while CT scanning showed an improvement of laryngeal wall thickening.
Overall, current data on JAKi in RP are mainly based on case series. Randomized, prospective trials are needed to evaluate the efficacy of JAKi in this indication.

### 4.5.4. Giant cell arteritis

In patients with giant cell arteritis (GCA), recent therapeutic advances, including the more widespread use of tocilizumab, are related to a better understanding of the pathophysiology of this vasculitis. Activation of dendritic cells within the vascular walls, which follows a still unknown triggering event, initiates the recruitment of CD4+ cells with a Th1 profile. This Th1 environment induces the recruitment of macrophages secreting pro-inflammatory cytokines, including IL-6 and IL-1. In addition to the Th1 signature, it is now known that there is a Th17 signature during GCA [117].

No preclinical studies available. Case report, observational studies and/or control trial are available for the following molecules.

#### 4.5.4.1. Upadacitinib.
The efficacy of tocilizumab in large vessel vasculitis suggests the potential value of JAKi in this indication. One trial evaluated the safety and efficacy of upadacitinib in participants with GCA (SELECT-GCA) (phase III) (NCT03725202). This study consists of two periods. The objective of Period 1 is to evaluate the efficacy of upadacitinib in combination with a 26-week corticosteroid (CS) taper regimen compared to placebo in combination with a 52-week CS taper regimen, as measured by the proportion of participants in sustained remission at Week 52, and to assess the safety and tolerability of upadacitinib in participants with giant cell arteritis (GCA). The objective of period 2 is to evaluate the safety and efficacy of continuing versus withdrawing upadacitinib in maintaining remission in participants who achieved remission in Period 1. In total, 420 patients were enrolled. The primary endpoint was the percentage of participants achieving sustained remission (at week 52). The results showed that sustained remission at 52 weeks: 46% of patients treated with upadacitinib achieved sustained remission, compared to 29% in the placebo group, showing a statistically significant advantage (P=0.0019). Sustained complete remission (absence of symptoms along with normalized inflammatory markers such as ESR and CRP): this was observed in 37% of patients in the upadacitinib group, versus 16% in the placebo group (*P*<0.0001). Reduced flare-ups: Only 34% of patients in the upadacitinib group experienced disease flares, compared to 56% in the placebo group (*P*=0.0014). Serious infections were slightly lower in the upadacitinib group (6% vs. 11% in placebo).

#### 4.5.4.2. Baricitinib.
One trial will assess the safety and efficacy of baricitinib in relapsing GCA (phase II) (NCT03026504). All participants will be taking prednisone at the start of the study. The prednisone will be reduced according to a standardized tapering schedule while participants continue to take one tablet of baricitinib daily for 52 weeks. The study will be an open-label pilot study assessing the safety and tolerability of baricitinib (4 mg daily, oral, for 52 weeks) in addition to a standardized glucocorticoid taper. It is anticipated that adjunct baricitinib will be safe and well tolerated by patients with GCA and demonstrate preliminary efficacy as measured by reducing inflammatory markers, decreasing steroid requirements and increasing relapse-free survival. Fifteen patients were enrolled.

Prigent et al. [118] have reported a case of a 76-year-old woman with relapsing GCA and large vessel vasculitis demonstrated on 18F-FDG-PET/CT. Methotrexate and tocilizumab failed to achieve remission, and the patient ultimately exhibited a favorable clinical and radiological response to baricitinib. This case suggests that baricitinib may be a promising treatment for giant-cell arteritis-related

large-vessel vasculitis and that 18F-FDG-PET/CT may be used to monitor therapeutic response but needs prospective, randomized studies to evaluate efficacy JAKi on GCA.

Overall, current data on JAKi in GCA are mainly based on case series. A phase II trial is underway. Particular vigilance is required in patients who are often elderly and have cardiovascular risk factors.

### 4.5.5. Takayasu's disease

The pathogenesis of Takayasu arteritis is poorly understood. Cell-mediated mechanisms are thought to be of primary importance and may be similar to those in giant cell arteritis (GCA) [119]. Immunohistopathologic examination has shown that the infiltrating cells in aortic tissue mainly consist of cytotoxic lymphocytes, especially gamma delta T lymphocytes [120].

No preclinical studies are available. Case report, observational studies and/or control trial are available for the following molecules:

#### 4.5.5.1. Tofacitinib.
Kong et al. [121] have conducted a prospective observational trial to compare the treatment efficacy and safety of tofacitinib versus methotrexate (MTX) in Takayasu arteritis. Fifty-three patients with active disease from an ongoing prospective Takayasu cohort in China were included in this study. Twenty-seven patients were treated with glucocorticoids (GCs) and tofacitinib, and 26 patients were treated with GCs with MTX. The observation period was 12 months. Complete remission (CR), inflammatory parameter changes, GCs tapering and safety were assessed at the 6th, 9th and 12th month. Vascular lesions were evaluated at the 6th and 12th month, and relapse was analyzed during 12 months. The CR rate was higher in the Tofacitinib group than in the MTX group (6 months: 85.19% vs. 61.54%, P=0.07; 12 months: 88.46% vs. 56.52%, P=0.02). During 12 months' treatment, patients in the Tofacitinib group achieved a relatively lower relapse rate (11.54% vs. 34.78%, P=0.052) and a longer median relapse-free duration (11.65±0.98 vs. 10.48±2.31 months, P=0.03). Average GCs dose at the 3rd, 6th and 12th month was lower in the Tofacitinib group than that in the MTX group (*P*<0.05). A difference was not observed in disease improvement or disease progression on imaging between the two groups (*P*>0.05). Prevalence of side effects was low in both groups (3.70% vs. 15.38%, P=0.19).

#### 4.5.5.2. Upadacitinib.
The SELECT-TAK trial is a Phase III, multicenter, randomized, placebo-controlled study designed to evaluate the efficacy and safety of upadacitinib in patients with Takayasu arteritis. The primary endpoint is to assess whether upadacitinib, combined with a corticosteroid taper regimen, can prevent relapses of Takayasu arteritis more effectively than placebo. The study focuses on patients who have experienced recent disease relapses despite being on corticosteroid therapy. Results are in going.

Overall, current data on JAKi in Takayasu's disease are mainly based on case series. Randomized, prospective trials are needed to evaluate the efficacy of JAKi in this indication. We are waiting for the results of SLECT TAK.
### 4.5.6. Behçet's disease

Behçet's disease is an inflammatory pathology of unknown cause characterized by the presence of bipolar aphthosis associated with other systemic inflammatory involvement. In genomic studies, numerous polymorphisms associated with Behçet's disease have been identified, some of which involve the JAK STAT pathway, including STAT1 and 2, IL-6R, IL-10, SOCS1 and 3, the latter being endogenous inhibitors of JAK. The inflammatory profile of MB is the product of an entanglement of specific genetic profiles and an abnormal innate and adaptive immune response to an external stimulus. The key cytokines in this pathology are mainly the Th1 and Th17 pathway cytokines. These include IL12/23, TNF-, IFN, IL-6, and IL-1 [122].

No preclinical studies available. Case report, observational studies and/or control trial are available for the following molecules.

#### 4.5.6.1. Tofacitinib.
To date, a retrospective study of 13 patients has evaluated the efficacy of tofacitinib with vascular and joint improvement at 7 months [123]. All patients benefited from treatment with tofacitinib. After a median follow-up of 8 (IQR: 5.5-19) months, the overall BDAF score improved significantly (5 [IQR: 4-5] vs. 0 [IQR: 0-1.5], P < 0.001). More specifically, patients with vascular/cardiac and joint involvement achieved clinical and radiological remission; erythrocyte sedimentation rate (21 [IQR: 7-101] mm/h vs. 5 [IQR: 1-11] mm/h, P = 0.0028) and C-reactive protein level (21 [IQR: 1.24-67] mg/L vs. 0.5 [IQR: 0.32-1.3] mg/L, P = 0.019) decreased significantly. For patients with gastrointestinal involvement, intestinal ulceration was cured in one patient, while it persisted in the other five. The median prednisone-equivalent dose of glucocorticoids was reduced (baseline: 10 [IQR: 10-17.5] mg/day vs. last visit: 10 [IQR: 5-12.5] mg/day, P = 0.028), indicating a potential steroid-sparing effect. Cyclophosphamide was reduced and discontinued in five and one patient, respectively. One patient discontinued tofacitinib due to disease progression. Two patients discontinued tofacitinib due to herpes zoster (HZ) infection.

Overall, current data on JAKi in Behçet's disease are mainly based on case series and retrospective studies. Randomized, prospective trials are needed to evaluate the efficacy of JAKi in this indication.

### 4.5.7. Other vasculitis

Some pilot studies and case reports demonstrated the efficacy of JAKi (tofacitinib) for ANCA-associated vasculitis [124], polyarteritis nodosa [125], cutaneous leukocytoclastic vasculitis [126]; however, data on other forms of vasculitis are very limited, and we cannot get any conclusion from such limited data.

### 4.5.8. Auto-inflammatory diseases

The cytokine profile of auto inflammatory syndromes involves a number of pro-inflammatory cytokines, some of which are dependent on the JAK STAT pathway.

No preclinical studies available. Case report, observational studies and/or control trial are available for the following molecules.

#### 4.5.8.1. Tofacitinib.
Tofacitinib has been approved by the FDA in 2020 for juvenile idiopathic polyarticular arthritis refractory to methotrexate or another biologic agent [127].

#### 4.5.8.2. Baricitinib.
A randomized, double-blind, Phase III trial (NCT04088396) evaluating the efficacy of baricitinib in systemic juvenile idiopathic arthritis is currently underway.

Aicardi-Goutières syndrome (AGS) is a multisystem heritable disorder of the innate immunity resulting in excessive interferon production. Most characteristically, AGS manifests as an early-onset encephalopathy that results in severe intellectual and physical handicap. Interferon is thought to cause injury not only to the brain, but also the skin, liver, lungs, heart and many other organs. NCT03921554 is a clinical trial currently evaluating the efficacy of baricitinib in patients with AGS. The primary objective is to determine if the administration of baricitinib to patients with AGS results in an improvement or stability of the AGS scale at baseline at 52 weeks. The trial is currently recruiting participants and is expected to be completed in 2024.

A Phase 2/3, multicenter, open-label study (NCT04517253) is currently conducted across 52 weeks to evaluate the efficacy and safety of baricitinib in adult and pediatric Japanese patients with Nakajo-Nishimura syndrome/chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (NNS/CANDLE), stimulator of interferon genes-associated vasculopathy with onset during infancy (SAVI), or Aicardi-Goutières syndrome (AGS). Baricitinib may offer a potential therapeutic option for patients with NNS/CANDLE, SAVI, and AGS, with a positive benefit/risk profile in a vulnerable patient population with multiple comorbidities.

#### 4.5.8.3. Ruxolitinib.
VEXAS syndrome (vacuoles, E1 enzyme, X-linked, auto inflammatory, somatic) is due to a somatically acquired mutation of the E1-ubiquitin ligase UBA1, leading to the expression of a catalytically impaired isoform in myeloid cells. VEXAS syndrome combines severe auto-inflammatory manifestations and is frequently associated with myeloid neoplasia (MN). The outcome of VEXAS is poor, and most patients require high dose corticosteroids to reduce inflammation [128]. Therapeutic options besides steroids are currently limited in those patients. In this multicenter retrospective study, the authors reported some clinical efficacy of JAKi in VEXAS patients. They analyzed retrospectively 24 UBA1 mutated patients treated with JAKi (11 with ruxolitinib, 11 with tofacitinib, 1 with baricitinib, 1 with upadacitinib). Complete clinical (CCR) and complete biological response (CBR) were defined as complete resolution of clinical symptoms and normalization of inflammation markers (CRP) respectively. Partial clinical (PCR) and biological (PBR) response were defined by reduction of at least 50% of clinical or inflammation markers, respectively. Clinical manifestations at VEXAS diagnosis include skin involvement (87.5%), arthritis or arthralgia (83.3%), vasculitis (37.5%), fever (75%), ocular manifestations (29.2%) and pulmonary infiltrates (41.6%). Prior to JAKi onset, patients had received a median of 2.5 immunosuppressive/immunomodulatory treatments. After 1 month, 12/24 (50%) patients had achieved clinical and/or biological response. CCR and CBR was achieved in 7/11 (64%) and 6/11 (54%) patients treated with ruxolitinib, and in 3/13 (23%) and 2/13 (15%) patients treated with other JAKi. After 3 months, CCR and CBR was 100% and 80% (10 evaluable patients) in the ruxolitinib group as compared to 25% and 25% in patients treated with other JAKi (8 evaluable patients) (P = 0.0036 et 0.0055 respectively). In ruxolitinib treated patients, median CRP and steroid dose reduction was 72.5% and 66.25% respectively at 3 months. With a median follow-up of 4 months, only 1 ruxolitinib treated patient had lost response, whereas median time to next of treatment was 3.4 months with other JAKi. Those retrospective preliminary results, with limited follow up, must be interpreted with caution and will be updated at the meeting. The effect of ruxolitinib on VEXAS patients with concomitant myeloid neoplasia will soon be studied prospectively in a Groupe Francophone of Myelodysplasia (GFM) clinical study.

### 4.5.9. Refractory Blau syndrome

BS is an auto inflammatory disorder characterized by non-caseating granulomatous dermatitis, arthritis, and uveitis. It is a
The use of JAKi in certain auto-inflammatory syndromes, notably VEXAS syndrome, seems relevant but based mainly on retrospective studies. The molecule of choice in VEXAS syndrome seems to be ruxolitinib. Randomized trials are needed to complete these results.

rare familial disease transmitted as an autosomal dominant trait, characterized by arthritis, uveitis, skin rash and granulomatous inflammation. BS is distinguished from sarcoidosis by the absence of pulmonary involvement, absence of adenopathies, the pattern of arthritis and the familial pattern of inheritance. The gene responsible for BS has been identified in 2001 in the nucleotide-binding domain of caspase recruitment domain (CARD15/NOD2), also involved in pathogenesis of Crohn's disease. The disease usually starts in early childhood. The treatment of BS is empiric and usually requires corticoids with immunosuppressive agents. Reguera et al. [129] have presented a case of refractory and severe BS that was treated with the JAKi, tofacitinib and then baricitinib. Their objective was to describe the clinical and immunological outcomes after treatment with JAKi. Blood tests and serum samples were obtained during follow-up with Tofacitinib and Baricitinib. They assessed their effects on clinical outcomes, acute phase reactants, absolute lymphocyte counts (ALCs), lymphocyte subset counts, immunoglobulins, and cytokine levels. A review of the literature on the use of JAKi for the treatment of uveitis and sarcoidosis was also conducted. Tofacitinib led to a rapid and maintained disease control and a steroid-sparing effect. A decrease from baseline was observed in ALC, CD3+, CD4+, CD8+, and natural killer (NK) cell counts. B-cells were stable. Serum levels of interleukin (IL)-4 and tumor necrosis factor alpha (TNF-α) increased, whereas IL-2, IL-6, IL-10, and IL-17 maintained stable. Tofacitinib was discontinued after 19 months due to significant lymphopenia. The initiation of Baricitinib allowed maintaining adequate control of disease activity with an adequate safety profile.

Overall, current data on JAKi in refractory Blau syndrome are mainly based on case series. Randomized, prospective trials are needed to evaluate the efficacy of JAKi in this indication.

### 4.5.10. Hemophagocytic lymphohistiocytosis (HLH)

Maschalidi et al. [130] used ruxolitinib to treat LCMV infected perforin- or RAB27A-deficient mice (models of primary HLH), as well wild-type mice exposed to repeated injections of CpG DNA (model of secondary HLH). Through these approaches, they demonstrated that ruxolitinib reversed many HLH manifestations, including splenomegaly, cytopenias, hypercytokinemias, peripheral organ and central nervous system inflammation, and it significantly prolonged survival.

Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome driven by overactive T cells and macrophages that abundantly secrete numerous pro-inflammatory cytokines, including interferon (IFN)-gamma, interleukin (IL)-1-beta, IL-2, IL-6, IL-10, IL-18, and tumor necrosis factor (TNF). The release of these and other cytokines underlies many of the clinical and pathologic manifestations of HLH, which if left untreated, can lead to multi-organ failure and death. The advent of etoposide-based regimens, such as the Histiocyte Society HLH-94 and HLH-2004 protocols, has substantially decreased the mortality associated with HLH. Nevertheless, the 5-year survival remains low at ~60%. To improve upon these results, studies have focused on the

use of novel cytokine-directed therapies to dampen inflammation in HLH. Among the agents being tested is ruxolitinib, a potent inhibitor of the Janus Kinase (JAK) and signal transducer and activation of transcription (STAT) pathway, which functions downstream of many HLH-associated cytokines.

Case report, observational studies and/or control trial are available for the following molecules.

### 4.5.11. Ruxolitinib

HLH is complex. It reflects a real cytokine storm [131]. Ruxolitinib has been shown in mouse models to reduce the adverse consequences of this macrophage over activation [132]. A single-center, open-label pilot study evaluated the efficacy of ruxolitinib in 5 patients with secondary HLH and reported an improvement [133]. Wang et al. [134] evaluated the efficacy of ruxolitinib in refractory secondary HLH with 73% partial or complete response in an observational study. A prospective, multicenter, non-randomized clinical trial evaluated the combination of ruxolitinib + doxorubicin + etoposide + methylprednisolone in refractory HLH. They observed 78% partial or complete response [135].

### 4.5.12. Itacitinib

Prospective phase II trial assess the treatment of sporadic non severe HLH with itacitinib (HLH-JAK). It is proposed to evaluate the efficacy of itacitinib in a new indication replacing corticosteroid therapy in patients with HLH without signs of severity, bearing in mind that: corticosteroids are not specific to HLH and may hamper the diagnosis of certain associated pathologies, in particular the anatomopathological diagnosis of certain blood diseases. They also increase the risk of infection. Their prescription (dose and duration) is not codified, which explains some long-term prescriptions and the many known side effects. The treatment under study, itacitinib, is administered orally every day as follows: from day 1 to day 15, at a dose of 300 mg, with no special premedication. Efficacy is assessed at D15. At D15, if there is no clinical improvement and the treatment is well tolerated, the dose of itacitinib may be increased to 400 mg per day. The treatment may be continued for up to 30 days, depending on the progress of the disease and the medical's assessment. The results are pending.

The use of JAKi in HLH seems relevant but is mainly based on retrospective studies. The molecule of choice seems to be ruxolitinib. Randomized trials are needed to complete these results.

## 5. Conclusion

In this review, we have detailed the progress of knowledge and the current uses and different perspectives of JAKi in the field of autoimmune and systemic diseases. More randomized controlled trials are needed to precise the exact place of JAKi in the armamentarium in these diseases, while their spectrum of use is increasingly broader. Nevertheless, their use is not without risk, and requires special precautions and monitoring, as detailed by Moreau et al. in the second part of this review.

## Human and animal rights

The authors declare that the work described has not involved experimentation on humans or animals.
## Informed consent and patient details

The authors declare that the work described does not involve patients or volunteers.

## Funding

This work did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.

## Author contributions

All authors attest that they meet the current International Committee of Medical Journal Editors (ICMJE) criteria for Authorship.

## Disclosure of interest

The authors declare that they have no competing interest.

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