# Safety profile of JAK inhibitors in inflammatory or autoimmune diseases.

J. Moreau, L. Chikhoune, C. Poggi, Sarah Stabler, Jean-Guillaume Letarouilly, Eric Hachulla, David Launay

## ► To cite this version:

J. Moreau, L. Chikhoune, C. Poggi, Sarah Stabler, Jean-Guillaume Letarouilly, et al., Safety profile of JAK inhibitors in inflammatory or autoimmune diseases., La Revue de Médecine Interne, 2025, La Revue de Médecine Interne, 46 (7), pp.386-396. 10.1016/j.revmed.2025.06.003. hal-05329908

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## Review article

# Safety profile of JAK inhibitors in inflammatory or autoimmune diseases

<figure><img src="image_3.png" /></figure>

## Profil de sécurité des inhibiteurs de JAK dans les maladies inflammatoires et auto-immunes

Julie Moreau<sup>a</sup>, Liticia Chikhoune<sup>a</sup>, Claire Poggi<sup>a</sup>, Sarah Stabler<sup>b,c</sup>,
Jean-Guillaume Letarouilly<sup>d,e,f</sup>, Éric Hachulla<sup>a,e,f</sup>, David Launay<sup>a,e,f,*</sup>

## INFO ARTICLE

## ABSTRACT

Over the past decade, Janus kinase inhibitors (JAKi) have emerged as a promising treatment for inflammatory and autoimmune diseases. Concurrently, there has been increasing attention to their potential side effects, particularly infectious and cardiovascular risks. In this review, we outline the various adverse effects of these treatments and emphasize the importance of their prevention. First, we examine the risk of infection and the preventive measures through screening, vaccination, and prophylaxis. Subsequently, we explore the risk of developing malignant tumors, venous thromboembolism, and major cardiovascular events. Although the data are sometimes inconsistent, they indicate the existence of a subpopulation at increased risk of JAKi side effects, including patients over 65 years of age, those with cardiovascular and malignancy risk factors, and smokers. Finally, we discuss the risk and prevention strategies for gastrointestinal perforation, as well as the risk of biological abnormalities, such as cytopenias, cytolysis, dyslipidemia, and elevated CPK levels.

© 2025 The Author(s). Published by Elsevier Masson SAS on behalf of Société Nationale Française de Médecine Interne (SNFMI). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## RÉSUMÉ

Au cours de la dernière décennie, les inhibiteurs de Janus kinase (JAKi) sont apparus comme un traitement prometteur des maladies inflammatoires et auto-immunes. Parallèlement, leurs effets secondaires potentiels, en particulier les risques infectieux et cardiovasculaires, ont fait l'objet d'une précaution croissante. Dans cette revue, nous décrivons les différents effets indésirables de ces traitements et soulignons l'importance de leur prévention. Dans un premier temps, nous examinons le risque infectieux et les mesures préventives par le dépistage, la vaccination et la prophylaxie. Ensuite, nous explorons le risque de développer des tumeurs malignes, ainsi que des événements thromboemboliques veineuses et cardiovasculaires majeurs. Bien que les données soient parfois incohérentes, elles indiquent l'existence d'une sous-population présentant un risque accru d'effets secondaires des JAKi, notamment des patients âgés de plus de 65 ans, ceux qui présentent des facteurs de risque cardiovasculaire et de malignité, ainsi que les fumeurs. Enfin, nous discutons du risque et des stratégies de prévention des perforations

**Keywords :**
JAK inhibitors
Systemic diseases
Autoimmune diseases
Tolerance
Safety

**Mots clés :**
JAKi
Maladie systémique
Maladie auto-immune
Tolérance
Sécurité

<footnote><sup>a</sup> 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><sup>b</sup> Service des maladies infectieuses, 59000 Lille, France</footnote>

<footnote><sup>c</sup> Université de Lille, U1019, UMR 9017, Center for Infection and Immunity of Lille (CIIL), 59000 Lille, France</footnote>

<footnote><sup>d</sup> Université de Lille, CHU de Lille, FHU PRECISE, service de rhumatologie, 59000 Lille, France</footnote>

<footnote><sup>e</sup> U1286-INFINITE-Institute for Translational Research in Inflammation, université de Lille, 59000 Lille, France</footnote>

<footnote><sup>f</sup> Inserm, 59000 Lille, France</footnote>

<footnote>* Corresponding author at: 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.
Adresse e-mail : david.launay@univ-lille.fr (D. Launay).</footnote>
gastro-intestinales et des anomalies biologiques, telles que les cytopénies, la cytolysse hépatique, les dyslipidémie et l'élévation des CPK.

© 2025 Les Auteurs. Published by Elsevier Masson SAS au nom de Société Nationale Française de Médecine Interne (SNFMI). This article is published in Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

# 1. Introduction

Janus kinase inhibitors (JAKi) are molecules involved in modulating the JAK/STAT pathway. Inhibiting this pathway effectively reduces immune cell activation, crucial in treating autoimmune diseases. Over the past decade, the emergence of targeted therapies has highlighted the increasingly significant role of JAKi in treating inflammatory and autoimmune diseases. The application spectrum of these small molecules is continuously expanding. Numerous clinical trials have been conducted to assess the efficacy of these molecules in various inflammatory or autoimmune diseases, including rheumatoid arthritis (RA) [1-9], axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) [10-13], ulcerative colitis (UC) [14] and atopic dermatitis (AD) [15-18]. The efficacy of JAKi has been explored in systemic lupus erythematosus (SLE) [19,20], dermatomyositis [21,22], systemic sclerosis [23-25] and Sjögren's syndrome [26]. The potential applications of JAKi in systemic and autoimmune diseases are broadening, as evidenced by their off-label use described in Chikhoune et al. study. With increasing data on the safety of JAKi, it is imperative for physicians to be well-informed. Therefore, this review will primarily focus on safety concerns, i.e. infection risk, hematological adverse events (AE), malignancy risks, venous thromboembolism (VTE), major adverse cardiovascular events (MACE), lipid abnormalities, gastrointestinal perforations, hepatobiliary and renal elimination, and elevated creatine phosphokinase (CK) levels in the blood. Given the scarcity of data on autoimmune diseases relevant to internal medicine, we have predominantly relied on generalized data from rheumatologic, dermatologic, and gastrointestinal diseases. These data were obtained from an extensive review of the existing literature.

# 2. Infection risk

## 2.1. *Commons infections*

Infections are frequent AEs of JAKi, often ranging from mild to moderate intensity. As reported by the systematic review and meta-analysis conducted by Bechman et al., the incidence of serious infections at licensed doses of JAKi remains low with an annual incidence rate (IR) per 100 patient-years between 1.97 and 3.16 per year according to molecule [27,28]. These data are comparable to those obtained with baricitinib for AD in a pooled safety data derived from six clinical studies, one labeling study, and one open-label study [29]. Similarly, the Cohen et al. study, which encompassed all clinical trials involving over 6000 RA patients with follow-ups of up to 8.5 years, reported an incidence rate (IR: i.e. number of patients with event/100 patient-years) of severe infections in patients treated with tofacitinib of 2.7 for all causes [30]. JAK1 selective drugs (upadacitinib & filgotinib) are associated with a modest increase in the risk of infection [31]. Evaluating the safety profile of upadacitinib over 15,000 patient-years, it was observed that severe infections occurred at comparable rates among RA, PsA, axSpA, and AD, and these infections rarely led to treatment discontinuation [32]. The phase IIIb JUMP trial, which evaluated the efficacy and safety of ruxolitinib in myelofibrosis in over 2000 patients, reported that 5% experienced all-grade infections [33]. Notably, only a small

number of these infection cases led to discontinuation of treatment [33].

The most frequent infections include upper respiratory, urinary tract, and digestive tract infections, cellulitis, and oral candidiasis [31,34] and the underlying disease can influence the type of infection. For example, *Clostridioides* infections (5.4%) were reported in cases of UC [35]. No increase risk of *Clostridioides* infections was reported in patients with AD treated by JAKi. Also, using JAKi in a dermatological condition such as AD does not appear to be associated with an increased risk of skin infection [29]. Infections are the first cause of death in VEXAS syndrome and recurrent infections represent a major complication [36,37]. One case of legionellosis has been reported in VEXAS syndrome, although the imputability of the JAKi is uncertain [36,37].

Serious infections are comparable to those observed with both conventional synthetic and biological disease-modifying antirheumatic drugs (bDMARDs) [27,28]. Similar incidences of serious infections were identified for non-TNF inhibitor (TNFi) bDMARDs (3 to 5.5 per 100 patient-years) - especially abatacept, rituximab and tocilizumab - in a systematic review and meta-analysis [38] and TNFi - in particular adalimumab, infliximab and etanercept - (3.2 to 4.6 serious infections per 100 patient-years) in RA clinical trials [39-41]. In the case of SLE, the phase 3 SLE-BRAVE-II trial reported comparable levels of overall infections across different treatment groups (baricitinib 2 mg, 4 mg or placebo) [19].

Notable risk factors of infection include combination therapy with corticosteroids, older age, presence of chronic obstructive pulmonary disease, high rheumatoid factor and Health Assessment Questionnaire-Disability Index-score (HAQ-DI score), high Body Mass Index (BMI), lymphopenia (< 500/mm³), diabetes, female gender, geographic region (Asia versus the United States of America [US] and Canada), and tofacitinib dose [30].

## 2.2. *Varicella zoster virus and herpes simplex virus reactivation*

A characteristic infectious adverse event due to JAKi is herpes zoster (HZ), caused by the reactivation of the varicella zoster virus (VZV) [27]. Considering the high seroprevalence rates in adults (>99% of adults in France in 2011, Lepoutre A, InVS, 2011), cases of varicella in adults are exceptional. The IR of HZ with JAKi is higher than that observed with TNFi and non-TNFi bDMARDs [27,28]. The risk of HZ appears to be dependent on the specific JAK complex targeted. JAKs form complexes to mediate distinct signaling pathways, each playing a crucial role in immune response regulation. JAK1 is key for type 1 and 2 interferon signaling pathways, while JAK3 is essential for lymphocyte development and function. Cellular immunity may be more critical in preventing VZV reactivation than humoral immunity. During the immune response to VZV, signaling is mediated via the JAK-STAT pathway, involving type 1 interferon (mediated by JAK1/tyrosine kinase 2 [TYK2] complexes) and type 2 interferon (mediated by JAK1-JAK2 complexes). Therapeutics targeting these JAK complexes can disrupt the normal VZV response, thereby increasing the risk of reactivation [42]. The risk of HZ with pan-JAK inhibitors such as baricitinib and tofacitinib, which primarily target JAK-1 and JAK-2 (baricitinib) and JAK-1 and JAK-3 (tofacitinib), is particularly noted [35,43]. The risk of HZ appears lower with upadacitinib compared to tofacitinib and bari-
citinib, without reaching the statistical significance [27]. In patients exposed to filgotinib, serious HZ risk is very low, independent of the dose [35]. In a phase 2 study for Sjögren's syndrome, ophthalmic HZ was reported with filgotinib [26]. In AD, almost all opportunistic infections reported with upadacitinib were eczema herpeticum [29,32,44].

### 2.2.1. Tofacitinib

The Cohen et al. trial reported an IR of 3.9 per year for HZ in over 6000 patients receiving tofacitinib at any dose (5 mg or 10 mg twice a day) for RA over a period of 8.5 years; no time-related factors were noted [30]. Severe HZ was reported in 0.3% of patients, with 92% of cases affecting a single dermatome [30]. Significant risk factors identified included the combination with corticosteroids (hazard ratio [HR] 1.6 for doses > 7.5 mg/day), older age, geographic region (particularly Asia), smoking status (active or cessation), and dose dependency [30]. These findings align with the earlier study by Winthrop et al. in 2014, which found an IR of 4.4 per year for HZ in over 4700 patients receiving tofacitinib at any dose for RA [45]. This data was collated from phase II, phase III, and long-term extension clinical trials of the tofacitinib development program. Notably, only one case involving multiple dermatomes was reported, with no instances of visceral involvement or death [45]. Similar to the Cohen et al. study, older age and geographical region (Asia) were also significant risk factors [46]. This is corroborated by a subsequent publication by Winthrop et al. in 2017, which reviewed data from over 6000 patients across two phase 1, nine phase 2, six phase 3 studies, and two long-term studies, reporting an IR of 4 for all HZ cases, including 7.2% classified as severe, with no death [46]. It is important to note that RA patients inherently have a 2-3-fold increased risk of developing HZ. However, the HZ rate in patients on tofacitinib is higher than other treatments and is independent of the risk induced by the disease itself [30,47-49].

### 2.2.2. Baricitinib

The risk of HZ associated with baricitinib (4 mg once daily) was higher compared to placebo in RA. It appears elevated compared to tofacitinib (5 mg twice a day) and upadacitinib (15 mg once daily), with an IR per year of 3.16 [27]. Smolen et al. found a similar rate over an average of 5.5 years [50]. In AD, safety evaluation from 8 clinical trials indicated a lower incidence of HZ compared to RA, likely due to the inherently increased risk in RA patients independent of treatment [29]. In patients taking baricitinib (2 mg or 4 mg once daily) for AD, the IR of herpetic infection (primary and recurrence) was 10.3 over a median follow-up of 310 days in over 2500 patients [29,44]. This AE is more commonly observed in AD than RA. However, long-term safety studies suggest that prolonged treatment with baricitinib does not continuously increase the risk of herpetic infections, correlating more with the extent and severity of the underlying disease [29,44]. Lesion improvement seems to reduce the risk of herpetic infection. Eczema herpeticum, a severe complication of AD, is observed in patients treated with baricitinib, occurring in approximately 3% of patients [29,44].

### 2.2.3. Ruxolitinib

HZ was found in 5.2% of patients, including 0.5% with grade 3 and 4 severity [33]. In the phase III RESPONSE trial, most HZ cases were grade 1 or 2 [51].

These findings align with the World Health Organization's (WHO) pharmacovigilance study, which reported a significant increase in infectious AEs related to viral infections, particularly HZ, ranked in descending order for baricitinib, tofacitinib, and ruxolitinib. The increased risk of herpes viral infections with baricitinib may be attributed to the underlying disorder, as its primary indication is RA. The lower risk of HZ reactivation in patients treated

with ruxolitinib for hematopoietic neoplasms could be due to prophylactic valaciclovir administration in many cases [34,51].

## 2.3. Other opportunistic infections related to T-cell deficiency induced by JAK inhibitors

Assessing the risk of tuberculosis (TB) is challenging, as patients with latent TB are typically treated and those with active TB are excluded from clinical trials. Most reported cases are likely de novo infections. JAK inhibitors block the signaling of interleukin-12 (IL-12) and interleukin-23 (IL-23), which act through JAK2/TYK2 and inhibit interferon-gamma production by T cells [52], which is essential to granuloma formation and control of TB.

The Cohen et al. study demonstrated a 0.3 annual IR of opportunistic infections (excluding TB) and a 0.2 annual IR of active TB in over 6000 patients on full-dose tofacitinib (5 mg or 10 mg twice a day) for RA over 8.5 years, with no time-related factors observed. Most TB infections occurred in endemic areas, and all latent TB infections had been treated (either prior to trial inclusion or after the positive screening, with JAKi treatment initiated > 1-month after starting isoniazid). These patients did not present with active infection during the follow-up [30]. Winthrop et al., assessing the risk of opportunistic infections in 5671 RA patients treated with tofacitinib, reported that TB was the most common opportunistic infection, with a median time of 64 weeks from drug initiation to diagnosis. Notably, 81% of cases occurred in countries with high background TB IRs [53]. TB cases appeared to present more extrapulmonary manifestations in these datasets [52].

Opportunistic infections such as cryptococcosis, coccidioidomycosis, oral and esophageal candidiasis, pneumocystis, other mycobacterial infections, sino-orbital mucormycosis, cytomegalovirus infections, and toxoplasmosis have been described [31,34,54-58]. There is a significant reported increase in pneumocystis infections for each all JAKi, with over-reporting for baricitinib compared to tofacitinib and ruxolitinib [34]. A few cases of progressive multifocal leukoencephalopathy secondary to the John Cunningham virus have also been reported with ruxolitinib [59]. Additionally, hepatitis reactivation, including hepatitis B reactivation, has been described in a systematic review and meta-analysis of ruxolitinib-associated infections [60].

## 2.4. Prevention of infectious risk: screening, vaccinations, treatment of latent tuberculosis infections, anti-infective prophylaxis and follow-up

JAKi have a shorter half-life and rapid onset of action when compared to biologics. This allows for their quick discontinuation in case of infection.

### 2.4.1. Screening

It is essential to test for hepatitis B (including hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, and possibly hepatitis B virus [HBV] DNA testing) and hepatitis C (hepatitis C antibody with follow-up hepatitis C virus [HCV] RNA testing if antibody positive). Human immunodeficiency virus (HIV) screening is recommended in high-risk populations [28].

JAKi are contraindicated in patients with active hepatitis B, hepatitis C, or HIV infection. For chronic HBV infection (HBsAg+), JAKi should be avoided, or antiviral treatment must be initiated. In cases of previous HBV exposure (anti-HBc antibody positive) without protective antibody (anti-HBs antibody negative), a baseline HBV DNA is crucial due to the risk of occult viremia. Then, HBV DNA and HBsAg should be routinely monitored, because of the risk of reactivation. In case of viral reactivation, JAKi should be temporarily stopped to initiate antiviral therapy, allowing a JAKi reintroduction [28,61-63]. A screening and treatment strategy for
latent TB infection, similar to that used with TNFi, is recommended [54,61,62].

### 2.4.2. Vaccinations

Primary prevention through vaccination is advised, including annual influenza and COVID-19 vaccination [64] and pneumococcal vaccination with the conjugate pneumococcal vaccine (VPC20), following the very recently published national guidelines [65]. Due to more intense and longer-lasting immunity, the need for revaccination with a subsequent dose has not yet been established. For VZV, J07BK03 (recombinant vaccine) is available for early access in France. The primary vaccination schedule of J07BK03 consists of administration in two doses, with a two-month interval between each dose. If needed, the interval may be between two and six months. It is also not necessary to restart the vaccination schedule if the six-month interval is exceeded. It is preferred to administer J07BK03 vaccine prior to commencing immunosuppressant therapy. It is recommended to administer the vaccine as early as possible, so that vaccination is complete ideally 14 days prior to commencing the treatment. In this context, the interval between the two vaccine doses may be reduced to one month. Without a varicella history and with a negative serology, varicella vaccination should be considered 4 weeks before treatment initiation [31,61,64,66].

### 2.4.3. Prophylaxis

There is no established recommendation. We suggest antiviral primary prophylaxis with valaciclovir 1000 mg/day, especially where there are risk factors, such as age over 50 years old. Discontinuation of valaciclovir prophylaxis, if initially prescribed due to the risk of VZV reactivation, may be considered following completion of the full J07BK03 vaccination schedule. In such cases, discontinuation should occur one month after the second vaccine dose. However, in the presence of recurrent HSV infections, valaciclovir may still be indicated for secondary prevention, as HSV recurrences are not prevented by the J07BK03 vaccination [28]. In case of HZ, no recommendation exists concerning continuing or stopping JAKi. However, as HZ is considered as an opportunistic infection, JAKi are often stopped until healing and antiviral therapy should be started as soon as possible. Resumption of JAKi should be secondary discussed on a case-by-case basis according to its efficacy, possible alternatives, severity of the HZ and preventive measures such as long-term valaciclovir or J07BK03 vaccination.

Regarding the management of recurrent herpes, there is no specific recommendation for JAKi. However, in the event of recurrence > 6/year (whatever the context), it is usual to recommend secondary prophylaxis with valaciclovir 500 mg/day.

Anti-pneumocystis prophylaxis with sulfamethoxazole-trimethoprim should be considered for patients with additional risk factors such as associated corticosteroids or according to the underlying disease, such as myelofibrosis [62].

## 3. Hematologic adverse events

Cytopenias, including lymphopenia, neutropenia, anemia, and thrombocytopenia, are observed with JAKi, mainly due to JAK2 inhibition [67]. This inhibition impacts signaling pathways of erythropoietin, thrombopoietin, and G-CSF. Such cytopenias are more frequent with ruxolitinib than tofacitinib, attributable to its more potent JAK2 inhibition [67]. Interestingly, neutropenia does not correlate with an increased risk of severe infection. Cases of polycythemia and thrombocytosis have also been reported [29,54], without an increased thromboembolism risk [61]. Lymphopenia, neutropenia, and anemia have also been reported in RA, PsA, axSpA and AD with upadacitinib [32]. Consequently, regular monitoring of blood count is recommended. Temporary discontinuation of JAKi

should be considered if lymphopenia falls below 500/mm³, followed by a potential dose reduction upon resuming. The dose should be reduced or discontinued if neutrophil count is between 500 and 1000/mm³ and continuously discontinued if it falls below 500/mm³ in the absence of other causes. Treatment should also be stopped if hemoglobin drops below 8 g/dL or if there is a loss of 2 hemoglobin points [61]. The recommendations for each product must be respected.

Regarding ruxolitinib, the JUMP trial, assessing its efficacy and safety in myelofibrosis, reported anemia as the most common hematological adverse events (59.5% all grades, 34.8% grades 3 and 4) and thrombocytopenia (53.5% all grades, 19.3% grades 3 and 4). These cytopenias were more frequent in patients with lower initial platelet counts. A minority of patients required discontinuation of treatment. A decline in hemoglobin levels is initially observed, reaching a nadir at 8-12 weeks, followed by normalization; transfusion support and/or erythropoietin may be needed during this period. A decrease in platelet count is typically seen within the first four weeks, then stabilizes over time [33]. These findings align with the COMFORT phase III conducted in 2015 in 309 patients with myelofibrosis, which reported a decrease in hemoglobin and platelet levels of about 10-12% as frequent adverse events, seldom leading to discontinuation, but potentially necessitating dose adjustment [68].

## 4. Malignant tumors including non-melanoma skin cancer

Malignant tumors including non-melanoma skin cancer have been reported during treatment with JAKi, with an initial warning for tofacitinib, later extended other JAKi.

### 4.1. Tofacitinib

In RA, the ORAL Surveillance trial, a phase 3b-4 safety endpoint trial comparing combined doses of tofacitinib with TNFi, highlighted a higher risk of cancer (excluding non-melanoma skin cancer [NMSC]) in patients aged 50 years or older with at least one additional cardiovascular (CV) risk factor. Over 5.5 years, the estimated cumulative probability of cancer was 6.1% for tofacitinib compared with 3.8% for TNFi, representing a HR of 1.48 (95% CI: 1.04-2.09). Lung cancer was more common with tofacitinib, especially in patients aged 65 years and older. A higher risk of NMSC with tofacitinib (10 mg bid) than TNFi was also observed [69]. A post-hoc analysis of ORAL Surveillance data described a similar risk of non-NMSC malignancy between tofacitinib and TNFi up until month 18, then diverging from month 18 onwards. The incidence of malignancy was higher in patients with a history of atherosclerotic cardiovascular disease (ASCVD) or a high baseline CV risk score in patients treated with tofacitinib and TNFi. IRs of non-NMSC malignancy were higher in patients from North America versus the rest of the world, regardless of baseline ASCVD risk score. Nevertheless, it was not able to disentangle the impact of region from the possibility of a drug-specific effect for adalimumab (North America) versus etanercept (rest of the world), since region and TNFi use were completely confounded [70]. Another post-hoc analysis of ORAL Surveillance data identified two subpopulations at higher risk of malignancy (excluding NMSC): patients aged 65 years and older and smokers [71]. However, this contrasts with earlier safety data from integrated RA development studies over up to 9.5 years, which did not report on an increased risk cancer [72]. In UC, based on five clinical studies with treatment durations up to 6.8 years, malignancy were uncommon, with no apparent clustering or time-related increase in risk, showing rates comparable to those in RA and PsA [73]. Following ORAL Surveillance criteria, US real-world cohorts (STAR-RA study) did not find any increased risk of mali-
gnancy in more than 80,000 RA patients compared to TNFi users, contrary to ORAL Surveillance data, with follow-up periods of less than one year [74].

## 4.2. Baricitinib

Cases of cancer (T- and B-lymphoma, colorectal adenocarcinoma, prostate adenocarcinoma) and NMSC have been reported in AD. However, a direct correlation was not established due to limited numbers of case [29]. The safety profile in RA patients, with a median treatment duration of over 2 years, showed no difference in malignancy rates [50]; long-term extension study and integrated database results also identified no new safety signals [75]. The phase 3b/4 RA-BRIDGE study (NCT03915964) will investigate the risk of malignancy with baricitinib in RA patients, over a 5.5 years period. Results are expected by 2025-2026 [76].

## 4.3. Ruxolitinib

In the JUMP trial, NMSC was reported in 2.7%, the most frequently reported malignancy, with caution due to prior treatment with hydroxyurea. Lymphoma was reported in 0.2% of patients. In addition, a low rate of transformation to acute myeloid leukemia (AML) (2%) was observed. The median duration of follow-up was short, about 13.6 months (range <0.1-60.6 months) [33]. The RESPONSE trial in polycythemia vera over 5 years indicated higher NMSC rates in patients assigned to ruxolitinib, potentially linked to longer prior hydroxyurea exposure. The rates of transformation to myelofibrosis and AML were 2.1 and 0.1 per 100 patients-years with ruxolitinib versus 1.4 and 0 per 100 patients-years with best available therapy group [51]. WHO's pharmacovigilance data suggests a significant increase in reports of leukemia on ruxolitinib, likely related to the disease [34]. As expected, high HR of 46 (95% IC: 36.6-64.9) for developing AML were described in a population-based Swedish study of patients with myeloproliferative neoplasms, without exposure to ruxolitinib [77].

In summary, in 2020, a consensus statement reported that the overall rate of non-NMSC malignancy did not seem higher with JAKi (subject to limited data). An increased risk of NMSC was reported, and annual dermatological examinations are thus recommended for oncological risk assessment. History of active neoplasia is a contraindication to JAKi initiation [28]. Nevertheless, ORAL Surveillance data suggest higher cancer risk as described above [69-71]. In addition, WHO's pharmacovigilance data also frequently report "malignant respiratory and mediastinal neoplasms" for all three JAKi (tofacitinib, baricitinib, ruxolitinib), aligning with Pfizer's warning regarding lung cancer as the most frequent cancer (excluding NMSC) with tofacitinib [34]. Long-term studies are needed to determine this and achieve specific recommendations.

# 5. Venous thromboembolic risk, major adverse cardiovascular events and lipid abnormalities

A number of concerns have been raised about the risk of venous and arterial thromboembolic events, which we show by JAKi category; initially with baricitinib with Food and Drugs Administration (FDA)'s report; then tofacitinib, JAK1 inhibitors and ruxolitinib. Recommendations have resulted from these studies, as described below.

## 5.1. Venous thromboembolic risk & major cardiovascular event

Assessing venous and arterial thromboembolic risk associated with JAKi is challenging due to limited data, heterogeneity patient

populations, compounded by potential risk factors inherent to the underlying diseases.

### 5.1.1. Baricitinib

In AD, an analysis of eight studies involving over 2500 patients with up to two years of exposure (including long-term extension studies) reported no significant excess risk of venous and arterial thromboembolic events, subject to the small number of cases [29]. However, a 2018-2019 Food and Drugs Administration (FDA)'s report raised concerns about an increased risk of blood clots and death with baricitinib 4 mg, particularly in RA and chronic bowel disease patients. A 2022 meta-analysis from multi-database studies showed a statistically significant increased risk of VTE (IR: 1.51, 95% CI: 1.10-2.08) and a non-significant increased risk of MACE compared to TNFi in RA patients [78]. The SLE-BRAVE-II trial in 775 SLE patients noted two (1%) MACE in the baricitinib 4 mg group and one in the 2 mg group [19].

### 5.1.2. Tofacitinib

A cohort study of over 50,000 RA patients reported a higher but non-significant risk of VTE with tofacitinib compared to TNFi (HR: 1.33) [79,80]. The European Medicines Agency's (EMA) pharmacovigilance warning in 2019, based on a long-term RA trial, highlighted a risk of VTE and all-cause mortality with tofacitinib 10 mg twice daily. The recommended dose is 5 mg twice daily or 11 mg once daily extended release [81]. The prospective, randomized, open-label, noninferiority, phase 3b-4 trial (ORAL Surveillance) published in 2022 comparing combined doses of tofacitinib (5 mg or 10 mg twice a day) with TNFi (adalimumab 40 mg every 2 weeks or etanercept 50 mg once day) randomized 4362 patients in patient aged 50 years (mean age 61.2 years) with at least one additional CV risk (smoking, hypertension, hypercholesterolemia, type 2 diabetes mellitus, history of myocardial infarction, family history of CV disease and/or extra-articular RA), with a median follow-up of 4 years. It has been demonstrated a higher incidence of CV events with tofacitinib over a median of 4 years (3.4%) than with TNFi (2.5%), particularly in patients aged 65 years and older in North America. Secondary safety end points revealed a higher VTE risk with tofacitinib at a dose of 10 mg bid than with a TNFi. Regarding efficacy, tofacitinib and TNFi were similar multiple outcomes [69]. Then, a post-hoc analysis of ORAL Surveillance compared tofacitinib 5 mg bid or 10 mg bid or TNFi in patients with or without history of atherosclerotic CV disease (history of coronary artery disease, cerebrovascular disease or peripheral artery disease) for RA within population aged 50 years or older with at least one additional CV risk. The risk of MACE with tofacitinib 5 mg and 10 mg twice a day versus TNFi was increased in patients with a history of ASCVD at baseline. Among patients without history of ASCVD, all with prevalent CV risk factors, MACE risk did not appear different [82]. US real-world cohorts (STAR-RA study), paralleling ORAL Surveillance findings, showed a non-significant increased CV risk in more than 100,000 RA patients with CV risk factors, with a follow-up period of less than one year [83].

### 5.1.3. Upadacitinib

The SELECT-COMPARE study showed no significant difference in MACE or VTE compared to adalimumab. Most participants were aged 50 years or older with at least one CV risk factor [84].

In 2021, the FDA extended its recommendations to include tofacitinib and upadacitinib, alongside baricitinib, cautioning that the benefit-risk balance of these treatments must be carefully evaluated [85].

### 5.1.4. Ruxolitinib

In polycythemia vera, the phase III RESPONSE trial indicated that ruxolitinib may reduce VTE through sustained hematocrit
control. Thrombosis rate was lower compared to the best available treatment, though not significantly different [51,86]. The risk of thrombosis with JAKi for VEXAS syndrome is to consider because of the intrinsic higher risk observed in VEXAS both for venous and arterial thrombosis [87]. Whether patients with VEXAS syndrome should be treated with prophylactic anticoagulation is an ongoing area of discussion. In the accompanying editorial, Guedon et al. highlights the need for better thrombosis risk stratification among patients with VEXAS syndrome and further studies investigating anticoagulant strategies in terms of dosages and duration, especially as patients with VEXAS syndrome have multiple risk factors that put them at increased bleeding risk, including older age, disease-related comorbidities, chronic steroid use, and thrombocytopenia [88]. Kusne et al. Suggest, as an expert opinion, that in the absence of contraindications, patients should receive thromboprophylaxis in high-risk situations such as hospitalization or surgery and be considered for thromboprophylaxis with individual risk assessment for other situations such as immobilization outside of hospitalization, immobilization of a limb, or administration of certain medications such as JAKi or lenalidomide [87]. Heiblig et al. reported that the most frequent adverse events of patients with VEXAS treated with JAKi were infections (36.7%) and thromboembolic complications (20%) but questioned whether JAKi had a causal role in these VTEs [37]. Altogether, whether a patient with VEXAS should be treated by prophylactic anticoagulation remains a case by case decision, with no evidence based data.

EULAR recommendations (2020) identified risk factors for VTE with JAKi, used for autoimmune diseases, including history of VTE, age (especially over 65 years), obesity, selective COX-2 inhibitor use, corticosteroids ≥ 7.5 mg/day, thrombophilia, prolonged immobilization, major surgery, and CV risk factors [28]. Recurrent thromboembolic events are a contraindication to JAKi unless the patient is on curative anticoagulation [28].

A Swedish comparative safety study on VTE induced by JAKi and other immune-modulatory drugs in RA treatment showed a higher IR per 1000 person-years for JAKi (11.33, 95% CI: 8.54-15.04), with a fully adjusted HR of 1.73 (95% CI: 1.24-2.24) compared to TNFi, particularly highlighting an increase in pulmonary embolism risk with tofacitinib and baricitinib [89].

In light of the identified risks, the EMA and the French Agency for the Safety of Medicines and Health Products (ANSM) have endorsed the measures recommended by the Pharmacovigilance Risk Assessment Committee (PRAC). These measures are designed to minimize the risk of serious side effects associated with JAKi. Accordingly, the use of JAKi is no longer recommended, unless no therapeutic alternatives are available, in patients aged 65 years and older, particularly those with CV and malignancy risk factors, as well as current or former smokers [90,91]. This recommendation reflects a cautious approach, prioritizing patient safety in the context of the complex risk profile of these medications.

## 5.2. Lipid abnormalities

In both phase II and III studies for RA, tofacitinib at doses of 5 mg or 10 mg twice daily increased both low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) levels by approximately 10 to 20% [92]. This lipid elevation typically occurred within the first 4 weeks of treatment and then stabilized after three months. No decrease in levels has been observed, except when atorvastatin is used. Notably, the LDL-c/HDL-c ratio seems to have limited predictive value for CV risk [92]. In the context of UC, a similar pattern was observed based on 4.4 years of data from global clinical trials, where both LDL-c and HDL-c concentrations increased after eight weeks of treatment. Yet, the total/HDL-c ratio remained stable. Lipid abnormalities normalized upon drug discontinuation [35,93]. In UC patients, reversible lipid increases

were noted after 8-61 weeks of treatment, with no significant impact on the 10-year CV risk [94]. A comprehensive meta-analysis encompassing 18 studies indicated that all five JAKi (tofacitinib, baricitinib, upadacitinib, filgotinib, and peficitinib) used in RA led to increased LDL-c and HDL-c levels. However, the risk of CV disease did not significantly differ between patients receiving JAKi and those on placebo or an active comparator, though further long-term research is necessary to fully understand these implications [95]. The long-term clinical significance of these findings are still unclear. Lipid monitoring is recommended 2 to 3 months following the initiation of JAKi treatment [61]. In addition, optimizing cardiovascular risk factors is a priority for diseases that use JAKi, such as RA. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders have been published on this specific topic [96].

## 6. Gastrointestinal perforation

In 2022, the WHO's pharmacovigilance database has highlighted cases of gastrointestinal perforations, especially with tofacitinib, where a statistically significant association was found only for tofacitinib [34]. In the Cohen et al. trial, gastrointestinal perforation cases were reported with an IR of 0.11 (95% CI: 0.07-0.17) in over 6000 patients receiving tofacitinib for RA over 8.5 years. Most of these patients add concurrent corticosteroid therapy or non-steroidal anti-inflammatory drugs or a history of diverticula/diverticulitis or gastric ulcers [30]. Xie et al. estimated a twofold risk of gastrointestinal perforation with tocilizumab and tofacitinib compared to TNFi in a cohort of 167,109 RA patients, though the differences in rates remained relatively small. While the risk of gastrointestinal perforation with JAKi is very low, particular caution is advised in at-risk populations, especially older patients with comorbidities, previous diverticulitis, or other gastrointestinal disorders, and those on corticosteroid therapy [54,97]. In a baricitinib safety study evaluating 3492 RA patients over 2 years, three cases of digestive perforation were reported. All these patients were on methotrexate and anti-inflammatory drugs, with two also on corticosteroids. The IR of gastrointestinal perforations for baricitinib appears lower than that observed for tofacitinib, tocilizumab, and other bDMARDs [50]. However, despite these warnings about the risk of digestive perforation, the latest data are reassuring. The studies by Sathapanasiri et al. and Hoisnard et al., evaluating this risk in 20,023 and 12,335 patients respectively, found no additional risk compared with conventional synthetic DMARDs and adalimumab [98,99].

## 7. Hepatobiliary disorders

Hepatic cytolysis has been reported in patients treated with JAKi, necessitating initial and periodic monitoring of complete liver function tests. According to the product's Summary of Product Characteristics, if hepatic cytolysis is observed and drug-induced liver toxicity is suspected, treatment should be temporarily interrupted until this diagnosis is excluded. A proposed approach in cases of elevated hepatic transaminases with an inconclusive etiological workup (i.e. by evaluating for the presence of a previously unknown liver disease, testing for reactivation of hepatotropic viruses or autoimmune hepatitis or potential cases of other or associated drug-induced liver injury) is as follows: if liver enzymes are elevated to between 3 and 5 times the upper limit of normal, or between 1.5 and 3 times after three months of treatment, the JAKi dose should be reduced by half, accompanied by further investigations, such as testing for reactivation of hepatotropic viruses or autoimmune hepatitis [61,100]. If liver enzyme levels normalize
on two controls performed 15 days apart, resumption of the initial JAKi dose may be considered if disease activity warrants it, but always with close monitoring. If liver enzymes remain elevated, the JAKi must be discontinued and hepatologist advice sought. If liver enzymes rise to more than five times the upper limit of normal, the JAKi must be stopped and hepatologist advice sought [101]. The established recommendations advise liver function testing at 1 and 3 months after initiating therapy, followed by periodic evaluations every 3 months [28]. It is important to note that JAKi should not be used in patients with severe hepatic disease (Child Pugh C). Doses should be adjusted in patients with moderate hepatic disease (Child Pugh B) [28]. In a phase 2, double-blind, placebo-controlled study for Sjögren's syndrome, hepatic cytolysis was observed in 2.6% of patients receiving filgotinib, 13.5% receiving lanraplenib (potent and selective oral inhibitor of sleen tyrosine kinase [SYK]), and 2.6% receiving tirabrutinib (potent and selective inhibitor of Bruton's tyrosine kinase -BTK-) after 24 weeks [26]. Hepatic disorders were also reported in patients receiving baricitinib at doses of 2 mg (7%) and 4 mg (4%) for SLE in the SLE-BRAVE II study, a randomized, phase 3, double-blind, placebo-controlled trial [19]. No cholestasis was reported.

## 8. Renal function

In patients with severe renal disease (creatinine clearance < 30 mL/min) before or during treatment by JAKi, specific adjustments in the dosing of JAKi are recommended. For tofacitinib, a dosage reduction to 5 mg once daily is advised. On the other hand, baricitinib is not recommended for use in patients whose creatinine clearance is below 30 mL/min. However, for those with creatinine clearance between 30-60 mL/min, baricitinib can be administered at a reduced dose of 2 mg twice daily. Currently, no dosage adjustment is recommended for other JAKi in the context of renal impairment [28]. The established recommendations advise renal function testing at 1 and 3 months after initiating therapy, followed by periodic evaluations every 3 months [28].

## 9. Blood creatine phosphokinase (CK) level increase

Elevation in blood CK levels have been observed in patients treated with various JAKi, including baricitinib [29,50], tofacitinib [93,102], upadacitinib [5,32], and filgotinib [3,35], with these elevations appearing to be dose-dependent and commonly associated with physical exercise. In vitro studies show that JAK1 activation phosphorylates STAT3, which is involved in muscle activation;

however, there is no significant difference in CK elevation between JAK1-selective inhibitors and non-selective JAKi [31]. Despite the increase in CK levels, most patients remain asymptomatic, though a few may report muscle pain [29,103,104]. Usually, elevation in blood CK is observed after 8 weeks of treatment. For instance, in a pooled safety analysis of baricitinib for AD, with a median follow-up of 310 days, 19.3% of patients on a 2 mg dose and 23.8% of patients on a 4 mg dose experienced elevated CK levels, with most being asymptomatic [29]. This elevation in CK does not generally correlate with a clinical event, and routine CK testing is not recommended in asymptomatic patients treated with JAKi [28]. A few symptomatic patients discontinued treatment. CPK elevation and pain are reversible. No persistent myopathy has been described [103,104].

## 10. Conclusion

When JAKi are considered, it is crucial to assess various risk factors to anticipate their safety profile and minimize the risk of side effects (Table 1). These risk factors include the concurrent use of corticosteroids, lymphopenia (< 500/mm³), age over 65 years, obesity, diabetes, smoking habits, and a history of atherosclerotic CV disease, thromboembolism, or malignancy. The side effects of JAKi can vary depending on the underlying disease and JAKi molecule. As the indications for JAKi in systemic and autoimmune diseases expand, it becomes essential to stratify risks for AEs based on each patient's comorbidities, aiding in treatment decision-making.

Bacterial infection, a common AE associated with JAKi, is often mild to moderate in intensity. Preventive strategies (Table 1) include screening, vaccinations and prophylaxis on an individual basis to mitigate the risk of OI. Patients over 65 years of age, those with CV and malignancy risk factors, and current or former smokers are particularly at risk for malignant tumors, VTE, and MACE. Risk factors must be considered when assessing the benefit-risk balance. Primary and secondary prevention of cardiovascular risk factors is central to follow-up. Finally, it is essential to follow-up the patient's treatment, particularly with a dermatological visit, and to update systematic screening (for breast and colorectal cancer). The latest data are reassuring regarding the risk of digestive perforation. Biological abnormalities such as cytopenia, cytolysis, increases in LDL and HDL levels (without a direct correlation to CV disease risk), and elevated CPK levels (rarely associated with symptoms) have been observed. Importantly, JAKi dosages should be adjusted according to renal function to ensure safe and effective treatment.

<table><caption>**Table 1**
JAKi tolerance.</caption><thead><tr><th></th><th>Clinical features/risk factors</th><th>Recommendations</th></tr></thead><tbody><tr><td>Infection risk</td><td>Bacterial infections: upper respiratory tract infections, urinary and digestive tract infections, cellulitis<br>Most common infectious event (2-4%)<br>Incidence comparable to bDMARDS & TNFi<br><br>Herpes zoster (VZV reactivation):<br>Higher incidence for baricitinib & tofacitinib<br>Higher incidence than observed with bDMARDS & TNFi<br><br>Opportunistic infections related to T-cell deficiency including Pneumocystis related pneumoniae: rare event<br><br>Risk factors:<br>- Associated Corticosteroid dose<br>- Associated other immunosuppressors<br>- Lymphopenia &lt; 500/mm³<br>- High number of prior lines of therapy<br>- Dose-dependant</td><td>Before initiation: HBV, HVC and HIV serology, TB-spot<br><br>Vaccinations:<br>- Herpes zoster vaccine (recombinant, adjuvanted vaccine)<br>- Pneumococcal vaccine - Prevenar 20 (conjugated vaccine, can be administered after JAKi initiation)<br>- HBV vaccine<br>- Influenza vaccine (annually)<br>- COVID-19 vaccine: according to local recommendations<br><br>Prophylaxis: case-by-case (no established recommendation), antiviral and pneumocystis prophylaxis suggested in case of additional risk factor</td></tr></tbody></table>
<table><caption>Table 1 (Suite)</caption><thead><tr><th></th><th>Clinical features/risk factors</th><th>Recommendations</th></tr></thead><tbody><tr><td>Hematologic adverse events</td><td>Lymphopenia<br>Neutropenia<br>Anemia<br>Thrombocytopenia<br><br>Rare: polycythemia and thrombocytosis</td><td>Blood counts at baseline, 4-8 weeks after initiation of therapy and every 6 months:<br>- Consider stop if lymphopenia &lt; 500/mm³ and possibly restarting with lower dosage,<br>- Stop or decrease if neutropenia 500-1000/mm³,<br>- Discontinued continuously if neutropenia &lt; 500/mm³ occurs in the absence of other causes,<br>- Discontinued if anemia &lt; 8 g/dL or loss of 2 hemoglobin points</td></tr><tr><td>Malignant tumors</td><td>Risk of N<br>MSC: warning regarding lung cancer (ORAL Surveillance &amp; WHO pharmacovigilance)</td><td>Before initiation: history of active neoplasia = contraindication to the introduction of a JAKi<br><br>Follow-up: annual dermatological examination</td></tr><tr><td>Major cardiovascular event</td><td>Risk factors: age &gt; 65yo and smoking<br>Risk factors:<br>- History of atherosclerotic cardiovascular disease<br>- Patients over 65 years<br>- Patient in North America<br>- Dose-dependent</td><td>Precaution (EMA/ANSM/PRAC):<br>The use of JAKi is now advised against, unless no therapeutic alternatives are available:<br>- Patients over 65 years<br>- Cardiovascular and malignancy risk factor<br>- Current of former smokers</td></tr><tr><td>Venous thromboembolic risk</td><td>Risk factors:<br>- History of venous thromboembolic events<br>- Age, particularly over 65 years<br>- Selective COX-2 inhibitor/Prednisone equivalent corticosteroids &gt; 7.5 mg/day<br>- Cardiovascular risk factors</td><td>Recurrent thromboembolic events are a contraindication to JAKi introduction unless the patient is on curative anticoagulation</td></tr><tr><td>Lipid abnormalities</td><td>LDL-c and HDL-c elevation (10-20%); total/HDL-c ratio stable: within the first 4 weeks, and stabilized after 3 months</td><td>At baseline and 4-8 weeks after initiation of therapy followed by periodic evaluations every 6 months</td></tr><tr><td>Gastrointestinal perforation</td><td>Tofacitinib ++<br>Risk factors: age, previous diverticulitis or other gastrointestinal conditions, corticosteroid therapy</td><td>While the risk of gastrointestinal perforation with JAKi is very low, the benefit/risk balance must be assessed in patients with a history of intestinal diverticula or diverticulitis</td></tr><tr><td>Hepatobiliary disorders</td><td>Cytolysis 3-5xN<br>Reactivation of hepatotropic virus or autoimmune hepatitis</td><td>At baseline, M1, M3, then every 3 months<br>Contraindication in patients with severe hepatic disease (Child Pugh C). Adjusted dose with moderate hepatic disease (Child Pugh B)<br>At baseline, M1, M3, then every 3 months</td></tr><tr><td>Renal function</td><td></td><td>Dose adjustment:<br>- Tofacitinib: decrease dose to 5 mg × 1 if creatinine clearance &lt; 30 mL/min<br>- Baricitinib: not recommended if creatinine clearance &lt; 30 mL/min; decrease dose to 2 mg × 2 if creatinine clearance 30-60 mL/min<br>- No dosage adjustment for other JAKi</td></tr><tr><td>CK level increase</td><td>CK level increase: dose-dependent<br>Most patients remain asymptomatic, few reports of muscle pain - no correlated with any associated clinical event</td><td>Routine CK testing not recommended</td></tr></tbody></table>

bDMARDS: biological disease-modifying antirheumatic drugs; TNFi: TNF inhibitors; VZV: varicella zoster virus; JAKi: JAK inhibitor; WHO pharmacovigilance: World Health Organization's pharmacovigilance; NMSC: non-melanoma skin cancer; LDL-c: low density lipoprotein cholesterol; HDL-c: high density lipoprotein cholesterol; CK: creatine phosphokinase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; EMA: European Medicines Agency; ANSM: French Agency for the Safety of Medicines and Health Products; PRAC: Pharmacovigilance Risk Assessment Committee.

## 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

Jean-Guillaume Letarouilly: received a research grant from Pfizer and honorarium for lectures from Lilly, Pfizer, Abbvie, and Alfasigma.

The other authors declare that they have no competing interest.

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