InfectionsInfections and JAK Inhibition

The JAK/STAT pathway is involved in immune regulation, thereby modulating defences against infection [118]. Increased risk of infection versus placebo has been reported with JAKis, with the risk of serious infections being comparable to that of biologics in rheumatologic diseases [118]. In common with all JAKis [119,120,121,122], baricitinib has been associated with upper respiratory tract infections, urinary tract infections, herpes zoster [91], and in patients with AD, herpes simplex [99]. Herpes zoster has been the most recognised opportunistic infection associated with JAKis [47], which might be linked to the critical role of interferon (IFN) and also interleukin (IL)-15 [5]. This finding might be of particular concern for patients with SLE, AD or RA, who have an increased baseline risk of herpes zoster relative to the general population [5, 53, 123, 124].

Rheumatoid ArthritisDisease-Specific Risk of Infections in RA

Patients with RA are susceptible to infections (Table 1), particularly bacterial infections, most commonly pulmonary, urinary, skin/soft tissue and joint infections, rather than viral or fungal infections [45,46,47, 83, 84]. This increased infectious risk has been attributed to RA itself, comorbid conditions and immunosuppressive therapies used to treat the disease [45, 46, 83, 118, 125,126,127,128]. Indeed, the risk of infection is increased in those with high RA activity, advanced age and male sex, in smokers and with the use of immunosuppressive treatment [45, 118, 125,126,127].

Risk of Infections in Baricitinib RA Clinical TrialsSerious Infections

In the baricitinib RA integrated safety analysis, serious infections occurred at an IR of 2.58/100 PYE and did not increase with prolonged exposure (ranging from 3.48/100 PYE during weeks 0–48 to 1.57/100 PYE in the period after week 336) or show a dose relationship (2.13/100 PYE vs 2.62/100 PYE with baricitinib 2 mg vs 4 mg) [91]. The most common serious infections occurring in baricitinib-treated patients in the RA integrated analysis included pneumonia (IR 0.6/100 PYE), herpes zoster (IR 0.3/PYE), urinary tract infection (0.2/100 PYE) and cellulitis (0.2/100 PYE) [91]. Infections were more frequent in patients aged 65 years or older than in those aged less than 65 years (IR, 5.5/100 PYE vs 2.1/100 PYE) [91] and slightly more frequent in East Asian patients with RA treated with baricitinib (IR, 4.15/100 PYE) [115] than in the total baricitinib-treated population. The infection-related integrated safety analysis by Winthrop and colleagues [111] (Table 2) revealed that the risk of serious infection with baricitinib was similar to that with placebo (Table 3) and was increased in those with advancing age (≥ 65 years), abnormal body mass index (BMI; < 18 or ≥ 30 kg/m2 vs 18–24 kg/m2) and in those receiving concomitant glucocorticoid therapy [111].

Table 3 Incidence rate (95% confidence interval) of infections in patients treated with baricitinib in the placebo-controlled periods of clinical trials and the All baricitinib data set (integrated safety database results [91, 99, 104, 107]) by disease being treatedHerpes Zoster

Herpes zoster was reported at an IR of 3.0/100 PYR in the baricitinib integrated RA analysis, although cases were generally mild or moderate (94%) in severity and monodermatomal [91, 115], and were most frequent in Asia (IR 5.2/100 PYR) [91]. When specific Asian countries were considered, the IR was 6.49/100 PYR in Japan, 6.43/100 PYR in Taiwan, 6.75/100 PYR in Korea and 1.31/100 PYR in China [115]. In the placebo-controlled periods of baricitinib clinical trials [111], the IR of herpes zoster was higher with baricitinib 4 mg than with placebo (p ≤ 0.01), with the IR with baricitinib 2 mg being between those of these groups (Table 3); importantly, there was no increase in the IR of herpes zoster with prolonged exposure [111]. Advancing age and Asian ethnicity were associated with an increased risk of herpes zoster [111].

Atopic DermatitisDisease-Specific Risk of Infections in AD

It is well established that patients with AD are at increased risk of bacterial, fungal and viral infections, particularly, but not limited to, skin infections (Table 1) [33, 51,52,53,54, 129]. The risk of serious infection and Staphylococcus aureus, herpes simplex, including eczema herpeticum (EH), and varicella zoster virus infections are all increased in patients with AD, particularly those with severe AD [52, 53, 130, 131]. Accordingly, the tendency to S. aureus or herpes simplex cutaneous infections was included as minor diagnostic criteria for AD more than 40 years ago [132]. Similarly, patients with AD are more likely to develop extracutaneous infections, including ear infection, streptococcal pharyngitis and urinary tract infection [133], with some studies also showing increased rates of influenza/pneumonia or gastroenteritis [134].

The increased susceptibility to infections in AD might be linked to the defective skin barrier, alterations in bacterial colonisation and lower antimicrobial peptide expression, as well as to inherent immune dysregulation [33, 51, 54, 129, 131]. Serious infections are associated with increasing age and comorbid diabetes mellitus or obesity in patients with AD and are decreased in those of female sex [54].

Risk of Infections in Baricitinib AD Clinical TrialsSerious Infections

In the baricitinib AD integrated analysis of safety data, the IR of serious infection with baricitinib was comparable to that of placebo in the 16-week placebo-controlled period of the trials (Table 3) [99]. Overall, serious infections had an IR of 2.1/100 PYR in patients with AD treated with baricitinib irrespective of dose; the IR was 1.5/100 PYR with baricitinib 2 mg and 3.0/100 PYR with baricitinib 4 mg in the extended data set [99]. The most common serious infections reported with baricitinib in patients with AD were EH (IR, 0.5/100 PYR), cellulitis (0.3/100 PYR) and pneumonia (0.1/100 PYR).

Herpes Zoster

Herpes zoster was reported more frequently with baricitinib 2 mg than placebo and was not reported in the baricitinib 4 mg group during the placebo-controlled periods of AD clinical trials (Table 3). When extended exposure was considered, the number of herpes zoster events remained higher with baricitinib 2 mg (3.8/100 PYR) versus 4 mg (1.8/100 PYR) in the extended data set [99]. The IR of herpes zoster overall was 2.3/100 PYR, with no cases of serious herpes zoster [99].

Herpes Simplex

Herpes simplex infections occurred more frequently with baricitinib 4 mg than with baricitinib 2 mg or placebo in the placebo-controlled phase of clinical trials (Table 3) [99]. IRs decreased with extended exposure, with an IR of 10. 3/100 PYR reported overall (Table 3). Most cases of treatment-emergent herpes simplex infections were rated by investigators as mild or moderate in severity (93%) and were most commonly oral herpes (IR 4.9/100 PYR), unspecified herpes simplex (4.0/100 PYR) and EH (including the preferred terms EH and Kaposi’s varicelliform eruption; 1.9/100 PYR). Of note, EH events were linked to poor disease control prior to the event in the majority of patients, supporting the notion that EH is linked to more severe AD [99].

Skin Infections Requiring Antibiotic Treatment

Skin infections requiring antibiotic treatment were reported with similar frequency in patients treated with baricitinib 2 mg (4.8%) or placebo (4.4%), but with lower frequency in patients treated with baricitinib 4 mg (3.4%) versus placebo, which might be linked to improved skin barrier integrity or improvement of the skin microbiome with baricitinib treatment [99].

Alopecia AreataDisease-Specific Risk of Infections in AA

It has been postulated that several infections, such as Helicobacter pylori, Cytomegalovirus, Epstein–Barr virus, hepatitis B virus, hepatitis C virus and human immunodeficiency virus, may act as triggers for AA [55]. Patients with AA may therefore have an increased prevalence of these bacterial and viral infections (Table 1). However, it is also possible that the genetic predisposition for AA is caused by genetic factors that confer protection against common infections [55].

Risk of Infections in Baricitinib AA Clinical TrialsSerious Infections

During the placebo-controlled periods, serious infections occurred with a similar IR in patients treated with placebo, baricitinib 2 mg and baricitinib 4 mg (Table 3), with few patients experiencing these events (none, two and one, respectively); the overall IR for baricitinib was 0.6/100 PYR [104].

Herpes Zoster

Herpes zoster occurred infrequently and showed no baricitinib dose dependency (Table 3); the overall IR for baricitinib was 1.4/100 PYR [104].

Herpes Simplex

The occurrence of herpes simplex infections was comparable in patients treated with baricitinib and placebo (Table 3), with an overall IR for baricitinib of 2.5/100 PYR [104].

Systemic Lupus ErythematosusDisease-Specific Risk of Infections in SLE

Risk of infection is significantly increased in patients with SLE (Table 1) compared with the general population or healthy controls [56]. The risk of infection is not affected by gender or disease duration but is increased by glucocorticoid treatment. This increased risk may result from impaired immune function, comorbidities common in patients with SLE and the use of glucocorticoids and immunosuppressive drugs [135] and translates into infection being one of the leading causes of morbidity and mortality in patients with SLE [136].

Risk of Infections in Baricitinib SLE Clinical TrialsSerious Infections

In the pooled analysis of data from clinical trials of baricitinib in SLE, the IRs for serious infections showed a dose-relationship (Table 3), with an overall IR for baricitinib of 5.2/100 PYR [107].

Herpes Zoster

The IRs of herpes zoster were similar for placebo and baricitinib 2 mg but increased with baricitinib 4 mg (Table 3), with an overall IR for baricitinib of 4.8/100 PYR [107].

Other Autoimmune Disease

Clinical trials evaluating a range of doses of baricitinib in relatively small groups of patients with moderate-to-severe psoriasis [16], DKD [17] and autoimmune interferonopathies [12] (Table 2) revealed no new safety concerns with respect to infection risk.

COVID-19

Patients with SARS-CoV-2 infection can develop an intense hyperinflammatory state with cytokine storm, leading to multiple organ dysfunction and death. Baricitinib has anti-cytokine effects and inhibits host cell viral propagation, making it a useful treatment for severe COVID-19 [9].

Risk of Infections in Baricitinib COVID-19 Clinical TrialsSerious Infections

In 1502 hospitalised patients with severe COVID-19 infection and multiple comorbidities (33% were obese, 30% had diabetes mellitus, almost half had hypertension and almost 90% required some form of supplemental oxygen at study entry; Table 2), the risk of non-COVID-19 serious infections was comparable for patients who received baricitinib 4 mg (8.5%) and those who received placebo (9.8%) in addition to standard of care (including systemic glucocorticoids and, in some instances, remdesivir). Of note, 91% and 85% of patients who had a serious infection during baricitinib therapy or whilst receiving placebo, respectively, were also receiving glucocorticoids [108]. In 99 patients with more severe COVID-19 infection (using IMV or ECMO at baseline) and a similar prevalence of comorbidities (Table