Risk of hepatitis B reactivation in rheumatologic patients treated with Janus kinase inhibitors

Authors

Abstract

Aim Hepatitis B virus (HBV) is a major public health problem that infects people worldwide. Janus kinase (JAK) inhibitors, while effective in the treatment of rheumatologic diseases, carry a potential risk of HBV reactivation. This study aimed to evaluate the risk of HBV reactivation and the effect of antiviral prophylaxis in rheumatologic patients treated with JAK inhibitors.
Materials and Methods Fifty patients who were initiated on JAK inhibitors (tofacitinib, upadacitinib, baricitinib) in the rheumatology clinic between January 2020 and February 2025 and followed for at least 6 months were retrospectively evaluated. All patients underwent HBsAg, anti-HBc IgG, and anti-HBs testing before treatment. HBV reactivation was defined as HBV DNA positivity or seroconversion in an HBsAg-negative patient, or a ≥ 10-fold increase in HBV DNA in an HBsAg-positive patient.
Results 78% of the patients were female, and the mean age was 54.5 ± 12.4 years. The most common diagnosis was rheumatoid arthritis (80%). One patient (2%) was HBsAg positive, and 19 (38%) had anti-HBc IgG positivity. Antiviral prophylaxis was initiated in 12 patients (24%); 9 of these patients were HBsAg negative/anti-HBc positive. The agents used were entecavir (n = 6), tenofovir disoproxil (n = 4), and tenofovir alafenamide (n = 2). During a mean follow-up of 29.4 ± 20.3 months, no patient developed HBV reactivation.
Discussion JAK inhibitor therapy appears to be safe in rheumatological patients who receive appropriate prophylaxis after HBV serological screening. Regular monitoring of at-risk patients is effective in preventing HBV reactivation.

Keywords

Introduction

Janus kinase (JAK) inhibitors are increasingly used in the treatment of inflammatory rheumatic diseases, particularly rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA). These agents suppress cytokine signaling by targeting the JAK/signal transducer and activator of transcription proteins (STAT) pathways, thereby controlling inflammation. However, this immunosuppressive effect poses potential risks, particularly regarding the reactivation of latent infections such as hepatitis B virus (HBV) and tuberculosis [1]. HBV is a major public health problem, infecting approximately 296 million people worldwide. Although the virus can remain inactive in chronic carrier states, immunosuppression carries a risk of HBV reactivation [2]. HBV reactivation under rituximab and anti-tumor necrosis factor alpha (TNF) therapy is well documented, with the risk of reactivation reaching up to 8–10%, particularly with rituximab, in HBsAg-negative/anti-HBc- positive patients [3, 4, 5]. In contrast, HBV reactivation associated with JAK inhibitors has been rarely reported, and available data are limited and based mostly on pharmacovigilance reports [6, 7].
Current data suggest that the risk of HBV reactivation in patients treated with JAK inhibitors varies depending on the type of drug used and the patient’s serologic status. One study reported a 14.3% HBV reactivation rate after tofacitinib treatment in HBsAg-negative/anti-HBc-positive patients. A retrospective study using the FAERS database found 41 cases of HBV reactivation associated with JAK inhibitors, with the highest reporting rate for baricitinib [6, 8]. Another study demonstrated that the reactivation rate can be as high as 14.4% in HBsAg-positive patients, while it was below 5.1% in patients with only anti-HBc positivity [9]. These findings emphasize the importance of HBV serologic assessment before treatment planning and the necessity of antiviral prophylaxis. Therefore, studies evaluating real-world data continue to be needed.
The aim of this study was to evaluate the risk of HBV reactivation in inflammatory rheumatic patients receiving JAK inhibitor therapy and to assess the effect of antiviral prophylaxis applications.

Materials and Methods

Study Design This retrospective, single-center study was conducted in the Department of Rheumatology at Recep Tayyip Erdogan University Faculty of Medicine. Medical records of patients diagnosed with inflammatory rheumatic diseases—rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS)—based on the classification criteria of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), who initiated JAK inhibitor therapy (tofacitinib, upadacitinib, or baricitinib) between January 2020 and February 2025, were retrospectively reviewed. Data were retrieved from the hospital’s electronic medical record system and archived paper files. The analysis included patient diagnoses, demographic characteristics, initiation and duration of JAK inhibitor treatment, HBV serology results before and after therapy, clinical follow-up findings, and relevant laboratory parameters.
Patient Selection – Inclusion Criteria • Patients who have received treatment with a Janus kinase (JAK) inhibitor—specifically tofacitinib, upadacitinib, or baricitinib— for a minimum duration of three months.
• Documentation of a complete hepatitis B virus (HBV) serological screening (including HBsAg, anti-HBc IgG, and anti- HBs) prior to initiation of JAK inhibitor therapy.
• A history of consistent clinical follow-up for at least six months.
• Age of 18 years or older at the time of enrollment.
Exclusion Criteria • Individuals lacking complete hepatitis B virus (HBV) serological results.
• Patients with a prior history of HBV reactivation associated with the use of other immunosuppressive therapies (such as rituximab or chemotherapy).
• Individuals younger than 18 years of age.
• Patients with a confirmed diagnosis of any malignancy.
• Those whose duration of JAK inhibitor therapy was shorter than three months.
• Patients with inadequate clinical data or insufficient follow-up for study evaluation.
Data Collection Demographic data (age, gender), clinical diagnosis (RA, AS, psoriatic arthritis (PsA)), concomitant diseases (hypertension, diabetes, coronary artery disease, chronic obstructive pulmonary disease), type of JAK inhibitor used (tofacitinib, upadacitinib or baricitinib), treatment duration (time between the first prescription date and the last dose date), HBV serological profile (HBsAg, Anti-HBc IgG, Anti-HBs), antiviral treatment status and presence of HBV reactivation during follow-up were recorded.
Serological markers associated with hepatitis B infection— namely HBsAg, anti-HBs, and anti-HBc—were evaluated using an electrochemiluminescence immunoassay on the Cobas e6001 analyzer (Roche Diagnostics, Mannheim, Germany). Quantitative analysis of HBV DNA in serum samples was performed using real-time polymerase chain reaction (PCR) on the Rotor-Gene Q platform (QIAGEN, Hilden, Germany), with a detection limit of 12 IU/mL. Standard biochemical parameters were measured using the Cobas 8000 modular analyzer (Roche Diagnostics, Germany).
Definitions of HBV Infection Status and Reactivation Risk • HBV Screening: Testing for HBsAg and/or anti-HBc within six months prior to the initiation of treatment.
• Chronic Hepatitis B Infection: Defined by the presence of a positive HBsAg result.
• Resolved (Past) HBV Infection: Characterized by a negative HBsAg and a positive anti-HBc IgG result.
• HBV Reactivation (HBVr):
-Detection of HBV DNA in a previously HBsAg-negative individual or a shift from negative to positive HBsAg status (seroconversion),
-A ≥ 10-fold rise in HBV DNA levels compared to baseline in
patients who are HBsAg-positive,
-HBV-related hepatitis is identified when HBV DNA levels increase concurrently with at least a threefold elevation in serum ALT levels (upper limit of normal: 45 U/L).
Prophylactic Antiviral Therapy: In patients with evidence of past HBV infection (anti-HBc IgG positivity), prophylaxis with entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide was initiated concurrently with JAK inhibitor therapy [10, 11].
Statistical Analysis SPSS for Windows version 22 was used for statistical analysis. Continuous variables were assessed for normal distribution using histograms, Q-Q plots, and Shapiro-Wilk or Kolmogorov- Smirnov tests, depending on the number of variables. Continuous variables with normal distribution were presented as mean ± standard deviation throughout the study, and the independent variables t-test was used to compare two groups. Tests with a p value of 0.05 or less at the 95 percent confidence interval were considered statistically significant.
Ethical Approval This study was approved by the Ethics Committee of Recep Tayyip Erdogan University, Faculty of Medicine (Date: 2025-04- 24, No: 2025/176).

Results

Fifty patients were included in the study. 78% were female, and the mean age was 54.54 ± 12.46 years. The mean age of women was higher than that of men (p = 0.027). The most common cause of rheumatoid arthritis (RA) was JAK inhibitor therapy (80%). 70% of patients were receiving tofacitinip, 18% were receiving updacitinip, and 12% were receiving barcitinip. The mean follow-up was 29.4 ± 20.3 months, and the most common comorbidities were hypertension (46%) and diabetes mellitus (6%) (Table 1).
Before treatment, all patients were asked for Hbs Ag, anti-Hbc Ig G, and anti-HBs tests. Of the 50 patients, 1 (2%) was Hbs Ag positive, and 19 (38%) were anti-Hbc Ig G positive. Twelve (24%) of the patients were started on antiviral therapy, 6 on entecavir 4 on tenofovir disoproxil, and 2 on tenofovir alafenamide. Nine of those treated were Hbs Ag negative, anti-Hbc Ig G positive, and 1 was Hbs Ag positive. No hepatitis B reactivation occurred during treatment.

Discussion

In this study, no HBV reactivation was observed in rheumatological patients treated with Janus kinase inhibitors. The absence of reactivation, particularly in the anti-HBc-positive/HBsAg- negative group, demonstrates the effectiveness of appropriate antiviral prophylaxis and close monitoring strategies. This supports the systematic prevention of potential risks beyond those reported in the literature for baricitinib and tofacitinib [12].
On the other hand, a retrospective study from Taiwan reported a 33% reactivation rate after tofacitinib in HBsAg-positive RA patients not receiving antiviral prophylaxis, compared with 3.1% in anti-HBc-positive patients [13]. Similarly, in a comprehensive analysis of baricitinib clinical trials, HBV DNA became detectable in 14.9% of patients in the HBsAg-negative/ anti-HBc-positive group, while only 1.9% met reactivation criteria but did not develop clinical hepatitis [14, 15]. These data suggest that antiviral prophylaxis transforms the treatment course and dramatically reduces the likelihood of reactivation. In contrast, HBsAg-positive patients without prophylaxis are at high risk. Therefore, the evidence for both HBV serology screening and, when necessary, antiviral initiation while using JAK inhibitors is growing.
HBV reactivation can occur for many reasons. Immune suppression disrupts the latency of the hepatitis B virus and promotes viral replication. Cancer chemotherapy, immunosuppressive therapy after organ transplantation, corticosteroids, or biologic agents (especially B-cell-targeted rituximab) are the most important risk factors for HBV reactivation [16, 17]. Another study found that HBV is permanently stored in liver cells in the form of “covalently closed circular DNA,” cccDNA, and when the immune system is suppressed, this viral reservoir can be activated and replicate. Therefore, the risk of viral reactivation persists even in HBsAg-negative, anti-HBc-positive patients [18]. Furthermore, the rapid recovery of the immune system after withdrawal of immunosuppression generates an excessive inflammatory response to HBV infection and can lead to reactivation. Both viral load and liver enzymes can increase during this period [19]. Similar to the literature, studies have shown that JAK inhibitors (tofacitinib, upadacitinib, or baricitinib) also induce immunosuppression by suppressing pathways affecting T and B cell activation. This may pose a risk for HBV reactivation [20, 21]. However, in this study, no reactivation was detected during approximately 29.4 ± 20.3 months of follow-up. This demonstrates the importance of both effective antiviral prophylaxis and careful patient monitoring.
In this study, only 12 of 19 anti-HBc-positive rheumatic fever patients were started on antiviral prophylaxis. The absence of reactivation in the 7 patients who did not receive prophylaxis suggests that this patient group may be at low risk. However, due to the lack of regular HBV DNA monitoring, the possibility of silent reactivation should not be ignored. Similarly, in the literature, Perrillo et al. noted that the risk of reactivation varies in anti-HBc-positive/HBsAg-negative patients under immunosuppressive therapy, but they stated that antiviral prophylaxis is a safe approach [22].
In our study, a single HBsAg-positive rheumatoid arthritis patient received antiviral prophylaxis, and reactivation did not occur. While this finding highlights the strong protective effect of prophylaxis in HBsAg-positive patients, generalizations are limited because it is based on a single case. A previous study reported reactivation rates reaching 20-30% in HBsAg-positive patients who did not receive prophylaxis [23]. Therefore, antiviral therapy should be initiated in HBsAg-positive patients before initiating JAK inhibitor therapy.

Limitations

Among the study’s limitations is the limited number of patients (n = 50) included in this retrospective, single-center study without a parallel control group. Therefore, the absence of reactivation observed cannot be causally attributed solely to JAK inhibitor exposure. The limited sample size reduces statistical power, and the single-center design may limit the generalizability of the findings. However, the study is valuable because it reflects real-world data. Larger, prospective, multicenter studies with matched controls are needed to confirm these findings.

Conclusion

In this study, no HBV reactivation was observed in rheumatological patients treated with JAK inhibitors who received regular follow- up and appropriate antiviral prophylaxis. The findings support the possibility of safe treatment with careful monitoring in anti-HBc-positive/HBsAg-negative patients. However, due to the limited number of patients and the retrospective design, the results cannot be generalized; larger, prospective studies are needed.

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