Tuberculosis with tofacitinib: Analysis of adverse drug reaction reporting trends in the World Health Organisation global drug safety database

INTRODUCTION

Janus Kinase (JAK) inhibitors have revolutionised the landscape for the treatment of autoimmune disorders over the past decade. While ruxolitinib was the first JAK inhibitor to receive approval in November 2011 for myelofibrosis, polycythemia vera and steroid-resistant Graft-versus-Host Disease, a multitude of biologic drugs with a similar mechanism of action have since been approved and marketed for various arthritic disorders.^[1]

Tofacitinib, approved by the United States Food and Drug Administration (US-FDA) in 2012 and the Central Drugs Standard Control Organisation (CDSCO) in 2016, is a first-generation JAK inhibitor marketed across the globe for moderate to severe cases of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis.^[2] Tofacitinib is a small-molecule oral JAK inhibitor, indicated in suboptimal responders or those intolerant to other biologics.^[2] It has various off-label uses as well.

A preferential inhibitor of JAK3 and JAK1, Tofacitinib, downregulates several cytokines to modulate the immune responses in autoimmune conditions. Real-world data have proven its efficacy in patients who were previously treated with other biologics.

With the increasing use of tofacitinib, several cases of bacterial, invasive fungal and viral have been reported. Amongst these, tuberculosis (TB) was reported as a serious adverse drug reaction (ADR) of tofacitinib.^[3] USFDA recommended testing for latent TB before therapy initiation.

There is a paucity of studies analysing the reporting trends of TB with tofacitinib use, hence this study was undertaken.

MATERIALS AND METHODS

RESULTS

A total of 234 ICSR with TB (both primary and reactivated) as adverse reactions were noted worldwide, and only four were from India. Table 1 depicts the patients profile. Almost 78% of these reports were contributed by the United States of America, while only 7% of the reports were from Asian nations. Table 1 depicts the patients profile.

About 45.3% of the patients belonged to the age group of 45–64 years, 22.2% in the 65–74 years age group. Female preponderance (67.9%) was noted. These reports originated from physicians, pharmacists, other health professionals, as well as consumers of the medicine. About 68% of the reporters were healthcare professionals.

Almost half of the reported ICSRs date back to 2018 (17.9%) and 2019 (27.4%), with only 17 reports each in 2023 and 2024. Since the turn of the decade, TB reports with tofacitinib has declined, probably due to an increased emphasis on screening for latent infections before therapy and monitoring for opportunistic infections in those receiving therapy.

Rheumatoid arthritis was the most commonly reported indication for tofacitinib use. Table 2 depicts the drug details. However, the distinct lack of completeness in ADR reporting makes it difficult to analyse whether off-label uses outweigh the labelled use in most countries.

The most common co-administered drug was methotrexate (11.5%), followed by prednisolone (4.7%). Etanercept and adalimumab were identified as suspect or interacting active ingredients in six and five cases, respectively. The median daily dose of tofacitinib was 11 mg, while the median time to onset was 30 weeks (although the range varied from as low as 15 days to as high as 8 years).

There were 228 serious cases with four fatalities. In addition, two of these experienced life-threatening situation, and 22 required initial or prolonged hospitalisation. Globally, cases have been reported from 19 different countries. Table 3 shows the global viewpoints. Tofacitinib was the sole suspect drug in a 92.7%, ICSRs, (217 cases). The drug was withdrawn in 95 patients, in 63 cases, there was no dosage change, 11 cases were dechallenge positive.

From an Indian perspective, only four cases have been reported in the past 10 years, the first report dates back to June 2021. This involved a 79-year-old male who took tofacitinib for a period of 8 years from March 2013 to February 2021. The dosage regimen, the indication, as well as the outcome remain unknown, but the drug was withdrawn. As per the ICSR, this was a case of TB disease recurrence.

The second report in November 2023 is that of a 65-year-old female, who was prescribed a 5mg daily dose of tofacitinib for rheumatoid arthritis. The drug was withdrawn. The median time to onset was unavailable, but the patient was recovering at the time of initial reporting to the VigiBase.

The two latest reports in June 2024 were from the younger population, both 35-year-old males who were prescribed tofacitinib for seronegative rheumatoid arthritis. Dechallenge information was unavailable, but both patients were recovering at the time of reporting.

Worldwide, the IC value was 2.3 and IC₀₂₅ was 2.2, indicating that it could be considered statistically as a ‘signal’.

The lower limit of the credibility interval for both PRR and ROR was 4.6. Table 4 shows the results of disproportionality analysis.

Figure 1 depicts the yearly trend of the IC value over the search duration.

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Figure 1:

Yearly trend of the information component value. Measure of X axis: Years.

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The yearly trend of the IC value for the search duration suggests that the criterion for signal detection was not fulfilled in the initial years of 2014, 2015 and 2016. However, with the rapid rise of Tofacitinib usage, the IC value has ranged between 2.3 and 2.5 in the past 6 years.

DISCUSSION

As per WHO UMC criteria, a safety “signal” was generated between TB and tofacitinib.^[9] A devastating disease in all aspects, the burden of TB depends not only on the active cases but also on those harbouring latent infection.

A higher risk of opportunistic infections has been traditionally noted in patients with autoimmune disorders, mostly due to their therapies.^[10] Studies have shown that in the case of anti-tumour necrosis factor therapies, organisms causing granulomatous inflammation are mainly implicated.^[11] A similar trend has been observed with tofacitinib.

A 2012 study conducted at USA concluded that tofacitinib administration led to increased bacterial replication in a mouse model of chronic paucibacillary TB, suggesting the drug had the propensity to reactivate latent TB infections in humans.^[12]

According to a case report published in 2023 a 54-year-old rheumatoid arthritis patient from Uttar Pradesh, India, developed reactivation of latent TB following 6 weeks of tofacitinib therapy.^[3]

A synthetic disease-modifying agent, tofacitinib, is a specific and selective inhibitor of pro-inflammatory receptor signalling mechanisms.^[13] Certain cytokines are implicated in the pathogenesis of varied autoimmune diseases, which utilise the JAK/STAT pathway for their effects, making them a suitable target for JAK inhibitors.^[14] Critical for immunoregulation, genetic polymorphisms of type I cytokine receptors confer susceptibility towards psoriasis, rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel disease.^[15]

Tofacitinib mechanistically inhibits the activity of JAK1 and JAK3 and, to a small extent, JAK2 and Tyrosine kinase 2 (TYK2). As a result, γc cytokines such as interleukin (IL)-4, IL-7, IL-2, IL-9, IL-15 and IL-21, which are mediated through JAK3, are blocked by tofacitinib.^[13] In addition, inhibition of JAK1 blocks gp130 family cytokines such as IL-11 and IL-6, as well as type II cytokine receptor family, which includes IL-10, interferon (IFN)-α/β and IFN-γ.

Inhibition of JAK2 results in blockade of βc family of cytokines such as granulocyte-macrophage colony-stimulating factor, erythropoietin, IFN-γ, IL-3 and IL-5. It also interferes with pathogenic Th17 cells generation that is dependent on IL-23, and Th1 cells differentiation, which produce IFN-γ. Inhibition of intracellular signalling of IL-12, IFN-γ and similar other cytokines, which play a crucial role in the development of pathogen-specific memory T cells, contributes to the augmented risk of TB and other invasive infections in patients receiving tofacitinib.^[16]

Genetic predisposition to serious TB infections has been previously documented in individuals with Mendelian susceptibility to mycobacterial diseases due to germline mutations in seven autosomal and two X-linked genes, including those encoding IL-12, IFN-γ and STAT1 pathways.^[17] Tofacitinib’s suppression of both innate and active immune response, hence, is responsible for the development of TB-a fact which could have disastrous consequences on the public health of countries like India, which have a very high prevalence of TB.^[18]

A three-pronged approach is necessary to tackle this growing concern. The patients must be made aware of the possible infectious complications of tofacitinib therapy and the signs and symptoms that they should look out for, to ensure early reporting of any such events. More importantly, the onus lies on the treating physician to screen for latent TB before tofacitinib administration and stringent supervision of the patient’s clinical status post-therapy initiation. Although mandated by the US-FDA, screening for latent TB is not a routine practice in India, which, along with inadequate follow-up, plays a significant role in under-reporting of TB as an adverse reaction.

Finally, regulatory authorities must ensure that the marketing authorisation holders mention TB as an opportunistic infection on their packaging label. Strengthening the post-marketing surveillance system is the need of the hour in our country. Risk benefit analysis and risk minimisation strategies must be adopted.

This was the first study to systematically evaluate worldwide reporting trends of TB with tofacitinib. However, reporting patterns from various countries were not uniform, and the quality of reports were highly variable. In most ICSRs, distinctions were not made between pulmonary and extra-pulmonary TB. The fact that a statistical signal does not necessarily implicate causation is the other limitation of the study.

CONCLUSION

This study highlights the importance of screening and close monitoring of patients on tofacitinib to ensure the early detection of TB. It also re-emphasises the need for routine screening for TB before initiating therapy especially in countries like India where the prevalence of TB is high.

Health care providers should be encouraged to report such serious adverse events. Additional evidence is necessary to compare the risk of tofacitinib with that of other biologics and immunosuppressive agents in development of opportunistic infections in different population groups.