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17th August 2023
JAK inhibitors are known to increase the risk of major adverse cardiovascular events when used in rheumatoid arthritis, but does this elevated risk also apply when this class of drugs is used in atopic eczema? Clinical writer Rod Tucker investigates.
Since the 1990s, the treatment of severe rheumatoid arthritis (RA) has centred on biologics such as tumour necrosis factor (TNF) inhibitors. However, a better understanding of cell signalling pathways and, in particular, intracellular signal transduction, led to the development of alternative therapies, one of which being oral Janus kinase (JAK) inhibitors. Several of these have been approved for use in RA since 2011.
What’s more, as JAK inhibitors disrupt intracellular signalling through a variety of cytokine and haematopoietic growth factor receptors, this mode of action suggests the drug class may have a much wider role in a number of immune-mediated inflammatory diseases. As such, approvals for JAK inhibitors in Crohn‘s disease, psoriasis and atopic eczema have been seen in recent years.
Despite their apparent effectiveness in RA, a recent post-marketing study has raised safety concerns over JAK inhibitors compared to TNF inhibitors. The Oral Rheumatoid Arthritis Trial (ORAL) was a randomised, post-authorisation, non-inferiority trial designed to evaluate the safety and efficacy of the JAK inhibitor tofacitinib compared to a TNF inhibitor such as etanercept or adalimumab. It focused on patients with RA who were aged 50 or older and had at least one additional cardiovascular risk factor.
The findings were somewhat disturbing. JAK inhibitor use led to a significantly higher incidence of both major adverse cardiovascular events (MACE) and cancers compared to a TNF inhibitor, even though the efficacies were broadly similar.
The ORAL trial served to highlight how JAK inhibitors may increase the risk of MACE when used in patients with RA who are already at an elevated risk due to their condition. Indeed, a meta-analysis of 24 studies with over 111,000 RA patients estimated a 50% higher risk of cardiovascular mortality.
So, with three JAK inhibitors (upadacitinib, baricitinib and abrocitinib) approved for atopic eczema, and representing an important and promising development for its treatment, should dermatologists be concerned over the risk of MACE when using this class of drugs?
Before considering whether JAK inhibitors might increase the risk of adverse cardiovascular sequelae in those with atopic eczema, its worth exploring whether atopic eczema, itself an inflammatory condition, is linked to a higher risk of MACE. After all, such a risk is theoretically possible, given the emerging evidence of the pivotal role of inflammation in the development and progression of both cardiac and vascular diseases.
The current evidence of an association between atopic eczema and MACE is equivocal. Some work, for instance, clearly demonstrates that atopic eczema is associated with increased risk of myocardial infarction compared to the general population. In contrast, another study found no such independent association in women.
Nevertheless, pooling data from several studies does suggest a positive relationship. For example, a 2018 meta-analysis of 15 studies, which included over 3.5 million participants, did show that atopic eczema was independently associated with an increased risk of stroke and myocardial infarction, especially in male subjects and those with more severe disease.
In addition, a recent Danish study, looked at what happened to patients over time following a diagnosis of atopic eczema. It included over 40,000 atopic eczema patients and an equal number of matched controls and found that adults were at a significantly higher risk of experiencing a subsequent cardiovascular disease.
Finally, a UK prospective study including 387,439 patients with atopic eczema followed for over five years, concluded that severe active atopic eczema was associated with an increased risk of cardiovascular outcomes.
While prospective studies are subject to confounding, Mendelian randomisation studies, are able to provide an estimate causality without the influence of confounders. One such study showed that asthma and atopic eczema were causal risk factors for heart failure and suggested that the underlying inflammatory nature of both diseases was a major contributory factor.
As ever, things are never that straightforward. In a recent bidirectional Mendelian randomisation study, it was found that there was no robust association between cardiovascular disease and atopic eczema.
In trying to establish if there was a higher risk of MACE in patients with atopic eczema prescribed a JAK inhibitor, researchers recently undertook a systematic review and meta-analysis. The findings were published in July 2023 in the British Journal of Dermatology and included phase 2b or 3 randomised controlled trials and controlled cohort studies.
The primary outcome was the occurrence of MACE, which the researchers defined as a composite of acute coronary syndrome (ACS), ischaemic stroke and CV death.
A total of 23 studies were included in the analysis. Very few cases of MACE were found, leading the researchers to suggest that JAK inhibitors may have little-to-no effect on the occurrence of MACE in patients with atopic eczema compared to placebo. However, they did add the caveat that the evidence was uncertain.
In addition, MACE generally occurred in patients at a high cardiovascular risk and not in the younger, healthy patients typically seen in routine clinical practice.
Further and reassuring evidence of the absence of a possible association with MACE comes from real-world studies on the use of JAK inhibitors in atopic eczema. There have been at least four such studies, none of which have identified any cases of MACE, even though some have been conducted in patients with more severe disease.
Although patients with atopic eczema may have a higher risk of MACE, this is more likely to occur either in those with severe disease or for patients at a greater risk of cardiovascular disease. Over time, pharmacovigilance data will no doubt shed further light on the level of risk associated with JAK inhibitors.
For now, the European Medicines Agency (EMA) issued advice in January 2023 on the use of JAK inhibitors in all chronic inflammatory disorders, including atopic eczema. This recommended avoiding against the use of a JAK inhibitor in those aged 65 years or above, in patients at an increased risk of major cardiovascular problems, smokers and individuals at a higher risk of cancer, unless there are no suitable alternatives.
For most patients with atopic eczema, JAK inhibitors represent a potentially game-changing addition to a dermatologist’s armamentarium for their treatment. Provided that clinicians heed the current safety guidance, those prescribed a JAK inhibitor for atopic eczema have much to gain but without the attendant risk of MACE.
28th June 2021
It has become increasing clear that severe manifestations of COVID-19 are largely driven by an exaggerated immune response by interleukin-6, tumour necrosis factor and other cytokines and which has been described as a cytokine storm. Tofacitinib is an oral Janus kinase inhibitor which blocks signal transduction once a cytokine has attached to its cell surface receptor, hence attenuating the cellular response. Furthermore, tofacitinib suppresses the production of both interleukin-17 and interferon-gamma which are implicated in the pathogenesis of acute respiratory distress syndrome, a common complication from infection with COVID-19. Thus, tofacitinib has the potential to act on more than one pathway to help ameliorate the damage that occurs in those infected with COVID-19. Based on these likely benefits, a team from the Hospital Israelita, Albert Einstein, Sao Paulo, Brazil, undertook a randomised, double-blind, placebo, controlled trial, to investigate the safety and efficacy of tofacitinib in patients hospitalised with COVID-19 pneumonia and who were not in receipt of either non-invasive or invasive ventilation. Patients were 18 years and over and a positive PCR test for COVID-19 and who had radiographic evidence of pneumonia and randomised (1:1) to tofacitinib or placebo. Tofacitinib was given as an oral dose of 10mg twice daily for up to 14 days or until hospital discharge. All participants received standard care and which included the use of glucocorticosteroids, antibiotics, anticoagulants and antiviral agents although concomitant use of other JAK inhibitors or interleukin-6 inhibitors were not permitted. All patients were assessed daily up to day 28 while in hospital. The primary outcome was death or respiratory failure during the 28-day follow-up period and a secondary outcome was the cumulative incidence of death through any cause up to day 28.
A total of 289 patients with a mean age of 56 years (34.9% female) were included and randomised to tofacitinib (144) or matching placebo (145). Furthermore, a third (34.9%) of patients were aged 65 years and over and the majority (83.4%) of White ethnicity. The most common co-morbidity was hypertension (50.2%) followed by diabetes (23.5%) and dyslipidaemia (17.3%) and the median body mass index was 29.7. Death or respiratory failure (the primary outcome) occurred in 18.1% of those receiving tofacitinib and in 29% of those assigned to placebo (risk ratio, RR = 0.63, 95% CI 0.41–0.97, P = 0.04). In addition, death due to any cause (a secondary outcome) occurred in 2.8% of the tofacitinib group and 5.5% of the placebo group although this difference was not statistically significant.
Discussing their findings, the authors commented how the beneficial effects of tofacitinib appeared to be independent of age, gender or use of standard care therapy such as corticosteroids. They proposed that the data in the current study suggested an added benefit from the use of JAK inhibitors in patients with COVID-19-related pneumonia.
Guimaraes PO et al. Tofacitinib in Patients Hospitalised with Covid-19 Pneumonia. N Eng J Med 2021