JAK Inhibitors: Updated Safety Signals, Patient Selection and Post-ORAL Surveillance

CLINICALIQ DRUG CLASS EXPLAINERS
Episode 03: JAK Inhibitors
Host: Sarah Mitchell | Expert: Dr Anzal Qurbain, Pharmaceutical Physician
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[HOST] Hello and welcome back to ClinicaliQ Drug Class Explainers. Sarah Mitchell here, with Dr Anzal Qurbain, pharmaceutical physician. Today we're looking at JAK inhibitors — a newer class of oral drugs that have quietly become major players across rheumatology, dermatology, and gastroenterology. Anzal, set the scene for us — what is a JAK inhibitor actually doing?

[EXPERT] JAK stands for Janus kinase. There are four of them in the body — JAK1, JAK2, JAK3, and TYK2. They're enzymes that sit just inside the cell membrane, and their job is to pass signals from the cell surface into the nucleus. Specifically, they're part of what's called the JAK-STAT signalling pathway, which is how a huge number of inflammatory cytokines — immune messenger molecules like interleukins and interferons — communicate with cells.

[HOST] So they're like a relay in the inflammatory signalling chain?

[EXPERT] Exactly. A cytokine binds to a receptor on the outside of the cell, that activates a JAK, the JAK activates a STAT protein, and the STAT goes into the nucleus and switches on genes that drive inflammation. Block the JAK, and you interrupt that whole cascade in one go.

[HOST] And that's what JAK inhibitors do — block those enzymes?

[EXPERT] Right. And because multiple inflammatory cytokines use JAK signalling, you get a very broad anti-inflammatory effect from a single oral tablet. That's the appeal — you're not blocking one cytokine like a biologic would, you're blocking the signal transduction for dozens of cytokines simultaneously.

[HOST] Which drugs are we talking about? There seem to be quite a few in this class now.

[EXPERT] The main ones licensed in the UK are tofacitinib — brand name Xeljanz — baricitinib, which is Olumiant, upadacitinib, Rinvoq, abrocitinib, Cibinqo, and filgotinib, Jyseleca. They differ in which JAKs they preferentially inhibit, which influences both their efficacy in different conditions and their side effect profiles.

[HOST] Can you briefly map which drug goes with which condition?

[EXPERT] Tofacitinib is licensed for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. Baricitinib covers rheumatoid arthritis, atopic dermatitis — eczema — and alopecia areata, which is the patchy hair loss condition. Upadacitinib probably has the broadest licence now — rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, Crohn's disease, and atopic dermatitis. Abrocitinib is specifically for atopic dermatitis in adults. Filgotinib covers rheumatoid arthritis and ulcerative colitis.

[HOST] That's a remarkable range of conditions for one drug class. What's the advantage over biologics, which we'll cover in the next episode?

[EXPERT] The big one is that they're oral. Biologics — like the TNF inhibitors — are injections or infusions. JAK inhibitors are tablets, taken once or twice a day at home. For patients who are needle-phobic, or who struggle with injections, that's a significant quality of life improvement. They also have rapid onset — you can often see meaningful clinical benefit within two to four weeks, which is faster than many conventional DMARDs like methotrexate.

[HOST] That speed of onset sounds clinically useful. What about efficacy overall?

[EXPERT] Very good. In rheumatoid arthritis, upadacitinib has shown efficacy data comparable to — and in some head-to-head trials, slightly better than — adalimumab, which is the most widely used biologic in RA. In atopic dermatitis, the data for upadacitinib and abrocitinib has been transformative for patients with severe disease. Baricitinib showed efficacy in alopecia areata in trials that genuinely changed what was thought possible for that condition.

[HOST] Let's talk about the safety concerns, because I know there's been significant regulatory attention on this class.

[EXPERT] Yes, and it's important to be clear-eyed about this. The big trial is the ORAL Surveillance study, which compared tofacitinib against TNF inhibitors in patients with RA who were over 50 and had at least one cardiovascular risk factor. The study found that tofacitinib was associated with a higher rate of major adverse cardiovascular events — what we call MACE — and a higher rate of malignancy, particularly lung cancer and lymphoma.

[HOST] That sounds serious. What happened as a result?

[EXPERT] The regulators acted. The EMA and MHRA added class-wide boxed warnings — the strongest type of warning — to all JAK inhibitors, not just tofacitinib, because they considered the risk plausibly a class effect. The warnings cover MACE, malignancy, serious infections, and venous thromboembolism — blood clots. NICE has incorporated these warnings into its guidance, and prescribers are now required to use JAK inhibitors with particular caution in patients who are over 65, smokers, have a history of cardiovascular disease, or have risk factors for malignancy.

[HOST] So these drugs haven't been pulled from the market, but there are stricter rules on who gets them?

[EXPERT] Exactly. They remain effective, important medications. The key is appropriate patient selection. For a 45-year-old with severe refractory RA who has no cardiovascular risk factors, the risk-benefit calculation may be very favourable. For a 70-year-old smoker with known cardiovascular disease, you'd want to think very carefully and discuss the risks explicitly with the patient.

[HOST] What about the infection risks — you mentioned serious infections?

[EXPERT] Yes, serious infections are a genuine concern with any immunosuppressant, and JAK inhibitors are no exception. The most clinically important ones to know about are reactivation of latent tuberculosis — so you must screen for latent TB before starting, exactly as you would with a biologic — and reactivation of herpes zoster, which is shingles. The risk of shingles with JAK inhibitors is meaningfully higher than with biologics. That's why the shingles vaccine — Shingrix, the inactivated one — should be offered before starting if possible.

[HOST] And you can't use the live vaccine once they're on treatment?

[EXPERT] Correct. Shingrix is non-live, so it's fine in immunosuppressed patients. The old live attenuated zoster vaccine, Zostavax, should not be given on treatment. Another thing to check is varicella immunity — if a patient has never had chickenpox and isn't immune, they're at risk of primary varicella infection, which can be severe in immunosuppressed adults.

[HOST] What about VTE — the blood clot risk?

[EXPERT] This was identified particularly with tofacitinib at higher doses, and there's a plausible mechanism involving JAK2 inhibition and its effects on platelet function and the coagulation system. Current guidance recommends avoiding JAK inhibitors in patients at high VTE risk — for example, those with a prior history of DVT or pulmonary embolism, or significant immobility.

[HOST] What monitoring does a patient on a JAK inhibitor need?

[EXPERT] Before starting: a full blood count, liver function tests, renal function, lipid profile, TB screening with an IGRA test — that's a blood test for latent TB — and a check of hepatitis B and C status. Once on treatment: LFTs and FBC at 4 to 8 weeks initially, then every 3 months, and lipids at 12 weeks. JAK inhibitors can raise LDL cholesterol, which is worth managing. Blood pressure monitoring is also worthwhile.

[HOST] Where do JAK inhibitors sit in the treatment pathway? When does a patient get to one?

[EXPERT] In rheumatoid arthritis, current NICE guidance positions them after failure of at least two conventional DMARDs — usually including methotrexate — and generally after failure of or contraindication to a biologic. So for most patients it's a third or fourth line option in RA. In atopic dermatitis, abrocitinib and upadacitinib come in after topicals and dupilumab have failed or aren't suitable. The NICE Technology Appraisals are worth checking because they're updated regularly and the positioning does shift.

[HOST] Is there a JAK inhibitor you'd choose over others for any particular reason?

[EXPERT] It depends heavily on the indication. For atopic dermatitis, the head-to-head data for upadacitinib is particularly strong. For RA with cardiovascular risk factors, you might lean towards filgotinib, which is a more selective JAK1 inhibitor and didn't show the same MACE signal, though the regulatory caution has been applied class-wide. For alopecia areata, baricitinib is the licensed option. It's very indication-specific.

[HOST] Any clinical pearls before we wrap up?

[EXPERT] The one I always come back to is: screen before you start. TB, varicella, hepatitis B — these are the infections that can be catastrophic if you trigger a reactivation in an immunosuppressed patient. Get the shingles vaccine in if you can. And make sure patients understand they should tell any doctor they see — including A&E — that they're on an immunosuppressant, because the signs of serious infection can be blunted.

[HOST] Let me summarise. JAK inhibitors block the JAK-STAT signalling pathway, knocking out a broad range of inflammatory cytokines in one go. They're oral, work quickly, and cover a remarkable range of conditions from RA to eczema to alopecia. The safety profile — particularly after ORAL Surveillance — means they come with boxed warnings for MACE, malignancy, VTE, and serious infections. Patient selection is critical: use caution in those over 65, smokers, or with cardiovascular risk. Screen for TB and check varicella immunity before starting. Is there anything I've missed?

[EXPERT] That's comprehensive. The only thing I'd add is that for the right patient, these drugs can be genuinely life-changing. Patients with severe eczema who've been told nothing can be done — some of them have had near-complete clearance on JAK inhibitors. The art is matching the drug to the right patient with a proper informed consent conversation.

[HOST] Brilliantly put. Thank you, Anzal. That's our episode on JAK inhibitors. Next time on ClinicaliQ Drug Class Explainers, we're tackling TNF inhibitors — the original biologic class that changed inflammatory disease treatment, and which now has a whole ecosystem of biosimilars saving the NHS significant amounts of money. I'm Sarah Mitchell — join us next time.

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