Biologics, biosimilars and JAK inhibitors

A biologic is made from proteins produced by genetically engineered cells grown in a laboratory, rather than built up as a chemical step by step. Each is designed to block one particular part of the immune system, most often a chemical messenger, or a kind of cell, that drives inflammation.

That single target is what separates a biologic from the conventional disease-modifying anti-rheumatic drugs (DMARDs), methotrexate and sulfasalazine among them, which calm the immune system more broadly. The goal of both is the same: to turn down the inflammation behind conditions such as rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis, rather than to cover up the pain. The conventional tablets are explained in our guide to DMARDs in rheumatology; this page deals with the targeted ones.

A protein swallowed as a tablet would be broken down in the gut like food, so biologics are given as an injection under the skin or through a drip into a vein. In UK practice for rheumatoid and psoriatic arthritis, a biologic usually comes in once the conventional tablets have not brought the disease under control or have not suited you, and it is often taken together with one of them rather than in its place. Axial spondyloarthritis is the exception: conventional DMARDs do not settle inflammation in the spine, so there biologics follow anti-inflammatory tablets (NSAIDs) instead.

Biologics are grouped by what they block, and three groups account for most of those used in rheumatology.

TNF blockers. Tumour necrosis factor (TNF) is one of the chief messengers that drives inflammation in the joints, and anti-TNF medicines such as adalimumab and etanercept catch it before it can work. They have been used since the late 1990s, more widely than any other group, in rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis alike, and some also treat related problems such as uveitis.

Interleukin blockers. The interleukins are a second family of messengers, with different members mattering in different conditions. Tocilizumab blocks the action of a messenger called interleukin-6, a major driver of rheumatoid arthritis, and secukinumab blocks the action of a messenger called interleukin-17, which plays a large part in psoriatic arthritis and axial spondyloarthritis.

B-cell therapy. Rituximab takes a different route. Instead of catching a messenger, it attaches to a type of white blood cell, the B cell, and makes it break down. B cells make antibodies, and in rheumatoid arthritis some of those antibodies stir other parts of the immune system into causing inflammation. Rituximab is given through a drip in a hospital day unit, and a single course keeps working for many months.

None of these targets is simply the strongest. A biologic that does little for one person may suit the next, and when the first target turns out not to be the right one for someone's disease, a medicine with another target can follow.

The company that develops a biologic holds a patent on it for a time, and when that runs out other companies may make their own. Because living cells make the medicine, no copy can match it molecule for molecule, the way a copy of a simple chemical like paracetamol can, which is why these versions are called biosimilars: medicines shown to match the original so closely that they act the same way, work as well and are as safe. Before approving one, the UK regulator compares it in detail with the original; adalimumab, for instance, now comes as several biosimilars, each under its own brand name.

A move from an original biologic to a biosimilar, or from one biosimilar to another, is a normal and tightly regulated part of UK care, and the studies of these moves show the medicine keeps working and stays as safe. A new name on the box does not mean a different treatment in any way that matters, though anything new you notice is still worth mentioning to your team.

Tofacitinib, baricitinib and upadacitinib belong to the newest group of targeted treatments, the JAK inhibitors. Chemically they are small molecules, not proteins, so a JAK inhibitor can be swallowed as a tablet; their class name is targeted synthetic DMARDs, and they are not biologics. They switch off enzymes known as Janus kinases, which are involved in the inflammation of rheumatoid and psoriatic arthritis.

For many people the attraction is simple: swallowing a tablet beats injecting, and there are no pens to store in the fridge and no technique to learn.

They also carry a safety issue that is best weighed calmly and plainly. One large study followed people aged 50 or over with existing risk factors for heart disease, some given a JAK inhibitor and some an anti-TNF biologic; with the JAK inhibitor there were more heart attacks and strokes, blood clots, serious infections and certain cancers. The UK medicines regulator, the MHRA, has since advised that people aged 65 or over, people who smoke or have smoked for a long time, and people with other risk factors for heart disease or cancer should be given a JAK inhibitor only when nothing else suitable is available, and that extra care is needed where there are risk factors for clots. It is not a ban, and outside those groups JAK inhibitors remain effective medicines in wide use. What it means is that the decision is made for you as an individual, with your own risks set out openly, and that in the higher-risk groups other options usually come first. The regulator also asks people on a JAK inhibitor to look over their skin from time to time and to tell their doctor or nurse about any new growth on the skin, or a mole that has changed.

Every one of these medicines turns down part of the immune system, so some checks come first. You will have blood tests, and screening for tuberculosis, hepatitis B and hepatitis C. The tuberculosis check runs from questions about earlier contact with it, or treatment for it, to an examination, a chest X-ray and a skin or blood test. These infections can lie quiet in the body for many years while the immune system keeps them in check, and a treatment that lowers that guard can let them flare, so they are looked for beforehand and, if found, treated before the new medicine starts.

Vaccinations are reviewed at the same time, because live vaccines such as MMR and yellow fever are generally avoided once treatment is under way. Vaccines that are not live, among them those against flu, COVID-19 and pneumonia, are safe and recommended. Shingles is worth a special word with JAK inhibitors, which make it more common, and a vaccine that is not live is available to those who qualify.

The infection risk is real but should be kept in proportion. Most infections on these medicines are the everyday coughs, colds, skin infections and water infections that anyone can catch, and they usually clear with the usual treatment; serious ones are uncommon. What matters is to act on an infection early rather than wait to see whether it passes: a fever or other signs of an infection go to your rheumatology team, your GP or NHS 111 the same day, though the signs of sepsis under When to seek help are a 999 or A&E emergency. There is more on this in our guide to infections and arthritis medicines.

Which medicine to use is decided with your specialist, taking in your diagnosis, the treatments you have already had, any other health conditions, and your own preferences, injections or tablets among them.

A biologic you inject at home usually comes as a ready-filled pen or syringe stored in the fridge, and a specialist nurse shows you how to use it before you do it on your own. Drip medicines such as rituximab are given over a few hours in a hospital day unit, with staff keeping watch. JAK inhibitors are simply swallowed.

Once you have started, the monitoring carries on, with regular blood tests and specialist reviews to make sure the disease really is under control. Biologics differ in how quickly they help: some begin to work within a few weeks, others take a couple of months, and the full effect can build over several months. If things are hard before it starts working, the gap can be bridged, which our guide to managing flares explains. Ongoing symptoms are not always active inflammation, and when that is in doubt, point-of-care ultrasound at a review can show whether the joints are still inflamed, helping your team judge whether the treatment is working.

These are costly medicines that only specialists prescribe, and the way they are prescribed, supplied and monitored is not the same in NHS and private care. Dr Borukhson advises whether one of them is right for you and, where it is, talks through how the prescribing and monitoring would be run, including where NHS services come in.

Carry on with the medicine unless your team advises otherwise. Stopping on your own often lets the disease come back, and for some of these medicines starting again after a long gap needs care, so any break is best planned with your team.

A pregnancy needs planning too. JAK inhibitors are not taken during pregnancy, and the timing of the other medicines is worked out case by case, so if you think you might be pregnant while taking one of them, tell your rheumatology team at once, and let the team decide about the next dose. Our guide to arthritis, autoimmune conditions and pregnancy is the place to read about planning ahead.

Routine questions about these medicines can wait for your next review. The two lists below are for the signs that cannot, the gravest first.

Treat any of these as a 999 or A&E emergency: call 999 and do not drive yourself to A&E.

• Severe illness with suspected sepsis: a high fever with shaking, confusion, rapid breathing, or feeling dramatically worse over hours
• With a fever or feeling unwell, a rash that does not fade when you press it, a stiff neck with eyes that cannot bear bright light, or skin, lips or tongue turning blue, grey, pale or blotchy, since these can be signs of meningitis or sepsis, as can a very bad headache, confusion or a first seizure with a fever or feeling unwell; on black or brown skin the rash and the change of colour may be easier to see on the palms of the hands or the soles of the feet
• Chest pain that is crushing, tight or like a pressure, that spreads to an arm, the jaw, the neck, the stomach or the back, that comes with breathlessness, sweating, feeling sick or feeling light-headed, or that came on suddenly and does not go away
• Breathlessness that is severe, with gasping, choking or no breath to get words out; or coughing up blood
• Palpitations happening now that do not stop, or that come with chest pain, breathlessness, feeling faint or fainting, since a heart whose muscle or rhythm is affected has to be checked at once
• A rash that spreads across the body, skin that blisters or peels, or lips, mouth or eyes that turn sore or swollen, since this can be a severe reaction to a medicine, such as Stevens-Johnson syndrome, which needs treating in hospital straight away; a painful band of blisters on one side of the face or body is more likely to be shingles, which belongs to the second list
• Sudden weakness or numbness on one side, a drooping face or difficulty speaking, a sudden severe headache, sudden confusion or a seizure, or sudden loss of vision, any of which can be a stroke, even if it stops after a short time
• An eye that suddenly and completely loses its sight
• Lips, mouth, throat or tongue that suddenly swell, a throat that feels tight, very fast breathing or a struggle to breathe or to swallow, skin, tongue or lips turning blue, grey or pale (on black or brown skin this may be easier to see on the palms of the hands or the soles of the feet), becoming suddenly very confused, drowsy or dizzy, or fainting and not being able to be woken, since this can be a severe allergic reaction, anaphylaxis, which can follow a dose of any medicine

Any of these needs an assessment that is urgent, on the same day, from your GP, your rheumatology team or NHS 111:

• A fever, or feeling generally unwell, on immunosuppressant, biologic or steroid treatment, since an infection has to be treated early; the first sign may be a cough that brings up phlegm or will not settle, a burning feeling when you pass urine, or an area of skin that is hot and spreading, and your team may pause the medicine until the infection has gone, which is not the same as stopping it yourself
• A joint that is hot and swollen, with a fever or feeling unwell, since an infected joint has to be ruled out at once, at A&E or through NHS 111
• A joint that has become hot and very swollen suddenly, or is worsening quickly, even without a fever, since an infected joint does not always announce itself with one; a joint that will take no weight at all, or that cannot be moved, is a 999 or A&E emergency, whether or not there is a fever
• New chest pain, new palpitations, or breathlessness that is new or getting worse, since JAK inhibitors have been linked with clots on the lung and with heart problems, and on any of these medicines a chest infection can begin this way; palpitations happening now that do not stop, or that come with chest pain, breathlessness, feeling faint or fainting, belong to the first list; in pregnancy, breathlessness that comes on suddenly, or when you lie down, or with dizziness, is for your midwife or maternity unit straight away
• A calf that is swollen, hot or painful, or a limb that is painful, swollen or discoloured, which can mean a clot, and JAK inhibitors can make clots likelier; with breathlessness, chest pain, palpitations or feeling faint, this is a 999 or A&E emergency: call 999 and do not drive yourself to A&E
• A painful rash of blisters in a band on one side of the face or body, since this is likely to be shingles, which is more common on JAK inhibitors and can be worse on some of these medicines, and the medicine for it works best started within three days of the rash appearing; a rash that spreads across the body, or skin that blisters or peels beyond that band, belongs to the first list
• Being near someone with measles, chickenpox or shingles, while you take a medicine that weakens the immune system, since measles and chickenpox can be dangerous when the immune system is weakened, and you can catch chickenpox from someone with shingles if you have never had chickenpox; NHS 111 can tell you what to do that day

If you also take a conventional DMARD such as methotrexate, the warning signs that belong to it are set out in our guides to DMARDs and methotrexate. A side effect that bothers you but appears in neither list is one to raise with your rheumatology team, who can advise on it; stopping the medicine yourself is not the answer. If you cannot tell how urgent something is, asking is never a mistake.

Few developments have altered rheumatology as much as these targeted treatments. Conditions that once meant joint damage building year on year can now usually be controlled, and most people on these medicines get on with work and daily life. The price of that power is close oversight: the right medicine for the right person, thorough screening before the first dose, monitoring that is kept up rather than left to lapse, and sound decisions when an infection, an operation or plans for a pregnancy come along. None of it is complicated, but it all needs a team that knows you to take charge of it. Whether one of these medicines has just been suggested to you or you have taken one for years, a specialist review can talk through the options and the practicalities, so that you know why you take it as well as how.

How does a biologic differ from a conventional DMARD such as methotrexate?

Both act on the disease itself, not only on the pain it causes. Conventional DMARDs such as methotrexate are chemical tablets that calm the immune system as a whole, whereas a biologic is made from proteins produced by engineered cells and blocks a single target such as TNF or one of the interleukins. In the UK the conventional tablets are usually tried first in rheumatoid and psoriatic arthritis, and a biologic or a JAK inhibitor is added, or swapped in, when they have not done enough. Axial spondyloarthritis takes a different path, because the conventional tablets do not help the spine: anti-inflammatory tablets come first there, then a biologic. The conventional medicines have a guide of their own, DMARDs in rheumatology.

Are JAK inhibitors biologics?

No, though the two are often mentioned together. Both are targeted treatments that act on the immune response, but a JAK inhibitor is a small chemical molecule rather than a protein, which is why it comes as a tablet. JAK inhibitors are classed as targeted synthetic DMARDs, and this guide's section on them explains how they work and the safety advice that goes with them.

Should a switch to a biosimilar worry me?

No. A biosimilar is another manufacturer's version of an original biologic, made once the original's patent has run out, and it is approved only when the regulator is satisfied that it works as well and is as safe. Moving to one is a routine, closely regulated step in UK care, and the studies of such switches are reassuring. The pen may carry a new name; the medicine in it does the same job. Anything that seems different after a switch is worth telling your team about; it is not a reason to stop.

What about the heart and clot risks I have read about? Are JAK inhibitors safe?

Most people take them without trouble, and the risk is best understood calmly and accurately. In a large safety study of older people who already had risk factors for heart disease, one JAK inhibitor was followed by more heart attacks and strokes, more clots, more serious infections and more of certain cancers than an anti-TNF biologic. The UK regulator's advice is that for people aged 65 or over, people who smoke or smoked for a long time, and people with other risk factors for heart disease or cancer, a JAK inhibitor is used only when there is no suitable alternative, with extra caution where there is a risk of clots. For others they stay a widely used choice, and the decision rests on a frank look at your own risks before you start.

Will I need to give myself injections?

Only for some of these medicines, and never without being shown how. Most of the biologics used at home come in a ready-filled pen, a specialist nurse teaches you to use it, and most people find it much easier than they expected. Rituximab and a few others are given instead through a drip in a hospital day unit. A JAK inhibitor needs no injections, being a tablet.

How long until it works, and can I stop once I am better?

Expect weeks rather than days: the timescale varies from one biologic to another. Some start to help within a few weeks, others take a couple of months, and the full effect can build over several months. Feeling well usually means the medicine is working, not that it can go. Stop only on your specialist's advice: the condition often comes back, and starting again after a gap is not always straightforward. If you fall ill, your team can tell you whether to pause it, and our guide to infections and arthritis medicines covers what to do while you are unwell.