Treatment of rheumatic diseases with biologic and biosimilar drugs

01Definition and overview

Biologic drugs are medicines whose active substance is made by living cells, usually genetically engineered mammalian cells: monoclonal antibodies, receptor fusion proteins and recombinant proteins. They are large, cannot be absorbed from the gut, and are given by subcutaneous injection or intravenous infusion. In rheumatology they belong to the disease-modifying antirheumatic drugs (DMARDs), which are now named by how they were made:

Names give the structure away: -cept is a fusion protein of a receptor with the Fc part of IgG; -mab is a monoclonal antibody, -ximab chimeric (part mouse), -zumab humanised, -umab fully human. These stems hold for the antibodies in this topic; antibodies named since 2017 follow a newer scheme that no longer shows their source. The less foreign the antibody, the fewer antibodies the patient makes against it.

A biosimilar is a biologic that is highly similar to one already approved in the EU, its reference product, with no clinically meaningful differences in quality, safety or efficacy. It is not a generic: a generic is a small molecule identical to the original, while proteins made by living cells always vary slightly, in sugar chains for example, from batch to batch. The originator varies too, and its maker has to prove each change of manufacturing process harmless in the same way.

02Etiology and pathophysiology

The targets and why blocking them works

Not every disease answers to every target, and the failures teach as much as the successes. IL-17 and IL-23 blockers do too little in RA to be used there. IL-23 blockers help the skin and peripheral joints in psoriatic arthritis but not the spine in axial spondyloarthritis. IL-17 blockers can trigger Crohn's disease, because IL-17 protects the gut barrier. TNF inhibitors worsen multiple sclerosis.

How the molecules behave

• The Fab arms bind the target. The Fc part binds the neonatal Fc receptor, which rescues IgG from breakdown and gives antibodies a half-life of 2 to 3 weeks; the same receptor carries them across the placenta from the second trimester.
• Some antibodies kill the cells they bind: rituximab removes B cells by antibody-dependent cytotoxicity and complement. Plasma cells lack CD20, so existing antibody levels fall only slowly.
• Etanercept binds soluble TNF and lymphotoxin but does not kill TNF-bearing cells, which may be why it fails in Crohn's disease and uveitis and reactivates tuberculosis less often than the monoclonal antibodies.
• Anti-drug antibodies can neutralise a biologic or speed its clearance, a common cause of lost response. They are commonest with the chimeric infliximab and with adalimumab, and methotrexate given alongside reduces them.

JAK inhibitors

Many cytokine receptors have no enzyme of their own: they signal through pairs of Janus kinases (JAK1, JAK2, JAK3 and TYK2), which switch on STAT proteins that enter the nucleus. A JAK inhibitor therefore blocks several cytokines at once: IL-6 and the interferons through JAK1, erythropoietin and GM-CSF through JAK2, and IL-2, IL-7, IL-15 and IL-21, needed by lymphocytes and natural killer cells, through JAK3. This explains their speed and breadth, and their effects: shingles from weakened antiviral immunity, anaemia and cytopenias, and raised lipids.

03Clinical features

What each class is used for

Good effects

In RA that has not responded to methotrexate, adding a biologic or JAK inhibitor brings a good response in roughly two thirds of patients, and remission in a substantial minority. TNF inhibitors slow or halt erosions in up to 70 per cent, and fatigue and wellbeing improve in a way rarely seen with conventional DMARDs. JAK inhibitors act within 1 to 2 weeks; most biologics within 4 to 12. In giant cell arteritis and polymyalgia rheumatica, IL-6 blockade allows steroids to be stopped sooner with fewer relapses.

Harmful effects

04Diagnosis and management

Before starting

1. 1

   History

   Infections, tuberculosis exposure or birth in a high-incidence country, heart failure, demyelination, cancer, bowel, skin and eye disease, pregnancy plans, vaccines.
2. 2

   Screening tests

   An interferon-gamma release assay (preferred to the tuberculin skin test) and a chest X-ray; hepatitis B surface antigen, core antibody and surface antibody; hepatitis C antibody; HIV; varicella antibody without a history of chickenpox; blood count, liver and kidney tests; lipids before IL-6 or JAK inhibitors; immunoglobulins before rituximab.
3. 3

   Treat what is found

   Latent tuberculosis is treated, for example with 3 months of isoniazid and rifampicin, and the biologic started once that treatment is under way, when national guidance allows. Hepatitis C RNA means referral for antiviral treatment.
4. 4

   Vaccinate

   Non-live vaccines ideally at least 2 weeks before starting; live vaccines at least 4 weeks before.

Hepatitis B needs particular care. A surface-antigen-positive patient takes an antiviral, entecavir or tenofovir, throughout treatment and for months afterwards. A patient with only core antibody, a past infection, has HBV DNA and liver tests monitored, or takes prophylaxis when the drug is rituximab or high-dose steroids. Prophylaxis against Pneumocystis jirovecii with co-trimoxazole is given with high-dose steroids (more than 15 to 30 mg of prednisolone a day for more than 2 to 4 weeks), and commonly with rituximab in vasculitis.

Vaccination

• Non-live vaccines can be given on any drug: influenza every year, pneumococcal, COVID-19, the recombinant (non-live) shingles vaccine, which matters most before a JAK inhibitor, and hepatitis B, HPV and tetanus as indicated.
• Live vaccines (MMR, varicella, yellow fever, BCG, oral typhoid) are not given during treatment or for some months after stopping; the interval depends on the drug.
• Rituximab blunts the response for 6 months or more, so vaccines are given at least 2 weeks before the first course, or late in the cycle, at least 6 months after the last course and some weeks before the next.
• Household members can have their routine vaccines, except oral polio.

Choosing

Where a biosimilar exists it is usually the first choice. The 2023 European restrictions on JAK inhibitors, and their place in RA, are set out in rheumatoid arthritis.

Monitoring and loss of response

Response is judged with the disease's own score at 3 months, and the target should be met by 6. Blood tests follow the drug: counts and liver tests for all, lipids on IL-6 and JAK inhibitors, immunoglobulins on rituximab. Skin is checked for cancer on TNF and JAK inhibitors. Patients carry an alert card and pause the drug during an infection needing antibiotics.

• Primary failure, no response from the start: the target was probably wrong, and a different mechanism is chosen.
• Secondary failure, a response that fades: for monoclonal TNF inhibitors, a low drug level with anti-drug antibodies favours another drug of the same class; a good level without response favours a new mechanism. In RA, after a first biologic or JAK inhibitor fails, European recommendations accept either route: another drug of the same class or a new mechanism.
• Two biologics are not combined: infections rise without added benefit.
• In sustained remission the dose may be lowered or spaced out, but stopping usually brings a flare.

Pregnancy and breastfeeding

Antibodies with an Fc part reach the fetus in rising amounts through the second half of pregnancy. Non-live vaccines are given to exposed infants on schedule. Whether a live vaccine can be given in the first 6 months depends on when the mother last had the drug, how much of it crosses the placenta and which vaccine it is; rotavirus vaccine has been given to exposed infants without serious harm. BCG and other live vaccines wait until 6 months of age in an infant exposed in the second half of pregnancy to a biologic that crosses the placenta; certolizumab needs no change. Rituximab late in pregnancy can leave the newborn without B cells.

Surgery

American guidance for elective hip and knee replacement, widely applied to other operations:

• Conventional DMARDs, including methotrexate, are continued.
• A biologic is withheld for one dose, and surgery is planned for when the next dose would be due: in week 3 for adalimumab every 2 weeks, in month 7 for rituximab every 6 months.
• JAK inhibitors are stopped 3 days before.
• Treatment restarts once the wound has healed and there is no infection, usually after about 2 weeks.
• The usual daily steroid dose is continued, without extra stress doses.

Biosimilars in practice

• Approval: the biosimilar is compared with its reference product in a stepwise exercise, most weight resting on analytical and functional tests, followed by pharmacokinetic studies. A comparative efficacy trial was long required; in March 2026 the EMA adopted a reflection paper stating that such trials are no longer expected for most biosimilars that can be fully characterised analytically. Once similarity is shown, the biosimilar receives the reference product's indications, extrapolated from the studied ones.
• Interchangeability: in 2022 the EMA and the heads of the national medicines agencies stated that biosimilars approved in the EU are interchangeable with their reference product and with each other. Whether a pharmacist may substitute one without the prescriber is decided by each country.
• Switching: a randomised trial in Norway found switching from originator infliximab to a biosimilar non-inferior, with disease worsening in about 26 per cent on the originator and 30 per cent after the switch over a year. Repeated switches between biosimilars have not shown harm.
• The nocebo effect: patients switched without explanation stop the new drug more often, mostly for subjective complaints. A clear explanation, agreed with the patient, reduces it.
• Traceability: every biologic is prescribed and recorded by brand name and batch number, so that a side effect can be traced to the exact product.

05Epidemiology

Biologics are among the costliest drugs in European health budgets; for years adalimumab was the best-selling drug in the world. Access has been more restricted in lower-income European countries, a gap biosimilars are narrowing.

The EU approved the first biosimilar, a growth hormone, in 2006, and the first biosimilar antibody, infliximab, in 2013. Etanercept (2016), rituximab (2017) and adalimumab (approved 2017, on the market from 2018, when its patent expired) followed, and later tocilizumab and ustekinumab; 86 biosimilars had been approved by September 2022. By mid-2024, competition from biosimilars had saved an estimated 56 billion euros at list prices in Europe, and prices of the reference products usually fell as well. Uptake is fastest where national tenders and prescribing policies support it, as in the Nordic countries, and slower elsewhere.

06Prognosis

Biologics transformed the outlook of inflammatory arthritis: fewer erosions, deformities and joint replacements, better function and more people in work. Many patients stop their first biologic within a few years, because it never worked, its effect faded or it caused a side effect; each later drug is somewhat less likely to succeed.

Long-term registers in several European countries, following patients for more than 20 years, are reassuring for TNF inhibitors: serious infections are highest early and then decline, and overall rates of lymphoma and solid cancers are not raised beyond those of the disease itself, apart from a small excess of non-melanoma skin cancer. JAK inhibitors are different: in a trial of patients aged 50 or more with a cardiovascular risk factor, tofacitinib caused more major cardiovascular events (3.4 against 2.5 per cent) and cancers (4.2 against 2.9 per cent) than a TNF inhibitor over about 4 years, which led to the European restrictions of 2023. Repeated rituximab can leave low immunoglobulins and recurrent infection. Biosimilars have matched their reference products in trials and in practice.