One Signal at a Time

Antibodies made to order changed the treatment of rheumatoid arthritis, Crohn’s disease, psoriasis and multiple sclerosis. How biological medicines work, how well, at what risk and price, and why they block the immune system one signal at a time.

In 2022 one medicine, adalimumab, sold under the name Humira, brought its maker $21.2 billion.[1] It is an antibody, a protein made by living cells grown in steel tanks, and it does one thing: it captures a single signalling molecule of the immune system, TNF, before it can reach its target. It and its relatives are used in rheumatoid arthritis, Crohn’s disease, ulcerative colitis, psoriasis and ankylosing spondylitis.

The earlier essays in this series were about the newest ideas: The Second Lock about strengthening the immune system’s brakes and resetting it with CAR-T cells, The Brakes Released about releasing them against cancer. This one is about the medicines most patients with autoimmune disease actually take today, the biologics: antibodies and related proteins designed to block one part of the immune system each. They are among the great successes of modern medicine. They also show its limits, because blocking one signal at a time is not the same as fixing the system that sends them.

19/24patients with rheumatoid arthritis who responded within four weeks of one infusion of a TNF blocker in 1994, against 2 of 24 on placebo

70cases of tuberculosis reported in people taking infliximab by 2001, most after three infusions or fewer

≤30%remission with new drugs in ulcerative colitis induction trials, typically 20–30%: the “therapeutic ceiling”

€145 ma year that Portugal’s health service estimates it saves by using biosimilar copies of five biologics

Origins

Antibodies to order

The story begins in 1975, when Georges Köhler and César Milstein fused antibody-producing cells with cancer cells that never stop dividing, producing “continuous cultures of fused cells secreting antibody of predefined specificity”.[2] For the first time, a single antibody against a chosen target could be made in unlimited amounts. The first antibody medicine, muromonab-CD3, which suppresses T cells, was approved in the US in 1986 to treat the rejection of transplanted organs.[3]

Fig. 1 — Fifty years of antibody medicines for immune disease: the events described in this essay. Pink marks the first major safety warning.

The breakthrough in autoimmune disease came from a hypothesis about rheumatoid arthritis. Marc Feldmann and Ravinder Maini suspected that one molecule, TNF, was driving the inflammation in the joints. In an open study in 1993, twenty patients with severe rheumatoid arthritis were given an antibody against TNF. Within six weeks the median number of tender joints, on a standard index, fell from 28 to 6 and swollen joints from 18 to 5, with “no serious adverse events”.[4] A randomised trial followed in 1994: four weeks after a single infusion, 19 of 24 patients on the higher dose had responded, against 2 of 24 on placebo. The authors called it “the first good evidence that specific cytokine blockade can be effective in human inflammatory disease”.[5]

Fig. 2 — The first randomised trial of a TNF blocker. Patients with rheumatoid arthritis responding four weeks after one infusion of placebo or of the antibody cA2, later named infliximab, at two doses (Elliott et al. 1994).

The antibody, infliximab, went on to show that it could also stop the joint damage that disables patients: in a 428-patient trial, combined with methotrexate, it “halted the progression of joint damage”.[6] It worked in Crohn’s disease too, where 81 per cent of patients responded at four weeks against 17 per cent on placebo.[7] Feldmann and Maini received the Lasker Award in 2003 “for the discovery of anti-TNF therapy as an effective treatment for rheumatoid arthritis and other autoimmune diseases”.[8]

The map

Eight places to block

TNF opened the door, and other targets followed. Each biologic blocks one signal or one cell type: a cytokine such as TNF, interleukin-6 or interleukin-17; the interferon alarm that, as The Second Lock described, is switched on in lupus; the B cells that make antibodies; the second signal that T cells need to activate; the molecules that let immune cells leave the blood and enter tissues; or the receptor that keeps antibodies in circulation.

Fig. 3 — Where the main biological medicines act, with example drugs and the diseases they are used in. The list is not complete; many diseases have several options, and the names are examples.

The B-cell drugs show how one target can serve several diseases. Rituximab, an antibody against CD20 on B cells developed for lymphoma, helped rheumatoid arthritis, with 43 per cent of patients reaching a 50 per cent improvement (ACR50) against 13 per cent on methotrexate alone,[9] and in ANCA vasculitis it matched cyclophosphamide, which had been the “cornerstone” of treatment “for 40 years”, and did better in relapsing disease.[10] Ocrelizumab, a relative, reduced relapses in multiple sclerosis by nearly half compared with interferon, and slowed the primary progressive form, if modestly (32.9 against 39.3 per cent progressing).[11][12] The anti-integrin drugs work by keeping immune cells out of a tissue: vedolizumab out of the gut,[13] natalizumab out of the brain.

How well

Large effects and a ceiling

Figure 4 sets ten pivotal trials side by side. The endpoints differ, so the bars cannot be compared across diseases, but within each trial the gap between the biologic and the comparison is the effect. Some are very large. In giant cell arteritis, an inflammation of large arteries in older people, 56 per cent of patients on tocilizumab, which blocks interleukin-6, were in sustained remission at a year against 14 per cent on a steroid taper, with half the cumulative dose of prednisone.[14] In rheumatoid arthritis, the same drug brought a 20 per cent improvement (ACR20) to 59 per cent of patients against 26 per cent on placebo, both groups also taking methotrexate.[15] In psoriasis, the interleukin-17 blockers secukinumab and ixekizumab cleared at least three-quarters of the skin disease (PASI 75) in 77 to 90 per cent of patients at twelve weeks, against 42 to 53 per cent on etanercept, a TNF blocker.[16][17] Risankizumab, which blocks interleukin-23, cleared at least 90 per cent of the skin disease in 75 per cent of patients at 16 weeks, against 42 per cent on ustekinumab and 5 per cent on placebo.[18] A Cochrane network analysis of the psoriasis drugs found that infliximab and the interleukin-17 and interleukin-23 blockers outperformed the older biologics, and that “clinical effectiveness of these drugs was similar when compared against each other”.[19]

Fig. 4 — How often patients met each trial’s main goal on the biologic (teal) and in the comparison group (grey). Endpoints and comparators differ: placebo or standard treatment in most, a steroid taper in giant cell arteritis, methotrexate alone in the rheumatoid arthritis trials. Sources: Lipsky 2000; Edwards 2004; Stone 2017; Gordon 2018; Howard 2021; Feagan 2013; Navarra 2011; Morand 2020; Furie 2025; D’Haens 2023.

Others are smaller. Lupus has been the hardest disease for biologics. Belimumab, which deprives B cells of a growth signal, was approved in 2011 after trials in which 58 per cent of patients on the higher dose responded at a year, against 44 per cent on placebo; in its second trial the difference at 52 weeks (43.2 against 33.5 per cent) was no longer significant at 76.[20][21] Anifrolumab, which blocks the receptor for type I interferon, the alarm that The Second Lock traced to the U1 RNA of the cell nucleus, improved responses from 31.5 to 47.8 per cent.[22] In lupus nephritis, belimumab and the B-cell antibody obinutuzumab each added about ten to thirteen percentage points of complete kidney response to standard treatment.[23][24]

In inflammatory bowel disease, gastroenterologists speak of a “therapeutic ceiling”: “remission rates of patients with ulcerative colitis given new therapeutic agents in induction trials remain at a modest 20–30%”.[25] Ustekinumab induced remission at eight weeks in 15.6 per cent of patients against 5.3 per cent on placebo,[26] mirikizumab in 24.2 against 13.3 per cent at twelve.[27] With TNF blockers, primary failure “occur[s] in up to 40% of patients in clinical trials and in 10–20% in clinical series”, and a further quarter to a half of those who respond lose the response within a year.[28] In the Portuguese rheumatology register, Reuma.pt, a good response by European criteria was reached by 52 to 60 per cent of 617 patients with rheumatoid arthritis on TNF blockers, depending on the drug.[29]

That pattern, a large effect in some and none in others, is what one would expect if each patient’s disease is driven by a different mix of signals. Blocking TNF helps when TNF is the main driver; when it is not, the disease goes on.

The price in safety

What the blocked signal was for

Each blocked signal had a job, and the side effects show what it was. TNF is one of the signals the body uses to keep tuberculosis in check. By May 2001, 70 cases of tuberculosis had been reported among about 147,000 people treated with infliximab, most after three or fewer infusions, and more than half outside the lungs; the authors urged that patients be screened for latent infection before treatment,[30] which has been standard ever since. A meta-analysis of 106 trials in rheumatoid arthritis found that biologics at standard doses raised the odds of serious infection by about a third compared with traditional drugs, an excess of about 6 infections per 1,000 patients a year, rising to 55 per 1,000 with combinations of biologics.[31]

The anti-integrin drugs show the same logic more starkly. Natalizumab keeps immune cells out of the brain, which is what helps in multiple sclerosis, and also keeps out the cells that control the JC virus, which many people carry harmlessly. In 212 of nearly 100,000 patients, the virus caused progressive multifocal leukoencephalopathy, a brain infection that is often fatal or disabling. The risk depends on the patient: at most 0.09 per 1,000 in those without antibodies to the virus, 11.1 per 1,000 in the highest-risk group (Figure 5).[32] Testing for the antibodies can therefore guide who receives the drug and for how long.

Fig. 5 — The risk of progressive multifocal leukoencephalopathy with natalizumab, per 1,000 patients: without antibodies to the JC virus, in all patients, and in those with antibodies, prior immunosuppression and 25–48 months of treatment (Bloomgren et al. 2012). Log scale.

The paradox

The same signal, opposite effects

The most instructive results are the ones that went wrong. In 1999 a TNF blocker, lenercept, was tested in multiple sclerosis, a disease of brain inflammation in which TNF seemed a natural target. The trial was stopped: “the number of lenercept-treated patients experiencing exacerbations was significantly increased compared with patients receiving placebo”.[33] Blocking the signal that drives inflammation in the joints made the brain disease worse.

TNF blockers can also cause the diseases they treat elsewhere. In patients with inflammatory bowel disease, a meta-analysis of 30 studies and 24,547 patients found that 6 per cent developed psoriasis or psoriasis-like skin lesions on anti-TNF treatment,[34] although TNF blockers are themselves used to treat psoriasis. A review of 379 cases of autoimmune disease induced by TNF blockers found skin vasculitis, lupus-like syndromes and lung disease among them.[35] The immune system is a network, not a chain: suppressing one signal shifts the balance among the others, and in some tissues and some people the new balance is a different disease. The toy model of The Second Lock had one brake and one loop; real patients have dozens.

Beyond blocking

Removing antibodies, and resetting

Two newer approaches go beyond blocking one signal. The first lowers the antibodies themselves. A receptor called FcRn rescues antibodies from being broken down, which is why they last weeks in the blood. Efgartigimod, a fragment that blocks FcRn, lowers all antibodies, including the harmful ones. In myasthenia gravis, where antibodies attack the junction between nerve and muscle, 68 per cent of patients with the main antibody responded against 30 per cent on placebo,[36] and the FDA approved it in December 2021 as “the first approval of a new class of medication”.[37]

The second is the closest relative of the CAR-T cells in The Second Lock. T-cell engagers are antibodies with two arms: one grips a T cell, the other a target cell, and the T cell kills it, without the need to engineer and grow cells for each patient. Developed for leukaemia and myeloma, they have now been given to small numbers of patients with refractory autoimmune disease in Erlangen. In six patients with rheumatoid arthritis, blinatumomab, which targets CD19 on B cells, produced a “rapid decline in RA clinical disease activity in all patients”;[38] in 2026 the group reported ten more, five with antisynthetase syndrome and five with systemic sclerosis; cytokine release syndrome, up to grade 3, occurred in all five with systemic sclerosis and in two of the others.[39] These are first reports, without control groups, but the aim is the same as with CAR-T cells: not to block a signal forever, but to remove the cells that sustain the disease and let the system rebuild.

Copies and cost

Biosimilars

Biologics are expensive to make and to buy. When their patents expired, copies followed. Because a living cell does not make an exactly identical protein twice, these copies are called biosimilars, not generics, and must show in trials that they work as well. In June 2013 the European Medicines Agency recommended the first two biosimilar antibodies, both copies of infliximab, calling it “the first time that the biosimilar concept has been successfully applied to such a complex molecule”.[40] The copy matched the original in rheumatoid arthritis (60.9 against 58.6 per cent responding),[41] and in the Norwegian NOR-SWITCH trial, 482 patients who switched from the original to the copy did no worse than those who stayed (disease worsening in 30 against 26 per cent, within the trial’s margin).[42]

Fig. 6 — What biosimilars did to the price of TNF blockers in European markets: change in the volume-weighted average price per defined daily dose after the first and the second biosimilar entered, using IQVIA data for 2008–2020 (Car et al. 2023).

Competition lowered prices, but not at once. Across European markets, the first biosimilar cut the average price per daily dose of infliximab by 13.6 per cent and of adalimumab by only 0.9 per cent; the second cut both by about 27 per cent, and use rose.[43] In Portugal, the medicines agency Infarmed estimated in 2025 that biosimilars of five hospital biologics, adalimumab, infliximab, rituximab, trastuzumab and bevacizumab, save the national health service about €145 million a year.[44] Money saved on copies is money for the newer drugs, which are still under patent and expensive.

Coda

What is known and what is not

Established

Biologics against TNF, interleukin-6, interleukin-17/23, B cells and other targets control rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis and vasculitis in many patients, and can stop joint damage. They raise the risk of infection, and some carry specific risks: tuberculosis with TNF blockers, PML with natalizumab. Biosimilars work as well as the originals.

Strong evidence

Modest benefits in lupus and lupus nephritis (belimumab, anifrolumab, obinutuzumab). A ceiling of about 20–30% remission in ulcerative colitis induction trials. Blocking one signal can cause disease elsewhere.

Early

T-cell engagers to reset autoimmune disease, in small uncontrolled series.

Biologics turned diseases that once crippled people into conditions that most can live with, and they did it by aiming at single molecules. That precision is also their limit. Each patient’s disease runs on a different mix of signals, so each drug helps some and not others; the blocked signal had a job, so each brings its own risks; and the disease often returns when the drug stops, because the self-sustaining state described in The Second Lock is still there. The newest treatments, CAR-T cells and T-cell engagers, try a different strategy: instead of blocking a signal for life, remove the cells that carry the disease and let the system start again. Whether that works, for whom and for how long, is the question the next decade of trials will answer. For now, for most patients, the medicines that work are the ones that block one signal at a time.

Open threads

Where this could go

Choosing the drug. Most patients still find the right biologic by trial and error. Measuring which signals drive each patient’s disease before treatment, from blood or tissue, would let doctors choose the first time.

Stopping safely. Biologics are usually taken for life. Which patients in long remission can stop, and which need a different kind of treatment to stay well without drugs, is still largely untested.

Cost and access. Biosimilars lowered prices for the older drugs; the newer ones remain expensive. How health systems, including Portugal’s, pay for them will decide who receives them.

On method and tools

This essay was researched and written with Claude Opus 5.5 (Anthropic): human specification, editorial direction and critical review; machine research, drafting and figure generation. The question came from Luis, who asked whether the series had covered biological medicines. A research agent (Claude) gathered the sources, and every reference was then checked against its PubMed record. For most studies the figures and quotations come from the abstracts; Lu et al. (2020) and Car et al. (2023) were read in their open-access full text, and the AbbVie annual report, the Lasker citation and the FDA, EMA and Infarmed releases at the source. The figures are drawn by scripts/biologics.py from the published numbers named in their captions; there is no model in this essay. The cover is a drawing, not data. This essay describes what studies have found; it is not medical advice.

Authored by: Luis Matos Ferreira — Physicist, Developer, Writer

Related essays on this blog

1. The Second Lock — regulatory T cells, autoimmune disease, prevention, and treatments that reset the immune system.
2. The Disease in the Middle — mixed connective tissue disease, between lupus, scleroderma and myositis.
3. The Brakes Released — the same immune system turned against cancer.

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