Self & Other · Autoimmune Disease: Friendly Fire
What Might Help Soon
The dramatic change came in the late 1990s and accelerated through the 2000s and 2010s. It is called the biologic revolution, and it has reshaped autoimmune treatment in ways that, if you got your sense of what’s possible from a textbook from 1995, you would not believe.
A biologic is, broadly, a drug made of a large biological molecule — typically an antibody, or a piece of an antibody, or a protein engineered to bind a specific target. The first widely successful autoimmune biologics blocked a single cytokine called TNF (tumor necrosis factor), which turns out to be central to the inflammation in rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriasis, and several other conditions. The drugs — infliximab, adalimumab, etanercept, and others — work by binding TNF and preventing it from activating other immune cells. For many people who had spent years in joint pain or with severe inflammatory bowel symptoms, the response to a TNF blocker has been life-altering. Not for everyone. Not always permanently. But for enough people that the standard of care has been rewritten.
Since then, more biologics have been approved that block other specific cytokines or specific cells. Drugs that block IL-17 work very well for psoriasis. Drugs that block IL-6 work for rheumatoid arthritis and other conditions. Drugs that target specific kinds of B cells (rituximab, for instance) work for several autoimmune diseases including some forms of vasculitis and multiple sclerosis. Drugs that block the trafficking of immune cells into the brain (natalizumab) work for multiple sclerosis. The toolkit, as of the mid-2020s, is large and growing.
A newer category is the JAK inhibitors, which are not biologics but small molecules. They block a specific signaling pathway inside cells that many cytokines use to deliver their messages. Drugs like tofacitinib, baricitinib, and upadacitinib are now used in rheumatoid arthritis, certain inflammatory bowel diseases, severe atopic dermatitis, and a growing list of other conditions. They work in some patients where biologics didn’t, and they have their own profile of benefits and risks.
Type 1 diabetes, until very recently, had no specific immunological treatment — the standard of care was, and largely still is, replacing the missing insulin from outside, with injections or pumps. In 2022, however, a drug called teplizumab was approved that, given to people in the very earliest stages of Type 1 diabetes (before symptoms, when only autoantibodies are detectable), can delay the onset of clinical disease by about two years. It is the first treatment that has been shown to alter the course of the autoimmune attack on beta cells. Two years is not a cure, but for a child whose diagnosis it pushes back from age twelve to age fourteen, two years is a great deal. Other immunological approaches to Type 1 diabetes, including some that aim to actively rebuild tolerance, are in active clinical trials.
The general pattern across all these treatments is the same. We have moved from broad suppression of the entire immune system (steroids), to broad suppression of dividing cells (methotrexate, azathioprine), to specific blockade of single cytokines or cell types (biologics, JAK inhibitors). The trajectory is toward more precision and fewer side effects. We are not at the end of that trajectory. We are well past the beginning.
What Might Help Soon
There are several approaches in current research that, if they work, will change autoimmune treatment again.
The most promising in concept is antigen-specific therapy. The idea is to retrain the immune system to tolerate the specific protein it has learned to attack — not by suppressing the whole immune system, but by reintroducing the offending protein in a context that promotes tolerance rather than attack. Several techniques are being explored: nanoparticles carrying the relevant antigen, modified versions of the protein delivered in tolerizing ways, even injection of the antigen directly into specific tissues that promote regulatory responses. If antigen-specific therapy works, it would offer the dream that has been on the horizon of immunology for fifty years: a treatment that fixes the actual problem (one specific lapse in tolerance) without breaking the rest of the system. Several trials are underway. Results, in human disease, are mixed but encouraging in some cases. The next ten years will tell us a great deal.
Another promising direction is Treg therapy. The idea is to take regulatory T cells from a patient (or, in some versions, engineer them in a lab), expand them in number, and infuse them back. The expanded Tregs would, in theory, do the calming work that the patient’s own Tregs have apparently failed to do. Early human trials are underway in transplant rejection, in Type 1 diabetes, in lupus, and in other conditions. The biology is plausible. The execution is hard. The results so far are promising in some settings, less clear in others.
A third direction, which sounds dramatic and is, involves CAR-T cells — the engineered T cells that have already transformed certain cancer treatments, which we will meet properly in Chapter 12. CAR-T cells engineered to attack specific B cells have, in a small number of recent trials, produced striking improvements in patients with severe lupus and other antibody-driven autoimmune diseases. The treatment essentially wipes out the rogue B cell populations and lets the body rebuild a fresh, naive B cell population from the bone marrow — a kind of immunological reset. The early results, in 2022 and 2023, were dramatic enough that this approach is now being tested seriously in larger trials. If it holds up, it may turn out to be one of the more important developments of the decade.