Tumor Necrosis Factor (TNF) inhibitors are a class of medications that help to stop inflammation. They are prescribed for a range of autoimmune diseases, including rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, ulcerative colitis, and Crohn’s disease. These drugs are a type of treatment known as biologics, which means they are complex molecules derived from living organisms, such as human or animal tissue.
These biologic therapies are designed to target a specific component of the immune system. The target is a protein called Tumor Necrosis Factor-alpha (TNF-alpha), which, in a balanced immune system, helps fight infection. In autoimmune conditions, the body produces an excess of TNF, leading to persistent inflammation. All approved TNF inhibitors have been administered either through a subcutaneous injection, which a patient can learn to do at home, or an intravenous (IV) infusion performed at a healthcare facility.
How Traditional TNF Inhibitors Work
Traditional TNF inhibitors were developed as large-molecule biologic drugs. These medications are lab-created antibodies or receptor fusion proteins designed to intercept and neutralize TNF. They function outside the cells, circulating through the bloodstream and tissues where they physically bind to TNF proteins. This action prevents TNF from attaching to its receptors on the surface of cells, thereby blocking the inflammatory cascade before it can begin.
This mechanism can be visualized like a specific key fitting into a lock. The TNF inhibitor is the key, and it is uniquely shaped to bind only to the TNF protein, which is the lock. By occupying the lock, the inhibitor prevents TNF from activating the cellular machinery that leads to inflammation. Well-known examples of these injectable or infused medications include adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade).
The Rise of Oral Immunomodulators
The search for a pill-based alternative to injectable therapies has shifted focus from blocking TNF directly to interrupting the signals that lead to its production. This has led to the development of a different class of drugs known as oral immunomodulators. While a true “oral TNF inhibitor” that works identically to its injectable counterparts is not a common therapeutic class, other oral medications achieve similar anti-inflammatory results through a different mechanism. The most prominent of these are the Janus kinase (JAK) inhibitors.
JAK inhibitors are small-molecule drugs, which allows them to be absorbed through the digestive system and work from inside the cell. They function by disrupting specific communication pathways within immune cells. When signaling proteins, including those stimulated by TNF, attach to a cell’s surface, they activate JAK enzymes inside the cell. These enzymes then relay the message to the cell’s nucleus, instructing it to produce more inflammatory proteins, called cytokines.
By blocking the action of these JAK enzymes, these oral medications effectively cut the wire on this internal communication system. This prevents the inflammatory signals from ever reaching the nucleus, reducing the overall production of cytokines that cause inflammation. This approach offers a different strategy for controlling the immune response, targeting the intracellular signaling process rather than the TNF proteins outside the cell.
This class of therapy has produced several approved oral medications for various autoimmune conditions. Drugs such as tofacitinib (Xeljanz), baricitinib (Olumiant), and upadacitinib (Rinvoq) are prescribed for diseases like rheumatoid arthritis and ulcerative colitis. They provide an oral treatment route for patients who may prefer it over injections or infusions.
Comparing Oral and Injectable Treatments
The primary distinction between JAK inhibitors and traditional TNF inhibitors is the administration method. Oral therapies involve a daily pill, while TNF inhibitors require subcutaneous injections or intravenous infusions. The convenience of a pill eliminates potential injection-site reactions.
This difference is a result of their molecular structure. TNF inhibitors are large biologic proteins that would be broken down by digestion, requiring injection. JAK inhibitors are small molecules that can survive the digestive process and be absorbed into the bloodstream.
Their mode of action also differs. TNF inhibitors work outside the cells to neutralize TNF proteins. In contrast, JAK inhibitors work inside the cell to block signaling pathways that produce inflammatory cytokines. Both approaches reduce inflammation by intervening at different points in the biological process.
Safety Profile of Oral Therapies
The safety profile of oral immunomodulators, particularly JAK inhibitors, is an important consideration for patients and healthcare providers. While offering a convenient administration method, these therapies carry a distinct set of potential side effects and risks. Common side effects can include nausea, headache, and an increased risk of upper respiratory infections like the common cold or sinus infections.
More significantly, this class of medication comes with a boxed warning from the U.S. Food and Drug Administration (FDA) highlighting more serious potential risks. These warnings were issued after studies revealed an increased risk of serious heart-related events, such as heart attack or stroke. The data also pointed to a higher incidence of blood clots, including deep vein thrombosis (DVT) and pulmonary embolism.
Because JAK inhibitors modify the immune system’s internal signaling, there is an increased risk of serious infections. The FDA warning also notes a potential for an increased risk of certain cancers, such as lymphoma and lung cancer, compared to patients treated with TNF inhibitors. These risks are carefully weighed against the therapeutic benefits by a healthcare provider when determining if this class of medication is the appropriate choice for a patient.