Your body is constantly seeking balance. Think of it as a finely tuned seesaw. This is especially true for your immune system and a key player called tumor necrosis factor or TNF. Some of the most lucrative drugs in modern medicine are TNF blockers. They include Enbrel (etanercept), Cimzia (certolizumab pegol), Humira (adalimumab), Remicade (infliximab) and Simponi (golimumab). TNF blockers (also called TNF inhibitors or anti-TNF therapy) are prescribed to treat immune-mediated inflammatory diseases (IMIDs). Can such drugs also trigger IMIDs?
Remicade and Scalp Psoriasis?
Q. I have been on Remicade for eight years. Recently I developed a severe scalp rash which required antibiotic and steroid treatment to get it under control.
My dermatologist is concerned that it could be scalp psoriasis triggered by Remicade. Is that possible?
A. Remicade (infliximab) is a powerful immune modulating drug prescribed for inflammatory bowel diseases, autoimmune arthritis and psoriasis.
Your dermatologist may be right, as shown by a new study (Clinical Gastroenterology and Hepatology, July 10, 2023). People taking medications like Remicade for inflammatory bowel disease had a higher rate of developing psoriasis or rheumatoid arthritis.
What Are Immune-Mediated Inflammatory Diseases (IMIDs)?
IMIDs are challenging conditions. They include a wide range of disorders that involve an overactive immune response.
Some Common IMIDs:
- Ankylosing spondylitis (AS)
- Crohn’s disease (CD)
- Hidradenitis suppurativa
- Juvenile idiopathic arthritis
- Rheumatoid arthritis (RA)
- Psoriatic arthritis (PsA)
- Ulcerative colitis
Such IMIDs are, to quote an overview in Nature Reviews Immunology (Sept. 13, 2021):
“…a common, clinically diverse group of conditions for which there are no current cures…Thus, they pose significant systemic medical challenges. Moreover, these diseases are often accompanied by various co-morbidities, including cardiovascular disease, metabolic and bone disorders and cognitive deficit, that further unfavourably impact quality of life and mortality.”
What Is TNF and What Does It Do?
This gets very complicated very fast. Please hang in here with me for a minute or two as I try to make this understandable. First, tumor necrosis factor (TNF) is a “cytokine.”
Do you remember the early days of the pandemic? We were hearing about patients with severe COVID-19 experiencing a “cytokine storm.” It is an overreaction to infection. The immune system goes overboard and starts to cause more harm than help.
Goldilocks wanted the porridge to be neither too cold nor too hot. If we were to borrow this metaphor, a cytokine storm would be the equivalent of boiling hot porridge. It would do damage instead of soothing hunger. You can learn more about cytokine storm in this article by a friend, David Fajgenbaum, MD, and his colleague Carl June, MD (New England Journal of Medicine, Dec. 3, 2020).
In a nutshell, cytokines are small proteins that signal the immune system to go to work. In addition to regulating immunity, they also have a direct effect on the body’s inflammatory response.
Infection triggers the body to make TNF. A cascade of events leads to inflammation and immune reactions that in turn help fight off bacterial or viral invaders.
The Pros and Cons of TNF:
Sometimes the inflammatory response continues after an infection has been defeated. In overdrive, TNF stimulates inflammation, which can lead to conditions like psoriasis, inflammatory bowel disease and rheumatoid arthritis.
The bottom line is that TNF helps manage immune cells. It is also a “cancer killer.” Remember, TNF stands for tumor necrosis factor. The definition of necrosis is basically death of cells or tissue. So, according to the National Cancer Institute:
“tumor necrosis factor-related apoptosis-inducing ligand is:
A cell protein that can attach to certain molecules in some cancer cells and may kill the cells.”
Paradoxically, TNF may also promote cancer as a result of uncontrolled inflammation. So, to make things more complex, TNF appears to be both a tumor promoter and a tumor destroyer.
What Do TNF Blockers Actually Do?
In the most simplistic explanation, TNF blockers block inflammation. Drug companies learned how to make monoclonal antibodies (mabs or mAbs) or “biologicals” to target tumor necrosis factor.
So, TNF blockers dampen down the immune system. By suppressing tumor necrosis factor, these pricey biologicals help control a range of inflammatory conditions in the skin, intestines and gastrointestinal tract.
The High Cost of TNF Blockers:
The price of drugs like Enbrel or Humira can be breathtaking. According to GoodRx, a month’s treatment with such medications could carry a retail cost of anywhere from $8,000 to $12,00 without a coupon. With a GoodRx coupon, the cost would still run over $6,000. Some people have good insurance. But if they have to kick in a co-pay, the cost could still be significant.
Some TNF blockers have lost patents. That means there are now competitors called “biosimilars.”
Think generics with a twist. These monoclonal antibodies are complicated to make. Unlike “small-molecule” meds for blood pressure or depression, biologic drugs are complex. Cells must be manipulated to create these tailored proteins.
That is, in part, why the price has been astronomical. The biosimilar TNF blockers will not be inexpensive. We’ve heard that one biosimilar for Humira could cost close to $1,000 a month. That is way less than the brand, but still pricey.
TNF Blockers and the Immune System:
Most health professionals agree that TNF blockers have revolutionized the treatment of immune-mediated inflammatory diseases. But is there a downside to IMIDs?
If you watch any television, you have no doubt seen commercials for TNF blockers. Did you pay attention to the warnings?
The announcer provides this caution about Humira:
“Humira can lower your ability to fight infection. Serious and sometimes fatal infections including tuberculosis and cancers including lymphoma have happened, as have blood, liver and nervous system problems, serious allergic reactions and new or worsening heart failure. Tell your doctor if you’ve been to areas where certain fungal infections are common and if you’ve had TB, hepatitis B, are prone to infections or have flu-like symptoms or sores. Don’t start Humira if you’ve had an infection.”
An Enbrel commercial has somewhat similar warnings:
“Enbrel may lower your ability to fight infection. Serious, sometimes fatal events including infections, tuberculosis, lymphoma, other cancers, nervous system and blood disorders, and allergic reactions have occurred. Tell your doctor if you’ve been someplace where fungal infections are common or if you’re prone to infection, have cuts or sores, have hepatitis B, have been treated for heart failure or if you have a persistent fever, bruising, bleeding or paleness. Don’t start Enbrel if you have an infection like the flu.”
Do you begin to get the idea that TNF blockers can affect the immune system in a way that might not always be desirable?
The TNF Blocker Boomerang:
A new study analyzed data from more than 100,000 patients in Denmark and France (Clinical Gastroenterology and Hepatology, July 10, 2023). Until now, doctors thought that using TNF blockers for one autoimmune condition would reduce the risk for others. To their surprise, the investigators found that patients taking these drugs were instead at 76% increased risk for developing other IMIDs such as rheumatoid arthritis, psoriasis and hidradenitis suppurativa.
The authors of this research note that TNF blockers are used to treat inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD) and a very nasty skin condition called hidradenitis suppurativa.
They then go on to note:
“Unexpectedly, however, treatment with anti-TNF alternately for IBD, rheumatoid arthritis, psoriasis, and hidradenitis suppurativa has been reported to lead to the occurrence of each of the other disorders. Such occurrences of these IMIDs have been referred to as paradoxical adverse events, defined as ‘the occurrence during biological agent therapy of a pathological condition that usually responds to this class of drug.’ If correct, the paradoxical effect of anti-TNF could have serious clinical implications.”
Their study was designed to determine if TNF blockers could actually trigger other auto-immune conditions. Remember, these were two large databases in France and Denmark.
The researchers propose that anti-TNF treatment could “dysregulate the immune system” in susceptible individuals. Put more bluntly, the very expensive drugs that are designed to reduce inflammation and calm an overactive immune system may actually be causing inflammation in some people. That could lead to the development of conditions like psoriasis and rheumatoid arthritis.
The researchers conclude:
“Our findings are unexpected and warrant further research into the mechanisms behind the paradoxical anti-TNF-caused occurrence of diseases that are normally indications for anti-TNF.”
Patients should not stop taking drugs such as Humira, Remicade or Simponi, but they may want to discuss this paradox with their clinicians.
Have you taken Humira, Enbrel or any other TNF blockers? How well did these drugs work? Did you develop any other IMIDs (immune-mediated inflammatory diseases)? Have you ever tried to stop an anti-TNF therapy? How did that go? Have you had to pay for access to a TNF inhibitor? Please give us some idea how much such drugs cost. Thank you for sharing your experience with these medications in the comment section below.