TNF Inhibitor Induced Psoriasis

Tumor Necrosis Factor Alpha (TNF-alpha) Inhibitors Trigger “Paradoxical Psoriasis” in 1-7% of Patients

TNF Inhibitors have been used in treating a variety of immune mediated conditions since the first drugs (Etanercept and Infliximab) were first approved in 1998. To date, there are 5 main TNF inhibitors and these include etanercept, infliximab, adalimumab, certolizumab pegol and golimumab.

These drugs are used to treat a wide array of immune mediated conditions including rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ulcerative colitis, Crohn’s disease

TNF inhibitors can be helpful in treating psoriasis, a disease that affects about 2-3 % of the world’s population. In fact, until recently, they had a key first line position for treating refractory plaque psoriasis. Newer biological medications, including the IL-17 inhibitors, IL-23 inhibitors and IL-12/23 inhibitors are to some degree replacing the TNF inhibitors as first line agents in the treatment of psoriasis. Nevertheless, TNF inhibitors remain a top option.

TNF Inhibitors Can Treat Psoriasis and can Also Paradoxically Cause Psoriasis.

It is very well recognized that some medications can cause or exacerbate psoriasis. Well recognized drugs in this group include lithium, beta-blockers, imiquimod, chloroquine, terbinafine, ACE-inhibitors, bupropion and interferon. Newer, ‘targeted’ therapies with the potential to cause psoriasis include TNF inhibitors, anti-PD1 immune checkpoint inhibitors, VEGF antagonists, and rituximab.

Paradoxical Psoriasis

The ability of TNF inhibitors to cause psoriasis rather than be used to treat psoriasis is called “paradoxical psoriasis”. The terms TNF inhibitor induced Psoriasis and paradoxical psoriasis can be used interchangeably.

The histopathology of paradoxical psoriasis is quite similar to typical psoriasis - although experts debate back and forth as to whether there are actually some features that don’t perfectly match up to true psoriasis. For the most part, paradoxical mimics typical psoriasis.

How common is TNF inhibitor induced Psoriasis?

The prevalence of anti-TNF-induced psoriasis ranges from 1-7 %. In inflammatory bowel disease was estimated by Gurerra et al to be about 1.72%. In other studies, including a study by Lian et al, the phenomenon was estimated to be as high as 7.7 %.

Not all studies have suggested that TNF inhibitors cause psoriasis in all disease states. Despite the view that TNF inhibitor use by patients with rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis cause psoriasis, a 2022 meta-analysis of 14 articles by Yu Kyung Jun et al did not find that TNF inhibitors actually increased the risk of psoriasis in patients with inflammatory bowel disease.

In the pediatric literature, Cyrenne et al identified 210 patients with TNF induced psoriasis out of 4564 pediatric patients treated with these drugs. That put the frequency of the condition at 4.6 %.

What is the Epidemiology of TNF Induced Psoriasis?

TNF induced psoriasis can occur in both children and adults.

Many authors have shown that females comprised a greater number of cases. It ranges from just a slightly greater proportion of females than males to upwards of 70 % females affected by the phenomenon. The time from initiation of treatment to onset of lesions is around 8-11 months on average. Most cases therefore develop within the first year of treatment.

Patients with paradoxical psoriasis can have many underlying conditions. However, rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease account for the vast majority of background disease states in patients who develop TNF Inhibitor Induced Psoriasis. In a 2020 study of 102 patients with TNF Inhibitor Induced Psoriasis by Mazloom aet al, Crohn's disease accounted for 48% of cases and rheumatoid arthritis accounted for 24.5% of cases.

Which TNF inhibitors are most likely to cause TNF Inhibitor Induced Psoriasis?

Most cases of TNF Inhibitor-induced psoriasis are linked to infliximab, with fewer cases described with adalimumab, certolizumab, and etanercept.

In 2009, Ko et al evaluated 127 cases of TNF Inhibitor-induced psoriasis. Inflixmimab topped the list of TNF inhibitors implicated. There were 70 in patients on infliximab (55.1%), 35 using etanercept (27.6%), and 22 with adalimumab (17.3%).

Infliximab also stands out in the pediatric literature as also being the number one cause of paradoxical psoriasis from TNF inhibitor use. In 2021, Cyrenne et al showed that infliximab was the drug most likely to induce psoriasis in pediatric patients followed by adalimumab.

Types of Psoriasis that Medications can Cause

TNF inhibitors can cause all sorts of different types of psoriasis. Morphological types that have been described as drug reaction included plaque psoriatic skin lesions, palmoplantar psoriasis, nail psoriasis, scalp psoriasis leading to alopecia, pustular psoriasis, and erythrodermic psoriasis and inverse psoriasis.

Some studies suggest that palmoplantar psoriasis is a bit more common than plaque type psoriasis but other studies have suggested the opposite. In a 2020 study by Mazloom et al, the most common TNFI-induced psoriasis subtypes were plaque-type psoriasis (49.5%), scalp psoriasis (47.5%), and palmoplantar pustulosis (41%).

Among pediatric patients, Cyrenne et al found that the scalp was the most commonly affected area in TNF Inhibitor induced psoriasis (47.5%), followed by the ears (30.8%).

Risk factors for TNF inhibitors induced psoriasis

Female sex and smoking were more frequently associated with TNF-alpha inhibitor-induced psoriasis. A previous retrospective cohort study in inflammatory bowel disease patients also reported smoking as an important predictor of TNF inhibitor induced psoriasis.

In 2020, Ya et al also proposed that family history and psychological stresses in addition to smoking were important risk factors for TNF inhibitor induced psoriasis.

How is TNF inhibitor induced psoriasis best treated?

There are three options for treatment of TNF inhibitor induced psoriasis. Option 1 is to “treat through” the TNF inhibitor - in other words, one has the option to continue the TNF inhibitor and try to aggressively treat the psoriasis. Option 2 involves switching to a different TNF inhibitor and option 3 is to completely abandon the TNF inhibitor therapy altogether.

Option 1: Continuing the Same TNF I and Treating the Psoriasis (Treating through

Continuing the TNF inhibitor and trying to aggressively treat the skin disease is among the top option. This is often worth trying first as some patients with TNF inhibitor induced psoriasis respond well to basic psoriasis treatments.

In 2022, Lian et al described 10 patients who developed paradoxical psoriasis on TNF inhibitors. 8 of the 10 patients regained control of their skin disease despite continuing the TNF Inhibitor. In other words, 80 % of patients did well using option 1.

A 2020 study by Mazloom et al showed that topical medications alone improved or resolved TNFI-induced psoriasis in 63.5% of adult patients. Cyclosporine and methotrexate (>10 mg weekly) were often effective if topicals failed.

In a systematic review of pediatric patients by Cyrenne et al, it was found that the majority of patients continued the TNF inhibitor and treated the psoriasis they had with psoriasis-directed therapies.

Option 2: Switching to a New TNF Inhibitor

Changing to another TNF inhibitor is rarely a good option as it often does not clear psoriasis lesions. Nevertheless, it is an option.

In 2009, Ko et al showed that switching to a different anti-TNF agent led to resolution in only 15.4% of cases.

Among pediatric patients, a 2021 study by Cyrenne et al found in a systematic review that only 32.0% of those who switched to a new TNF inhibitor had complete clearance of their skin lesions.

Option 3: Stopping TNF Inhibitor Therapy

Stopping the TNF inhibitor group of drugs altogether is probably the option with the best chance of helping. Of course, that may not be the first step but it is one with a good chance of helping. In fact, many researchers have the view that TNF inhibitor psoriasis is different from regular psoriasis in that psoriasis caused by TNF inhibitors is not really a de novo type of psoriasis but simply a type of psoriasis that is maintained by blocking TNF signalling. For this reason, stopping TNF inhibitor therapy often proves extremely helpful in challenging cases of paradoxical psoriasis.

This is by no means a guarantee and in mild cases one may still consider option 1 (treating through). Ko et al suggested that cessation of anti-TNF therapy with systemic therapy led to resolution in 64.3% of cases. A 2020 study showed that discontinuation of the TNFI with or without other interventions improved or resolved TNFI-induced psoriasis in 67% of refractory cases.

In a series of 125 patients by Guerra et al, 37 % of patients with TNF Inhibitor Induced Psoriasis ultimately needed to stop their TNF inhibitors.

In the pediatric age group, stopping TNF inhibitors frequently helps a great deal as well. For example, Cyrenne et al found that among patients who were switched to another drug rather than a TNF inhibitor, 81% had complete clearance of their paradoxical psoriasis.

Summary and Final Comment

One needs to be on the lookout for paradoxical psoriasis or development of psoriasis-like skin lesions in those patients using TNF inhibitors. The phenomenon occurs in up to 7% of patients. There are three options for treatment of TNF inhibitor induced psoriasis including continuing the drug, changing to a new TNF inhibitor and stopping altogether.

References

Alessia Nidegger et al. [Paradoxical psoriasis induced by anti-TNF - a clinical challenge]. Rev Med Suisse. 2019 Mar 27;15(644):668-671.

Boggs J et al. Paradoxical psoriasis caused by tumour necrosis factor inhibitor therapy. Clin Exp Dermatol. 2021 Apr;46(3):580-582.

Brown G, Wang E, Leon A, et al. Tumor necrosis factor-alpha inhibitor-induced psoriasis: systematic review of clinical features, histopathological findings, and management experience. J Am Acad Dermatol. 2017;76(2):334–341.

Cyrenne et al. Paradoxical psoriasis in pediatric patients: A systematic review. Pediatr Dermatol . 2021 Sep;38(5):1086-1093.

Guerra I, Perez-Jeldres T, Iborra M, et al. Incidence, clinical characteristics, and management of psoriasis induced by anti-TNF therapy in patients with inflammatory bowel disease: a nationwide cohort study. Inflamm Bowel Dis. 2016;22(4):894–901.

Ko J et al. Induction and exacerbation of psoriasis with TNF-blockade therapy: a review and analysis of 127 cases. J Dermatolog Treat . 2009;20(2):100-8.

Lian N et al. Tumor necrosis factors-α inhibition-induced paradoxical psoriasis: A case series and literature review. Dermatol Ther . 2020 Nov;33(6):e14225.

Jun et al Antitumor necrosis factor treatment in patients with inflammatory bowel disease does not promote psoriasis development: A meta-analysis. Medicine (Baltimore). 2022 Jul 8;101(27):e29872.

Mazloom et al. TNF-α inhibitor-induced psoriasis: A decade of experience at the Cleveland Clinic. J Am Acad Dermatol . 2020 Dec;83(6):1590-1598.

Olteanu R, Zota A. Paradoxical reactions induced by tumor necrosis factor-alpha antagonists: a literature review based on 46 cases. Indian J Dermatol Venereol Leprol. 2016;82(1):7–12.

Pugliese D, Guidi L, Ferraro PM, et al. Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study. Aliment Pharmacol Ther. 2015;42(7):880–888.

Ya et al. Family history of psoriasis, psychological stressors, and tobacco use are associated with the development of tumor necrosis factor-α inhibitor-induced psoriasis: A case-control study. J Am Acad Dermatol . 2020 Dec;83(6):1599-1605.