Paradoxical Toxicities with TNF Inhibitors Save

Something is curiously wrong when a drug induces the disease it is intended to treat. Yet this phenomenon has been described with all five FDA-approved TNF inhibitors.

There are odd and surprising reports of TNF inhibitors (TNFi) implicated in causing psoriasis, inflammatory bowel disease, sarcoidosis, and demyelinating diseases – all conditions for which TNFi treatment has been advocated.

Here are the reports and evidence for several of the drug-induced syndromes seen with TNFi.

Inflammatory Bowel Disease

• The Journal of Rheumatology reports 3 cases of etanercept associated, endoscopically-proven IBD.  They present 3 cases of adult ETN-treated patients who developed IBD that improved after ETN discontinuation and initiation of adalimumab (ADA). Their review of literature disclosed 53 cases of IBD after etanercept use. Most of these were in a juvenile population. The average age at IBD onset was 17.3 years, and the average time from ETN introduction to IBD onset was 27 months (± 24). All were unified by the improvement in IBD symptoms after discontinuing ETN. (Citation source: http://buff.ly/2oUrfOx)
• Another French report of 16 patients found the same TNFi-induced IBD in 16 patients, 14 patients received etanercept and two had infliximab. They had a mean age of 41 yrs and were taking TNFi for AS (12 patients), JIA (2 patients) and one each with RA and PsA. The onset time from TNFi to IBD was 29.3 ± 20.1 months. Endoscopic and histological studies found typical Crohn's disease (8 patients), Crohn's-like disease (6 patients), and one each with ulcerative colitis and indeterminate colitis. In all cases, improvement was seen by TNFi discontinuation and replacement with another monoclonal anti TNF-α antibody.  (Citation source http://buff.ly/2oUIuzs) 

Psoriasis Induced by TNFi

This issue was previously covered by RheumNow here.

• This rare adverse event is estimated to occur in 1/1000 and been described with all TNFi used to treat patients with RA, IBD or even psoriasis. A systematic review of 216 cases of new-onset TNF-α inhibitor-induced psoriasis, showed the mean age to be 38.5 years, with psoriasis onset after an average of 14.0 months of TNFi.  The most common presentations included plaque (44.8%), palmoplantar pustular (36.3%) psoriasiss and psoriasiform dermatitis (19.9%), severe scalp involvement (7.5%), and generalized pustular psoriasis (10.9%). The most effective management of this was: 1) TNFi discontinuation leading to resolution or improvement in 94%; 2) switching TNFi inhibitors had nearly 55% improving or resolved; and 3) continued TNFi therapy showed only 33% resolved and 57% improving their psoriasis.

Sarcoidosis Induced by TNFi

• There are several individual case reports of sarcoidosis developing in patients receiving TNFi. These were largely in older adults, all manifesting Hilar and mediastinal lymphadenopathy, pulmonary nodules and noncaseating granulomas after 1-2 years of therapy. A literature review of 27 histological proven sarcoidosis  shows most cases arising in ETN treated patients with nearly all resolving with drug discontinuation. (Citation source: http://buff.ly/2oUtr8T)

Demyelinating Disease Complicating TNFi Use

• TNFα has been shown to be integral to the pathogenesis of multiple sclerosis and thus, the TNFi lenercept and infliximab were studied in clinical trials of MS patients. While no clinical benefit was seen, there was a paradoxical, and unexplained, worsening of both clinical manifestations and CNS imaging evidence of MS in these trials. Consequently the FDA has added  “demyelinating disease” as a warning and potential complication of TNFi use.
• A recent report from the dermatology literature examined the frequency of such events. A systematic review of 6990 psoriasis patients receiving etanercept resulted in one reported case of multiple sclerosis. Similarly, 5204 patients treated with adalimumab found no cases and 2322 psoriasis patients treated with infliximab resulted in one case of demyelinating polyneuropathy. The literature identified only 19 individual cases of demyelinating disorders resulting from TNFi treatment, suggesting overall, this was a very, very rare event. (Citation source http://buff.ly/2pHQRB0)

Conclusion.

The mechanisms underlying these paradoxical adverse events is unknown but many suggest that TNF inhibition may lead to a rebound excess of interferon-α and, under certain host genetics or factors, this may drive the development of drug-induced toxicities (e.g., lupus, psoriasis, MS, sarcoidosis, etc).