Paradoxical Inflammatory Bowel Disease Following Anti-TNF Alpha Therapy for Rheumatoid Arthritis
Background:
Paradoxical adverse events (PAEs) have emerged as a well-recognized phenomenon in individuals undergoing biological treatment for chronic immune-mediated disorders. Dermatologic, ocular, and gastrointestinal issues have been documented as side effects of agents targeting tumor necrosis factor-alpha (TNF-α). Potential pathophysiological mechanisms underlying PAEs include cytokine dysregulation, variations in immunological characteristics of monoclonal antibodies and soluble TNF-α receptors, and unopposed type I interferon production. The risk factors for paradoxical inflammatory bowel disease (IBD) in patients taking TNF-α inhibitors are not fully understood. The purpose of this study is to report the incidence of IBD following the use of TNF-α inhibitors in patients with rheumatoid arthritis (RA).
Methods:
A database study using the TriNetX platform – a real-time research network of 59 U.S. healthcare organizations – identified patients diagnosed with RA and subsequently treated with infliximab, adalimumab, etanercept, certolizumab, or golimumab. Patients with prior history of Crohn’s Disease or Ulcerative Colitis diagnosis were excluded from the sample. Demographics and clinical features were collected, including comorbidities of circulatory, nervous, and endocrine systems. The primary outcome analyzed was incidence of Crohn’s Disease or Ulcerative Colitis within 5 years of initiating TNF-α inhibitor therapy. Secondary outcomes included incidence of other autoimmune conditions within 5 years following TNF-α inhibitor initiation.
Results:
105,706 patients met the inclusion criteria. The average age at initiation of TNF-α inhibitor therapy was 54 +/- 15.6 years. The gender distribution was 74% female, 25% male, and 1% unknown. The racial distribution was 72% Caucasian, 10% African American, and 18% other. The most common comorbidities within the sample included hypertension (30%), dyslipidemia (23%), thyroid disorder (15%), diabetes mellitus (12%), and dermatitis/eczema (10%). 541 patients (0.5%) presented with IBD within 5 years of initiating TNF-α inhibitor therapy for RA. For these patients, Kaplan-Meier analysis revealed a 99.2% 5-year survival probability. 785 patients (0.8%) of patients were diagnosed with autoimmune thyroiditis, 136 (0.1%) were diagnosed with autoimmune hepatitis, 26 (0.03%) were diagnosed with encephalitis/encephalomyelitis, 18 patients (0.02%) were diagnosed with autoimmune hemolytic anemia, and 12 patients (0.01%) were diagnosed with autoimmune polyglandular failure with 5 years of beginning TNF-α inhibitor therapy.
Conclusions:
In conclusion, this study evidences IBD as a rare complication of TNF-α inhibitor therapy for RA, occurring in < 1% of this patient population. Our findings suggest that this paradoxical adverse event does not compromise 5-year mortality rates in patients with RA. Incidence of other adverse immune conditions - hepatitis, encephalitis/encephalomyelitis, hemolytic anemia, and polyglandular failure - occur with much less frequency than IBD in this patient population following administration of TNF-α inhibitors, whereas incidence of autoimmune thyroiditis occurs more often than paradoxical IBD. Further studies are needed in order to elucidate whether paradoxical IBD occurs solely due to TNF-α inhibitor therapy, or arises independently of this therapeutic regimen.
