Addition of an immunomodulator can reverse antibody formation and loss of response in patients treated with adalimumab

Abstract

Summary Background Anti‐adalimumab antibodies (AAA) are associated with loss of clinical response (LOR). Addition of an immunomodulator has been shown to reverse immunogenicity and regain response with infliximab monotherapy. Similar data on adalimumab are lacking. Aim To study the impact of immunomodulator addition on the emergence of AAA and LOR among adalimumab therapy patients. Methods The databases of three tertiary medical centres were reviewed to identify patients who developed AAA during adalimumab monotherapy with resultant LOR, and received an immunomodulator as a salvage combination therapy. All sera were prospectively analysed using previously described ELISA assays. Clinical response was determined using appropriate clinical scores. Elimination of AAA, designated as ‘sero‐reversal’, elevation of drug levels and regained clinical response were the sought outcomes. Results Twenty‐three patients (21 Crohn's disease, and 2 ulcerative colitis) developed AAA with subsequent LOR and were thereafter prescribed an immunomodulator as salvage therapy (thiopurine n = 14, methotrexate n = 9). Eleven patients (48%) underwent sero‐reversal with gradual elimination of AAA, increase in drug trough levels and restoration of clinical response (median time to sero‐reversal 5 months). In 12 patients (52%), immunogenicity and loss of response could not be reversed. There was no difference between responders and nonresponders in the type of immunomodulators used or baseline clinical characteristics. Conclusions In almost half of inflammatory bowel disease patients developing anti‐adalimumab antibodies and loss of response, established immunogenicity of adalimumab can be gradually reversed by the addition of immunomodulator therapy with restoration of a clinico‐biological response. However, these observations need to be confirmed with larger studies.

Combination therapy for inflammatory bowel disease

“…Despite the questionable efficacy of CT when the anti-TNF is ADA, the same group has recently shown a similar result when adding IMM as salvage therapy to failing ADA in 23 patients (21 with CD, 2 with UC) with confirmed antibodies to ADA. Salvage therapy with IMM (14 with thiopurines, 9 with MTX) was associated with elimination of antibodies to ADA, increased ADA levels, and recapturing of response (median time to sero-reversal 5 mo) in 11 patients (48%)[26]. …”

Update on anti-tumor necrosis factor agents and other new drugs for inflammatory bowel disease

“…They had confirmed antibodies on repeat measurements, and they underwent sero-reversal after the addition of a thiopurine or methotrexate, which resulted in a clinical response and normalization of biomarkers. 157 In unresponsive patients with therapeutic anti-TNF drug levels and undetectable ADAs, the inflammation may not be TNF mediated; hence, the patient may need to switch to a drug with an alternative mechanism of action. 151 Patients with therapeutic anti-TNF drug levels in the presence of detectable ADAs may have either transient ADAs or a false positive ADA test.…”

“…164 165 However, infliximab rescue therapy may be even less efficacious in hospital inpatients with more severe, steroid refractory disease, with 90 day colectomy rates reported as 29-60%. [155][156][157][158][159][160][161][162][163][164][165][166][167][168] A cohort study of 115 patients found that standard three dose infliximab induction was associated with lower rates of clinical response (70% v 41%; P=0.004), clinical remission (41% v 17%; P=0.015), and endoscopic remission (26% v 4%; P=0.046) in patients with severe ulcerative colitis than in those with only moderately severe disease. 155 Similarly, patients with severe ulcerative colitis who did not respond to infliximab induction had significantly more fecal loss of drug, 169 and lower day 14 trough levels 170 compared with infliximab responders.…”

Golimumab for the treatment of ulcerative colitis

“…Association with an immunomodulatory drug also seems to be a good option. Indeed, based on previous infliximab and adalimumab studies, we could consider that adding a concomitant immunosuppressive therapy for patients treated with golimumab monotherapy has a possible impact on antidrug antibody formation, and hence on a beneficial clinical outcome [31,32]. Moreover, it has been demonstrated in several clinical trials that the risk of serious adverse events with combination therapy is not greater than that with TNF antagonist monotherapy [33,34].…”