**Author details**

the above-mentioned manifestations of anti-TNF-alpha treatment occur, we first need to think of possible extraintestinal manifestations. Erythema nodosum (EN) is the most common skin manifestation of IBD, affecting 4–15% of the patients with CD and 3–10% of the patients with UC. EN is a reactive manifestation and correlates with the severity of the intestinal disease; it

Conversely, erythema nodosum may also be the first manifestation of paradoxically induced sarcoidosis. Pyoderma gangrenosum is also problematic. Pyoderma gangrenosum (PG) is the second most common, most serious and most debilitating skin manifestation in IBD. Unlike EN, the manifestations are more frequent in UC (5–12%) than in CD (1–2%) [55]. As we have already stated, pyoderma gangrenosum may also be a paradoxical response to anti-TNFalpha treatment. The issue of comorbidity or paradoxical reaction is also in the case of vasculitis present in IBD, as well as with inflammatory rheumatic diseases. As we have stated in the previous section, only discontinuation of the biologically medicinal product and spontaneous disappearance of skin manifestations is evidence of the adverse drug reaction. Acquiring a unified view of immune-mediated adverse effects requires thorough pharmacovigilance, reporting of adverse effects, long-term monitoring of safety registry data and complementing the polymorphism research. Each biological agent is original, and even the batches do not have to be absolutely identical. By introducing biological similar molecules (biosimilars), the situation can get even more complicated. The biosimilar does not need to have the same

Today, we know that antibodies against biologic agents are more likely to play a role in drug efficacy and hypersensitivity reactions, but some of the theories of pathogenesis of immunemediated reactions are also associated with their production. An important fact is that there are cases where a number of immune-mediated reactions have occurred in one patient [44]. We assume that in susceptible individuals, each new biological agent may interfere with a new mechanism of action with natural physiological processes and induce still new immunemediated adverse effects. Therefore, there is a tendency to apply one biological agent as long as possible to prevent further intervention in the cytokine cascade. We also know that the clinical response to the second and other biological agent is weaker than in treatment-naive patients, and the production of antibodies against biological medicinal products is more pronounced. The question of whether immune-mediated reactions are associated with the formation of antinuclear antibodies is also unclear. The literature describes cases of monitoring the efficacy of a biological medicinal product and the formation of antinuclear antibodies [17]. However, firm data have not yet been established; similarly, we only assume that some type of immune-mediated reactions may be associated with anti-dsDNA formation and lupus-like

reactions may be induced by TNF-alpha treatment with the formation of ANA.

simultaneously in one patient, e.g. alopecia areata and psoriasis.

Our work draws attention to the issue of adverse effects that occur due to the disruption of natural mechanisms—by dysregulation of the immune system and by starting various inflammatory pathways in genetically susceptible individuals. Some of the above-mentioned reactions have a common hypothesis of formation, such as the theory of interferon induction. This knowledge may lead to the assumption that one biological agent can cause two reactions

is aggravated in the case of colitis attacks [54].

270 Antibody Engineering

immunogenicity as the original molecule.

Karolína Vorčáková1 \*, Péč Juraj1 , Péčová Tatiana1 and Martinásková Klára2

\*Address all correspondence to: karolina.vorcakova@gmail.com

1 Department of Dermatology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Slovakia

2 Department of Dermatovenerology, University Hospital JA Reiman Prešov, Slovakia
