**12. Discussion**

pro-inflammatory cytokines and TNF-alpha play a key role [45]. Studies point to increased TNF-alpha levels in saliva and plasma in the patients with lichen planus [46, 47]. Papers indicating good therapeutic effect of TNF-alpha inhibitors on lichenoid lesions were also published. Some authors describe a similar theory of etiopathogenesis of lichen planus as in paradoxical psoriasis. As we have already mentioned in case of other immune-mediated reactions, the model in which anti-TNF-alpha induces IFN-alpha may also be valid for lichen and lichenoid reactions. Other studies indicate that type 1 IFN including IFN-alpha can induce

Morphea, also called localised scleroderma, is manifested by thickening of the skin and subcutaneous tissue due to the deposition of excessive amounts of collagen. There are only a few cases of morphea induced by TNF-alpha reported in the literature. Morphea may be induced by mechanical effects or by medications. The exact etiopathogenesis of TNF-alpha-induced morphea is not known, although there are several theories of possible etiopathogenesis. TNF inhibitors can act on tumour growth factor beta (TGF beta 1), a profibrotic cytokine that effects the growth and accumulation of extracellular matrix by the action of fibroblasts and endothelial cells. An increase in Th1 and Th17 proinflammatory cytokines has been demonstrated in the early stage of localised scleroderma. Th2 lymphocytes correlate with the severity of the disease and the extent of fibrosis. Inhibition of Th1 response induced by TNF-alpha inhibitors may lead to the prevalence of Th2 lymphocytes, which may be the cause of morphea [48].

Vitiligo is one of the other rare skin disorders that can occur with anti-TNF-alpha treatment. The role of anti-TNF-alpha inhibition in the development of vitiligo is complex and controversial. As with other paradoxical immune-mediated reactions, there are case studies where vitiligo has been significantly improved in anti-TNF-alpha therapy in vitiligo patients. The therapeutic effect of anti-TNF-alpha treatment on vitiligo is believed to be blocking the physiological effect of TNF-alpha on melanogenesis. According to the literature, TNF-alpha reduces tyrosinase lev-

Cases of newly developed dermatomyositis and polymyositis have been described in a number of papers. Most of the patients belonged to the group of patients treated for rheumatic disease. The authors predict a possible association between the presence of myositis-specific anti-Jo-1 autoantibodies and anti-TNF-alpha treatment in relation to newly developed derma-

els. The melanocytic effect of TNF-alpha on vitiligo has also been demonstrated [49].

tomyositis and polymyositis in patients with rheumatoid arthritis [50].

lichen planus through the activation of cytotoxic CD8 + T cells [45].

**9. Morphea-like reactions**

268 Antibody Engineering

**10. Vitiligo**

**11. Other skin manifestations**

TNF-alpha inhibitors are biotechnologically produced medicinal products that differ from conventional drugs in their properties, size and structure. These large molecules, even with the same mechanism of action in the form of inhibiting TNF-alpha, may act differently and they may have other adverse effects. Therefore, each biological agent is unique. Pre-clinical studies did not foreseen that TNF-alpha inhibitors will disrupt and change immunological pathways. In 2004, the first case of TNF-alpha-induced psoriasis [51] was described, and since then a number of papers have been published with immune-mediated skin reactions induced by TNF-alpha inhibitors. Their clinical spectrum is still widening; although in some cases, there are just a few case reports worldwide. Paradoxical psoriasis is the most researched and most common skin immune-mediated adverse effect. Its exact etiopathogenesis is still unclear. Development in the area of psoriasis etiopathogenesis is significantly moving forward; the Th17 pathway, which is now considered to be crucial, was discovered only a few years ago, and now we are using anti-IL17 inhibitors in clinical practice.

In conventional systemic therapy, the emergence of immune-mediated reactions is considered a comorbidity of the disease. Comorbidities are diseases that occur more frequently with the primary disease than in the general population [52]. It is assumed that the diseases have a common genetic predisposition that encodes certain inflammatory pathways. A very good example is the IL23 receptor gene, which explains the increased incidence of psoriasis in patients with ankylosing spondylitis, Crohn's disease and ulcerative colitis [52]. The literature contains only very little data about gene polymorphisms in paradoxical psoriasis. One study of gene polymorphisms that might be responsible for the above-mentioned reactions was published in 2015 by Cabaleiro et al., who observed in a group of 161 patients with psoriasis that 25 patients experienced a change in the morphology of psoriasis and 88% of the patients in the group had guttate psoriasis [16]. From a clinical point of view, it is debatable whether the monitored group had a real paradoxical psoriasis or whether it was just a worsening of the clinical condition, which is manifested in guttate form. The definition of a paradoxical psoriasiform reaction is newly induced or markedly clinically worsened psoriasis. As mentioned earlier, Collmar et al. reported that the most common clinical manifestations were palmoplantar pustulosis and chronic plaque psoriasis. Guttate forms are found in only 12% of the patients [11]. The problem of determining whether it is an adverse effect or not is encountered also with other immune-mediated reactions.

Wang et al. highlight in their paper the importance of properly diagnosing the adverse effect. The Naranjo Adverse Drug Reaction Probability Scale is used for determining the adverse effects. Based on this scoring system, it is possible to calculate the likelihood if it is an adverse drug reaction or not [41]. A very difficult situation is when determining the adverse effects in patients with IBD. More than 40% of the patients with chronic inflammatory bowel disease have extraintestinal manifestations. They are more common in the case of Crohn's disease (CD) than in patients with ulcerative colitis (UC). The most common manifestations are peripheral arthritis, aphthous stomatitis, uveitis and erythema nodosum and pyoderma gangrenosum. Skin is the most frequently affected organ in extraintestinal manifestations [53]. Therefore, if 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 is aggravated in the case of colitis attacks [54].

**Author details**

Karolína Vorčáková1

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Immune-Mediated Skin Reactions Induced by Recombinant Antibodies and Other TNF-Alpha…

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 immunogenicity as the original molecule.

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.

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