**8. Lichen ruber planus and lichen planus-like reaction**

Several cases of lichen planus and lichen planus-like paradoxically incurred lesions induced by anti-TNF-alpha therapy were reported in the literature. The manifestations have different clinical variability, including mucosal signs, but histologically they have signs of lichen planus.

The clear cause of lichenoid reactions in the treatment of anti-TNF-alpha is not known. Lichen is T-cells and dendritic cells mediated dermatosis. As with other immune-mediated diseases, 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 lichen planus through the activation of cytotoxic CD8 + T cells [45].

**12. Discussion**

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

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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

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

years ago, and now we are using anti-IL17 inhibitors in clinical practice.

also with other immune-mediated reactions.
