**2. Psoriasis**

TNF-alpha inhibitors have become a revolutionary medication in the treatment of chronic psoriasis in recent years. Conversely, psoriasis or psoriasiform reaction is one of the most common immune-mediated reactions. Therefore, the formation of TNF alpha-induced psoriasis is also called a paradoxical reaction. All of the mentioned TNF-alpha antagonists can induce psoriasis. Cases have been reported from all indications where anti-TNF-alpha treatment is given. According to the literature, the incidence of paradoxical psoriasis is 1.04–3.0 cases per 1000 patient-years, the percentages varying widely from 0.6 to 5.3% [8]. The incidence of the manifestation is not age and gender related; some studies also show other controversial data. Manifestation may occur in any period of time during the treatment, from weeks, months, up to the years. The average time of developing psoriasis is 10 months [9, 10]. Concomitant treatment with another immunosuppressant does not appear to prevent paradoxical psoriasis, although combined suppression is used in the treatment of immune-mediated reactions.

is a link to possible significant interference of the anti-TNF-alpha therapy with the immune system, which subsequently induces the above-mentioned responses. Others associate the diseases with the production of antibodies against the biologic agents and include the symptoms among hypersensitivity reactions. However, the individual genetic predisposition, which may be essential in detecting of immune-mediated reactions, must not be overlooked. The reactions include a broad variety of diseases such as lupus-like syndrome, autoimmune arthralgia, psoriasis, sarcoidosis, dermatomyositis, hepatitis, vasculitis, neurological demyelinating diseases and the like. In this chapter, we will briefly characterise the most common skin immune-

TNF is produced as a transmembrane protein (tmTNF), which is later cleaved by an enzyme metalloproteinase to its soluble form, sTNF [1]. Both TNFR1 and TNFR2 receptors signal through pathways that are proinflammatory and anti-apoptotic. Moreover, TNFR1 can signal directly through death domain caspase-dependent pathways that lead to apoptosis [2]. TNFR1 plays a role in response to bacterial infection [3] and TNFR2 may downregulate

Currently, five complete recombinant antibodies—infliximab, etanercept, adalimumab, golimumab and certolizumab pegol—are available TNF-α inhibitors. They are biotechnologically produced and administered as systemic drugs modifying the biological response and signalisation on the molecular level. The structural differences are key to different risk for adverse effects such as granulomatous infections, with TNF antibodies associated with higher risk compared to soluble receptor, possibly due to binding to tmTNF receptor on the activated cells [5]. Infliximab is a recombinant chimeric monoclonal antibody containing human IgG1 Fc and variable murine regions, which forms complexes with both sTNF and tmTNF. It induces the lysis of macrophages and monocytes by cytotoxicity dependent on complement and antibodies [6]. The intravenous administration is applied by a weight-dependent dose. Drugmediated apoptosis and monocytopenia are linked to infliximab as well as its ability to bind more avidly to different forms of TNF-α [7]. Adalimumab is a humanised monoclonal antibody containing human IgG1 Fc and human variable regions that bind sTNF as well as tmTNF. The other available humanised monoclonal antibody, cetrolizumab pegol is a pegylated monoclonal Fab fragment with polyethylene glycol binding to soluble and membrane-bound TNF-α, inhibiting the proinflammatory actions of this cytokine. Unlike other TNF inhibitors, owing to its lack of the Fc component, it is incapable of fixing complement or binding to Fc receptors. Golimumab is a human anti-TNF monoclonal antibody containing the IgG1 constant region. The other group of TNF inhibitors consists solely of etanercept, which is soluble TNF receptor containing the human IgG1 Fc portion fused to the extracellular portion of human TNFRp75. It creates less stable complexes with tmTNF and firmly binds to trimeric forms of soluble TNF.

TNF-alpha inhibitors have become a revolutionary medication in the treatment of chronic psoriasis in recent years. Conversely, psoriasis or psoriasiform reaction is one of the most common

mediated reactions induced by TNF-alpha inhibitors.

inflammatory signals driven by TNF [4].

260 Antibody Engineering

**2. Psoriasis**

The clinical manifestation of paradoxical psoriasis may be variable in nature. Paradoxical psoriasis includes not only newly developed psoriasis but also a radical worsening of already existing psoriasis. The disease is most commonly manifested in the area of palms and soles in the form of palmoplantar pustulosis, which is reported in 56% of cases, other most common forms include chronic plaque psoriasis in 50% of the patients and guttate manifestations, which affect 12% of the patients. Patients may also suffer from multiple forms of disease simultaneously (15%) [11]. Other manifestations include scalp or nail involvement. There are also cases of alopecia areata and paradoxical psoriasis. Some authors assume that monoclonal antibodies are associated with development of de novo-induced psoriasis, while the etanercept fusion protein causes a worsening of pre-existing psoriasis [12] (**Figure 1**).

The exact etiopathogenesis of paradoxical psoriasis is not clear, and there are several opinions and theories. The first of them states that the manifestations are a hypersensitive reaction to a drug, not a newly developed classical disease. There are papers that due to the increased production of antibodies against biologics describe manifestations of induced generalised pustulosis that could fit into the spectrum of hypersensitivity reactions. Other papers disprove this theory on the basis of skin biopsy of the patients with TNF-alpha-induced psoriasis. The incidence of palmoplantar pustulous psoriasis in the common psoriatic population is significantly lower, representing 1.7% compared to 46.2% in patients with paradoxical reaction. This fact supports the theory that it should not be a new classical form of psoriasis [13].

The most widespread theory links the relationship between TNF-alpha and type 1 interferon alpha. TNF-alpha inhibits the maturation of plasma dendritic cells that produce IFN-alpha.

**Figure 1.** Patient with severe palmoplantar pustular psoriasis induced after 4 weeks of using adalimumab, this severe reaction lead to discontinuation of adalimumab.

The central role of INF-alpha in the etiopathogenesis of paradoxical psoriasiform reaction consists of cross-regulation between TNF-alpha and IFN-alpha. TNF-alpha blockers can lead to overproduction of INF-alpha. In papers that confirm this theory, increased expression of interferon alpha was demonstrated in skin biopsy compared to common psoriatic findings [14]. It is also believed that the expression of CXCL9 and CXCR3 chemokine receptors is increased, which promote the migration of lymphocytes into psoriatic dermis resulting in skin damage. IFN-alpha induces the expression of chemokine receptors on T lymphocytes [15].

The therapeutic approach for anti-TNF-alpha-induced psoriasis is individual in each patient. A very important factor is the condition of the underlying disease, for which the treatment was indicated. In case of a serious condition that was stabilised with the treatment, we try to keep the biologic agent as long as possible. Equally important is what other therapeutic options are available. While in rheumatology we have a wide variety of biological medications for most diseases, including some others than anti-TNF-alpha inhibitors, the situation in

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Literature sources mention the following procedures: if the skin psoriatic manifestations involve up to 5% of the body surface, the first-line therapy should be topical (corticosteroid therapy, keratolytic therapy, treatment with vitamin D derivatives) followed by phototherapy and, in case of resistance, introducing methotrexate to the patient's therapy. In case that more than 5% of the body surface is involved, the recommended first-line therapy consists of topical corticosteroids and phototherapy, followed by methotrexate, cyclosporine and retinoids [11]. When setting up the combined suppression, the patient's comorbidities are very important. Most patients with underlying rheumatologic disease were treated with methotrexate in the past. For IBD patients, it is important to use the injection form of methotrexate, otherwise the drug may not be resorbed. In case of refractory manifestations and contraindications of combined systemic therapy, we consider discontinuing the anti-TNF-alpha agent. Interdisciplinary cooperation, consideration of the underlying disease and reassessment of

One of the so-called paradoxical reactions is also newly developed sarcoidosis during the anti-TNF-alpha therapy. The anti-TNF-alpha therapy was described as a possible successful therapeutic modality in severe sarcoidosis manifestations. On the other hand, there is a growing number of cases that are caused by the treatment. More than 50 cases of TNF-alphainduced sarcoidosis have been reported in the literature. Treatment with etanercept induced nearly 2/3 of the cases, and others were caused equally by infliximab and adalimumab. In most patients, the symptoms appeared after several months (1–69). Concomitant diseases include rheumatoid arthritis (in 60%), ankylosing spondylitis (in 20%), as well as psoriasis, Juvenile idiopathic arthritis (JIA) and IBD. In the clinical picture of anti-TNF-alpha-induced sarcoidosis, the pulmonary and cutaneous forms of the disease were dominant. In an aggregate paper including 38 patients, 74% of the patients suffered from the pulmonary form and 29% from the skin manifestations. The skin symptoms were manifested as erythema nodosum, pigmented scars and nodular lesions [19]. Literature data indicate a possible occurrence of sarcoidosis in 0.04% of the patients treated with TNF-alpha inhibitors [20]. Differential

The role of anti-TNF on granuloma [21] and the different behaviour of antibodies and soluble anti-TNF alpha receptor in granulomatous diseases, with a greater tendency of etanercept to induce granulomatous reactions, may account for the occurrence of lesions. Monoclonal antibodies may induce apoptosis in activated monocytes and T cells. Sarcoidosis-like lesions

diagnosis of symptoms along with histological examination is important.

patients with inflammatory bowel diseases (IBD) is much more complex.

further therapeutic procedure are all very important.

**3. Sarcoidosis**

One of the latest theories involves the Th17 pathway. In recent years, the Th17 signalling pathway is considered to be the major pathway of psoriasis etiopathogenesis. TNF-alpha may cause dysregulation in the immune system, which may cause the following changes. Activation of the IL-12/IL-23 pathway activates the Th17 signalling pathway followed by the production of IL-1b, IL-17, IL-21 and IL-22 together with an increased production of IL-17A and IL-22, hyperactivation of the Th17 and Th1 pathway and reduction of Treg activity [8, 15].

The genetic predisposition in patients with paradoxical reactions is not fully elucidated. Comorbidities are diseases that occur simultaneously with primary disease in higher prevalence compared to general population. Psoriasis comorbidities include a large group of diseases that are treated with anti-TNF-alpha therapies. It is believed that the genetic predisposition of an individual should also be essential for the development of immune-mediated reactions. There is a large group of "susceptibility" genes that are characteristic of several diseases and encode common inflammatory pathways. Polymorphisms of these genes are the subject of scientific research. Cabaleiro et al. presented the first paper studying 25 patients who developed paradoxical psoriasis genotyped for 173 single-nucleotide polymorphisms (SNPs) using the Illumina Veracode genotyping platform. Multivariate logistic regression revealed that five SNPs (rs11209026 in IL23R, rs10782001 in FBXL19, rs3087243 in CTLA4, rs651630 in SLC12A8 and rs1800453 in TAP1) were associated with paradoxical reactions [16].

Recently, we presented a study where we analysed antinuclear antibodies (ANA) and anti-double stranded DNA (dsDNA) antibodies in 10 patients with anti-TNF-alpha treatment induced psoriasis. ANA and anti-dsDNA antibodies were detected by ELISA. ANA serum samples were positive in 10% patients and anti-dsDNA antibody samples in 70% patients. The mechanism driving the formation of ANA and anti-dsDNA antibodies is poorly understood and their clinical significance is unknown [17]. In the literature, the frequency of ANA and anti-dsDNA antibodies in the patients after anti-TNF-alpha treatment varies extremely, possibly due to different methods of detection used. Pink et al. in their study, suggest that the development of ANA and anti-dsDNA antibodies on anti-TNF treatment may act as a marker of forthcoming treatment failure. In anti-TNF-alpha-induced lupus erythematosus, ANA and anti-dsDNA antibodies are well established and quite common (ANA, 90%; anti-dsDNA, 70–90%), but we have limited data about other immunological mediated adverse reactions [18]. Our data suggest that paradoxical psoriasis induced by anti-TNF inhibitors is associated with production of anti-dsDNA autoantibodies, but not with production of ANA antibodies. Further prospective research is necessary before general recommendations for daily practice can be announced. Genetic predisposition, clinical manifestation and production of anti-dsDNA antibodies seem to be fundamental in differentiation between adverse effects of anti-TNF-alpha treatment and associated disease comorbidity.

The therapeutic approach for anti-TNF-alpha-induced psoriasis is individual in each patient. A very important factor is the condition of the underlying disease, for which the treatment was indicated. In case of a serious condition that was stabilised with the treatment, we try to keep the biologic agent as long as possible. Equally important is what other therapeutic options are available. While in rheumatology we have a wide variety of biological medications for most diseases, including some others than anti-TNF-alpha inhibitors, the situation in patients with inflammatory bowel diseases (IBD) is much more complex.

Literature sources mention the following procedures: if the skin psoriatic manifestations involve up to 5% of the body surface, the first-line therapy should be topical (corticosteroid therapy, keratolytic therapy, treatment with vitamin D derivatives) followed by phototherapy and, in case of resistance, introducing methotrexate to the patient's therapy. In case that more than 5% of the body surface is involved, the recommended first-line therapy consists of topical corticosteroids and phototherapy, followed by methotrexate, cyclosporine and retinoids [11]. When setting up the combined suppression, the patient's comorbidities are very important. Most patients with underlying rheumatologic disease were treated with methotrexate in the past. For IBD patients, it is important to use the injection form of methotrexate, otherwise the drug may not be resorbed. In case of refractory manifestations and contraindications of combined systemic therapy, we consider discontinuing the anti-TNF-alpha agent. Interdisciplinary cooperation, consideration of the underlying disease and reassessment of further therapeutic procedure are all very important.
