**3. Sarcoidosis**

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.

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

IFN-alpha induces the expression of chemokine receptors on T lymphocytes [15].

associated disease comorbidity.

262 Antibody Engineering

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 diagnosis of symptoms along with histological examination is important.

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 may develop during the anti-TNF-alpha treatment. The anti-TNF-alpha treatment increases the IL-17 and IFN-ϒ expression and disturbs the balance between Th17 and Treg in favour of Th17. These two factors may result in the development of sarcoidosis [22].
