**4. Lupus-like syndrome**

Systemic lupus erythematosus (SLE) is a common autoimmune disease, with 10% of SLE cases being drug-induced. The autoimmune drug-induced response is idiosyncratic, influenced by multiple factors, such as genetics, comorbidities, interactions with other medicinal products and external environmental factors [23]. Drug-induced lupus erythematosus (DILE) is defined as a lupus-like disease that is temporally related to drug exposure (from 1 month after the commencement of drug application but sometimes even more than 10 years) [24].

DILE may not meet all the SLE criteria. The most common manifestations are arthritis, serositis, the presence of ANA antibodies and anti-histone antibodies. The most important criterion is that the symptoms cease after discontinuing application of the suspected drug [25].

plaque psoriasis is ustekinumab. Ustekinumab is also a good alternative in the treatment of inflammatory bowel disease and in the treatment of spondylarthritis or psoriatic arthritis [31]. However, the literature contains also cases of an ustekinumab-induced DILE. Biologics with a different mechanism of action are alternative treatments, but it cannot be said whether other mechanisms of action (anti-IL13/23, anti-IL-17, anti-IL 6) will be a potential threat to DILE

**Figure 2.** Significant facial erythema, total weakness and laboratory elevated ANA antibodies were observed. After discontinuation of the treatment, gradual regression of skin manifestations and neutralisation of ANA antibodies took

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

http://dx.doi.org/10.5772/intechopen.72449

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The manifestations of vasculitis are another disease that is associated with the anti-TNF-alpha treatment. Several case reports and patient groups have been described in the literature. In almost half of the cases, leukocytoclastic vasculitis was histologically described, while the other patients included cases of necrotising vasculitis, lymphocytic vasculitis and urticarial

An aggregate paper of 118 cases of vasculitis newly formed during the anti-TNF-alpha treatment (99 cases of rheumatoid arthritis, 8 Crohn's disease, 5 juvenile rheumatoid arthritis, 3 ankylosing spondylitis, 3 psoriasis) presented skin manifestations in 86% of patients. The anti-TNF agent administered was etanercept in 60 (51%) cases, infliximab in 51 (43%), adalimumab in 5 (4%) and other agents in 2 (2%). Purpura was manifested in 63% of the patients, whereas others had other skin manifestations of vasculitis, such as ulcerations, nodosities, maculopapular manifestations, etc. Systemic involvement was observed in 24% of patients. Immunological examinations showed that the antinuclear antibodies (ANAs) were positive in 27 patients and antineutrophil cytoplasmic antibodies (ANCAs) in 11 patients (pANCA in 5 patients and cANCA in 1 patient). Treatment in the form of anti-TNF-alpha discontinuation was used in 11 patients, 71 of whom completely recovered (41% of them had additional immunosuppressive therapy) [33]. Mohan et al. describe in an aggregate paper including 50 patients that almost 63% of patients experienced a complete recovery of the manifestations

induction in genetically predisposed individuals.

place. Manifestations were assessed as DILE after infliximab.

after discontinuation of the anti-TNF-alpha treatment [34].

**5. Vasculitis**

vasculitis [32].

DILE induced by TNF-alpha inhibitors appears to be a separate DILE group with different signs compared to classical DILE. Women are more often affected than men, with an average age between 46.2 and 50.9 years. The average time to the manifestation of symptoms is 40.6 weeks from the commencement of drug treatment. Skin manifestations occur more frequently than in classical DILE and include butterfly erythema, photosensitivity and other skin manifestations of systemic and sub-acute lupus. The exact mechanism of DILE formation during anti-TNF-alpha treatment is unknown. Post-marketing follow-ups have demonstrated that DILE induced by TNF-alpha inhibitors may occur across all anti-TNF-alpha inhibitors. However, it is more often reported with the use of infliximab (0.19–0.22%) and etanercept (0.18%) compared to adalimumab (0.10%). An increase in ANA or anti-DNA antibodies in patients treated with anti-TNF-alpha therapy is known and relatively common [26]. The frequency of elevated ANA antibodies was higher in a greater number of patients treated with infliximab compared to a group of patients treated with etanercept [27]. Anti-dsDNA antibodies as well as ENAs (extractable nuclear antibodies) and low complement levels have been described more often than in case of classical DILE. Particularly, anti-histone antibodies have been more common in DILE induced by anti-TNF-alpha treatment [28, 29] (**Figure 2**).

The basic therapeutic procedure is the discontinuation of the treatment with the drug that induced the symptoms. In more severe conditions, it is necessary to add suppressors—corticosteroids, azathioprine, cyclosporine and methotrexate. Treatment selection is also based on the status of the underlying disease and comorbidities of the patient. In psoriasis, it is recommended to avoid systemic corticosteroids for a possible rebound phenomenon after discontinuation. There is no need to discontinue the treatment of anti-TNF-alpha in the case of ANA positivity or in very mild DILE manifestations [26]. Only limited data are available in the literature describing a switch of the treatment to another anti-TNF-alpha agent. Some authors claim that a similar reaction can be caused by any of the agents from the group of anti-TNF-alpha inhibitors [30]. As stated by Lomicova et al., an alternative treatment for chronic Immune-Mediated Skin Reactions Induced by Recombinant Antibodies and Other TNF-Alpha… http://dx.doi.org/10.5772/intechopen.72449 265

**Figure 2.** Significant facial erythema, total weakness and laboratory elevated ANA antibodies were observed. After discontinuation of the treatment, gradual regression of skin manifestations and neutralisation of ANA antibodies took place. Manifestations were assessed as DILE after infliximab.

plaque psoriasis is ustekinumab. Ustekinumab is also a good alternative in the treatment of inflammatory bowel disease and in the treatment of spondylarthritis or psoriatic arthritis [31]. However, the literature contains also cases of an ustekinumab-induced DILE. Biologics with a different mechanism of action are alternative treatments, but it cannot be said whether other mechanisms of action (anti-IL13/23, anti-IL-17, anti-IL 6) will be a potential threat to DILE induction in genetically predisposed individuals.
