**5. Vasculitis**

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

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

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

is that the symptoms cease after discontinuing application of the suspected drug [25].

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

Th17. These two factors may result in the development of sarcoidosis [22].

**4. Lupus-like syndrome**

264 Antibody Engineering

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 vasculitis [32].

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

Vasculitis manifestations in patients with severe seropositive rheumatoid arthritis are debatable, because the manifestations may be evaluated as rheumatic vasculitis, which is an extraarticular manifestation of rheumatoid arthritis and not drug-induced vasculitis. In such cases, some authors recommend discontinuation of the anti-TNF-alpha treatment with possible reexposure to the given treatment [32]. The same situation applies also to patients with IBD, where leukocytoclastic vasculitis can be associated with the disease itself [35].

The pathogenesis of vasculitis associated with anti-TNF treatment is not completely explained. An immune complex-mediated hypersensitivity vasculitis may be related to the development of antibodies against anti-TNF agents, but in this hypothesis, the cases with etanercept should be less frequent since the treatment with the soluble receptor induces less antibody formation than monoclonal antibodies. Overexpression of type I interferon secondary to imbalance between Th1 and Th2 cytokine production under TNF inhibition may favour induction of autoimmune disorders such as vasculitis [15].

anti-TNF-alpha therapy for the alopecia areata was not confirmed. In the literature, however, there are cases of newly developed manifestations of alopecia areata, total and universal alope-

**Figure 3.** Adalimumab induced alopecia areata, spontaneous complete disappearance of the symptoms after 10 months

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

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

267

French authors present data from a multicentre prospective study of patients who received anti-TNF-alpha treatment due to dermatological (11 patients), rheumatological (11 patients) and gastroenterological indications (7 patients). From these patients, 10 were treated with infliximab, 11 with adalimumab and the following 8 with etanercept. In the population, a total of 29 patients were diagnosed with alopecia areata, which was confirmed by a dermatologist. The manifestations of alopecia areata were in the area of scalp and chin in 79% of the patients. There were interesting findings related to concomitantly associated immune-mediated diseases, namely the occurrence of vitiligo, psoriasis or psoriasis-like manifestations and autoimmune thyroiditis. In the study group, nine patients had a positive family history of alopecia areata or vitiligo. A total of 14 patients discontinued the anti-TNF-alpha treatment and 15 patients continued the treatment. From patients who discontinued treatment, four were treated with infliximab, six with adalimumab and four with etanercept. Improvement up to complete disappearance of the symptoms was observed in 76% of the patients, while there was no difference

between the groups in which the treatment discontinued or continued [44] (**Figure 3**).

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

Etiopathogenesis of alopecia areata is not clear. Some authors explain the occurrence of alopecia areata similar to TNF-alpha-induced psoriasis. Inhibition of TNF-alpha results in dysregulation of cytokines and subsequent production of IFN-alpha, which results in a pathological process [43]. However, further research is needed to better understand the occurrence of alo-

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,

cia during anti-TNF-alpha treatment [42, 43].

without the drug discontinuation.

pecia areata during anti-TNF-alpha therapy.

#### **6. Pyoderma gangrenosum**

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis. PG is manifested by severe painful non-infectious pustules, nodules and necrotising ulcerations. The defects are sharply demarcated, round, with distinctly dark red undermined edges. The manifestations occur mostly on the shins, but they can also be found on the torso and other body parts. The manifestations of PG can be divided into several clinical forms, namely pustulous, bullous, a vegetative form of the disease and a separate peristomic form [36]. The peristomic form is a sign of pyoderma gangrenosum with pathergy; any trauma and injury of skin cover can cause new manifestations of the disease. The peristomic form may develop from 2 weeks to 3 years after the initial creation of the stoma [37]. Key factors in the etiopathogenesis of the disease are IL1B, IL-17, TNF-alpha and other chemokines that activate neutrophils for their activity. Genetic examinations point to several autoinflammatory genes, including pyrin innate immunity regulator (MEFV) and prolineserine-threonine phosphatase interacting protein-1 (PSTPIP1) [38]. About 50% of PG cases are associated with underlying diseases, such as inflammatory bowel disease, rheumatoid arthritis, myelodysplastic syndrome and haematological malignancies [39, 40]. Several papers indicate that refractory forms of PG are well responsive to the treatment with TNF-alpha inhibitors. One of the latest summary papers on drug-induced manifestations of pyoderma gangrenosum describes five case reports of pyoderma gangrenosum induced by an anti-TNF-alpha therapy. Three patients had manifestations induced by infliximab, one case of PG was induced by etanercept and one by adalimumab. Etiopathogenesis of PG induced by TNF-alpha inhibitors may represent paradoxical reaction due to a shift towards Th-17 polarisation [41].

### **7. Alopecia areata**

Pathogenesis of alopecia areata is associated with TNF-alpha, which, as demonstrated in *in vitro* studies, inhibits hair follicle growth. However, in clinical trials with etanercept, the efficacy of Immune-Mediated Skin Reactions Induced by Recombinant Antibodies and Other TNF-Alpha… http://dx.doi.org/10.5772/intechopen.72449 267

Vasculitis manifestations in patients with severe seropositive rheumatoid arthritis are debatable, because the manifestations may be evaluated as rheumatic vasculitis, which is an extraarticular manifestation of rheumatoid arthritis and not drug-induced vasculitis. In such cases, some authors recommend discontinuation of the anti-TNF-alpha treatment with possible reexposure to the given treatment [32]. The same situation applies also to patients with IBD,

The pathogenesis of vasculitis associated with anti-TNF treatment is not completely explained. An immune complex-mediated hypersensitivity vasculitis may be related to the development of antibodies against anti-TNF agents, but in this hypothesis, the cases with etanercept should be less frequent since the treatment with the soluble receptor induces less antibody formation than monoclonal antibodies. Overexpression of type I interferon secondary to imbalance between Th1 and Th2 cytokine production under TNF inhibition may favour induction of

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis. PG is manifested by severe painful non-infectious pustules, nodules and necrotising ulcerations. The defects are sharply demarcated, round, with distinctly dark red undermined edges. The manifestations occur mostly on the shins, but they can also be found on the torso and other body parts. The manifestations of PG can be divided into several clinical forms, namely pustulous, bullous, a vegetative form of the disease and a separate peristomic form [36]. The peristomic form is a sign of pyoderma gangrenosum with pathergy; any trauma and injury of skin cover can cause new manifestations of the disease. The peristomic form may develop from 2 weeks to 3 years after the initial creation of the stoma [37]. Key factors in the etiopathogenesis of the disease are IL1B, IL-17, TNF-alpha and other chemokines that activate neutrophils for their activity. Genetic examinations point to several autoinflammatory genes, including pyrin innate immunity regulator (MEFV) and prolineserine-threonine phosphatase interacting protein-1 (PSTPIP1) [38]. About 50% of PG cases are associated with underlying diseases, such as inflammatory bowel disease, rheumatoid arthritis, myelodysplastic syndrome and haematological malignancies [39, 40]. Several papers indicate that refractory forms of PG are well responsive to the treatment with TNF-alpha inhibitors. One of the latest summary papers on drug-induced manifestations of pyoderma gangrenosum describes five case reports of pyoderma gangrenosum induced by an anti-TNF-alpha therapy. Three patients had manifestations induced by infliximab, one case of PG was induced by etanercept and one by adalimumab. Etiopathogenesis of PG induced by TNF-alpha inhibitors may

represent paradoxical reaction due to a shift towards Th-17 polarisation [41].

Pathogenesis of alopecia areata is associated with TNF-alpha, which, as demonstrated in *in vitro* studies, inhibits hair follicle growth. However, in clinical trials with etanercept, the efficacy of

where leukocytoclastic vasculitis can be associated with the disease itself [35].

autoimmune disorders such as vasculitis [15].

**6. Pyoderma gangrenosum**

266 Antibody Engineering

**7. Alopecia areata**

**Figure 3.** Adalimumab induced alopecia areata, spontaneous complete disappearance of the symptoms after 10 months without the drug discontinuation.

anti-TNF-alpha therapy for the alopecia areata was not confirmed. In the literature, however, there are cases of newly developed manifestations of alopecia areata, total and universal alopecia during anti-TNF-alpha treatment [42, 43].

French authors present data from a multicentre prospective study of patients who received anti-TNF-alpha treatment due to dermatological (11 patients), rheumatological (11 patients) and gastroenterological indications (7 patients). From these patients, 10 were treated with infliximab, 11 with adalimumab and the following 8 with etanercept. In the population, a total of 29 patients were diagnosed with alopecia areata, which was confirmed by a dermatologist. The manifestations of alopecia areata were in the area of scalp and chin in 79% of the patients. There were interesting findings related to concomitantly associated immune-mediated diseases, namely the occurrence of vitiligo, psoriasis or psoriasis-like manifestations and autoimmune thyroiditis. In the study group, nine patients had a positive family history of alopecia areata or vitiligo. A total of 14 patients discontinued the anti-TNF-alpha treatment and 15 patients continued the treatment. From patients who discontinued treatment, four were treated with infliximab, six with adalimumab and four with etanercept. Improvement up to complete disappearance of the symptoms was observed in 76% of the patients, while there was no difference between the groups in which the treatment discontinued or continued [44] (**Figure 3**).

Etiopathogenesis of alopecia areata is not clear. Some authors explain the occurrence of alopecia areata similar to TNF-alpha-induced psoriasis. Inhibition of TNF-alpha results in dysregulation of cytokines and subsequent production of IFN-alpha, which results in a pathological process [43]. However, further research is needed to better understand the occurrence of alopecia areata during anti-TNF-alpha therapy.
