It is also used to manage signs and symptoms of polyarticular idiopathic arthritis in those aged 4 to 17 after insufficient response to one or more disease-modifying anti-rheumatic drugs. Etanercept is also used to improve psoriatic arthritis and ankylosing spondylitis. DB Golimumab Used in adults i as an adjunct to methotrexate treatment in patients with moderate to severe active rheumatoid arthritis RA , ii alone or as an adjunct to methotrexate treatment in patients with active psoriatic arthritis PsA , iii as a single agent in patients with active ankylosing spondylitis AS , and iv as a single agent in patients with moderate to severe ulcerative colitis UC who require chronic steroids or have experienced intolerance or only a partial response to previous medications.
DB Certolizumab pegol Certolizumab pegol has been approved for several different conditions listed below: - Symptomatic management of Chron's disease patients and for the maintenance of clinical response in patients with moderate to severe disease with inadequate response to conventional therapy. This response can be normal but in certain conditions, the immune system can attack the body's normal cells or tissues which causes an abnormal inflammation. Infectious skin complications can be divided into three groups: Viral infections. Herpes infections are the most common viral complications.
Varicella-zoster virus VZV reactivation and occurrence of herpes zoster infection is a common serious adverse event. Yet in contrast, one of the most recent publications regarding the long-term follow-up of psoriatic patients did not confirm the association of increased HZ risk in patients treated with ustekinumab, TNF alpha inhibitors, and methotrexate.
However these authors also stated that a larger number of HZ events would be needed to assess the presence or absence of risk [ 15 ]. In the case of the VZV infection, early diagnosis and timely treatment are a precondition for the prevention of VZV complications. Most feared complications include meningoencephalitis, myositis, pneumonitis, hepatitis, and herpes zoster ophthalmicus. The most frequent complication is postherpetic neuralgia. Caution is required in patients on combined immunosuppressive treatment, in whom the disease may take a severe course.
In the case of a localized infection, oral virostatic agents are the treatment of choice Table 2. Disseminated herpetic manifestations require patient hospitalization in order to administer intravenous treatment. Biologic treatment is immediately suspended due to the severity of herpes infection. Further doses of biologics are never administered in the acute stage of the disease. Biologic agents are subsequently not contraindicated, and biological treatment may continue after the complete return of body temperature to normal and the suppression of skin manifestations.
Complicated cases require diagnostic examinations. Serologic tests are most important for the diagnosis of previous disease and also at the acute stage. PCR, viral culture, and IHC or hybridization methods are more sensitive for the confirmation of a diagnosis of current VZV infection or reactivation in the event of clinical uncertainty [ 16 ]. Management of herpesvirus infections in patients on anti-TNF alpha treatment adapted from [ 16 , 17 ].
A gynecologist was consulted on the first day of symptoms; on the fourth day, the patient was examined in an emergency room due to urine retention, with permanent catheter insertion and the initiation of oral virostatic therapy which, however, was ineffective. The disease was complicated by neuralgia and temporary defecation disorder.
Herpes simplex virus 1 HSV1 and herpes simplex virus 2 HSV2 herpes infections are a relatively frequent complication which may if recurrent impact patient quality of life. Due to the relatively benign course of HSV infections, the majority are not recorded in registries—hence the limited data on incidence in patients on anti-TNF alpha therapy. In the general population, an occurrence of more than five episodes a year is regarded as a recurrent HSV infection that initiates prophylactic virostatic therapy.
Repeated or disseminated infection in patients on anti-TNF alpha therapy is an indication for prophylactic treatment Table 2. In adult patients, acute primary infections are not encountered which may be manifested as herpetic gingivostomatitis. In the majority of herpes simplex labialis infections, anti-TNF alpha therapy is not suspended.
If the disease has a more severe course, therapy is suspended until the suppression of skin or system manifestations [ 16 ]. HPV and molluscum contagiosum MC viral proteins seem to interfere with the apoptotic pathway of the host cell signaled by TNF receptors. Clinically, HPV infection is manifested as verrucae vulgaris and condylomata acccuminata. When treating condylomata accuminata, we avoid topical treatment with imiquimod, since this may induce the formation of psoriatic lesions or psoriasis-like plaque.
Erysipelas and cellulitis are common severe skin bacterial complications. Cellulitis is one of the most common infectious skin diseases that occur in the course of biological therapy 0. The first manifestations of cellulitis and erysipelas require immediate antibiotic treatment. These data have been confirmed not only in all patients rheumatological, gastroenterological, and dermatological undergoing anti-TNF alpha therapy [ 14 ]. The early initiation of therapy may prevent subsequent complications. If the disease is resistant to the oral form, intravenous antibiotic treatment or sometimes combined therapy is initiated.
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In the case of acute manifestations of the disease, biological therapy is suspended immediately. After the successful treatment of an acute attack, long-term antibiotic prophylaxis may continue. Psoriatic patients are likely to have less abscesses, since IBD diseases have specific extraintestinal manifestations and are also associated with hidradenitis suppurativa comorbidity which may be evaluated as folliculitis and abscesses [ 19 ]. Fungal infections are not as frequent as viral and bacterial infections.
Likewise, such depend on whether the patient is on combined immunosuppression. In the case of opportunistic infections, association between anti-TNF alpha and oral candidiasis has been described but only in a very small number of cases less than 0. Rare cases of aspergillosis, candida sepsis, and coccidioidomycosis have been reported [ 14 ].
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To a large degree incidence is impacted by concurrent systemic corticosteroid treatment, which is not indicated for the treatment of psoriasis [ 20 ]. In practice we can observe cases of tinea pedis and onychomycosis, which are also very common in the general population; data on comparison of incidence with the general population are very limited.
If joints are severely affected by psoriatic arthritis with deformation of toes, interdigital fungal manifestations are more common. Treatment of the fungal infection is essential in prevention of skin cracking, which is a portal for the entry of bacterial infections. Superficial skin mycoses in patients on anti-TNF alpha therapy may be mistaken for psoriasis, and if such occur following anti-TNF alpha therapy, they may be mistaken for paradoxically induced psoriasis.
In complicated cases, it is therefore necessary to conduct a direct microscopic and culture fungal examination Figure 2. Female patient treated with adalimumab, who was working as a nurse at a psychiatric department. A follow-up examination revealed green-brown nail color A. Topical antibiotic treatment in combination with antimycotic therapy was initiated. Reactions associated with therapy administration have a heterogeneous nature.
Their classification and etiopathogenesis are complicated. Due to the different structure and properties of anti-TNF alpha preparations, reactions are described separately for infliximab, adalimumab, and etanercept. Most data in literature and reactions following administration are associated with infliximab.
Due to its chimeric element and intravenous administration, patients are premedicated prior to therapy. In some cases, a serum sickness-like reaction develops [ 21 , 22 ]. Acute reactions can be divided into mild, moderate, and severe. Mild and moderate reactions may be dealt with by slowing the infusion rate or momentary interruption or infusion, with symptoms spontaneously resolving.
Clinical manifestation is accompanied by headache, itching, nausea, and erythema [ 21 , 22 ]. Treatment must be suspended and readministration of the biologic agent is not recommended. It is assumed that the reaction is not a standard anaphylactic reaction, but rather an anaphylactoid one. In recent years, many papers describing the formation of antibodies against biologic agents have been published. The formation of antibodies against biologics is called immunogenicity of biological treatment and is associated with acute reactions. Their work confirmed that serious acute reactions following infliximab are closely associated with the production of anti-IFX IgG antibodies while having no relation to anti-IFX IgE antibodies.
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The reactions are therefore not called anaphylactic but rather anaphylactoid. In the observed set, reactions occurred most frequently with second administration. Low levels of anti-IFX IgG antibodies prior to subsequent administration do not exclude the possibility of reaction [ 23 ]. In contrast, works confirm the association between the occurrence of acute reactions and specific IgEs against a biologic agent [ 24 , 25 ].
Likewise, works have successfully implemented desensitization with a biologic agent following acute urticarial and anaphylactic reaction [ 26 ].
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While the precise mechanisms of individual reactions have not been explained, it transpires that monitoring the formation of antibodies against biologics may be important to differentiate certain reaction types. In daily practice it has become common to administer combined suppressing biologics with low doses of methotrexate or in the case of chronic inflammatory bowel disease in combination with azathioprine. Combined suppression should reduce the formation of antibodies against biologics and thus reduce adverse reactions [ 27 ]. Anaphylactic and anaphylactoid reactions are rare.
Nevertheless, serum-specific IgE to adalimumab results were not detectable. This was the first case of immunologic but not IgE-mediated immediate systemic reaction to adalimumab [ 29 ]. Etanercept is a dimeric human recombinant protein constituted by the binding of two soluble TNF receptors p75 and human IgG1 Fc.
As described in the case of adalimumab, the reaction resolves within several 3—5 days. Although the overall risk of urticaria appears low, clinicians should be aware of this reaction. Due to various mechanisms of injection site reactions, as well as anaphylactic or anaphylactoid reactions, it is appropriate to supplement patient testing. Literature contains publications which describe various protocols for the dilution of biologic agents when testing using prick and intradermal tests; some authors have also conducted patch tests [ 30 , 34 ].
Likewise, various procedures invoking drug tolerance and the detection of antibodies against biologics from IgG and IgE class are becoming more available. In the case of serious reactions, it is preferred to switch biological therapy prior to desensitization, which is only carried out in exceptional cases when there is no other therapeutic modality available.
As we mentioned at the beginning, immune-mediated adverse effects are a new group of diseases. We recently published a chapter on immune-mediated adverse effects, analyzing pathogenesis and reactions in all indications of anti-TNF alpha therapy [ 35 ]. The following section is therefore only about diseases that occur in psoriasis patients on anti-TNF alpha therapy, followed by a description of the potential therapeutic procedures in the event of immune-mediated complications.
Psoriasis or psoriasiform reaction is one of the most common immune-mediated reactions. This reaction may occur in psoriasis patients successfully treated with anti-TNF alpha therapy. The formation of anti-TNF alpha-induced psoriasis is also called a paradoxical reaction. Patient with positive family history for psoriasis with palmar ragadiform eczema, nail lesions, and erythema around wrist.
Fungal culture proves Trichophyton rubrum. In the time of adverse event, the patient was already without chronic plaque psoriasis. Discontinuation of anti-TNF alpha and switch to secukinumab resolve skin reactions B. The clinical symptom of paradoxical psoriasis can be of variable nature. Paradoxical psoriasis includes newly developed psoriasis as well as the significant worsening of existing psoriasis. Other manifestations include scalp or nail involvement.
The clinical picture of the disease in patients with chronic plaque psoriasis most often includes the formation of palmoplantar pustulosis, which they did not suffer before Figures 3 and 4. While the pathogenic mechanism of this paradox reaction remains unclear, the most widespread theory links the relationship between TNF alpha and type 1 interferon alpha: TNF alpha blockers can lead to the overproduction of INF-alpha.
In papers that confirm this theory, the increased expression of interferon alpha was demonstrated in skin biopsy compared to common psoriatic findings [ 37 ]. One of the latest theories involves the Th 17 pathway.