Biologics in dermatology

Biologics are recombinant proteins, biotechnologically produced proteins, which are usually applied parenterally (subcutaneously or intravenously). Biologics mimic the body's own regulatory mechanisms and are used to correct a dysregulation of the immune system, for example in psoriasis, psoriatic arthritis, atopic eczema and urticaria. They intervene in the development of the disease at an earlier stage than conventional therapy options (e.g. in psoriasis the blockade of TNF-alpha or cytokines of the IL-17 family - see below. Th17 cell). Initially, biologics were only used in case of failure of conventional preparations, in the meantime, some of them also have the first-line indication, see under the respective preparations.

According to WHO, the name of each monoclonal antibody should consist of a prefix, a word stem extension A and B and the word stem as a suffix.

Thus,:

• -mab- for monoclonal antibody
• -xi- for chimeric
• -zu- for humanized
• -u- for fully human antibody

The part of the word in front of it indicates the group of the respective target structure.

Thus:

• -k(i) or ki(n) for interleukins as target antigens
• -l(i) or li(m) for the immune system in general.

If the molecule is pegylated by polyaethylene glycol, this is indicated by the appended "pegol".

Certo-li-to-mab pegol stands for: Certo - li - (immune system in general) -to- (humanized) - mab-(monoclonal antibody) -pegol - pegylated- .

In the following, the use and the side effects of the biologics in dermatological diseases are specifically dealt with! Thus, the development of biologics represents a groundbreaking step towards a completely new form of system therapy for psoriasis vulgaris and other immune diseases. The efficacy of biologics usually becomes apparent quickly within 4 to 6 weeks, but only reaches its maximum after several months. After discontinuation, the effect lasts for different lengths of time:

• Cytokines (INF-alpha; interleukin 2): autoimmune phenomena (psoriasis, vitiligo, systemic sclerosis, autoimmune thyroiditis, capillary leak syndrome).
• Cytokine inhibitors(TNF-alpha blockers such as infliximab, adalimumab, etanercept): immunosuppression, paradoxical reactions (reactivation of viral hepatitis, reactivation of tuberculosis, induction of psoriasis, multiple sclerosis, lupus erythematosus)
• Cytokine inhibitors(EGFR inhibitors such as cetuximab, panizumumab, erlotinib, gefitinib, afitinib): inhibition of MAP kinase pathway (papular exanthema, xerosis, blepharitis, paronychia, hair growth disorders (thinning/ brittle/ wavy hair/ trichomegaly)
• Cytokine inhibitors(BRAF inhibitors such as Vemurafinib, Dabrafinib): Paradoxical RAF activation (keratoses, squamous cell carcinomas, second melanomas)
• Cytokine inhibitors (MEK kinase inhibitors such as tramtenib, selumetinib, cobimetinib): inhibition of MAP kinase pathway (papulo-pustular exanthema, xerosis, paronychia, hair growth disorder
• Cytokine inhibitors(tyrosine kinase inhibitors such as imatinib, pazopanib, sorafinib, sunitinib, vendetanib): Tyrosine kinase inhibition (exanthema, pruritus, facial edema, stomatitis, alopecia, disruption of nail and hair growth, discoloration of skin and hair, hand-foot syndrome, neutrophilic eccrine hidradenitis, eruptive melanocytic nevi).
• Hedgehog inhibitors(vismodegib) Inhibition of the hedgehog signaling cascade (alopecia, mucosal lesions).
• Immune checkpoint inhibitors (anti-CTLA-4 antibody- ipilimumab, anti-PDI antibody- nivolumab, pembrolizmab): Autoimmune phenomena- inhibition of regulatory T cells (exanthema, pruritus, vitiligo, alopecia, ulcers, Sweet syndrome).

There are no controlled studies on humans with regard to biologicals and pregnancy, and no increased risk has been demonstrated in animal experiments (Seneschal J et al. 2012). Without doubt, this constellation will have to be weighed up very carefully on an individual basis.

The spectrum of their ADRs differs from that of classical, small-molecule agents for various reasons. The spectrum of their ADRs differs from that of classical, small-molecule drugs for various reasons. For example, MAHs are typically digested and not oxidatively metabolized. Therefore, they cannot be administered orally (they would be digested in the gastrointestinal tract like other peptides) but must be administered parenterally. Other special features are their origin (possibly non-endogenous proteins), their molecular size (proteins), and their mechanism of action (influencing the immune system) (Sachs B et al. 2018). Acute hypersensitivity reactions to mAbs may be pathophysiologically:

• true allergic, e.g. immunoglobulin (Ig) E-mediated
• or
• non-allergic (non-specific immunological) reactions.

Specifically, the following UAWs may occur:

• Acute infusion reactions: typically occur 1h at or after first use. They are not IgE-mediated and diminish with subsequent applications (Jung JW et al 2014). Clinical symptoms include a combination of fever, rigor, flushing, dyspnea, gastrointestinal discomfort, chest and back pain, and chills. Thus, classifications of: skin type, dyspnea type, pain type, anaphylaxis type, diffuse type are also proposed (Manigold T et al. 2013). Urticaria or angioedema do not belong to this spectrum of UAWs. Their severity varies from mild (common) to life-threatening (rare). Causes are e.g. cytokine inductions by direct interaction of the mAH with immune cells. Rituximab represents an example of this reaction mechanism. An acute and massive release of cytokines as it can occur under Rituximab is described as cytokine-release syndrome.
• Infections: Therapeutic neutralization of the biological properties of TNF-alpha may limit immunological control over infections. Possible infections are diverse (mycobacterioses, septic or nonseptic bacterial infections: attention should be paid to colon diverticulitis, suppurative dental cysts, latent Borrelia infections, viral and opportunistic infections). Reactivation of latent infections possible. Exclude tuberculosis and invasive fungal infections before starting therapy.
• Autoantibodies with TNF- alpha inhibitors: In one study, autoantibodies occurred in 33 of 128 patients (28.9%) during treatment with TNF-alpha inhibitors. Twenty-seven patients had ANA, and five patients had ANA, ENA, and anti DS DNA-AK. One patient developed thyroid-specific autoantibodies (1:5120). One patient developed drug-induced lupus erythematosus (ANA titer 1:2560). Mostly autoantibodies occurred during therapy with infliximab (48.4%). With eternacept, 26.6% of patients developed autoantibodies, and with adalimumab, 19.1% of patients. Treatment failure occurred in 45 of 128 cases. Antibodies to human mAbs (anti-drug antibodies) may also occur because even fully humanized mAbs may contain (foreign) amino acid sequences.
• Autoimmune syndromes: TNF-alpha antagonists induce the formation of ANA in up to 60% and DNS-Ak in about 15% of patients. These findings require monitoring, but do not necessitate discontinuation of therapy if no other clinical signs of autoimmune disease are present (see below Lupus-like syndrome with TNF-alpha antagonists).
• Neurologic disorders: Various forms of "multiple sclerosis-like" syndromes (signs of demyelization) and peripheral polyneuropathies may occur during therapy with TNF-alpha antagonists.
• Lymphomas: The incidence for lymphomas may be increased under long-term therapy with TNF-alpha antagonists. This is true for all indications. A special case seems to be hepatosplenic T-cell lymphoma (HSTZL), which has been observed several times.
• Tumors: The risk of spinocellular carcinoma or non-melanocytic tumors is increased during long-term therapy with TNF-alpha antagonists.
• Heart Failure: The worsening of pre-existing heart failure (NHYA III) may occur during therapy with TNF-alpha antagonists.

The biologics currently in use for dermatological indications include:

• Etanercept (^Enbrel®)(psoriasis and psoriatic arthritis)
• Infliximab (Remicade ^®I.V)(psoriasis and psoriatic arthritis)
• Efalizumab (^Raptiva®)(psoriasis)(Cave! off the market)
• Omalizumab (atopic eczema)
• Golimumab (^Simponi®) (psoriasis)
• Ustekinumab (^Stelara®) (psoriasis)
• Secukinumab (^Cosentyx®)(psoriasis - anti-IL17A antibody)
• Guselkumab ( ^Tremfya®)(psoriasis - anti-IL 23 antibody)
• Ixekizumab (^Taltz®) (psoriasis - anti-IL17A antibody)
• Brodalumab (^Kyntheum®)(psoriasis - monoclonal antibody against IL17 receptor A)
• Certolizumab (^Cimzia® tab.: approval only for rheumatoid arthritis).
• Adalimumab (^Humira® )(psoriasis)
• Dupilumab (^Dupixent®) (atopic dermatitis) human monoclonal antibody against the alpha subunit of the interleukin (IL)-4 receptor, inhibits the IL-4/IL-13 signaling pathways
• Baricitinib (Olumiant®), atopic dermatitis, Jak inhibitor
• Bimekizumab (^Bimzelx®) plaque psoriasis IL17A and IL17 F antibodies
• Tralokinumab (Adtralza) moderate to severe atopic dermatitis

• Drug costs: Due to the high costs of drugs, the criteria of indication and the economic efficiency requirement according to §12 Social Security Code V must be strictly observed when prescribing biologicals. The use of biologics is only justified by the fact that other, more cost-effective forms of therapy that have been established for the respective indication have proven to be either ineffective, unavailable, contraindicated or could not be administered due to undesired drug effects.
• Economic efficiency: The criteria of the economic efficiency requirement include the necessity of an adequate, appropriate and economical therapy. In conclusion, this means that a patient must have undergone the entire established spectrum of therapies of cheaper treatment measures until the lack of efficacy before the prescription of biologicals, taking into account the individual contraindications.

• Therapy discontinuation: Predictors for a discontinuation of a biologics therapy are manifold. In a multi-centre study, psoriatics were examined who were given a 2nd biological if a first-line therapy with biologicals failed. The general "drug survival rate" was 77% in the first year after the change of therapy and 58% in the third year. The following predictors for discontinuation of therapy were: female gender, multiple comorbidities, concomitant therapy with Ciclosporin A , high PASI value at the time of the change of therapy. Patients with ustekinumab showed the highest adherence to therapy, followed by patients with adalimumab and etanercept (Iskandar IYK et al. 2018)

  ADR/skin tests: If hypersensitivity reactions are suspected, the following skin tests can be performed:

  • Adalimumab (prick test: 50mg/ml; intradermal test: 50mg/ml)
    • Etanercept (prick test: 25mg/ml; intradermal test: 5mg/ml)
    • Infliximab (prick test: 10mg/ml; intradermal test: 10mg/ml)
    • Omalizumab (prick test: 1.25ug/ml; intradermal test: 1.25ug/ml)

1. Bardazzi F et al (2014) Autoantibodies in patients with psoriasis under anti-TNF-alpha therapy. JDDG 12: 401-407
2. Iskandar IYK et al (2018) Differential Drug Survival of Second-Line Biologic Therapies in Patients withPsoriasis: Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR). J Invest Dermatol 138:775-784.
3. Jung JW et al (2014) The incidence and risk factors of infusion-related reactions to rituximab fortreating B cell malignancies in a single tertiary hospital. Oncology 86:127-134.
4. Manigold T (2013) Biologics - Genesis and characteristics of immune-mediated side effects. Allergology 36: 452
5. Nast A et al (2006) S3 guideline for the therapy of psoriasis vulgaris. JDDG 4: 1-126
6. Prince JC (2010) Biologics. Dermatologist 61: 668-675
7. Sachs B et al (2018) Acute hypersensitivity reactions to monoclonal antibodies for targeted therapy. dermatologist 69: 268-277
8. Seneschal J et al (2012) Cutaneous drug eruptions associated with the use of biologic and cutaneous drug eruptions mimicking specific skin diseases. Chem Immunol Allergy 97:203-216.
9. Volc S et al (2016) Pathophysiological basis of systemic therapies for psoriasis. J Dtsch Dermatol 14:557-557