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 drugs for various reasons. The spectrum of their ADRs differs from that of classic, small-molecule active substances for various reasons. For example, mAbs 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 not endogenous proteins), their molecular size (proteins) and their mechanism of action (influencing the immune system) (Sachs B et al. 2018). The pathophysiology of acute hypersensitivity reactions to mAbs can be:

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

In detail, the following ADRs may occur:

• Acute infusion reactions: typically occur 1h during or after the first application. They are not IgE-mediated and decrease with subsequent applications (Jung JW et al. 2014). The clinical symptoms include a combination of fever, rigor, flushing, dyspnoea, gastrointestinal complaints, chest and back pain and chills. Classifications are also proposed according to: skin type, dyspnoea type, pain type, anaphylaxis type, diffuse type (Manigold T et al. 2013). Urticaria or angioedema do not belong to this spectrum of ADRs. Their severity varies from mild (frequent) to life-threatening (rare). Causes such as cytokine induction through direct interaction of the mAbs with immune cells are discussed. Rituximab is an example of this reaction mechanism. An acute and massive release of cytokines, such as can occur with rituximab, is described as cytokine-release syndrome.
• Infections: Therapeutic neutralization of the biological properties of TNF-alpha can limit immunological control over infections. The possible infections are manifold (mycobacterioses, septic or non-septic bacterial infections: attention should be paid to colonic diverticulitis, purulent dental cysts, latent borrelia infections, viral and opportunistic infections). Reactivation of latent infections possible. Tuberculosis and invasive fungal infections must be ruled out before starting therapy. Although older psoriatics generally have an approximately 2.2-fold higher risk of infection compared to non-psoriatics (!), there is no evidence that biologics pose a higher risk compared to other systemic therapeutics (Schneeweiss et al. 2020).
• Autoantibodies with TNF-alpha inhibitors: In one study, autoantibodies occurred in 33 of 128 patients (28.9 %) during treatment with TNF-alpha inhibitors. 27 patients had ANA, 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). Most autoantibodies occurred during therapy with infliximab (48.4 %). With Eternacept, 26.6 % of patients developed autoantibodies, with Adalimumab 19.1 % of patients. Treatment failure occurred in 45 of 128 cases. Antibodies against human mAbs (anti-drug antibodies) can also occur because fully humanized mAbs can also contain (foreign) amino acid sequences.
• Autoimmune-like syndromes: TNF-alpha antagonists induce the formation of ANA in up to 60% and DNA-Ak in about 15% of patients. These findings require monitoring, but do not necessitate discontinuation of therapy if no other clinical signs of an autoimmune disease are present (see below lupus-like syndrome with TNF-alpha antagonists).
• Neurological 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 of lymphomas may be increased during long-term therapy with TNF-alpha antagonists. This applies to all indications. A special case appears to be hepatosplenic T-cell lymphoma (HSTZL), which has been observed several times.
• Tumors: The risk of spinocellular carcinomas or non-melanocytic tumors is increased during long-term therapy with TNF-alpha antagonists.
• Heart failure: Therapy with TNF-alpha antagonists may lead to a worsening of pre-existing heart failure (NHYA III).

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 with Psoriasis: 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 treatment of psoriasis vulgaris. JDDG 4: 1-126
6. Prinz JC (2010) Biologics. Dermatologist 61: 668-675
7. Sachs B et al. (2018) Acute hypersensitivity reactions to monoclonal antibodies uur targeted therapy. Dermatology 69: 268-277
8. Schneeweiss MC et al. (2020) Older adults on systemic treatment for psoriasis and risk of infection: a propensity score-matched population-based study. Br J Dermatol 183:564-566.
9. Seneschal J et al. (2012) Cutaneous drug eruptions associated with the use of biologies and cutaneous drug eruptions mimicking specific skin diseases. Chem Immunol Allergy 97:203-216.
10. Volc S et al. (2016) Pathophysiological basis of systemic therapies for psoriasis. J Dtsch Dermatol 14:557-557