Tnf-alpha antagonists

TNF-alpha antagonists (TNF-alpha inhibitors) are antibodies or soluble receptors from the group of biologicals (they are produced biologically in genetically modified cells). Their therapeutic use aims to inhibit cytokines of the TNF-alpha type. TNF-alpha inhibitors are characterised by a high affinity and selectivity for tumour necrosis factor-alpha. Apart from 2 exceptions, they are monoclonal antibodies. Certolizumab pegol is a pegylated Fab fragment of a monoclonal antibody. Etanercept is a fusion protein which contains the binding domain of the TNF-receptor-2 and acts as a "false receptor". All TNF-alpha inhibitors are produced using biotechnological methods. The active ingredients have a long half-life.

The cytokine TNF-alpha is a transmembrane protein, a broad-acting proinflammatory cytokine. The soluble TNF-alpha is cleaved from this cytokine by the enzyme TACE (TNF-α-converting enzymes). The TNF-alpha inhibitors bind to both proteins.

TNF-alpha inhibitors are used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque-type psoriasis, inflammatory bowel disease (Crohn's disease), and Takayasu's arteritis, among others (Pache I et al. 2009). The biologics are usually injected subcutaneously. One representative (infliximab) is administered as an infusion.

Meanwhile, the preparations are used for a large number of diseases in "off-label use". In a larger study (n=118), the following diagnoses were found: severe aphthous stomatitis/genital aphthous lesions (26), chronic urticaria (25), hidradenitis suppurativa (29), acne conglobata (11), orofacial granulomatosis (4), sarcoidosis (4), pyoderma gangrenosum (4), Sweet syndrome (4),dissecting cellulitis of the scalp (2), granuloma anulare (2), granulomatous rosacea (1), granuloma faciale (1), subcorneal pustulosis (1), Wells syndrome (1), benign familial pemphigus (1), lichen planus (1), and folliculitis decalvans (1).

According to the technical information. Pre-filled syringes and pens are available for most products. Due to their long half-life, the dosage interval is e.g. 2, 4, 6 or 8 weeks. Pretreatment or a combination with methotrexate is prescribed for individual representatives.

The most common possible adverse effects include injection site reactions, headache, skin rashes, gastrointestinal disturbances, and infectious diseases. A serious side effect is the reactivation of latent tuberculosis and oppertunist fungal infections. Obviously, the risk differs depending on the preparation used. It seems to be highest for infliximab, followed by adalimumab and etanercept (Pfützner W 2018).

Furthermore, TNF-alpha antagonists can cause paradoxical reactions in rare cases. Paradoxical reactions refer to exacerbations or even the initial onset of disease by a biomodulator that was intended to therapeutically affect that disease (de Gannes GC et al 2007).

Increased INF-alpha production of plasmacytoid cells as well as increased stimulation of IL-23 receptor with pathognomically relevant Th17 cells by TNF-alpha blockers seems to lead in rare cases to induction of autoimmune diseases such as multiple sclerosis, lupus erythematosus, vitiligo, lichen planus, IgA nephropathy (Di Lernia V 2017).

Paradoxical reactions: Paradoxical reactions are described, i.e. reactions with pustular dermatitis e.g. of the scalp (also under the picture of folliculitis decalvans) or of the intertrigines(hidradenitis suppurativa) during systemic treatment of rheumatoid arthritis or Crohn's disease (Shimokata M et al. 2018; Zamperetti M et al. 2017, Salvador-Rodriguez L et al. 2020).

The simultaneous administration of similar cytokine inhibitors such as Anakinra (IL-1 receptor) or Abatacept is not recommended because there is a higher risk of infection. Live vaccines should not be given during therapy.

The simultaneous consumption of green tea and yellow ginger inhibits the effect of TNF-alpha blockers. In tea it is the catechins, in ginger the curcumin which is responsible for the inhibition of the effect.

Active tuberculosis (to be ruled out by means of an interferon-gamma-release assay), other serious infections such as HIV, chronic persistent viral hepatitis as well as sepsis and opportunistic infections. Moderate to severe heart failure. Full precautions are given in the respective drug information leaflet

The following active substances have been approved:

• Adalimumab (Humira®⁾
• Certolizumab pegol (Cimzia®)
• Etanercept (Enbrel®)
• Golimumab (Simponi®)
• Infliximab (Remicade®)

TNF-alpha inhibitors are commercially available as injection and infusion preparations. Infliximab (Remicade®) was the first active ingredient from this group to be approved in 1998. In the meantime, biosimilars are available from some representatives. Others will follow in the coming years

1. de Gannes GC et al (2007) Psoriasis and pustular dermatitis triggered by TNF-{alpha} inhibitors in patients with rheumatologic conditions. Arch Dermatol 143:223 231.
2. Di Lernia V (2017) IgA nephropathy during treatment with TNF-alpha blockers: could it be predicted? Med Hypotheses 107:12-13.
   Pache I et al (2009) TNF-alpha blockers in inflammatory bowel diseases: practical consensus recommendations and a user's guide. Swiss Med Wkly 139:278-287.
3. Pfützner W (2018) Cutaneous drug reactions. In: Plewig G et al (eds) Braun-Falco`s dermatology,venereology and allergology. Springer Verlag SS 559-624

4. Salvador-Rodriguez L et al (2020) Paradoxical hidradenitis suppurativa in patients receiving TNF-α inhibitors: case series, systematic review, and case meta-analysis. Dermatology 236:307-313

5. Shimokata M et al. (2018) Case of psoriasiform and pustular eruptions in addition to alopecia as a paradoxical reaction induced by infliximab. J Dermatol 45:e331-e333.

6. Zamperetti M et al. (2017) Pityriasis amiantacea and folliculitis decalvans An unusual manifestation associated with antitumor necrosis factor-α therapy [Pityriasis amiantacea and folliculitis decalvans: An unusual manifestation associated with antitumor necrosis factor-α therapy]. Dermatologist 68:1007-1010.