Anti-IL-17 Biological Therapies: Secukinumab and Ixekizumab

Mechanism

Pharmacological Class and Group

Selective monoclonal antibodies directed against the cytokine Interleukin-17A (IL-17A). Secukinumab is a fully human IgG1κ monoclonal antibody; Ixekizumab is a humanized IgG4 monoclonal antibody.

Mechanism of Action

IL-17A is the key effector cytokine produced by Th17 lymphocytes, γδ T cells, and innate lymphoid cells of the dermis in psoriasis. It acts synergistically on keratinocytes, stimulating the transcription of neutrophil recruitment chemokines (CXCL1, CXCL2, CXCL8) and perpetuating epidermal hyperplasia and psoriasiform scaling.

IL-23/IL-17 Axis Locking Mechanism

1. Selective Binding to the Homodimeric Cytokine IL-17A: Secukinumab and Ixekizumab bind specifically and selectively to the soluble homodimeric cytokine IL-17A and heterodimeric IL-17A/F, neutralizing its interaction with the heterotrimeric cellular receptor IL-17RA/RC.

2. Stop Neutrophilic and Keratolytic Recruitment: Neutralization interrupts the activation cascade of the cellular factor NF-κB, stopping the synthesis of cutaneous inflammatory antimicrobial peptides (psoriasin, defensins) and epidermal leukocyte infiltration (Munro microabscesses):

Anti-IL-17A Interaction Blockade IL-17A/RA-RC ↓ Neutrophils in Epidermis (Psoriasis)

This highly selectivity blockade translates into rapid clinical remission of psoriasis plaques (achieving high rates of complete whitening or PASI 100).

Pharmacokinetics

High Resolution Pharmacokinetics

• Routes and Bioavailability: Both drugs are administered strictly by the subcutaneous (SC) route. Secukinumab has a bioavailability of 73%, reaching the plasma peak (C_max) between 5 and 6 days. Ixekizumab has a bioavailability of 60-90% with serum peaks after 4 days.
• Distribution: Low tissue distribution volume, concentrating preferentially on the skin and inflamed tissues.
• Metabolism: Elimination by intracellular degradation to peptides and amino acids through the lysosomal immunoglobulin recycling pathway.
• Half-life (t_1/2): Secukinumab has an elimination half-life of 22 to 27 days. Ixekizumab has a terminal elimination half-life of approximately 13 days.

Indicators and dose

Clinical Indications and Off-Label Uses

• Moderate to Severe Plaque Psoriasis: Highly effective drugs with rapid onset of clinical response for total or almost total clearance of the skin.
• Active Psoriatic Arthritis: Priority treatment to control enthesitis, dactylitis and progressive erosive synovitis.
• Moderate to Severe Hidradenitis Suppurativa (Secukinumab): Recently approved after phase III clinical trials that demonstrate a reduction in inflammatory flares.
• Nail, Palmoplantar and Scalp Psoriasis: Difficult to manage areas that respond robustly to clearance mediated by IL-17A blockade.

Dosage and Clinical Adjustment

Secukinumab (Plaque Psoriasis):

• Loading Dose (Induction Phase): 300 mg subcutaneously administered in weeks 0, 1, 2, 3 and 4.
• Maintenance Dose: 300 mg subcutaneously administered once every 4 weeks (starting at week 4 of treatment). Each 300 mg dose is typically administered as two 150 mg injections or a single 300 mg autoinjector injection.

Ixekizumab (Plaque Psoriasis):

• Initial Loading Dose (Week 0): 160 mg subcutaneously (two injections of 80 mg in the same clinical event).
• Induction Phase: 80 mg subcutaneously every 2 weeks in weeks 2, 4, 6, 8, 10 and 12.
• Maintenance Dose: 80 mg subcutaneously every 4 weeks indefinitely starting from week 12.

Adjustment in Renal / Hepatic Failure: No dose adjustment is required in patients with renal or hepatic failure, since the clearance of immunoglobulins is carried out through non-specific proteolytic catabolic routes.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Known hypersensitivity to the active ingredient or excipients.
• Clinically important or severe chronic active infections (tuberculosis, sepsis, osteomyelitis).

Relative Contraindications

• Active Inflammatory Bowel Disease (Crohn's Disease / Ulcerative Colitis): Elevated risk of severe acute exacerbations of bowel disease, due to the protective physiological role of IL-17 in the integrity of the colonic mucus barrier.
• Recurrent yeast infections of the genus Candida.

Adverse Effects (ADR) and Specific Toxicity

• Very common (>10%): Nasopharyngitis, mild erythema reactions at the subcutaneous injection site.
• Common (1%-10%): Upper respiratory infections, headache, transient watery diarrhea, Fungal infections due to Candida (mainly recurrent oropharyngeal candidiasis, angular cheilitis and vulvovaginal candidiasis). It is explained by the physiological need for IL-17 for degranulation and chemotaxis of neutrophils in mucosal barrier defense against yeast.
• Rare (<0.1%): Transient grade 1-2 neutropenia, exacerbation or de novo debut of Inflammatory Bowel Disease.

Drug Interactions of Clinical Relevance

• Live Attenuated Vaccines: Absolute contraindication for co-administration due to risk of generalized viremia.
• No hepatic clearance interactions mediated by cytochrome CYP450 isoenzymes are described.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Not recommended. As monoclonal antibodies of the IgG isotype, they actively cross the placenta from the second gestational trimester. Although preclinical data do not suggest teratogenicity or direct fetal toxicity, it is preferred to discontinue the drug as a precaution and replace it with alternatives with proven safety such as certolizumab pegol (Fc portion-free anti-TNF that does not cross the placenta).
• Breastfeeding: Compatible with precautions. It is excreted in human breast milk in minute quantities that have not been shown to alter the development of the infant, but it is advisable to closely monitor the appearance of oral candidiasis in the neonate.

Clinical

Perla Clínica: Management of Candidiasis Associated with Anti-IL-17

The appearance of oropharyngeal candidiasis during therapy with secukinumab or ixekizumab is a common side effect but easy to manage clinically. It does not constitute an indication to permanently suspend highly effective immunobiological therapy. In the vast majority of cases, the mycosis responds completely to short courses of topical antifungals (Nystatin oral suspension) or systemic (Fluconazole 100-150 mg orally in a single dose or for 3 days).