Tumor Necrosis Factor in Dermatology: Pathogenesis and Therapeutic Role
TNF as a Central Pathogenic Cytokine in Psoriasis
TNF-α is a proinflammatory cytokine that plays a central role in the pathogenesis of psoriasis, psoriatic arthritis, and related inflammatory skin conditions, making it a critical therapeutic target in dermatology. 1
Biological Mechanisms
TNF is produced by multiple cell types including keratinocytes and exists in two biologically active forms: soluble TNF (sTNF) and transmembrane TNF (tmTNF), both binding to TNF receptor 1 (TNFR1, p55) and TNF receptor 2 (TNFR2, p75) 1
This cytokine binding leads to NF-κB activation, which promotes inflammation, and can trigger cell apoptosis 1
Elevated TNF concentrations are found in psoriatic plaques and synovial fluid of patients with psoriatic arthritis, directly correlating with disease severity 1, 2, 3
TNF modulates biological responses including expression of adhesion molecules responsible for leukocyte migration (E-selectin, ICAM-1, VCAM-1, ELAM-1) and increases serum cytokines (IL-6) and matrix metalloproteinases (MMP-1, MMP-3) that cause tissue remodeling and cartilage destruction 2, 3
TNF Inhibitors as Therapeutic Agents
Available TNF Antagonists
Three monoclonal antibodies (infliximab, adalimumab, golimumab) and one soluble receptor (etanercept) that inhibit TNF-α have received regulatory approval for psoriasis and/or psoriatic arthritis. 1
Infliximab is dosed at 5 mg/kg intravenously at weeks 0,2,6, and then every 8 weeks 1
Adalimumab is administered as 80 mg week 0,40 mg week 1, then 40 mg every other week subcutaneously 1
Etanercept is given as 25 mg twice weekly (or 50 mg once weekly up to 24 weeks), or 50 mg twice weekly up to 12 weeks reduced to once weekly thereafter 1
Eligibility Criteria for TNF Inhibitor Therapy
According to the British Association of Dermatologists, patients must have severe disease defined as PASI ≥10 (or BSA ≥10%) AND DLQI >10, plus meet at least one clinical category indicating failure, intolerance, or contraindication to standard systemic therapy. 1
The qualifying clinical categories include: 1
- Phototherapy and standard systemic therapy are contraindicated or cannot be used due to clinically important treatment-related toxicity
- Intolerance to standard systemic therapy
- Unresponsiveness to standard systemic therapy
Important caveat: In exceptional circumstances (disease affecting high-impact sites like genitalia, hands, feet, head and neck with significant functional or psychological morbidity), patients may fall outside the PASI/DLQI definition but should still be considered for treatment 1
Treatment Response Criteria
An adequate response is defined as either: (i) PASI 50 response AND 5-point or greater DLQI improvement, OR (ii) PASI 75 response. 1
For patients with both psoriasis and psoriatic arthritis on TNF antagonist treatment, therapy may be continued if there has been sufficient response in at least one component 1
Response should be assessed at time points appropriate for each drug: 14 weeks for infliximab, 12 weeks for etanercept, and 16 weeks for adalimumab 1
Cardiovascular Benefits of TNF Inhibitors
TNF inhibitors demonstrate significant cardioprotective effects in psoriasis patients, reducing major adverse cardiovascular events (MACEs) compared to other systemic therapies. 1
Evidence for Cardiovascular Risk Reduction
TNF inhibitors reduced myocardial infarction risk with a hazard ratio of 0.50 (95% CI 0.32-0.79, P=.003) compared to topical agents in psoriasis patients 1
TNF inhibitor users had fewer cardiovascular events than methotrexate users over 12 months (Kaplan-Meier rates 1.5% vs 4.1%, P<.01), with an overall hazard ratio of 0.55 (P<.01) 1
Cumulative exposure to TNF inhibitors over 24 months was associated with an 11% cardiovascular event risk reduction (P=.02) 1
A Danish nationwide cohort study showed TNF inhibitors reduced MACE risk with HR 0.46 (95% CI 0.22-0.98) compared to other medications 1
This cardiovascular benefit represents a critical quality of life and mortality advantage, as patients with severe psoriasis die on average 5 years younger than those without psoriasis, largely due to cardiovascular death. 1
Safety Considerations and Paradoxical Reactions
Infection Risk
Tuberculosis testing is mandatory before starting TNF inhibitor therapy due to increased risk of TB reactivation 4
TNF inhibitors should not be used in patients with active infections, and vigilance for opportunistic infections is required throughout treatment 4, 5
Malignancy Concerns
To date, there is no robust evidence of increased risk of malignancy with TNF antagonists in patients with psoriasis, though uncertainty remains regarding lymphoma risk. 1
Clinical trial data are reassuring, with no indication from registry data of increased risk of solid tumors and lymphoma with TNF antagonist therapy compared to standard DMARDs 1
All patients should be entered into registries (such as BADBIR) to establish long-term safety profiles 1
Paradoxical Psoriasis Induction
More than 120 cases of new-onset or worsening psoriasis have been reported in patients using TNF antagonist therapy, representing a rare but recognized paradoxical reaction. 1, 6
This can occur with all three TNF inhibitors (infliximab, etanercept, adalimumab), with timing varying from after a single application to 63 months after initiation 6
The response rate (complete plus partial remission) was 93-96% whether TNF inhibition was discontinued or continued with adjuvant anti-psoriatic therapy 6
Contraindications
TNF inhibitors should not be used in patients with multiple sclerosis or other demyelinating diseases, or in first-degree relatives of patients with MS 7, 4
Caution is warranted in patients with congestive heart failure due to reports of new onset and worsening CHF 4
Role in the Therapeutic Armamentarium
Despite the introduction of newer biologics targeting IL-17 and IL-23, TNF inhibitors remain essential first-line agents for moderate-to-severe psoriasis, particularly when psoriatic arthritis or cardiovascular comorbidities are present. 1
TNF inhibitors are dramatically effective in both psoriasis and psoriatic arthritis, inducing rapid disease resolution and long-lasting remission 5, 8
Primary and secondary failures affect 30-50% of patients in clinical practice, particularly those with long-standing disease, necessitating consideration of alternative biologics or JAK inhibitors 4
Topical therapies, phototherapy, and traditional systemic agents (methotrexate, acitretin, cyclosporine) continue to play essential roles and are commonly used in combination with biologics 1