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Pathway Producer Action in Psoriasis TNF-α (over expressed in psoriasis)5 Macrophages, T cells, mast cells, granulocytes, natural killer cells, fibroblasts, neurons, keratinocytes, and smooth muscle cells5 Increases the release of cytokines by lymphocytes and chemokines by macrophages6
Increases expression of adhesion molecules attracting neutrophils and macrophages to the lesions by activation of the vascular endothelium6
Induces keratinocyte and endothelial cell neovascularization stimulating the inflammatory process6IL-12/23 (upregulated in psoriasis)7 IL-12 promotes the differentiation of naive CD4+ T lymphocytes to Th1 cells.7
IL-12 triggers the specialization of CD4 and CD8 T lymphocytes by major histocompatibility complex class I and II, respectively, via antigen-presenting cells, which convert CD4+ cells into Th cells and CD8+ into cytotoxic T cells.6 As a result, TNF- α, IL-2, interferon-γ, and other cytokines are produced.6Th17 Th17 cells produce IL-17, a potent proinflammatory cytokine Il-17 directly perpetuates further inflammation of the keratinocyte, but it also indirectly stimulates production of IL-6.8 IL, interleukin; Th, T helper; TNF, tumor necrosis factor.
- Table 2. Risk Factors and Comorbidities for Moderate to Severe and Severe Psoriasis2,5,9,10
Psoriatic arthritis (25% of psoriatics develop PsA2)
Genetic predisposition to autoimmune disease
TNF-α deregulation
Elevated C-reactive protein increases risk of diseases like Crohn's, multiple sclerosis, cardiovascular disease (myocardial infarction and stroke), depression, and lymphoma (compared to the nonaffected age- and sex-matched population)*
More likely to smoke
Have HTN
Have diabetes, obesity, and hypercholesterolemia
Even when corrected for above risk factors (hypercholesterolemia, diabetes, HTN, and obesity), patients with severe psoriasis have an elevated incidence of myocardial infarction compared with age-matched patients without psoriasis2,11
Control of HTN, cholesterol, weight, and diabetes can assist in decreasing psoriasis burden and frequency of flares2
Moderate to severe psoriasis is associated with depression, suicide,9 and rarely lymphoma10; this risk increases with disease burden
↵* Because of this baseline elevation in inflammatory markers, especially in patients with moderate to severe plaque psoriasis, risk for certain diseases like multiple sclerosis,12 lymphoma,13 and myocardial infarction may be elevated even further with use of a TNF-α blocker.2,10 On the other hand, patients with moderate to severe psoriasis with depression and suicidal ideation who are placed on etanercept, a TNF-α blocker, may improve both their psoriasis and their depression.9,14
TNF, tumor necrosis factor; HTN, hypertension.
Presentation Features Additional Features Location Treatment(s) Plaque (psoriasis vulgaris is most common) Well-demarcated papule or plaque with silvery scale and punctuate bleeding when peeled (Auspitz's sign) Koebner's phenomenon, which is the development of psoriasis in areas of trauma16 Knees, elbows, trunk (extensor surfaces), nape of neck, postauricular, lumbosacral area, scalp, feet, hands, penis16 Topical and/or systemic, depending on severity and recalcitrance
Intralesional steroids for local recalcitrant diseaseNail Proximal nail matrix produces defects in keratinization that are translated as the nail grows out from the cuticle in the form of pits <1 mm in diameter
Psoriasis of the nail bed results in oil spots. Patients also get splinter hemorrhages.17Subungual hyperkeratosis (onchyolysis) starts as the free nail separates from the nail bed and can be demarcated by a yellow band; this allows for material from the nail bed to accumulate under the nail.16,17
Consider possible future development of PsA.Fingernails and/or toenails Intralesional steroids, CsA18 Inverse (uncommon) Painful, well-demarcated, symmetric, erythematous papules and plaques that may become macerated, often eroded, or secondarily infected because of location19 Intertriginous regions of the body: inframammary, neck, axillary, inguinal crease, and intergluteal Topical Erythrodermic >90% Involvement of BSA
Acute: develops over days, can be severe and even life threatening because of greater stress on the heart and other metabolic resources of the body
Chronic: develops more slowly over months to yearsAcute form can result in hospitalization and can be life threatening if severe because of loss of fluids (electrolytes, water, proteins) and unstable body temperature20 Widespread Systemic (acetretin,18 MTX, CsA18) Pustular (generalized type; rare; 4 types) Erythema and sterile pustules sometimes in preexisting plaques or in annular lesions Some can have metabolic disturbances.19 Causes include pregnancy, rapid steroid taper, infections, hypocalcemia, or topical local irritants19 Widespread in flexures Systemic (acitretin18) or biological Palmar/plantar pustular Vesicles lead to pain and/or significant itch in involved areas. Typically recalcitrant because of the thickness of the skin of the palms and soles, limiting penetration of topical treatments and trauma to hands and feet, causing the Koebner phenomenon Hands/feet UV light (PUVA/UVB), acitretin,18 CsA18 Guttate Abrupt eruption of psoriasis that is characterized by 2- to 5-mm teardrop-shaped papules. Preceded by a streptococcal infection or drug-induced (carbamazepine, α-interferon, antimalarials, abrupt cessation of systemic corticosteroids, lithium, β-blockers)2 Trunk and extremities With UV light and withdrawal of offending drugs or resolution of streptococcal disease, some patients have resolution.
Some patients will go on to have psoriasis later in life, with most developing plaque-type psoriasis.↵* Psoriasis is a disease that is diagnosed clinically, but if the condition fails to respond to therapy or lesions do not appear classic, a biopsy or dermatology referral may be warranted.
CsA, cyclosporin A; MTX, methotrexate; PsA, psoriatic arthritis; UV, ultraviolet; PUVA/UVB, psoralen + ultraviolet A/ultraviolet B; BSA, body surface area.
Psoriasis BSA* (%) Treatment Required Mild <5 Topical Moderate to severe† 5–10 Topical and systemic Severe >10 Systemic ↵* To determine a patient's body surface area (BSA) of plaque involvement, the doctor would use the patient's own palmar handprint as a guide while they perform their examination. The surface area for each handprint is equal to 0.8% of the total BSA for men,21 0.7% for women, and 0.94% for children.22
↵† Severe disease: significant involvement of the palms/soles, face or intertriginous areas as these may be significantly debilitating.
- Table 5. Summary of Systemic Drugs for Psoriasis Using Strength of Recommendation Taxonomy (SORT)4
Drug Mechanism of Action Dosing FDA-Approved Indication SORT Level Level of Evidence Studies Biologics Etanercept Soluble dimeric fusion protein that links the p75 TNF-α receptor to the Fc portion of IgG1, decreasing its activity33 SC injection of 50 mg twice/week for 3 months, followed by 50 mg weekly33 Moderate to severe plaque psoriasis and PsA36 A 1 Amgen-Pfizer has >3 years of clinical data for this drug; early studies for rheumatoid arthritis have shown that 25 mg SC twice/week over 2 years not only has good clinical responses but also provides better mental health and less bone damage.37 This response reverted to baseline once etanercept was discontinued and improved when use of the drug resumed.37 Later, as these studies were conducted in patient cohorts with PsA and psoriasis, similar positive results were found: psoriatic skin plaques improved, structural damage halted, and inflammatory markers decreased, and the patients reported feeling better both physically and mentally.37 Adalimumab Recombinant human Ig monoclonal antibody neutralizes the biological function of TNF-α by blocking its interaction with the p55 and p75 cell-surface TNF-α receptors38 SC injection at a dosage of 80 mg at week 0, followed by 40 mg every 2 weeks beginning at week 233 Moderate to severe plaque psoriasis and PsA A 1 Three major trials assessed the efficacy of adalimumab.39 After week 16 in each of these trials, approximately 80% of patients experienced a PASI 75* response.39 Infliximab Chimeric monoclonal antibody (75% human, 25% murine) in which the Fc portion is human IgG1 and the Fab portion is primarily of murine origin.40 Neutralizes soluble TNF-α and blocks membrane TNF-α.41 The drug is administered intravenously every 8 weeks following an initial loading dose Moderate to severe psoriasis
PsA (Preg Cat B)A 1 Three major trials assessed efficacy of infliximab.42–44 After maintenance phase (through week 50). patients remained at PASI 75.
Anti-infliximab antibodies commonly develop after prolonged therapy and can result in decreased drug efficacy or in some cases a severe infusion reaction with respiratory compromise.45Ustekinumab Human monoclonal antibody that blocks IL-12 and IL-23, binding the p40 subunit, which activates T cells in psoriasis.7 45 mg for patients weighing ≤100 kg; 90 mg for patients weighing >100 kg33
SC at weeks 0 and 4, repeated every 12 weeks33Moderate to severe plaque psoriasis A 1 Two phase III clinical trials showing that about two-thirds of patients achieved a PASI 75 response after 12 weeks of treatment.46,47* Systemic Acitretin Oral retinoid inhibits induction of helper T lymphocytes via IL-6 by modulating gene expression,33 which functions to regulate the keratinocyte turnover in psoriasis.18 Used in conjunction with phototherapy or topical steroids/vitamin D analog for plaque psoriasis at the lowest effective dose. Start at doses of 10–25 mg/day and increase dose every 2 weeks until xerosis (dry skin) to chelitis (or dry lips) appear; may take about 3 months to see a therapeutic response.18 Severe psoriasis, palmoplantar pustulosis, nail psoriasis, generalized pustular psoriasis18 A 1 After 12 weeks of therapy, the percentage reduction in the PASI score was 54%, 76%, and 54% for the groups taking acitretin 25, 35, and 50 mg/day, respectively.48 A PASI 75 response was achieved in 47%, 69%, and 53% patients in the acitretin 25, 35, and 50 mg/day groups, respectively.48 MTX Folic acid analog that irreversibly inhibits dihydrofolate reductase in the eukaryotic cell, decreasing DNA and protein synthesis, which prevents epidermal hyperproliferation. Also decreases DNA in activated T lymphocytes by inhibiting aminoimidazole carboxyamide ribocucleotide, an enzyme involved in purine metabolism.2 Single weekly dose or in 3 doses: 1 dose every 12 hours over 36 hours, or once weekly, starting at 5 to 10 mg and adjusting the dosage upward at 4-week intervals to a therapeutic dose between 15 and 25 mg/week, with a maximum dose of 25 mg/week.18,33 Low-dose folic acid (1–5 mg) is administered in 3 doses over 36 hours, starting 12–36 hours after the last MTX dose to avoid megaloblastic anemia with few reductions in efficacy.18,33,49 Or, can be given daily, except the day(s) the MTX is taken. Severe plaque psoriasis, erythrodermic, pustular, and other off-label uses50 A 1 92.7% of patients achieve a PASI 75 response after 12 weeks of high-dose MTX.51 Cyclosporine Binds to cyclophilins and forms a complex, blocking differentiation and activation of T cells by inhibiting calcineurin, thus preventing the production of IL-2 and its receptor. It also inhibits keratinocyte hyperproliferation.18 In the absence of comorbidities (obesity and older age) it is weight-based and dosed at 3 mg/kg/day; it is usually divided into 2 doses.18 Alternative dosing is 2.5 mg/kg/day in 1 or 2 divided doses for patients with stable moderate to severe psoriasis and 4.0–6.0 mg/kg/day in 1 or 2 divided doses for patients with severe or recalcitrant psoriasis.52 The goal is the lowest effective dose possible. Taking CsA before meals may result in better absorption and bioavailability of the drug, translating into a reduced disease burden.52 Severe, recalcitrant, or disabling psoriasis,53 as well as pustular, erythrodermic, and nail psoriasis52 B 2 PASI 75 responses in up to 97% of treated patients have been reported.54 ↵* Psoriasis Area and Severity Index (PASI) 75 score is reported here because it is a good tool used in clinical trials of psoriasis to determine treatment efficacy and response. A PASI 75 response indicates a 75% reduction in psoriasis lesions. Note that, because if its complexity, PASI is, in general, not calculated outside of the research setting; body surface area is another way to monitor treatment progress.
CsA, cyclosporine; Ig, immunoglobulin; IL, interleukin; MTX, methotrexate; PsA, psoriatic arthritis; SC, subcutaneous; TNF, tumor necrosis factor; FDA, U.S. Food and Drug Administration.
Latent TB dx without proper tx36,55,56* Blood dyscrasia Wegener's granulomatosis36,55 Recent illness Immunosuppressive disease Ustekinumab only for drug-induced psoriasis, any history of malignancy (except for basal or squamous cell carcinoma skin cancer and cervical cancer in situ treated at least 5 years before the initiation of ustekinumab), and a history of active TB (latent, treated TB can receive treatment)7 History of hepatitis, positive hepatitis B (which can be reactivated in chronic carriers, thus, the need for the vaccination), or active or untreated hepatitis C Multiple sclerosis (except for ustekinumab) Any demyelinating disorder7,36,55 ↵* Patients diagnosed with tuberculosis (TB) who have received at least 2 months of treatment can receive a tumor necrosis factor (TNF)-α inhibitor with close supervision and a multidisciplinary approach. TNF-α modulates granuloma homeostasis and contains latent disease.57 In patients with a history of latent TB, indurations on PPD of >5 mm, even with history of BCG vaccination, is considered positive and exclusionary without proper treatment for TB.36,55 The risk of TB reactivation is lower with etanercept, a TNF-α, than with other monoclonal antibody inhibitors.58
Biological Screen Lab Follow Labs Every 2 to 6 Months Vaccine/Frequency PPD/Frequency Etanercept CBC with differential CBC with differential Flu (standard for age) At baseline CMP CMP + Annual ANA (optional) Adalimumab CBC with differential CBC with differential Flu (standard for age) At baseline CMP CMP + Annual ANA (optional) Infliximab CBC with differential CBC with differential Flu (standard for age) At baseline CMP CMP + Annual ANA (optional) Ustekinumab CBC with differential CBC with differential Flu (standard for age) At baseline CMP CMP + Annual ANA (optional) CBC, complete blood count; CMP, complete metabolic panel; ANA, anti-nuclear antibody; PPD, purified protein derivative; Flu, inactivated influenza vaccine (avoid live vaccines).
