Drugs used in Psoriasis

Drugs used in Psoriasis

Psoriasis- autoimmune disease 

• five main types of psoriasis: plaque, guttate, inverse, pustular, and erythrodermic.
• Plaque psoriasis, also known as psoriasis vulgaris, makes up about 90% of cases.
• Psoriasis is characterized by an abnormally excessive and rapid growth of the epidermal layer of the skin.
• chronic, non-contagious disease of the skin, in which silvery white masses of epidermic scales are attached, more or less firmly to a reddish vascular base
• Sites -knees, elbows, scalp, hands, feet, and lower back.
• Skin cells are replaced every 3–5 days in psoriasis rather than the usual 28–30 days.
• premature maturation of keratinocytes induced by an inflammatory cascade in the dermis involving dendritic cells, macrophages, and T cells
• These immune cells move from the dermis to the epidermis and secrete inflammatory chemical signals (cytokines) such as tumor necrosis factor-α, IL-1β, IL-6, IL-36 and IL-22.
• These secreted inflammatory signals are believed to stimulate keratinocytes to proliferate.

Topical corticosteroids

• Most frequently prescribed medications for treating mild to moderate psoriasis and initially even in severe cases
• They slow cell turnover by suppressing the immune system, which reduces inflammation and itching
• Low-potency corticosteroid ointments are usually recommended for sensitive areas such as face or skin folds, and for treating widespread patches of damaged skin
• Amcinonide 0.1%, betamethasone dipropionate, betamethasone valerate as 0.1%, 0.12% and 1% , halcinonide 0.1%, desoximetasone 0.25% and mometasone furoate
• Highest potency is clobetasol propionate 0.05%
• Systemic therapy with corticosteroids and/or immunosuppressants is reserved for severe and refractory cases.
• S/e- Thinning of the skin, telangiectasia, systemic side effects such as diabetes, hypertension and HPA suppression

Acitretin in Psoriasis

• second-generation retinoid and a free acid form and active metabolite of its precursor etretinate.
• It has the advantage over its precursor of having a much shorter half-life.

Mechanism of Action

• acts by modulating the proliferation of epidermal keratinocytes.
• In psoriasis, this antiproliferative action reduces desquamation, erythema, and the overall thickness of the lesion.
• Acitretin binds to RAR and RXR nuclear receptors, activating all 3 subtypes (alpha, beta and gamma) and modulating the transcription of the genes that code for various proteins involved in the pathogenesis of psoriasis.
• In addition to its direct mechanism of positive transcription, acitretin also exerts an indirect effect by inhibiting certain genes that regulate proliferation, angiogenesis, and inflammation in psoriasis.

Indications

•            severe extensive psoriasis that is resistant to other forms of therapy,

•            palmoplantar pustular psoriasis

Acitretin is not indicated in the treatment of psoriatic arthritis.

Calcipotriene and Calcipotriol

• synthetic non-hypercalcaemic vit D analogue effective topically in plaque type psoriasis.
• It binds to the intracellular vit D receptor in epidermal keratinocytes and suppresses their proliferation while enhancing differentiation.
• Benefit in psoriasis is slow; but most cases respond in 4–8 weeks. Response is maintained till treatment is continued.
• Combination with a steroid is more effective than either drug alone.

Tazarotene

• synthetic retinoid applied as a topical gel (0.05–0.1%) is moderately effective in psoriasis.
• Tazarotene Like other vitamin A derivatives, it normalizes DNA activity in skin cells and may decrease inflammation
• Exerts antiproliferative and anti-inflammatory action by binding to the intracellular retinoic acid receptor and modification of gene function.

Salicylic acid

• Promotes sloughing of dead skin cells and reduces scaling
• Sometimes it’s combined with other medications, such as topical corticosteroids or coal tar, to increase its effectiveness.
• Medicated shampoos and scalp solutions to treat scalp psoriasis

Coal tar

• Thick, black byproduct obtained through distillation of bituminous coal
• The polycyclic aromatic hydrocarbons in coal tar make the skin more sensitive to UV light
• It reduces scaling, itching and inflammation
• It’s messy, stains clothing and bedding, and has a strong odour
• Available in over-the-counter shampoos, creams and oils

Calcineurin inhibitors —

Topical tacrolimus 0.1% and pimecrolimus 1% are effective in the treatment of psoriasis in sensitive areas . Facial and intertriginous areas may be well suited to these treatments, which can allow patients to avoid or minimize chronic topical corticosteroid use

PHOTOTHERAPY

              Induces apoptosis  & enhanced transcription and expression of IL-10 in keratinocytes

s/e – redness, itching and dry skin

Narrow band UVB therapy(311-313 nm) -More effective than broadband UVB treatment

Usually administered 2 to 3 times a week until the skin improves,  then maintenance may require only weekly sessions

Narrow band UVB therapy may cause more severe and longer lasting burns

PUVA (2 to 3 sessions a week) –

• Light-sensitizing medication psoralen before exposure to UVA makes the skin more responsive to UVA exposure

Psoralen sensitizes the skin to UV rays à More aggressive therapy

s/e – headache, burning and itching, wrinkled skin, freckles & skin cancer

Patients being considered for treatment with biologics should have severe disease defined by a total psoriasis area and severity index (PASI) score of 10 or more (20 for infliximab)

Tumor Necrosis Factor Inhibitors

• Blockade of TNF-α reduces inflammation, decreases keratinocyte proliferation, and decreases vascular adhesion, resulting in improvement in psoriatic lesions.
• Because TNF-α inhibitors alter immune responses, patients on all anti-TNF-α agents are at increased risk for serious infection and for malignancies.
• Other adverse events include exacerbation of congestive heart failure and demyelinating disease in predisposed patients.
• All patients should be screened for tuberculosis, history of demyelinating disorder, cardiac failure, active infection, or malignancy prior to therapy.
• TNF-α inhibitors include monoclonal antibodies directed against TNF-α (adalimumab, infliximab) or a soluble TNF receptor that can bind TNF-α (etanercept)
• All TNF-α inhibitors are able to bind both soluble and membrane-bound TNF, but the monoclonal antibodies against TNF-α with an IgG1 Fc portion are also able to activate complement dependent cytotoxicity on binding of membrane-bound TNF-α.
• This may explain the increased efficacy of these agents in comparison to etanercept for treating granulomatous conditions as well as the higher risk of infection with their use.
• Etanercept binds both TNF-α and TNF-β. Etanercept is approved for plaque psoriasis and psoriatic arthritis in adults.
• Infliximab, a mouse-human chimeric IgG1 monoclonal antibody directed against human TNF-α, is approved for treatment of chronic severe plaque psoriasis and psoriatic arthritis. Administrationàintravenous. Neutralizing antibodies to infliximab may develop and lead to decreased efficacy over time. Concomitant administration of methotrexate or glucocorticoids may suppress this neutralizing antibody formation.
• Adalimumab is a human IgG1 monoclonal antibody directed against TNF-α; thus, the risk for development of neutralizing antibodies is reduced compared to infliximab.
• Adalimumab is approved for treatment of plaque psoriasis and psoriatic arthritis in adults.

Because certolizumab pegol lacks the Fc portion, it is not able to activate complement-mediated cytotoxicity.

METHOTREXATE

DHFRase inhibitor – weekly administration

s/e – Myelosuppression, mucositis Hepatotoxicity, pulmonary fibrosis, Nephrotoxicity, neurotoxic 

IL-12/23 Inhibitors- Ustekinumab

• IL-12 promotes Th1 activity and related TNF-α and IFN-γ production, while IL-23 activates Th17 cells that produce IL-17A, which regulates tissue inflammation and autoimmune responses.
• Ustekinumab is approved for treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis.

IL-17 Inhibitors- Secukinumab (jan 2015), IXEKIZUMAB (march 2016)

• with IL-17 stimulation causing increased keratinocyte expression of inflammatory cytokines and other effects that contribute to epidermal hyperproliferation and

barrier dysfunction

• Secukinumab – approved for the treatment of moderate-to-severe plaque psoriasis in adults.

IL-17 A RECEPTOR INHIBITOR  – BRODALUMAB – Feb 2017 FDA approved. Black box warning- Suicidal ideation and behavior, including completed suicides, have occurred in patients treated with brodalumab. Prior to prescribing brodalumab, weigh the potential risks and benefits in patients with a history of depression and/or suicidal ideation or behavior.

IL-23 INHIBITOR  – GUSELKUMAB (July 2017)IL-23 INHIBITOR  – Tildrakizumab (March 2018)for the treatment of moderate to severe plaque psoriasisselectively blocks interleukin (IL)-23.

Certolizumab pegol —TNF-alpha inhibitorIn 2018, the FDA approved the drug for the treatment of adults with moderate to severe psoriasis who are candidates for systemic therapy or phototherapy

PDE4 Inhibitors- Apremilast

• oral PDE4 inhibitor that increases intracellular cyclic AMP levels, thereby decreasing expression of inflammatory cytokines such as TNF-α and IL-23 and increasing expression of anti-inflammatory cytokines such as IL-10.
• Apremilast is approved for treatment of moderate to-severe plaque psoriasis and psoriatic arthritis in adults.
• The most common side effects are weight loss and depression.

Jak Inhibitors

• Janus kinases are tyrosine kinases involved in cytokine receptor signaling, and Jak inhibition leads to decreased downstream activity of STAT, which modulates transcription of genes involved in cell growth, proliferation, and differentiation.
• Tofacitinib – oral Jak inhibitor approved for use in rheumatoid arthritis in adults. It has demonstrated efficacy for psoriasis in clinical trials and for atopic dermatitis in a pilot study.

IL-4 Inhibitors

• Dupilumab is a fully human monoclonal antibody against the alpha subunit

of IL-4R that inhibits both IL-4 and IL-13 signaling as they each exert their action through binding an IL-4Rα/IL-13Rα1 receptor complex

• IL-4 and IL-13 are important mediators of the Th2 immune response that is involved in acute atopic dermatitis.

• ALEFACEPT – blocks the interaction between LFA-3 and CD2 and interfering with T-cell activation