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A. Epidemiology

  1. Chronic Disease affects nearly 2% of US Population
    1. About 250,000 new cases per year in USA
    2. About 4.5 million patients in USA (2 million are treated)
  2. Prevalence Male = Female
  3. Any age, most patients >10 years
  4. Incidence has 2 peaks at16-22 years and ~60 years
  5. Most common form (~90%) is psoriasis vulgaris
  6. >50% of patients have family history of psoriasis
  7. Associated (Psoriatic) arthritis in ~10% of cases

B. Pathogenesis

  1. Etiology Unknown
    1. Clear genetic predisposition
    2. Unclear inheritance pattern
  2. Theories of Pathogenesis
    1. Primarily an epidermal disease - increased epidermal proliferation (turnover)
    2. Mitotic acivity in skin increased >50 fold compared with normal skin
    3. Epidermal cell progression from basal to cornified layers normally 28-30 days
    4. Progression in psoriasis 3-5 days
    5. Systemic autoimmune disease, probably initiated through CD4+ T helper cells
    6. Anti-T cell therapies significantly improve disease symptoms
    7. Associated with various HLA Types: HLA-Cw6 13-20X risk increase, DR7 increased
    8. Weak association with HLA-B27; stronger association with psoriatic arthritis
    9. PSOR1 locus in MHC on chromosome 6 is most highly linked to disease
    10. Chromosome 17q25 locus encodes gene involved in blood cell development
  3. Pathophysiology [1,5]
    1. CD4 T (mainly Th1) lymphocyte infiltration with lymphokine secretion
    2. These are CD4+ memory cells which express CLA and CD45RO (memory marker)
    3. Monocytes and dendritic cells in psoriasis produce IL12 and IL23, which are key (see below)
    4. Langherans type antigen presenting cells in skin also play a key role in T cell stimulation
    5. T cell signalling through Toll-like receptors (innate immunity) also plays a role
    6. IL1a is preformed in keratinocytes and released directly into surrounding skin
    7. These cytokines stimulate expansion of T helper type 1 (Th1) cells
    8. The specific antigenic activation stimulus for these T cells is unclear
    9. However, trauma or infection of the skin precipitates psoriatic flares
    10. Overall, thesex stimuli lead to T cell activation and homing to skin
    11. Levels of TNFa and IFNg (Th1 cytokines) are high in psoriatic lesions
    12. TNFa may be a particularly important cytokine in the development of psoriasis [4]
    13. IL1, IL6 and IL8 levels are also elevated
    14. IFNg causes hyperkeratosis, parakeratosis and loss of granular cell layer
    15. Increased Leukotriene B4 (LTB4)
    16. Natural killer (NK) cells and NK T cells are part of cutaneous infiltrate

C. Histology

  1. Three major findings:
    1. Epidermal hyperproliferation with thickening and overlying scale
    2. Dilated, prominent blood vessels in dermis (increased angiogenesis)
    3. Inflammatory leukocyte infiltrate, primarily in dermis
  2. Epidermal neutrophilic infiltrates called Muncro's microabscesses
  3. Elevated expression of keratin 6/16 heterodimers (marker of skin proliferation)
  4. Leukocytes
    1. Abnormal infiltration by (T) lymphocytes, monocytes, as well as neutrophils
    2. Elevated levels of ICAM-1 leading to increased T cell trafficking
    3. CD8+ T cells cells predominate in epidermis and interact with Langerhans cells
    4. CD4+ T cells found in both epidermis and dermis

D. Symptoms

  1. Dry, coarsely scaly, well-demarcated erythematous plaques often with white scales
    1. This classic presentation occurs in ~90% of patients
    2. Typically begins on elbows and knees most frequently, usually symmetric
    3. Usually affects elbows, knees, scalp, umbilicus, lumbar area
    4. Inverse type affects intertrigenous areas with minimal scaling
  2. Variant Psoriasis
    1. Acute generalized onset of numerous small papules is guttate psoriasis
    2. Guttate psoriasis is often preceded by 2-3 weeks by ß-hemolytic streptococcal infection
    3. Exfoliative erythroderma (>80% of body covered) can also occur with psoriasis
    4. Pustular psoriasis (see below)
    5. Intertriginous and genital psoriasis - more difficult to treat than others
    6. Scalp psoriasis - usually as part of other forms, very common
  3. Pustular Psoriasis
    1. Less comon than psoriasis vulgaris
    2. Generalized form characterized by deep red erythematous areas and pustules
    3. Generalized pustules may merge into extensive lakes of pus
    4. Patients with generalized form are systemically unwell and may bacterial superinfections
    5. Generalized form requires hospitalization and careful monitoring
    6. Localized forms include palmoplantar and acrodermatitis continua suppurativa
  4. Nail Changes
    1. Finger nails 50%, toe nails ~35%
    2. Onycholysis - lifting of nail from nailbed
    3. Pitting
    4. Oil spots - yellow macules beneath nail plate
  5. Arthritis
    1. Distal small joints, especially with destruction ("mutilans")
    2. Spinal / Axial Arthritis - especially in HLA-B27+ patients
  6. Risk factor for myocardial infarction [1,6]
    1. Particularly with severe psoriasis
    2. Up to 3X increased risk in 30 year old persons with severe psoriasis
    3. May be related to systemic inflammation

E. Exacerbating Factors

  1. Mechanical Trauma - elbows and knees
  2. Infection [1]
    1. ß-hemolytic (Strep pyogenes) streptococci - associated with guttate ("small drops") psoriasis, usually ages <30 years with resolution in 3-4 weeks
    2. Other viral infections in children can induce guttate psoriasis
    3. HIV Infection
  3. Medications
    1. Antimalarials: chloroquine, hydroxychloroquine
    2. ß-Adrenergic blockers
    3. Certain NSAIDS: indomethacin
    4. Lithium
    5. Interferon alpha
  4. UV Radiation - sunburn
  5. Exacerbations are usually idiopathic

F. Differential Diagnosis

  1. Seborrheic Dermatitis
  2. Chronic eczematous dermatitis - usually more pruritic than psoriasis
  3. Uncommon:
    1. Early cutaneous T cell lymphoma
    2. Pityriasis rubra pilaris
    3. Lichen planus
    4. Superficial fungal infections
    5. Subacute cutaneous lupus erythematosus
  4. Palmoplantar Pustulosis [1]
    1. ~25% of patients have concurrent psoriasis
    2. Female : Male 9:1
    3. Onset 4th-5th decade
    4. Yellow-brown sterile pustules on plams and soles

G. Therapy Overview [1,2,3]

  1. Severity of disease usually determines approach
  2. ~75% of patients are treated with topical drugs
  3. Mild and Moderate Disease
    1. Vitamin D analogs (calcipotriol and tacalcitol) and retinoids are first line
    2. These are used more than coal tars
    3. Topical glucocorticoids are very effective but must be used with slow taper to prevent flares (caution with long term use due to skin atrophy) [22]
    4. Psoralen + UVA is available for moderate disease, but falling out of favor
  4. Moderate and Severe Disease
    1. Phototherapy, systemic drugs, or both are used
    2. Methotrexate (MTX) and retinoids target immune system and keratinocyte proliferation
    3. Most biologics and cyclosporin target only immune system
    4. TNFa blockers are relatively safe and very effective
    5. Etanercept (a TNFa blocker) improves joint pain, depression symptoms, fatigue also [17]
    6. UVB (prefered) or Psoralen + UVA (PUVA) may be used in some moderate patients
    7. Particularly serious lesions may benefit from additional topical treatments
    8. Systemic retinoids - etretinate (out of favor) and acitretin (preferred)
  5. Biological Therapies [5]
    1. TNFa blockers: etanercept (Enbrel®), infliximab (Remicade®)
    2. CD2-LFA3 interruption: alefacept (Amevive®)
    3. LFA1-ICAM1 interruption: Efalizumab (Raptiva®)
    4. Anti-IL12/IL23 (anti-p40) monoclonal Antibody: Th1h CD4+ cell interruption [3]
  6. Efficacy in Moderate to Severe Disease [10]
    1. Cyclosporin >5mg/kg/d, methotrexate, TNFa blockers are most effective systemic agents
    2. Psoralen with ultraviolet A (PUVA) very effective
    3. Ultraviolet B (UVB) narrow band very effective and probably safest
    4. Biological agents (efalizumab, alefacept, low dose etanercept) good efficacy
    5. High dose etanercept (50mg sc twice weekly) most effective biological agent
    6. Infliximab 5mg/kg weeks 0, 2, 6 then every 8 weeks also very effective [21]

H. Topical Agents [3,5]

  1. Types
    1. Emollients - to decrease scale; ~35% have significant response
    2. Topical Glucocorticoids
    3. Retinoids (topical and systemic are available)
    4. Vitamin D3 Derivatives
    5. Keratolytic Agents - containing 2-10% salicyclic acid; to decrease scale
    6. Coal Tar - topical agents for skin, shampoo available for scalp disease
    7. Anthralin - apply to areas for one half hour, then wash off
    8. Topical T cell blockers: tacrolimus, pamicrolimus
  2. Vehicles for Topical Agents [22]
    1. Ointments - most effective glucocorticoid vehicle; oil base creates occlusive barrier, increases hydration and penetration of glucocorticoid into plaque
    2. Creams - oil in water emulsions, less potent than ointments
    3. Gels - similar to creams but colorless and contain alcohol, which may be irritating
    4. Lotions and solutions - water based, easily applied to large areas, but may be drying
    5. Foams and sprays - alcohol base, easy to apply to large areas, but may cause irritation
    6. For scalp applications, foams, solutions and shampoos recommended
    7. Acute Scalp Psoriasis: corticosteroid lotion or spray ± antifungal agent [22]
  3. Topical Glucocorticoids [22]
    1. Palliative treatments, mainly in mild to moderate disease
    2. Available in strengths from mild to mid to potent to super-potent
    3. Are applied 1-2 times per day to affected areas
    4. Super potent: clobetasol (Temovate®. Clobex®, Olux®), betamethasone 0.05% (Diprolene®), halobetasol (Ultravate®), Fluocinonide (Vanos®)
    5. Potent: amcinonide 0.1% (Cyclocort®), fluocinonide (Lidex-E®), halcinonide (Halog®)
    6. Mid-Potent: mometasone (Elocon®), fluocinolone (Synalar®), triamcinolone (Kenalog®)
    7. Mild: triamcinolone (Aristocort A®), betamethasone (Valisone®), flumethasone (Locorten®)
    8. Flucinonide (0.05%) is a high potency agent, clears lesions in ~60% of patients
    9. High potency topical glucocorticoids should not be used for >2-3 weeks
    10. These high potency agents, often fluorinated, cause skin atrophy and systemic absoprtion
    11. Critical to taper off use slowly otherwise flare will occur
    12. Combination betamethasone-calcipotriene (Taclonex®) available [23]
  4. Topical Retinoids [9]
    1. Calcipotriene
    2. Tacalcitol
    3. Tazarotene
    4. Combinations with betamethasone
  5. Calcipotriene Ointment (Dovonex®) [7]
    1. Inhibits proliferation and enhances differentiation of keratinocytes
    2. Similar activity to calcitriol, but much reduced systemic effects
    3. Causes some increased calcium absorption and calciuria
    4. Apply bid for up to 8 weeks - improvement in ~60% of patients
    5. Generally well tolerated, with some burning/itching
    6. Hypercalcemia in some patients
    7. Contraindicated in patients with renal failure and history of nephrolithiasis
    8. Maximum dose is 100gm tube per week
    9. Available in combination with betamethasone as Taclonex® [23]
  6. Tazarotene (Tazorac®) is now FDA approved for mild to moderate disease
    1. This is an acetylated retoid prodrug converted to active drug by skin
    2. Tazarotene (0.05% or 0.1%) qd for 6-12 weeks clears lesions in ~60% of patients
    3. In some patients, therapeutic benefits persist for ~3 months after stopping drug
    4. Skin irritation can occur, mostly with 0.1% gel
    5. May be absorbed systemically; not recommended in pregnancy
  7. Tacrolimus (Protopic®) [24]
    1. Topical tacrolimus formuation approved for moderate to severe eczema
    2. Strengths of 0.03% and 1.0% available for bid application
    3. Responses usually seen within 7 days
    4. Well tolerated; does not cause skin thinning or hypopigmentation
    5. Main side effects are mild burning sensation, erythema, pruritus on applied area
    6. Some concern about skin tumors (sunscreens should be used) and systemic absorption
  8. Pamicrolimus (Elidel®) [25]
    1. Topical pimecrolimus 1.0% cream for bid application
    2. Approved for use in patients 2 years or older for mild to moderate eczema
    3. Allows glucocorticoid-free control of atopic dermatitis
    4. May cause less systemic immunosuppression than tacrolimus or glucococorticoids
    5. Does not cause skin atrophy
    6. Concerns about skin tumors as for tacrolimus (sunscreens should be used)

I. UV Radiation [27]

  1. Types
    1. Ultraviolet B (UVB) - depletes intraepidermal T cells but is very safe [10]
    2. PUVA (psoralen with UVA)
      [Figure] "Structure of Psoralen"
    3. PUVA Bath Treatment
    4. UVA radiation activates phototoxic effects of psoralen forming psoralen-pyrimidine base cycloadducts (on C4 position) on DNA
  2. Efficacy
    1. UVB is very effective for moderate disease
    2. PUVA is very effective for moderate to severe disease
    3. PUVA may be used instead of systemic therapies such as methotrexate, TNFa blockers
    4. UV treatments are not effective for psoriatic arthritis
  3. Side Effects
    1. UV blocking glasses must be worn during PUVA treatments and ~12 hours afterwards
    2. PUVA ± Bath have increased risk for developing cutaneous squamous cancers
    3. In addition, risk for melanoma is ~5 increased after ~15 years of PUVA
    4. Avoid PUVA in patients with history of melanoma and in light colored skin (Types I and II)
    5. Caution in patients with family history of melanoma
    6. Avoid in patients with history of nonmelanomatous skin cancer
    7. This type of therapy is falling out of favor due to cancer risk and improved agents
  4. Patient should be ANA and anti-Ro antibody negative (lupus is exacerbated in sun)

J. Systemic and Biological Therapies

  1. Types
    1. Retinoids - etetrinate and acitretin
    2. Methotrexate (MTX)
    3. Cyclosporine (CsA)
    4. Sulfasalazine
    5. Parenteral TNFa Blockers: etancercept, infliximab, adalimumab
    6. Alefacept
    7. Efalizumab
  2. Etetrinate (Tegison®)
    1. About 70% of patients with erythrodermic and pustular psoriasis respond
    2. Less effective for chronic psoriasis
    3. Drug half life ~120 days; concentrated in adipose tissue with ~3 year duration
    4. Highly teratogenic and informed consent must be obtained for use
    5. Often causes cheilitis, hair loss, dry skin, hepatitis (30%), other liver dysfunction
    6. May be combined with PUVA therapy
    7. Dose is 50mg per day
  3. Acitretin (Soriatane®) [9]
    1. Major metabolite of etetrinate with half life ~50 hours
    2. Not stored in adipose tissue
    3. Efficacy similar to etetrinate and will eventually replace this agent
    4. Ethanol intake can induce conversion of acitretin to etetrinate in vivo
    5. Caution when used Vitamin A supplements or progesterone mini-pills
    6. Pregnancy and blood donation are contraindicated for >3 years after taking acitretin
    7. Side effects similar to etetrinate
    8. Dose is 25-50mg po qd, taken with large meal
  4. MTX (Rheumatrex®) [8]
    1. Inhibits keratinocyte proliferation (folate antagonist) and lymphokine secretion
    2. Very effective in moderate to severe disease, similar to ~5mg/kg/d cyclosporine [8,10]
    3. Probably more effective than biological agents
    4. Dose begins at 10-12.5mg po q week (as 3 divided doses every 12 hours, once weekly)
    5. Doses >15mg/week probably should be given sc up to ~25mg per week
    6. Side effects: cytopenias, liver damage (including cirrhosis), infections
    7. History of liver disease, alcohol consumption should prompt liver biopsy
    8. Liver biopsy after1.5gm cumulative dose is recommended by dermatologists
    9. Monitor liver function (with PT), blood counts, weekly for one month, then monthly
  5. Etanercept (Enbrel®) [12,16]
    1. Soluble TNF alpha receptor (TNF-R); blocks TNFa functions
    2. In 12 week study, provided substantial benefits to 87% of psoriatic arthritis patients
    3. Substantial improvement in joint symptoms as well as skin disease
    4. In phase 3 study in severe psoriasis, >75% improvement in up ~49% of patients [16]
    5. Significantly improved symptoms of depression and fatigue in psoriasis at 12 weeks [17]
    6. Significantly reduced severity in age 4-17 years persons with plaque psoriasis [28]
    7. Well tolerated in adults and children
    8. May be used in combination with methotrexate in adults; caution in children
    9. Dose is 25-50mg (0.8mg/kg in children to 50mg maximum) subcutaneously 1-2X per week
  6. Infliximab (Remicade®) [4,21]
    1. Chimeric mouse-human nti-TNF alpha monoclonal antibody (mAb)
    2. In moderate to severe plaque psoriasis, 82% achieved PASI 75 (very effective agent) [21]
    3. Responses occurred within 4 weeks with duration out to 1 year
    4. Dose is 5-10mg/kg given weeks 0, 2 and 6 then every 8 weeks
    5. No serious adverse events noted
  7. Adalimumab (Humira®) [3]
    1. Fully humanized anti-TNFa mAb
    2. Dose 40mg sc q2 weeks
    3. After 24 weeks, 54% of patients achieved PASI 75
    4. Well tolerated and convenient
  8. Efalizumab (Anti-CD11a McAb, Raptiva®) [18,19,20]
    1. Binds alpha subunit of LFA1 (CD11a) and blocks interaction with ICAM-1
    2. About 25% of patients receiving efalizumab 1-2mg/kg sc weekly for 12 weeks had 75% reduction in psoriasis activity and severity
    3. Generally well tolerated with some increase in headache, chills, fever, injection site pain
  9. Alefacept (LFA3-IgG1 fusion protein, Amevive®) [11,15]
    1. Soluble LFA3-IgG1 binds to CD2+ expressing CD4 T lymphocytes
    2. Main side effect: depletes CD4+ T cells in high doses
    3. In low and moderate doses, specifically depletes CD45RO (memory) CD4 or CD8 T cells
    4. Treatment with alefacept for 12 weeks led to complete clearance in 16%
    5. No rebound of psoriasis occurred after cessation of therapy
    6. Dose is 7.5mg qweek IV or 15mg qweek IM for 12 weeks
    7. CD4+ T lymphocyte counts must be monitored during therapy
    8. May repeat course (can lead to >1 year lasting remissions) if lymphocyte counts okay
    9. Chills occur primarily with IV administration, otherwise well tolerated
  10. Cyclosporine (CsA, Sandimmune®, Neoral®) [8,10]
    1. Very effective treatment approved for psoriasis in Europe, not in USA
    2. As effective as methotrexate, may be better tolerated, for moderate-severe disease [8]
    3. Microemulsion (Neoral®) is better tolerated, used only in severe, recalcitrant diseaes
    4. CsA 2.5-3mg/kg/d about as effective as biological agents
    5. CsA >5mg/kg/d is probably more effective than biological agents (increased side effects)
    6. Initial dose is 2.5-3mg/kg per day orally in patients with normal renal function
    7. Monitor renal function, 24 hour urine creatinine, blood counts, liver function
    8. Dose can be decreased once response is obtained (usually 4-8 weeks after start)
    9. Relapses are common 2-4 months after drug is stopped
    10. Side Effects: renal insufficiency (usually stablizes), hypertension, infection
    11. Small increased risk of lymphoproliferative disorders (in transplant patients)
    12. When combined with PUVA, increases risk of squamous cell cancer ~7X [13]
  11. Abatacept (CTLA4-Ig, Orencia®)
    1. Blocks T cell costimulation through CD28-CD80/86 (B7-1/2) system and is FDA- approvedfor rheumatoid arthritis
    2. Abatacept has shown efficacy in clinical studies for treatment of psoriasis
  12. Systemic Glucocorticoids
    1. Effective initially but severe disease rebound when tapering
    2. May be given to patients with erythroderma and systemic symptoms
    3. Beginning methotrexate prior to glucocorticoid taper can decrease rebound
    4. Systemic glucocorticoids are avoided in psoriasis and should only be used by experts
  13. Experimental Therapeutics [14]
    1. Anti-p40 mAb: blocakde of IL12/IL23 (see below)
    2. Anti-CD2 mAb
    3. Other immunosuppressants - rapamycin, leflonomide
    4. ISA247, a novel calcineurin inhibitor, has snown efficacy and little nephrotoxicity in Phase III [29]
    5. DAB389-IL2 leads to ablation of activated T cells expressing IL2R (CD25)
  14. Ustekinumab (anti-p40 mAb)
    1. mAb to p40 protein, which is a subunit of both IL12 and IL23 (Th1 cytokines)
    2. In phase II, single doses and 4 once weekly doses of 45mg or 90mg of ustekinumb significantly improved moderate-severe plaque psoriasis with good tolerability [26]
    3. Responses in phase II were sustained at 12, 16, and 20 weeks after single doses
    4. In a 12 week trial, ustekinumab subcutaneously 45mg or 90mg at weeks 0 and 4 lead to PASI 75 in 66-75% versus placebo <4% [30,31]
    5. Responses to ustekinumab are durable for up to 76 weeks after intermittent dosing [30]
    6. Very well tolerated with this regimen, with serious adverse events similar to placebo

K. Psoriatic Arthritis

  1. Occurs in 4-10% of Patients with psoriasis
    1. Most patients are HLA-B27+
    2. Severe mutilatory progression
  2. Good response to anti-TNFa therapy for psoriasis
    1. Methotrexate was previously first line
    2. TNFa blockers much more effective and safe for both skin and joint disease
  3. NSAIDS may help alleviate pain - high doses usually required

References

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