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1 Papulosquamous Dermatoses

Rania AlSaied MD

2 Rubra Pilaris

3  It is a chronic papulosquamous disorder of unknown etiology characterized by reddish orange scaly plaques, palmoplantar keratoderma, and keratotic follicular . The disease may progress to with distinct areas of uninvolved skin, the so-called islands of sparing.

4  Griffiths divided PRP into 5 categories: classic adult type, atypical adult type, classic juvenile type, circumscribed juvenile type, and atypical juvenile type. More recently, an HIV-associated type has been added to this classification system.

5 Pathophysiology

 The etiology is unknown. A familial form of the disease exists, with an autosomal dominant inheritance pattern; however, most cases are sporadic. One hypothesis is that PRP may be related to an abnormal immune response to an antigenic trigger. Case reports have described PRP occurring after streptococcal infections.

6 Mortality/Morbidity

 Patients with PRP can have painful and disabling palmoplantar keratoderma. Nail dystrophy and shedding may be present. However, most of the morbidity associated with PRP is associated with the erythroderma

7 Sex , Age

 PRP occurs equally among men and women  The familial form of PRP typically begins in early childhood and has an autosomal dominant inheritance pattern.  The acquired form of PRP has a bimodal age distribution, with peaks in the first and fifth decades of life, but it can begin at any age.

8 History

 The familial form of PRP has a gradual onset, whereas the acquired form has an acute onset.  The disease typically spreads in a craniocaudal direction.  Patients first notice redness and scales on the face and the scalp.  This is often followed by redness and thickening of the palms and the soles  The lesions may expand and coalesce to cover the entire body.

9 Physical

 Skin  PRP is characterized by orange-red or salmon-colored scaly plaques with sharp borders, which may expand to involve the entire body  Often, areas of uninvolved skin, referred to as islands of sparing, are present.  Follicular hyperkeratosis is commonly seen on the dorsal aspects of the proximal phalanges, the elbows, and the wrists

10 11 12  Palmoplantar keratoderma occurs in most patients and tends to have an orange hue. Painful fissures may develop in patients with palmoplantar keratoderma.  Pruritus, although not a major symptom, may occur in the early stages of the disease.

13  Nails  Nail changes include distal yellow- brown discoloration, subungual hyperkeratosis, longitudinal ridging, nail plate thickening, and splinter hemorrhages.  Nail pitting is not typical.

14 Histologic Findings

 Histologic features are not pathognomonic, but they are useful to rule out other possible papulosquamous and erythrodermic disorders. Features on light microscopy include hyperkeratosis with alternating orthokeratosis and parakeratosis forming a checkerboard pattern in the stratum corneum, focal or confluent hypergranulosis, follicular plugging with perifollicular parakeratosis forming a shoulder effect, thick suprapapillary plates, broad rete ridges, narrow dermal papillae, and sparse superficial dermal lymphocytic perivascular infiltration

15  Medical Care  Topical medications  Topical corticosteroids may provide some patient comfort, but they are believed to have little long- term therapeutic effect.  Emollients reduce fissuring and dryness, providing some patient comfort. Petroleum jelly or one of the many proprietary emollients may be used.

16 Systemic therapy

More severe cases may require:  Systemic retinoids  Immunosuppressants like Azathioprine Methotrexate Cyclosporin

17 Complications

 PRP can cause painful and disabling palmoplantar keratoderma.  Nail dystrophy and shedding may occur.  Erythroderma is a reaction pattern of the skin that can occur in the setting of several different skin disorders, most commonly including , eczema, lymphoma, drug reactions, and PRP. It is characterized by generalized erythema and scales, hair loss, and onycholysis.

18 Prognosis

 Each type of PRP has its own prognosis. In general, the familial form of the disease may be persistent throughout life, and the acquired form of the disease may resolve spontaneously within 1-3 years.

19

20 Background

 Pityriasis rosea (PR) is a common benign papulosquamous disease  . Pityriasis denotes fine scales, and rosea translates as rose colored or pink.  PR can have a number of clinical variations. Its diagnosis is important because it may resemble secondary syphilis.

21 Pathophysiology

 PR has often been considered to be a viral exanthem. Its clinical presentation supports this concept. PR has been linked to upper respiratory infections, it can cluster within families and close contacts, and it has an increased incidence in individuals who are immunocompromised. As with viral exanthems, the incidence may increase in the fall and the spring.

22  recent work demonstrated human herpesvirus (HHV)ƛ7 viral DNA in both the lesions and the plasma in patients with PR.

23  Sex PR is more common in women than in men. One study found it to be twice as common in women as in men.  Age PR commonly develops in children and young adults, although any age group can be affected. Most patients are aged 10-35 years.

24 History

 The history should include questions about close contacts with similar eruptions. This finding is uncommon because most cases of PR are sporadic, as PR is thought to reflect a weakly contagious disease. A history of medication intake should be obtained because several medications have been shown to cause a similar exanthem.

25  The disease typically begins with a solitary macule that heralds the eruption (called the herald spot/patch), which is usually a salmon-colored macule. This initial lesion enlarges over a few days to become a patch with a collarette of fine scale just inside the well-demarcated border.

26  Within the next 1-2 weeks, a generalized exanthem usually appears, although it may occur from hours to months after the herald patch. This secondary phase consists of bilateral and symmetric macules with a collarette scale oriented with their long axes along cleavage lines. This phase tends to resolve over the next 6 weeks, but variability is common.  Pruritus is common, usually of mild-to-moderate severity, and it occurs in 75% of patients.

27 Physical

 The herald patch is usually a single pink patch, 2-10 cm in diameter, on the neck or the trunk with a fine collarette scale. It is observed in more than 50% of patients, and it may occur as multiple lesions or in atypical locations.

28  About 1-2 weeks after the herald patch is seen, the generalized eruption appears, although it has been known to occur from hours to 3 months later. It consists of salmon-colored macules or patches, 0.5- 1.5 cm in diameter, with a collarette scale, often described as having a cigarette paperƛlike appearance. The long axes of the lesions are oriented in a parallel fashion along cleavage lines, giving the classic Christmas tree pattern.  These secondary lesions most commonly occur on the trunk, the abdomen, the back, and the proximal upper extremities.

29 30 31 D.D

 Nummular Dermatitis Psoriasis, Guttate Seborrheic Dermatitis Syphilis Tinea Corporis Drug induced PR like eruptions: captopril, levamisole, omeprazole, Barbiturates, aspirin, ketokonazole

32 Lab studies

 One must be careful to rule out syphilis.  A screening rapid plasma reagin (RPR) test or a VDRL test should be ordered for appropriate individuals.

33 Histopathology

 It shows superficial perivascular dermatitis  Focal parakeratosis in mounds, hyperplasia, and focal spongiosis are observed in the epidermis.  The epidermis may show exocytosis of lymphocytes, variable spongiosis, mild acanthosis, and a thinned granular layer.  In the dermis, extravasated red blood cells are a helpful finding along with a perivascular infiltrate of lymphocytes, histiocytes, and eosinophils. A number of monocytes are also commonly present.

34 35 Treatment

 Emollients  Antihistamines ( if there is pruritus)  UVB phototherapy ( for persistent PR)

36 Complications

 The main morbidity is from pigmentary changes, which are possible with the healing lesions.  Both postinflammatory hyperpigmentation and hypopigmentation may occur.

37 Prognosis

 The prognosis for PR is excellent. Patients may return to work or school because they are not considered to be contagious.

38 Psoriasis

39 Objectives

 Identify the pathogenic factors for development of psoriasis  List the clinical features of psoriasis  Describe the progressive management of the clinical features of psoriasis  List the adverse effects of psoriatic treatments

40 Psoriasis

 Chronic skin disorder; "itch" = psora

 Incidence

 Other derm conditions

41 Psoriasis

 T-cell mediated inflammatory dz  Epidermal hyperproliferation 2O to activation of immune system  Altered maturation of skin  Inflammation  Vascular changes

42 43 44 Background

 Epidemiology  Age  Genetic  Scandinavian/European descent  Risk Factors

45 Psoriasis, an inherited disease If you have psoriasis, what is the risk to:  Your unrelated neighbor? About 2%  Your sibling? 15-20%  Your identical twin? 65-70%  Your child? 25%

46 N P Disorganized O STRATUM S R CORNEUM O Neutrophil M STRATUM R accumulation GRANULOSUM A I L STRATUM A SPINOSUM S Immaturity I S Proliferation

STRATUM BASALE DERMIS 47 48 Psoriasis: Associated Factors

 Genetic Factors: - 30% of people with psoriasis have had psoriasis in family - Autosomal dominant inheritance  Nongenetic Factors: - Mechanical, ultraviolet, chemical injury - Infections: Strep, viral, HIV - Prescription Drugs, stress, endocrine, hormonal, obesity, alcohol, smoking

49 Clinical Presentation

 Erythematous, raised plaques with silvery scales  Symmetric  Pruritic/ Painful  Pitting Nails  Arthritis in 10-20% of patients

50 51 Psoriasis: Clinical Presentation Type Characteristics Plaque psoriasis Dry scaling patches (AKA common psoriasis) 75% Drop-like dots, occurs after strep or viral infection 12% Erythrodermic Exfoliation of fine scales (total body ³dandruff´), psoriasis widespread, often accompanied by severe itching and pain 7% Pustular Pus-like blisters, noninfectious, fluid contains white blood psoriasis cells 2% Nail psoriasis Seen on toenails and fingernails, starts as numerous pits, at times progresses to yellowing, crumbly, and thickened nail; nails may slough Palmar/Plantar Erythema, thickening and peeling of the skin, blistering is psoriasis often present. Can lead to disability. Inflammation, swelling, and joint destruction Scalp psoriasis Plaque-type lesion 52

Psoriatic Plaque

53 Chronic Plaque Psoriasis

54 Erythrodermic Psoriasis

55 Nail changes

56 Guttate Psoriasis

57 Nail Changes

 In 78% of psoriatic patients  Fingernails>Toenails  Four changes

1. Onycholysis (= separation from nail bed)

2. Pitting*

3. Subungual debris accumulation

4. Color alterations *Pitting rules out a fungal infection 58 59 Psoriatic Arthritis

 In 10-20% of psoriasis patients  Peripheral interphalangeal joints  No elevated serum levels of rheumatoid factors (as seen in rheumatoid arthritis, yet has all other features)  Often seen in patients with nail and

scalp psoriasis 60 OLA Photonumeric Guidelines (overall lesion assessment)

0 = none 1 = minimal 2 = mild

3 = moderate 4 = severe 5 = very severe61 62 The Majority of Moderate-Severe Psoriasis Patients Are Under-Treated

 50% of patients with moderate or worse disease are currently untreated1

 46% have topical therapy only Topicals  Reason dermatologists Other only therapies do not use more 46% 54% aggressive therapies2  Safety concerns  Time consuming  Cost 1 Leonardi, 20033;; 2 Market Measures/Cozint LLP, June 20033.. 63 Psoriasis: Treatment

 Lubrication  Removal of scales  Slow down lesion proliferation  Pruritus management  Prevent complications  Lessen patient stress  Season and climate

64 St

Coal Tar Topical Steroid

Ant ralin Calcipotriene Tazarotene Intralesional Steroid

Supplementary Climatot erapy Moisturizers Keratolytics Tx Step 2

PUV A + PUVA S t e p 1 a g e n t

Step 3 Rotational: Met otrexate Cyclosporine 12-24 mont s Acitretin of eac step 3 agent Step 4

Enbrel/Remicade/Amevive/Raptiva 65 Emollients and Moisturizers

 Moisturizes, lubricates and soothes dry and flaky skin.  Produces occlusive film to limit water evaporation from skin. Increased hydration allows stratum corneum to swell- scaling decreases, skin is more pliable.  Adverse Effect: contact dermatitis, folliculitis (rare)

66 Keratolytics = ƠSKIN LIFTERSơ

 Helps remove scales and reduce hyperkeratosis  Salicylic Acid 2-6%  Enhance absorption of other drugs  AE: N/V, tinnitus, hyperventilation (rare =salicylism)

67 Tars

 Coal Tar ƛ made from crude coal  Decreases epidermal cell mitosis and scale development  Reduces sebum production  Anti-inflammatory effects  5% coal tar concentration most effective (1%-6%)

68 Coal Tar

 Problems with coal tar:  Smell  Sting  Stain  Sensitize

69 Coal Tar

 Very useful in guttate psoriasis and for scalp psoriasis as a shampoo  Not recommended as 1st line tx:  Erythrodermic & Pustular  Irritation may lead to Koebnerƞs phenomenon  Use only on lesions that are well separated, not too big  Phototoxic response sunburn may become

erythematous 70 Corticosteroids

 Reduce inflammation, itching and scaling  Anti-inflammatory effect  Decrease in vascular permeability, decreasing dermal edema and leukocyte penetration into skin  Antiproliferative effect  Immunosuppressive effect

71 Corticosteroids

Level of Potency Corticosteroid Commercial Products

Ultr -high H l bet s l pr pi n te Ultr v te cr / int l bet s l pr pi n te Temov te crm/oint Bet eth s ne dipr pi n te Diprolene oint Difl r s ne di cet te Psorcon oint

High H lcinonide Halog crm mcinonide ylocort oint Bet meth sone dipropion te Diprolene AF crm Momet sone furoate Elocon oint Diflorasone diacetate Florone oint Fluocinonide Lidex crm,gel,oint Desoximetasone Topicort crm,oint,gel

Mild to high Halcinonide Halog oint,crm,soln Triamcinolone acetonide Aristocort A oint Betamethasone dipropionate Diprosone crm Fluocinonide Lidex-E crm 72 Corticosteroids

Level of Potency Corticosteroid Commercial Products

Mild Hydrocortisone valerate Westcort Triamcinolone acetonide Kenalog crm and oint Flurandrenolide Cordran oint Mometasone furoate Elocon crm Fluocinolone acetonide Synalar oint Low to mild Hydrocortisone valerate Westcort crm Triamcinolone acetonide Kenalog crm and oint Flurandrenolide Cordran crm Betamethasone dipropionate Diprosone lotion Hydrocortisone butyrate Locoid crm Flucolone acetonide Synalar crm Low Alclometasone dipropionate Aclovate crm and oint Betamethasone valerate Valisone lotion Fluocinolone acetonide Synalar soln and crm Hydrocortisone, dexamethasone, prednisolone, methylprednisolone 73 Corticosteroids

 Ointments: helps hydrate; good for dry, hyperkeratotic, scaly lesions  Cream: for use on all areas, useful for infected lesions  Solutions: for scalp psoriasis, often contain alcohols which can be painful with open lesions

74 Corticosteroids

 Adverse Effects: (esp. with occlusion)  Systemic absorption  Dermal atrophy  Telangiectasis  Ecchymoses  Peri-orbital acne  Poor wound healing  Pyogenic infections

75 Vitamin D3

 Isolated from cod liver oil in 1936  Made in human skin through reaction: 7-dehydrocholesterol & UV light  Calcitriolƞs properties in psoriasis:

1. Increase cellular differentiation

2. Inhibits cellular proliferation

76 Vitamin D3

 Adverse Effects:  Hypercalcemia  Hypercalciuria  Mild calcitriol intoxication: renal stones  Not for long term use, therefore analogues were developed

77 Vitamin D3 Analogue

 Calcipotriene (Dovonex®)  Indication = Moderate plaque psoriasis  Reduces scaling and thickness of plaque, but not the erythema; what would you use in combo?  Max weekly cumulative dose: 5mg = 100gm of 50 mcg/gm or 2 tubes  Applied BID x 8 weeks

78 Vitamin D3 Analogues

 Calcipotriene (Dovonex®)  Not for pustular or erythrodermic psoriasis due to increased systemic absorption  AE: irritation, hypercalcemia (when applied in large amounts)  CI in pregnancy, lactation, children

79 Retinoids

 Vitamin A derivatives

 MOA:

1. Normalization of abnormal keratinocyte differentiation

2. Reduction in keratinocyte proliferation

3. Reduction in inflammation

80 Oral Retinoids

 Etretinate & Acitretin (Soriatane®)  Second generation retinoids  For pustular and erythrodermic psoriasis  Etretinate withdrawn from US market- 1998  Acitretin= active metabolite of etretinate  Reserved for treatment of severe forms of psoriasis due to side effects.

81 Soriatane : Dosage

 Usual dose: 25-50mg/day as single dose  Dosage form: 10mg, 25mg capsules

82 Soriatane : Precautions

 Avoid in severe liver and kidney dz  Avoid in patients with h/o alcohol dz

 ETOH = reverse metab to etretinate  Teratogenic- CI in pregnancy

 Contraception one month before treatment and at least 3 years after  Monitor: serum lipids, LFTs, serum creatinine (problematic as alternatives have similar limitations)

83 Soriatane : Adverse Effects

 Peeling, drying skin  Diffuse alopecia  Nail changes  Sticky, clammy skin  Muscle pain  Calcification of ligaments

84 Soriatane

33% of patients had an elevation of AST (SGOT), Hepatotoxicity ALT (SGPT) or LDH Black Box Warning Alopecia 50-75% of patients

50-75% skin peeling Mucocutaneous 25-50% dry skin 25-50% pruritus 23% dry eyes

66% increase in triglycerides Lipid 33% increase in cholesterol Metabolism 40% reduction in HDL

85 Topical Retinoids

 Tazarotene (Tazorac®)  Third generation retinoid  Stable plaque psoriasis (up to 20% of body surface area involvement)  Severe facial psoriasis  Water based emollient gel or cream

86 Tazarotene (Tazorac®)

 Apply once daily x12 weeks  AE: pruritus, burning, erythema  ? More selective retinoid than Soriatane resulting in fewer ADRs  Oral formulation pending at FDA

87 Counseling points

 Apply a moisturizer to the skin before using the Tazorac; it can dry out the skin.

 Apply it once per day about 30 minutes before bedtime.

 Rub about a pea-sized amount only into each lesion; it can irritate normal skin.

 If it spreads to the unaffected skin, wash it off with water. Zinc oxide can protect the skin

 Apply sunscreen 88 Methotrexate

 For moderate-severe psoriasis non-responsive to topical treatment  MOA:  binds to DHFR which leads to reduction of tetrahydrofolate, which inhibits pyrimidine synthesis. Pyrimidine is needed for formation of DNA base pairs, therefore decrease in DNA replication esp rapidly dividing cells as in skin  Induces apoptosis of activated T cells 89 FOLIC ACID

METHOTREXATE 90 Response to Methotrexate

 Suppression of B cells and macrophages  Induces T-cell apoptosis  Suppresses IL-1 and IL-8 production by peripheral blood mononuclear cells  Reduces T cell production of interferon- gamma and TNF

91 Methotrexate: Precautions

 Contraindicated:  Pregnancy, lactating mothers  Renal & liver problems  Preexisting severe anemia, leukopenia, thrombocytopenia  Alcoholics  Active infectious disease

92 Methotrexate: Dosage

 Initial: 2.5-5mg q12h x3 doses qweek  Titrate up weekly by 2.5mg increments [if blood counts (weekly then monthly) and LFTs (q4 month)allow] until symptoms respond  Injections: IM or SQ  Max: 50mg/week, but some 75mg/week

93 Methotrexate: Adverse Effects

 Headache, chills, fever, fatigue, abdominal pain, nausea, vomiting, dizziness  Pruritus, alopecia, urticaria, ecchymosis, sunburn (phototoxicity)  Osteopathy- rare & at low doses  Pulmonary fibrosis- CXR yearly  Obtain liver biopsy after each 1.5gm  Folate rx on days NOT taking MTX

94 Cyclosporine

 For psoriatic lesions resistant to other therapies  MOA: prevention of IL-2 transcription, prevention of primary T-cell activation and reduction of T cell cytokines.

95 Cyclosporine: Dosage

 Oral Cyclosporine Microemulsion: Neoral  Capsules, solution  Initial: 2.5 mg/kg/day split BID x4 wks  May increase dose at 2 week intervals of ~0.5 mg/kg/day increments  Max: 5 mg/kg/day  Relapse:  6 weeks (50%)-16 weeks (75%)

96 Cyclosporine:Adverse Effects

 Headaches, paresthesias, flu-like symptoms, abdominal pain, nausea.  Hypertension  Nephrotoxicity:acute q blood flow; chronic form E dose and duration  Neurotoxicity  Hepatoxicity  Hyperglycemia  Should be used as short term therapy (<1 year) to avoid further adverse effects (gingival hyperplasia, hyperlipidemia, hirsutism, etc). 97 Phototherapy

 Used over 100 years for moderate- severe psoriasis  UVA (315-400 nm), UVB (290-315 nm)

 313 nm = most effective wavelength for psoriasis

98 Phototherapy

 Ultraviolet B  Relatively non-toxic  Can be used as a single-agent  Usually combined with lubricants  Ingramƞs regimen (Anthralin)  Goeckermanƞs regimen (Tar)

99 Phototherapy

100 Phototherapy

101 Phototherapy

102 Phototherapy

103 PUVA

 PUVA= Psoralen + Ultraviolet A  Theories of MOA:

1. Psoralen intercalates into DNA, inhibiting DNA replication and thus, inhibiting epidermal cell hyperproliferation

2. Free radical formation damages cell membrane, cytoplasmic contents and nucleus of epidermal cellsƦinhibiting growth of cells.

3. Increased apoptosis of activated T-cells

104 Oral PUVA

 Psoralen = ƠPơ in PUVA = a photosensitizer  Methoxsalen (Oxsoralen-Ultra, 8-MOP)  10 mg capsules  Given 2 hours before UVA irradiation  Symptomatic control of severe, recalcitrant disabling psoriasis, not responsive to other therapy after biopsy confirmed diagnosis

105 PUVA

 Phototoxicity  Related to quantity of psoralen and amount of UVA applied  Reaction peaks 48-72hrs after treatment  Erythema, blistering, edema  Administer 2-4x/ week  Tanning occurs, so gradually increase dose of UVA  ~20 sessions over 4-8 weeks clears lesions

106 Oral PUVA: Adverse Effects

 Constipation, diarrhea, nausea, vomiting, pruritus, delayed-onset erythema  Oral psoralens distribute to entire body and eyes: protect eyes and skin from sunlight 6 hours after treatment  Long-term: premature aging, cataracts, skin cancer (rare)

107 First Generation Biologicals

 Infliximab & Etanercept: immunomodulators  used initially for rheumatoid arthritis; work against TNF-alpha

108 TNF Inhibitors

 Both Remicade and Enbrel are quite effective (>75% of psoriatics respond) even if only skin is affected  Enbrel SQ once* or twice weekly; Remicade IV 0, 2 and 6 weeks  Concerns: exacerbate MS and TB, induce SLE and CHF, palliative not curative

109 New Therapies

 Alefacept (Amevive)  Inhibits CD45RO+ memory effector T lymphocytes, by binding to their CD2 receptor also leads to apoptosis  Administered IV or IM qweek x12 wks  AE: dizziness, chill, nausea, cough 110