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VILLASEÑOR-PARK AND COLLEAGUES
FIGURE 2. Patient with inverse psoriasis of
Photo courtesy of JosePh c. english iii, MD.
demarcated, scaly, pink-to-red plaques of vari- ous sizes with a relatively symmetric distribu- tion. Involvement of the extensor surfaces Psoriasis has
FIGURE 1. Well-demarcated erythematous,
scaly plaques characteristic of plaque pso- such as the elbows and knees and of the scalp, several clinical
riasis on the elbow.
trunk, and intergluteal cleft is common. variants,
Plaques can persist for several months to years, even in the same location, and only each with a
of the major histocompatibility complex, cyto- about 5% of patients report complete remis- distinct course
kines, receptors, and beta-defensins. sion for up to 5 years.
Of specific interest, polymorphisms in the and response
IL-12/IL-13 receptor, the p40 subunit of IL- to treatment
12 and IL-23, and the p19 subunit of IL-23 Involvement of the skin folds, including the strongly associate with psoriasis, supporting axillary, genital, perineal, intergluteal, and in- their critical role in the disease process and framammary regions with pink-to-red plaques providing targets for medical therapy.26 with minimal scale is the main clinical feature of inverse psoriasis (FIGURE 2). Absence of sat-
■ Psoriasis Has sEvEraL
ellite pustules clinically distinguishes it from Psoriasis has several clinical variants, each guttate psoriasis
with a distinct clinical course and response to Guttate psoriasis (named for its droplet- treatment.27 Moreover, many patients present shaped lesions) presents abruptly with 1-mm with more than one variant. to 10-mm pink papules with associated fine scale over the trunk and extremities (FIGURE 3).
This variant occurs in fewer than 2% of pa- Plaque psoriasis (FIGURE 1) accounts for more tients with psoriasis, who are usually younger
than 80% of cases. It is characterized by well- than 30 years. It is often preceded 2 to 3 weeks CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 79 • NUMBER 6 JUNE 2012

earlier by an upper respiratory tract infection with group A beta-hemolytic streptococci.
Approximately 1% to 2.25% of all patients with psoriasis develop this severe form, affect- ing more than 75% of the body surface area. It presents as generalized erythema, which is the most prominent feature, and it is often associ- ated with superficial desquamation, hair loss, nail dystrophy, and systemic symptoms such as fever, chills, malaise, or high-output cardiac failure. There may be a history of preceding characteristic psoriatic plaques, recent with- drawal of treatment (usually corticosteroids), phototoxicity, or infection. Conversely, approximately 25% of all pa- tients with erythroderma have underlying Pustular psoriasis (FIGURE 4) is uncommon. The
predominant lesions are large collections of neutrophils in the stratum corneum that clini- cally present as sterile pustules. The pustules FIGURE 3. Guttate psoriasis with characteristic erythema-
may be localized within or at the edge of exist- tous, scaly papules and small plaques on the back.
ing psoriatic plaques or may present as a gen- Photo courtesy of laura K. ferris, MD, PhD.
eralized eruption. There are several forms of pustular pso- riasis, including generalized pustular psoriasis, annular pustular psoriasis, impetigo herpeti- formis (pustular psoriasis of pregnancy), and palmoplantar pustulosis. However, there is some evidence to suggest that palmoplantar pustulosis may be distinct from psoriasis.29 Several triggers have been identified, in- cluding pregnancy, rapid tapering of medica- tions, hypocalcemia, infection, or topical ir- Generalized pustular psoriasis, annular pustular psoriasis, and impetigo herpetifor- mis often present in association with fever and other systemic symptoms and, if left un- treated, can result in life-threatening com- plications including bacterial superinfec- tion, sepsis, dehydration, and, in rare cases, acute respiratory distress secondary to aseptic FIGURE 4. Erythematous plaques studded with pustules
Placental insufficiency resulting in still- and red-brown macules on the acral surface of the foot in birth or neonatal death and other fetal abnor- malities can occur in severe pustular psoriasis Photo courtesy of JosePh c. english iii, MD.
416 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 79 • NUMBER 6 JUNE 2012

VILLASEÑOR-PARK AND COLLEAGUES
Psoriatic arthritis is a seronegative inflam- matory spondyloarthropathy that can result in erosive arthritis in up to 57% of cases and functional disability in up to 19%.32 Although rare in the general population, it affects ap- proximately 6% to 10% of psoriasis patients and up to 40% of patients with severe psoria- sis.33 In 70% of cases, psoriasis precedes the onset of arthritis by about 10 years, and ap- proximately 10% to 15% of patients simulta- neously present with psoriasis and arthritis or develop arthritis before skin involvement.5,34 Patients complain of joint discomfort that is most prominent after periods of prolonged rest. Patterns of involvement are extremely variable but have been reported as an asym- metric oligoarthritis (involving four or fewer joints) or polyarthritis (involving more than four joints) in most patients. A rheumatoid arthritis-like presentation with a symmet- ric polyarthropathy involving the small and medium-sized joints has also been reported, making it difficult to clinically distinguish this from rheumatoid arthritis. A distal interphalangeal-predominant pat- tern is reported in 5% to 10% of patients. Ax- ial disease resembling ankylosing spondylitis FIGURE 5. Nail pitting and onycholysis with
occurs only in 5% of patients. Arthritis muti- surrounding psoriatic plaques along the improvement
lans, characterized by severe, rapidly progres- perionychium and proximal nail fold.
sive joint inflammation, joint destruction, and in the PASI
Photo courtesy of JosePh c. english iii, MD.
deformity, occurs rarely. Enthesitis, ie, inflam- mation at the point of attachment of tendons is regarded as
or ligaments to bone, is present in up to 42% ing more than 5% of the body surface or in- volvement of the face, hands, feet, or genita- clinically
nail disease
The Psoriasis Area and Severity Index Nail psoriasis occurs in 35% to 50% of patients (PASI) is an objective measure used in clini- and can be seen with all forms of psoriasis.1 In- cal trials. It incorporates the amount of red- volvement of the nail matrix can result in nail ness, scaling, and induration of each psoriatic pitting and leukonychia. Oil spots, subungual lesion over the body surface involved. A 75% hyperkeratosis, and distal onycholysis are the improvement in the PASI score (PASI-75) is result of disease involvement of the nail bed regarded as clinically significant.37 (FIGURE 5). Up to 90% of patients with psoriatic
arthritis have nail changes, especially patients ■ Psoriasis is diagnosEd cLinicaLLy
with enthesitis.36 In most cases, the diagnosis of psoriasis is made disease severity also varies
clinically and is straightforward. However, in Disease severity also differs among patients. more difficult cases, biopsy may be needed. In An estimated 80% of patients have mild to moderate disease and 20% have moderate to • The plaques of psoriasis may be confused severe disease, which includes disease involv- with squamous cell carcinoma in situ, der- CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 79 • NUMBER 6 JUNE 2012 matophyte infection, or cutaneous T-cell lymphoma, especially if they are treat- Steroid-sparing agents include vitamin D analogues, retinoids, and tacrolimus ointment • Guttate psoriasis may be difficult to distin- guish from pityriasis rosea. Vitamin D analogues and retinoids are • Erythrodermic psoriasis must be distin- thought to decrease keratinocyte proliferation guished from other causes of erythroderma, and enhance keratinocyte differentiation.39 including Sézary syndrome, pityriasis rubra The vitamin D analogues are also considered pilaris, and drug reactions. first-line topical agents and include calcipot- • Intertrigo, candidiasis, extramammary Pag- riol (Dovonex), calcipotriene (Dovonex), et disease, squamous cell carcinoma, and and calcitriol (Vectical). To prevent hypercal- contact dermatitis all may mimic inverse cemia, use of more than 100 g of vitamin D analogues per week should be avoided.39 • Palmoplantar pustulosis may be difficult to differentiate from dyshidrotic eczema. treatment of inverse psoriasis
• Generalized pustular psoriasis should be and scalp psoriasis may be challenging
distinguished from a pustular drug eruption The areas affected in inverse psoriasis, such (acute generalized exanthematous pustular as the genitalia and axillae, are more prone to drug eruption or acute generalized exan- side effects when potent topical steroids are thematous pustulosis), impetigo, candidia- used because of increased absorption and oc- sis, or an autoimmune blistering disorder clusion in these areas. Agents that minimize such as pemphigus.
irritation and toxicity in sensitive areas, such as topical tacrolimus, less-potent topical ste- ■ trEatmEnt of LimitEd disEasE
roids, or calcitriol, can be used.39 For scalp psoriasis, alternative vehicles such as shampoos, gels, solutions, oils, sprays, A topical corticosteroid, either by itself or and foams have improved patient compliance Steroid-sparing combined with a steroid-sparing agent, is the and efficacy of treatment.40
agents include first-line therapy for patients with limited
vitamin D
disease. The potency required for treatment ■ PHototHEraPy for sEvErE disEasE
should be based on the extent of disease and analogues,
on the location, the choice of vehicle, and the narrow-band ultraviolet b
patient's preference and age. Narrow-band ultraviolet B, ie, light confined Several double-blind studies have assessed to wavelengths of 311 to 313 nm, is a first- retinoids, and
the efficacy of various topical corticosteroids line treatment for moderate to severe pso- tacrolimus
in treating psoriasis. In general, super-potent riasis, either as monotherapy or in combina- (class I) and potent (class II) topical corticoste- tion with other treatments. It is an especially roids are more efficacious than mild or moder- attractive option in patients who are on ate corticosteroids.38 Class I and class II steroids medications or who have comorbidities that include agents such as clobetasol propionate may preclude treatment with other systemic 0.05% (Temovate), betamethasone dipropio- nate 0.05% (Diprolene), fluocinonide 0.05% The mechanism of action may be via im- (Lidex), and desoximetasone 0.25% (Topicort). munosuppressive effects on Langerhans cells, Use of class I steroids should be limited alteration of cytokines and adhesion mol- to an initial treatment course of twice-daily ecules that lead to an increase in Th2 cells, application for 2 to 4 weeks in an effort to and induction of apoptosis of T lymphocytes. avoid some of the local toxicities such as skin Additionally, ultraviolet light affects the atrophy, telangiectasia, and striae. Decreas- proliferation and differentiation of keratino- ing class I topical steroid use to 1 to 2 times per week with the gradual introduction of a Dosing is based on skin type, and treat- steroid-sparing agent following the initial 2 to ment usually involves two or three visits per 4 weeks of treatment is advised.
week for a total of 15 to 20 treatments, with 418 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 79 • NUMBER 6 JUNE 2012 VILLASEÑOR-PARK AND COLLEAGUES
additional therapy for maintenance. Adding acitretin (Soriatane), with close monitoring In 1972, the US Food and Drug Administra- of aspartate aminotransferase and alanine tion (FDA) approved methotrexate for treat- aminotransferase levels and the patient's lipid ing severe psoriasis.42 In studies of methotrex- panel, can be considered in treatment-resis- ate at doses of 15 to 20 mg weekly, 36% to 68% of patients with severe plaque psoriasis achieved a PASI-75 score.40,42,47 Psoralen combined with ultraviolet a
Dosages of methotrexate for treating se- Psoralen combined with ultraviolet A is an- vere psoriasis range from 7.5 to 25 mg once other option. It can be considered if narrow- a week. Patients should also receive a folate band ultraviolet B treatment fails. It is also supplement of 1 to 5 mg every day except the useful for dark-skinned patients and those day they take methotrexate. The folate is to with thicker plaques because ultraviolet A protect against gastrointestinal side effects, penetrates deeper than ultraviolet B. Oral or bone marrow suppression, and hepatic toxic- topical treatment with psoralen is followed by ity associated with methotrexate. ultraviolet A treatment. Other side effects of methotrexate include The duration of remission is much longer pulmonary fibrosis and stomatitis. Pregnancy, with psoralen plus ultraviolet A than with nursing, alcoholism, chronic liver disease, im- narrow-band ultraviolet B. However, this munodeficiency syndromes, bone-marrow hy- treatment caries a significant risk of cutane- poplasia, leukopenia, thrombocytopenia, ane- ous squamous cell carcinoma and melanoma, mia, and hypersensitivity to methotrexate are especially in light-skinned people and those all contraindications to methotrexate use.
who receive high doses of ultraviolet A (200 The National Psoriasis Foundation, in its or more treatments) or cyclosporine.40,41,43–46 2009 guidelines for the use of methotrexate Long-term effects include photoaging, lentigi- in treating psoriasis,48 recommends obtaining nes, and telangiectasias. As a consequence of a complete blood cell count with platelets, these well-established side effects, this treat- blood urea nitrogen, creatinine, and liver ment is used less frequently.
function tests at baseline and at 1- to 3-month All retinoids,
intervals thereafter. including
cautions with phototherapy
Liver biopsies were previously recom- Careful screening and caution should be used mended for patients receiving methotrexate acitretin, are
in patients who have: long-term when the cumulative dose of thera- in pregnancy
• Fair skin that tends to burn easily py reached 1.5 g. However, given the invasive category X
• A history of arsenic intake or treatment nature of the liver biopsy procedure and the with ionizing radiation low incidence of methotrexate-induced hepa- and should
• A history of use of photosensitizing medi- totoxicity, this recommendation has been re- therefore
cations (fluoroquinolone antibiotics, doxy- For patients with no significant risk fac- be avoided
• A history of melanoma or atypical nevi tors for hepatic toxicity (eg, obesity, diabetes, during
• Multiple risk factors for melanoma hyperlipidemia, hepatitis, or history of or cur- • A history of nonmelanoma skin cancer rent alcohol consumption) and normal liver pregnancy
• Immunosuppression due to organ trans- function tests, liver biopsy should be consid- ered when a cumulative methotrexate dose of 3.5 to 4.0 g is reached. Alternatively, one may ■ oraL tHEraPiEs for sEvErE Psoriasis
choose to continue to monitor the patient without liver biopsy or to switch to another Patients who have severe psoriasis—ie, af- medication, if possible.42,48 fecting more than 5% of the body surface or Patients at high risk should be monitored debilitating disease affecting the palms, soles, more carefully, and liver biopsy should be con- or genitalia—are best managed with systemic sidered soon after starting methotrexate and medications, especially if they do not have ac- repeated after every 1.0 to 1.5 g.48 cess to phototherapy.20 No reliable noninvasive measures to eval- CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 79 • NUMBER 6 JUNE 2012 uate for liver fibrosis are routinely available tive as a maintenance therapy, usually after in the United States. Serial measurements of the disease has been stabilized by agents such serum type III procollagen aminopeptide have as cyclosporine, or in combination with other been reported to correlate with the risk of treatments such as phototherapy.42 Acitretin developing liver fibrosis; however, this test is has been shown to be effective in patients readily available only in Europe.49 with pustular psoriasis.54 Acitretin does not alter the immune sys- tem and has not been shown to have signifi- Cyclosporine (Gengraf, Neoral, Sandimmune) cant cumulative toxicities. Serum triglycer- is very effective for treating psoriasis, espe- ides are monitored closely, since acitretin can cially erythrodermic psoriasis. It is often used lead to hypertriglyceridemia. only short-term or as a bridge to other main- All retinoids, including acitretin, are in tenance therapies because it has a rapid onset pregnancy category X and should therefore be and because long-term therapy (3 to 5 years) is avoided during pregnancy. Although its half- associated with a risk of glomerulosclerosis.50 life is only 49 hours, acitretin may be trans- Cyclosporine works by decreasing T-cell formed to etretinate either spontaneously or activation by binding cyclophilin, which leads as a result of alcohol ingestion. Etretinate has to inhibition of transcription of calcineu- a half-life of 168 days and can take up to 3 rin and nuclear factor of activated T cells.51 years to be eliminated from the body. There- Given at doses of 2.5 to 5 mg/kg/day, cyclo- fore, acitretin is contraindicated in women sporine has been shown to result in rapid im- who plan to become pregnant or who do not provement in up to 80% to 90% of psoriatic agree to use adequate contraception for 3 years after the drug is discontinued.42 The initial recommended dose of cyclo- sporine is usually 2.5 to 3 mg/kg/day in two divided doses, which is maintained for 4 weeks Advances in our understanding of the patho- and then increased by 0.5 mg/kg/day until the genesis of psoriasis have resulted in more spe- In cases of
disease is stable.42 cific, targeted therapy. Nephrotoxicity and hypertension are cyclo- Alefacept (Amevive) is a human Fc IgG1
psoriatic
sporine's most serious side effects. Blood receptor fused to the alpha subunit of LFA3. It arthritis,
urea nitrogen, creatinine, and blood pressure binds to CD2, blocks costimulatory signaling, evaluation by a should be monitored at baseline and then and induces apoptosis in activated memory T
twice a month for the first 3 months and once rheumatologist monthly thereafter. Liver function tests, com- Alefacept was the first biologic agent ap-
is highly
plete blood cell count, lipid profile, magne- proved by the FDA for the treatment of pso- sium, uric acid, and potassium should also be riasis and one of the few biologic agents to in- recommended checked every month.
duce long-term remission.55 However, its use Cyclosporine also increases the risk of cu- has declined because few patients achieved taneous squamous cell carcinoma, especially significant clearance of their psoriasis and its in patients who have received psoralen plus onset of action was much slower than that of ultraviolet A treatment.42 other medications.56 Patients with hypersensitivity to cyclospo- The currently approved biologic therapies rine, a history of chronic infection (eg, tuber- commonly used for moderate to severe pso- culosis, hepatitis B, hepatitis C), renal insuf- riasis include the TNF-alpha inhibitors and ficiency, or a history of systemic malignancy should not receive cyclosporine.
The TNF-alpha inhibitors include inflix-
imab (Remicade), etanercept (Enbrel), and adalimumab (Humira). They are generally Acitretin, an oral retinoid, has been used for well tolerated and highly effective. Howev- several years to treat psoriasis. Its onset is slow, er, TNF-alpha inhibitors and other biologic typically ranging from 3 to 6 months, and its agents are contraindicated in patients with se- effects are dose-dependent. It is most effec- rious infection, a personal history or a family 420 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 79 • NUMBER 6 JUNE 2012 VILLASEÑOR-PARK AND COLLEAGUES
history in a first-degree relative of demyelinat- IL-12 and IL-23, which have been shown to ing disease, or class III or IV congestive heart be at increased levels in psoriatic lesions and failure. Patients should be screened for active important for the pathogenesis of psoriasis. infection, including tuberculosis and hepatitis Between 66% and 76% of patients treated B, since reactivation has been reported fol- with ustekinumab achieved significant clear- lowing initiation of TNF-alpha inhibitors.1 ance of their disease after 12 weeks of treat- Adalimumab is a human monoclonal an-
ment in two large phase III multicenter, ran- tibody against TNF-alpha. It binds to soluble domized, double-blind, placebo-controlled and membrane-bound TNF-alpha and pre- vents it from binding to p55 and p75 cell-sur- Dosing of ustekinumab is weight-based. For face TNF receptors.
those weighing less than 100 kg, ustekinumab The dosing schedule for adalimumab is 80 is given at 45 mg subcutaneously at baseline, mg subcutaneously for the first week, followed at 4 weeks, and every 12 weeks thereafter. The by 40 mg subcutaneously the next week, and same dosing schedule is used for those weigh- then 40 mg subcutaneously every 2 weeks ing more than 100 kg, but the dose is increased Etanercept is a recombinant human TNF-
Guidelines for monitoring patients while alpha receptor (p75) protein fused with the Fc on ustekinumab are similar to those for other portion of IgG1, which binds to soluble TNF- biologic agents. Information on long-term alpha.57 Dosing for etanercept is 50 mg subcu- toxicities is still being collected. However, taneously twice weekly for the first 12 weeks, injection-site reactions, serious infections, followed by 50 mg weekly thereafter.
malignancies, and a single case of reversible Infliximab is a chimeric antibody com-
posterior leukoencephalopathy have been re- posed of a human IgG1 constant region fused to a mouse variable region that binds to both While biologic agents are significantly soluble and membrane-bound TNF-alpha.58 more expensive than the conventional thera- Infliximab is given as an infusion at a dose of pies discussed above and insurance coverage 5 mg/kg over 2 to 3 hours at weeks 0, 2, and 6, for these agents varies, they have demonstrat- Before
and then every 8 weeks thereafter.
ed superior efficacy and may be indicated for starting a
Efficacy of TNF inhibitors. There are patients with recalcitrant moderate to severe
no specific guidelines for the sequence of ini- psoriasis for whom multiple types of treatment TNF-alpha
tiation of TNF inhibitors because no studies have failed.
inhibitor,
have directly compared the efficacy of these screen for
medications. However, response to infliximab ■ for Psoriatic artHritis:
is relatively rapid compared with adalimumab infection,
In a phase III clinical trial,59 as many as For patients with known or questionable pso- 80% of patients achieved PASI-75 clear- riatic arthritis, evaluation by a rheumatologist including
ance of their psoriasis after three doses of in- is highly recommended.
fliximab. Interestingly, only 61% of patients Nonsteroidal anti-inflammatory drugs
maintained PASI-75 clearance by week 50. (NSAIDs) are usually first-line in the treat- and hepatitis B
This loss of efficacy of infliximab is also re- ment of mild psoriatic arthritis. If after 2 to ported with other TNF-alpha inhibitors and is 3 months of therapy with NSAIDs no benefit thought to be secondary to the development is achieved, treatment with methotrexate as of antibodies to the drugs. For infliximab, this monotherapy is a practical consideration be- loss of efficacy is less when infliximab is given cause of its low cost. However, methotrexate continuously rather than on an as-needed ba- as a monotherapy has not been shown to pre- sis. Simultaneous treatment with methotrex- vent radiologic progression of disease.5,32 ate is also thought to decrease the develop- The TNF-alpha inhibitors have been
ment of antibodies to infliximab.60 shown to have similar efficacy when compared Ustekinumab is an monoclonal antibody
among each other in the treatment of psoriat- directed against the common p40 subunit of ic arthritis.32,63 Based on radiologic evidence, CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 79 • NUMBER 6 JUNE 2012 ustekinumab has not shown to be as effica- because of their associated systemic symp- cious as the TNF-alpha inhibitors for treating toms. Care should be taken to rule out sepsis, psoriatic arthritis. Therefore, TNF inhibitors as this is a reported trigger of erythrodermic should be considered first-line in the treat- ment of psoriatic arthritis.21,64 Systemic medications with a quick onset, Few studies have been done on the efficacy such as oral cyclosporine, are recommended. or sequence of therapies that should be used Infliximab has also been reported to be benefi- in the treatment of psoriatic arthritis. The cial because of its rapid onset.28 American Academy of Dermatology's Pso- riasis Guidelines of Care recommend adding ■ trEatmEnt basEd on tHE tyPE
a TNF-alpha inhibitor or switching to a TNF- and tHE sEvErity of Psoriasis
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tion of the various manifestations of psoriasis mEdications tHat act PromPtLy
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ADDRESS: Lisa M. Grandinetti, MD, FAAD, Department of Dermatology,
sis and the risk of malignancy. J Am Acad Dermatol 2009; 60:1001– University of Pittsburgh, Presby South Tower Suite 3880, 200 Lothrop Street, Pittsburgh, PA 15213; e-mail [email protected]. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 79 • NUMBER 6 JUNE 2012

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