Psoriasis Vulgaris: an Evidence-Based Guide for Primary Care

J Am Board Fam Med: first published as 10.3122/jabfm.2013.06.130055 on 7 November 2013. Downloaded from

CLINICAL REVIEW Psoriasis Vulgaris: An Evidence-Based Guide for Primary Care

Erine A. Kupetsky, DO, MSc, and Matthew Keller, MD

Psoriasis vulgaris is a chronic, sometimes debilitating, inﬂammatory disorder with multiple pathways of pathogenesis that can be associated with metabolic and cardiovascular disease. This article aims to be a comprehensive, literature-based review of the epidemiology, genetic factors, clinical diagnosis, treatments, and pharmacology for psoriasis as derived from articles published in PubMed. Levels of evidence and recommendations were made according to the strength of recommendation taxonomy. This article is divided into 2 sections: the ﬁrst is clinical and diagnostic, the second is therapeutic. This review serves as a practical, evidence-based, and unbiased guide for primary care practitioners. (J Am Board Fam Med 2013;26:787–801.)

Keywords: Dermatology, Primary Health Care, Psoriasis, Skin Diseases

Psoriasis is a chronic inflammatory disease that Methods affects up to 5% of the world’s population.1 Cur- The literature published in PubMed from 2000 to rent estimates put the prevalence of psoriasis at up 2012 was searched using the following key words: to 7.5 million cases in the United States. It is more psoriasis, treatments, clinical trials, and reviews. Ab- copyright. common in whites and those who live farther from stracts were included only if they were clinically the equator, and it is equally common in men and relevant; the articles were downloaded as portable women.2 Psoriasis is more common with certain document files. The first author (EAK) performed human leukocyte antigen (HLA) subtypes, but the literature search, captured and processed the these cannot be distinguished histologically or clin- articles, and determined the strength of recommen- ically and there is no apparent difference in the dation taxonomy (SORT) criteria with level of ev- 4 response to therapy.2 Psoriasis can generally be idence (1–3).

divided into 2 types: Type 1 psoriasis shows a http://www.jabfm.org/ strong family history for the disease, demonstrates Diagnostics 3 an association with HLA-CW6, and usually pres- Table 1 describes the pathogenesis of psoriasis, and 2 ents before 40 years of age. Type 2 is not familial Table 2 lists risk factors and comorbidities that can in presentation, has no association with HLA- contribute to the development of moderate or se- CW6,3 and usually presents after 40 years of age.2 vere psoriasis. The diagnosis of psoriasis can be determined clinically (Table 3) and histologically, if on 30 September 2021 by guest. Protected needed. Before treatment for psoriasis can be initiated, the grading and severity must be determined (Table 4).

This article was externally peer reviewed. Submitted 6 February 2013; revised 27 July 2013; accepted Topical Treatments 12 August 2013. From the Department of Dermatology and Cutaneous Topical Corticosteroids (SORT Criteria Biology, Thomas Jefferson University, Philadelphia, PA. Recommendation A, Level of Evidence 1) Funding: none. Conﬂict of interest: none declared. Dosing and Side Effects Corresponding author: Erine A. Kupetsky, DO, MSc, De- Choosing the strength of topical steroids and vehi- partment of Dermatology and Cutaneous Biology, Bluemle Life Sciences Building, 233 South 10th Street, Suite 450, cle of administration is important in order to obtain Philadelphia, PA 19107 (E-mail: [email protected]). the most beneﬁt with the least potential for side doi: 10.3122/jabfm.2013.06.130055 Psoriasis Vulgaris 787 J Am Board Fam Med: first published as 10.3122/jabfm.2013.06.130055 on 7 November 2013. Downloaded from

Table 1. Pathogenesis of Psoriasis

Pathway Producer Action in Psoriasis

TNF-␣ (over Macrophages, T cells, mast cells, Increases the release of cytokines by lymphocytes and chemokines expressed in granulocytes, natural killer cells, by macrophages6 psoriasis)5 fibroblasts, neurons, Increases expression of adhesion molecules attracting neutrophils keratinocytes, and smooth and macrophages to the lesions by activation of the vascular muscle cells5 endothelium6 Induces keratinocyte and endothelial cell neovascularization stimulating the inflammatory process6 IL-12/23 IL-12 promotes the differentiation of naive CD4ϩ T lymphocytes (upregulated to Th1 cells.7 in psoriasis)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 CD4ϩ cells into Th cells and CD8ϩ into cytotoxic T cells.6 As a result, TNF- ␣, IL-2, interferon-␥, and other cytokines are produced.6 Th17 Th17 cells produce IL-17, a potent Il-17 directly perpetuates further inflammation of the keratinocyte, proinflammatory cytokine but it also indirectly stimulates production of IL-6.8

IL, interleukin; Th, T helper; TNF, tumor necrosis factor. effects. It is possible to treat the majority of patients groin, axilla, and breasts because these areas are if a physician has a good grasp on the use of just 3 more sensitive to topical steroid penetration and classes of steroids: superhigh potency (class I), mid/ can develop striae.15 The usual dosage for topical high potency (class III), and low potency (class VI). steroids is twice per day for 2 weeks, but this can Steroids should be used with caution on the face, range depending on the severity and location of the psoriasis and the strength of the steroid used. For

Ͻ copyright. Table 2. Risk Factors and Comorbidities for Moderate example, a superpotent steroid limited to 5% to Severe and Severe Psoriasis2,5,9,10 body surface area can be used twice daily for up to 2 weeks on the body but avoiding the face and ● 2 Psoriatic arthritis (25% of psoriatics develop PsA ) intertriginous regions. Atrophy, telangiectasia, and ● Genetic predisposition to autoimmune disease striae15 are always a concern, especially when top- ● TNF-␣ deregulation ical steroids are used for long periods of time or ● Elevated C-reactive protein increases risk of diseases like Crohn’s, multiple sclerosis, cardiovascular disease used on the groin, axilla, or under occlusion. (myocardial infarction and stroke), depression, and lymphoma (compared to the nonaffected age- and sex- matched population)*

Vehicles http://www.jabfm.org/ ● More likely to smoke Topical steroid compounds come in various vehi- ● Have HTN cles, which can determine the area of application, ● Have diabetes, obesity, and hypercholesterolemia level of efficacy, and possible side effects. Lotions ● Even when corrected for above risk factors (hypercholesterolemia, diabetes, HTN, and obesity), are water-based, weakest in strength, and evapo- patients with severe psoriasis have an elevated incidence of rate. Shampoos may be used for psoriasis on the myocardial infarction compared with age-matched patients without psoriasis2,11 scalp but limited contact time limits efficacy, mak- on 30 September 2021 by guest. Protected ● Control of HTN, cholesterol, weight, and diabetes can ing solutions and sprays more effective for the assist in decreasing psoriasis burden and frequency of flares2 scalp. Gels are alcohol-based, evaporate quickly, ● Moderate to severe psoriasis is associated with depression, and sting but are equipotent with ointments and suicide,9 and rarely lymphoma10; this risk increases with disease burden solutions. Many patients prefer gels because they are easy to apply and do not stain clothing. Oint- *Because of this baseline elevation in inflammatory markers, ments are petrolatum-based, typically the most po- especially in patients with moderate to severe plaque psoriasis, tent, and usually do not irritate, making them the risk for certain diseases like multiple sclerosis,12 lymphoma,13 and myocardial infarction may be elevated even further with use best option for sensitive skin. Foams contain alco- of a TNF-␣ blocker.2,10 On the other hand, patients with mod- hol and therefore evaporate quickly, which make erate to severe psoriasis with depression and suicidal ideation them appropriate for application in the hair or for who are placed on etanercept, a TNF-␣ blocker, may improve both their psoriasis and their depression.9,14 patients (especially men) who prefer this clean type TNF, tumor necrosis factor; HTN, hypertension. of vehicle. Creams are lipid-based and do not evap-

788 JABFM November–December 2013 Vol. 26 No. 6 http://www.jabfm.org o:10.3122/jabfm.2013.06.130055 doi: Table 3. Diagnosis of Psoriasis*: Clinical Appearance and Types

Presentation Features Additional Features Location Treatment(s)

Plaque (psoriasis Well-demarcated papule or plaque with Koebner’s phenomenon, which is the Knees, elbows, trunk (extensor Topical and/or systemic, depending vulgaris is silvery scale and punctuate bleeding development of psoriasis in areas of surfaces), nape of neck, on severity and recalcitrance most common) when peeled (Auspitz’s sign) trauma16 postauricular, lumbosacral Intralesional steroids for local area, scalp, feet, hands, recalcitrant disease penis16 Nail Proximal nail matrix produces defects in Subungual hyperkeratosis (onchyolysis) starts Fingernails and/or toenails Intralesional steroids, CsA18 keratinization that are translated as as the free nail separates from the nail bed the nail grows out from the cuticle in and can be demarcated by a yellow band; the form of pits Ͻ1 mm in diameter this allows for material from the nail bed Psoriasis of the nail bed results in oil to accumulate under the nail.16,17 spots. Patients also get splinter Consider possible future development of hemorrhages.17 PsA. Inverse Painful, well-demarcated, symmetric, Intertriginous regions of the Topical (uncommon) erythematous papules and plaques body: inframammary, neck, that may become macerated, often axillary, inguinal crease, and eroded, or secondarily infected intergluteal because of location19 Erythrodermic Ͼ90% Involvement of BSA Acute form can result in hospitalization and Widespread Systemic (acetretin,18 MTX, CsA18 ) Acute: develops over days, can be severe can be life threatening if severe because of and even life threatening because of loss of fluids (electrolytes, water, proteins) greater stress on the heart and other and unstable body temperature20 metabolic resources of the body Chronic: develops more slowly over months to years Pustular Erythema and sterile pustules Some can have metabolic disturbances.19 Widespread in flexures Systemic (acitretin18 ) or biological (generalized sometimes in preexisting plaques or Causes include pregnancy, rapid steroid type; rare; 4 in annular lesions taper, infections, hypocalcemia, or topical types) local irritants19 Palmar/plantar Vesicles lead to pain and/or significant Typically recalcitrant because of the Hands/feet UV light (PUVA/UVB), acitretin,18 pustular itch in involved areas. thickness of the skin of the palms and CsA18 soles, limiting penetration of topical treatments and trauma to hands and feet, causing the Koebner phenomenon srai ugrs789 Vulgaris Psoriasis Guttate Abrupt eruption of psoriasis that is Preceded by a streptococcal infection or Trunk and extremities With UV light and withdrawal of characterized by 2- to 5-mm drug-induced (carbamazepine, ␣- offending drugs or resolution of teardrop-shaped papules. interferon, antimalarials, abrupt cessation streptococcal disease, some of systemic corticosteroids, lithium, ␤- patients have resolution. blockers)2 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 ϩ ultraviolet A/ultraviolet B; BSA, body surface area.

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Table 4. Psoriasis: Severity Grading19 or phototherapy. Calcipotriene 0.005% cream,

Psoriasis BSA* (%) Treatment Required ointment, and scalp solution 0.005% are available for use twice a day. Calcipotriene is also is available Mild Ͻ5 Topical combined with betamethasone dipropionate 0.064% in † Moderate to severe 5–10 Topical and systemic an ointment and suspension. The maximum dose Ͼ Severe 10 Systemic for these is 100 g/week. Calcitriol 3 ␮g/g ointment *To determine a patient’s body surface area (BSA) of plaque is also available, to be applied twice daily. The involvement, the doctor would use the patient’s own palmar maximum exposure to this drug is 200 g/week be- handprint as a guide while they perform their examination. The cause of the risk of hypercalcemia and hypercalci- 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 uria. Vitamin D analogs can be applied 2 hours †Severe disease: significant involvement of the palms/soles, face after ultraviolet (UV) light therapy, but they should or intertriginous areas as these may be significantly debilitating. not be applied before UV therapy since they are inactivated by UV light.24 The most common reaction is irritation at the site of application, which orate as quickly but may sting with application. In limits its use on the face and intertriginous areas. A general, anything that is not petrolatum-based will Cochrane review published in 2011 showed that almost definitely temporarily burn on the skin that the compounded vitamin D analog calcipotriene is excoriated or not intact. Most lotions are not true and betamethasone dipropionate was more effec- lotions but more along the line of alcohol-based tive for long-term treatment of mild to moderate solutions. psoriasis than using either drug alone.25

Classes and Compounds Topical Calcineurin Inhibitor (SORT Criteria Class I (superhigh potency) topical steroids in- Recommendation A, Level of Evidence 2) cludes clobetasol propionate, betamethasone dipro- The topical calcineurin inhibitors tacrolimus 0.1% pionate augmented, and halobetasol propionate. ointment and pimecrolimus 1.0% cream are avail- copyright. Class III (mid/high potency) includes triamcino- able. They are applied twice daily and mostly used lone acetonide 0.1%, fluticasone propionate, amci- for disease on the face and intertriginous areas, for nonide, fluocinonide. Class VI (low potency) topi- inverse psoriasis, or used anywhere on the body as cal steroids are alclometasone dipropionate and a steroid-sparing or maintenance therapy.26,27 desonide. Some pharmacies can “compound” these There has been no evidence of skin atrophy or steroids in combination with CeraVe (Valeant absorption by the body.3 It is important for the Pharmaceuticals North America, Bridgewater, NJ) primary care physician (PCP) to become familiar or Cetaphil (Galderma Laboratories, Fort Worth, with the “black box” warning from the US Food an http://www.jabfm.org/ TX), usually as 1:1. CeraVe and Cetaphil are pre- Drug Administration as well as articles refuting the ferred over Aquaphor or Eucerin (Beirsdorf, Inc., use of these inhibitors, which found 20 case reports Wilton, CT) because the latter contain lanolin, of lymphoma and 10 cases of skin neoplasms world- which can have chemicals like cetostearyl alcohol wide after treatment with these drugs, but no causal and potassium sorbate added during their chemical relationships were verified.28 These preparations preparation and cause irritation and allergies in are off-label, generally safe, and are recommended those who are susceptible to it, precipitating a Koe- for use in children Ͼ2 years old. on 30 September 2021 by guest. Protected bner phenomenon.23 Ultraviolet Light (SORT Criteria Recommendation B, Vitamin D Analog Preparations (SORT Criteria Level of Evidence 2) Recommendation A, Level of Evidence 1) Using UV light is probably one of the safest and Vitamin D analogs inhibit keratinocyte prolifera- oldest modalities for the treatment of psoriasis. tion through increased differentiation of cells and Historically, the combination of dead sea salts, inhibit the accumulation of inflammatory cells.3 which are rich in anti-inflammatory mediators, Vitamin D analogs can be used alone or in combi- with irradiation, called heliotherapy, was and is nation with topical steroids (compounded by the useful for the treatment of many skin and rheu- pharmacy) or alternating with topical steroids (ap- matic conditions.29 In general, UV light works by plied by the patient), acitretin, cyclosporin A (CsA), decreasing keratinocyte proliferation and has anti-

790 JABFM November–December 2013 Vol. 26 No. 6 http://www.jabfm.org J Am Board Fam Med: first published as 10.3122/jabfm.2013.06.130055 on 7 November 2013. Downloaded from inflammatory properties.3 As an anecdote, the rec- These procedures are painful for the patient, ommendation for patients with psoriasis who are especially injection of the nail bed. Injections using natural light should try to achieve only 5 to should be limited to no more than 6 to 8 weeks 10 minutes spent unprotected in the mid-day sun 3 apart and given only if necessary. times per week. Some PCPs who see a large num- It is important to note that there are rare cir- ber of dermatologic cases may own a light box or cumstances in which oral corticosteroids are pre- send patients to a hospital-based light therapy cen- scribed for psoriasis. In all cases, the benefits should ter. UV light therapy can be used in combination outweigh the risks. Abrupt discontinuation can pre- with certain systemic (eg, methotrexate and aci- cipitate an erythrodermic reaction, a flare-up of tretin) and topical medications (eg, topical ste- pustular psoriasis, or simply a significant rebound roids or calcipotriene); however, timing of the flare of classic psoriasis. application of topical steroids and tapering the dose of UV therapy to avoid burning are factors Anthralin (SORT Criteria Recommendation C, Level to consider. The current consensus is that nar- of Evidence 3) rowband UVB light is better than broadband Anthralin is a man-made version of a natural sub- UVB light and is considered first-line treatment stance found in goa powder, which is from the for extensive plaque psoriasis, especially if the araroba tree and functions by slowing the growth of 30–32 plaques are thin and the patient is young. keratinocytes. It can be used with caution in both UV therapy is also effective for psoriasis of the children and adults because it can cause contact palms and soles or guttate psoriasis. Although dermatitis if left on too long or if rubbed in the eyes treatments vary, doses of UV therapy generally or on the genital area.35 Anthralin is usually left on are administered 3 times per week for a minimum for 5 to 20 minutes then washed off to avoid brown 30 of 3 months. Psoralen plus UVA is useful for discoloration of clothing. Anthralin can be com- psoriasis of the hands and feet, in cases where pounded with salicylic acid for stability.35 narrowband UVB light fails, or for plaques that copyright. are too thick for light to penetrate.33 The risks of UV use are burning and skin cancer risk, but Systemic Treatments these are more common with the use of Psoralen Systemic treatments used to treat psoriasis are sum- plus UVA, so routine full skin examinations are marized in Table 5. recommended.30 Biological Drugs (SORT Criteria Recommendation A, Intralesional Corticosteroid Triamcinolone Level of Evidence 1)

Acetonide 2.5 to 10 mg/mL (SORT Criteria Screening before Administration of Biologic Therapy http://www.jabfm.org/ Recommendation C, Level of Evidence 3) Before starting a patient on any biologic drug, Intralesional injections are an effective method to much needs to be assessed by a history and physical deliver a small amount of corticosteroid to an examination, laboratory tests have to be analyzed area of psoriasis. In the case of nail psoriasis, (see Tables 6 and 7), and a closer follow-up must be injecting the proximal nail fold to target the considered. Though mostly well tolerated without proximal nail matrix reduces nail inflammation.34 significant side effects and because of the extensive Using a fine-gauge insulin needle that will not follow-up required with their use, many PCPs will on 30 September 2021 by guest. Protected pop off is recommended. The decision of use biologics, working in conjunction with derma- whether to use anesthesia depends on the patient; tologists who are familiar with their use. Drug however, injecting the deep proximal nail fold or allergies and current medications (dermatological the nail bed to target subungual hyperkeratosis and others) should be assessed, looking for those or onycholysis will require initial anesthesia medicines that may increase immunosuppression or block.34 In mild psoriatic disease, where 1 or 2 may exacerbate the psoriasis.2 In addition, a pa- plaques are resistant to topical treatments, for tient’s medical history should be carefully evaluated example, intralesional steroids may play a role. and medicine regime reconciled to ensure that if Skin atrophy is a concern with this modality; to the patient were to start taking a biologic drug, avoid this, the lowest effective dose of triamcin- there would be as few interactions as possible. For olone acetonide (3–5 mg/mL) should be used. example, reports of hypoglycemia in patients taking doi: 10.3122/jabfm.2013.06.130055 Psoriasis Vulgaris 791 792

JABFM Table 5. Summary of Systemic Drugs for Psoriasis Using Strength of Recommendation Taxonomy (SORT)

FDA-Approved SORT Level of Drug Mechanism of Action Dosing Indication Level Evidence Studies oebrDcme 03Vl 6N.6 No. 26 Vol. 2013 November–December Biologics Etanercept Soluble dimeric fusion protein that SC injection of 50 mg twice/week for 3 Moderate to severe A 1 Amgen-Pfizer has Ͼ3 years of clinical links the p75 TNF-␣ receptor to months, followed by 50 mg weekly33 plaque psoriasis data for this drug; early studies for the Fc portion of IgG1, and PsA36 rheumatoid arthritis have shown that decreasing its activity33 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 SC injection at a dosage of 80 mg at week Moderate to severe A 1 Three major trials assessed the efficacy of antibody neutralizes the 0, followed by 40 mg every 2 weeks plaque psoriasis adalimumab.39 After week 16 in each biological function of TNF-␣ by beginning at week 233 and PsA of these trials, approximately 80% of blocking its interaction with the patients experienced a PASI 75* p55 and p75 cell-surface TNF-␣ response.39 receptors38 Infliximab Chimeric monoclonal antibody The drug is administered intravenously Moderate to severe A 1 Three major trials assessed efficacy of (75% human, 25% murine) in every 8 weeks following an initial psoriasis infliximab.42–44 After maintenance which the Fc portion is human loading dose phase (through week 50). patients IgG1 and the Fab portion is remained at PASI 75. primarily of murine origin.40 PsA Anti-infliximab antibodies commonly Neutralizes soluble TNF-␣ and (Preg Cat B) develop after prolonged therapy and blocks membrane TNF-␣.41 can result in decreased drug efficacy or

http://www.jabfm.org in some cases a severe infusion reaction with respiratory compromise.45 Ustekinumab Human monoclonal antibody that 45 mg for patients weighing Յ100 kg; 90 Moderate to severe A 1 Two phase III clinical trials showing that blocks IL-12 and IL-23, binding mg for patients weighing Ͼ100 kg33 plaque psoriasis about two-thirds of patients achieved a the p40 subunit, which activates SC at weeks 0 and 4, repeated every 12 PASI 75 response after 12 weeks of T cells in psoriasis.7 weeks33 treatment.46,47 *

Continued

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FDA-Approved SORT Level of Drug Mechanism of Action Dosing Indication Level Evidence Studies

Systemic Acitretin Oral retinoid inhibits induction of Used in conjunction with phototherapy or Severe psoriasis, A 1 After 12 weeks of therapy, the percentage helper T lymphocytes via IL-6 topical steroids/vitamin D analog for palmoplantar reduction in the PASI score was 54%, by modulating gene expression,33 plaque psoriasis at the lowest effective pustulosis, nail 76%, and 54% for the groups taking which functions to regulate the dose. Start at doses of 10–25 mg/day psoriasis, acitretin 25, 35, and 50 mg/day, keratinocyte turnover in and increase dose every 2 weeks until generalized respectively.48 A PASI 75 response was psoriasis.18 xerosis (dry skin) to chelitis (or dry lips) pustular achieved in 47%, 69%, and 53% appear; may take about 3 months to see psoriasis18 patients in the acitretin 25, 35, and 50 a therapeutic response.18 mg/day groups, respectively.48 MTX Folic acid analog that irreversibly Single weekly dose or in 3 doses: 1 dose Severe plaque A 1 92.7% of patients achieve a PASI 75 inhibits dihydrofolate reductase every 12 hours over 36 hours, or once psoriasis, response after 12 weeks of high-dose in the eukaryotic cell, decreasing weekly, starting at 5 to 10 mg and erythrodermic, MTX.51 DNA and protein synthesis, adjusting the dosage upward at 4-week pustular, and which prevents epidermal intervals to a therapeutic dose between other off-label hyperproliferation. Also decreases 15 and 25 mg/week, with a maximum uses50 DNA in activated T lymphocytes dose of 25 mg/week.18,33 Low-dose folic by inhibiting aminoimidazole acid (1–5 mg) is administered in 3 doses carboxyamide ribocucleotide, an over 36 hours, starting 12–36 hours after enzyme involved in purine the last MTX dose to avoid metabolism.2 megaloblastic anemia with few reductions in efﬁcacy.18,33,49 Or, can be given daily, except the day(s) the MTX is taken. Cyclosporine Binds to cyclophilins and forms a In the absence of comorbidities (obesity Severe, recalcitrant, B 2 PASI 75 responses in up to 97% of complex, blocking differentiation and older age) it is weight-based and or disabling treated patients have been reported.54 and activation of T cells by dosed at 3 mg/kg/day; it is usually psoriasis,53 as inhibiting calcineurin, thus divided into 2 doses.18 Alternative well as pustular, preventing the production of IL- dosing is 2.5 mg/kg/day in 1 or 2 erythrodermic, 2 and its receptor. It also inhibits divided doses for patients with stable and nail keratinocyte hyperproliferation.18 moderate to severe psoriasis and 4.0–6.0 psoriasis52 mg/kg/day in 1 or 2 divided doses for patients with severe or recalcitrant psoriasis.52 The goal is the lowest srai ugrs793 Vulgaris Psoriasis effective dose possible. Taking CsA before meals may result in better absorption and bioavailability of the drug, translating into a reduced disease burden.52

*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.

Table 6. Exclusions for Biological Drugs Vaccines

Latent TB dx without proper tx36,55,56* Since patients taking these therapies may not re- Blood dyscrasia ceive live or live-attenuated vaccines (measles, Wegener’s granulomatosis36,55 mumps, rubella; oral polio vaccine; varicella zoster Recent illness vaccine [VZV]; Bacillus Calmette-Gue´rin; yellow Immunosuppressive disease fever; and influenza [nasal]), ensuring that these Ustekinumab only for drug-induced psoriasis, any history of patients are up to date with their age-appropriate malignancy (except for basal or squamous cell carcinoma skin cancer and cervical cancer in situ treated at least 5 vaccines is important. Annual inactivated influenza years before the initiation of ustekinumab), and a history and pneumococcal (at least one dose, if necessary)60 7 of active TB (latent, treated TB can receive treatment) vaccines should be given since these biologic drugs History of hepatitis, positive hepatitis B (which can be reactivated in chronic carriers, thus, the need for the can lower the immune system’s ability to fight in- vaccination), or active or untreated hepatitis C fection. Vaccination for hepatitis A and B also are Multiple sclerosis (except for ustekinumab) recommended before beginning a biologic. It usu- Any demyelinating disorder7,36,55 ally takes 2 to 6 weeks for the body to produce a significant amount of antibodies after immuniza- *Patients diagnosed with tuberculosis (TB) who have received at 59 least 2 months of treatment can receive a tumor necrosis factor tion. (TNF)-␣ inhibitor with close supervision and a multidisciplinary approach. TNF-␣ modulates granuloma homeostasis Other Risks and contains latent disease.57 In patients with a history of latent TB, indurations on PPD of Ͼ5 mm, even with history of BCG Lymphoma and Leukemia. Lupus-like symptoms vaccination, is considered positive and exclusionary without (butterfly sun-sensitive rash, oral ulcers, etc.) can 36,55 proper treatment for TB. The risk of TB reactivation is be a side effect of using tumor necrosis factor lower with etanercept, a TNF-␣, than with other monoclonal ␣ 36,55 antibody inhibitors.58 (TNF)- inhibitors. Some biological drugs also increase antinuclear antibody titers, so establishing a baseline antinuclear antibody titer is op- copyright. etanercept warrant a reduction of antidiabetic dos- tional.59 Biological drugs can also increase the risk ing and monitoring of glucose logs by PCPs for of cancer, mostly lymphoma10 and leukemia36,55; some of these patients.36 Because some patients however, it is uncertain whether it is the psoriasis who have plaque psoriasis have untreated antistrep- or the initiation TNF-␣ blocking treatment that is tolysin O titers from guttate psoriasis (that devel- the causative factor.5 According to some studies, oped into plaque psoriasis), it always is a good idea many of the original clinical trials conducted using to check an antistreptolysin O titer for every pa- adalimumab and etanercept in patients with rheu- tient with new psoriasis. matoid arthritis, psoriatic arthritis, ankylosing http://www.jabfm.org/

Table 7. Biologics Screening and Monitoring7,59

Follow Labs Every 2 Biological Screen Lab to 6 Months Vaccine/Frequency PPD/Frequency

Etanercept CBC with differential CBC with differential Flu (standard for age) At baseline CMP CMP ϩ Annual on 30 September 2021 by guest. Protected ANA (optional) Adalimumab CBC with differential CBC with differential Flu (standard for age) At baseline CMP CMP ϩ Annual ANA (optional) Inﬂiximab CBC with differential CBC with differential Flu (standard for age) At baseline CMP CMP ϩ Annual ANA (optional) Ustekinumab CBC with differential CBC with differential Flu (standard for age) At baseline CMP CMP ϩ 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).

794 JABFM November–December 2013 Vol. 26 No. 6 http://www.jabfm.org J Am Board Fam Med: first published as 10.3122/jabfm.2013.06.130055 on 7 November 2013. Downloaded from spondylitis, Crohn’s disease, and psoriasis showed a cated about any signs or symptoms of stroke or 3-fold higher rate of lymphoma compared with the transient ischemic attack and administration of general US population.36,55,57 However, when VZV intravenous immunoglobulin should be con- meta-analyses of these randomized controlled trials sidered. were considered, most of the patients who popu- lated the original trials were from cohorts with Basic Pharmacology of Biologicals rheumatoid arthritis and Crohn’s disease, which The half-life of etanercept is 4 days, that of adali- usually combined biological therapies with addi- mumab is 10 to 20 days, infliximab is 8 to 9.5 days, tional immunosuppressive agents, therefore intro- and ustekinumab is 14.9 to 45.6 days5; the time ducing selection bias and confounding.61 In the required for any of these drugs to be removed from absence of TNF-␣ blocking therapy, patients with the body once they are discontinued is approxi- moderate to severe rheumatoid arthritis, for exam- mately 4 to 5 half-lives.70 Once a patient begins ple, have a 5- to 25-fold increased risk of develop- taking a biologic drug, its important to closely ing lymphoma.57 It is therefore unclear whether follow them for drug-related adverse events. Rea- the increases in the rate of lymphoma observed in sons to stop a biologic drug are serious infection; these trials were related to TNF-␣ blocking ther- severe persistent neurological symptoms such as apy. headache, eye pain, loss of vision in one eye, or Congestive Heart Failure/Cardiac Events. Because numbness; Guillain-Barre´ syndrome; lymph node signs and symptoms of congestive heart failure can swelling; unintended weight loss; malaise; easy worsen while taking a biologic drug like a TNF-␣ bruising; bleeding; pallor; or serious allergic reac- inhibitor, physicians should monitor these patients tion such as anaphylaxis or angioedema.36,55 carefully and weigh the risk-to-benefit ratio.55 Ma- jor adverse cardiovascular events have been seen Indications and Dosing with the use of interleukin-12/23 inhibitors, Because of the significant cost of biologics, more namely briakinumab, which was pulled from clini- traditional medications should be tried first, if possi- copyright. cal trials.62,63 Ustekinumab data also show some ble, and biologics used only when those fail or there is events, but further research is needed to clarify the a contraindication to oral systemic therapy. 71 role that these drugs may play in risk of major adverse cardiovascular events and the mechanism Acitretin (SORT Criteria Recommendation A, Level by which they may occur.64 The rate of major of Evidence 1) adverse cardiac events in patients taking usteki- This drug should be completely avoided in women numab was no greater than rates in both the gen- of childbearing age because it is teratogenic and 7 eral population and a population with psoriasis. category X. Although acitretin may take 2 months http://www.jabfm.org/ Ustekinumab can cause reversible posterior leuko- to be eliminated from the body, when alcohol is encephalopathy syndrome, which presents as a per- consumed, eretinate, its metabolite, can have a half- sistent headache, seizures, sudden vision changes, life of up to 168 days.72 It is recommended that and mental and mood changes,7 so establishing a neu- women abstain from consuming alcohol in any rological history and physical examination at baseline is form while taking the drug and for at least 2 important. months after it is discontinued because the amount of metabolite is directly proportional to the amount on 30 September 2021 by guest. Protected of alcohol ingested.72 In fact, the teratogenic effects Reactivation of Varicella Zoster can occur for up to 2 to 3 years after acitretin While the risk of potential reactivation of VZV is discontinued in a patient who has consumed alco- very low when a patient is taking a biologic hol.33,72 Because of this, it is advised that if pre- drug,65,66 the risk increases when this patient is also scribing this for women of childbearing age, they taking oral prednisone for a comorbidity. Reacti- must (1) have 2 negative urine or serum pregnancy vation of VZV can lead to a potentially serious tests before receiving their first dose of acitretin; (2) neurological complication,67,68 and VZV vascu- have monthly pregnancy tests before receiving lopathies in immunocompromised patients have their acitretin prescriptions; (3) simultaneously use been described in the literature.69 In these cases the 2 effective forms of birth control for at least 1 patient should be closely monitored for and edu- month before starting the drug, during the therapy, doi: 10.3122/jabfm.2013.06.130055 Psoriasis Vulgaris 795 J Am Board Fam Med: first published as 10.3122/jabfm.2013.06.130055 on 7 November 2013. Downloaded from and for at least 3 years after discontinuing the including all salicylates, nonsteroidal anti-inflam- therapy; and (4) receive counseling about the risk of matory drugs, trimethoprim/sulfamethoxazole, sul- birth control failure and risk of birth defects and fonamides, and tetracyclines, to name a few.50 Al- abstain from every form of alcohol while taking the though it has oral, intramuscular, and intravenous drug and for at least 2 months after the drug has routes of administration, oral administration is been discontinued.72 most common in the primary care setting. Metho- trexate (MTX) should not be given to anyone plan- Monitoring ning to consume alcohol or women who are preg- A careful history and physical examination is im- nant or lactating. Risks versus benefits should be portant to identify those at risk for or with a family discussed because of possible adverse effects; con- history of hyperlipidemia; a medicine reconcilia- tinuous monitoring is required with this drug. tion is useful to note potential drug interactions. About 80% of patients with psoriasis who are Monitoring parameters include complete meta- treated with MTX respond usually within the first bolic and lipid panels at baseline, complete blood 4 weeks.50 In addition, for those couples planning count with differential, and urinalysis.73 Lipids can on having a family, it is advised that men taking be checked every 1 to 2 weeks once treatment is MTX should be off the drug for 3 months and started until they stabilize, which is usually in 4 to women should discontinue for 1 menstrual cycle 8 weeks, especially in patients with a personal or and have a negative pregnancy test at each visit.49,50 family history of hyperlipidemia.73 In those without a significant history of or baseline hyperlipidemia, Monitoring checking the lipid panel each month for 3 to 6 Before starting a patient on MTX, a complete months is recommended,73 especially to monitor blood count with differential is required at baseline. for acute pancreatitis, which is rare.73 Triglyceride This helps establish a baseline to follow for any levels Ͼ600 mg/dL or cholesterol levels Ͼ300 mg/dL possible MTX-induced pancytopenia.50 A com- warrant a discontinuation of acitretin and close mon- plete metabolic panel will examine for poor renal copyright. itoring of lipids until they return to baseline.73 Some- function, low albumin, and liver function at base- times, a fenofibrate is recommended for hypertriglyc- line, the first 2 of which can be potential sources of eridemia. Mild elevations in transaminases are rarely pancytopenia because of increased levels of the free seen 2 to 8 weeks after the start of acitretin, but these drug.50 In patients with renal disease, the dose of are transient and just require monitoring.73 Checking MTX can be adjusted according to the patient’s the following laboratory values monthly for the first 3 creatinine clearance (as calculated using the Cock- to 6 months then every 3 months in cases of chronic croft-Gault formula49). Testing for human immu-

acitretin therapy is recommended: complete blood nodeficiency virus, tuberculosis, and hepatitis B and http://www.jabfm.org/ count with differential, lipid and complete metabolic C is important before starting MTX49 because it is panels, and urinalysis. Common adverse reactions are an immunosuppressive drug. Not only can MTX xerostomia (dry mouth), cheilitis, alopecia, xerosis, induce pancytopenia and hepatotoxcity, it can also and sunburn/sensitivity (especially if combined with cause pulmonary fibrosis.49 If pulmonary symp- phototherapy). Because elevated intracerebral pres- toms develop, a chest radiograph is warranted.49 sure can also be an adverse event with acitretin, Once a patient is taking MTX, it is important to concomitant medications that have this adverse monitor for leukocytopenia or thrombocytopenia on 30 September 2021 by guest. Protected reaction (eg, tetracyclines) are contraindicated. with a complete blood count with differential 7 to Finally, because acitretin is a vitamin A deriva- 14 days after starting or increasing the dose, every tive, any vitamin A supplementation should be 2 to 4 weeks for the first few months, then every 1 avoided. Skeletal radiograph monitoring is not to 3 months until stable.49 Leukocytopenia or required.18 thrombocytopenia are most likely to occur 7 to 10 days after initiating MTX and clinically serious Methotrexate (SORT Criteria Recommendation A, cases can usually be corrected by 20 mg folinic acid Level of Evidence 1) (intravenous).49 Patients who are at highest risk of After a full history and physical examination, rec- MTX-induced pancytopenia, and therefore require onciling additional medications is important be- close monitoring, are those who have renal insuf- cause of potential interactions with various drugs, ficiency, the elderly, those at risk for drug interac-

796 JABFM November–December 2013 Vol. 26 No. 6 http://www.jabfm.org J Am Board Fam Med: first published as 10.3122/jabfm.2013.06.130055 on 7 November 2013. Downloaded from tions or taking multiple medications, those with Cyclosporine (SORT Criteria Recommendation A, hypoalbuminemia, or those who are not taking fo- Level of Evidence 2) late.49 A basic metabolic panel for renal function is CsA is not contraindicated during pregnancy or required every 2 to 3 months for patients taking lactation because it is a category C drug; however, MTX; for patients with impaired renal function, it is contraindicated in patients with severe renal glomerular filtration rate needs to be calculated and function, uncontrolled hypertension, and persistent 53 monitored.49 malignancy. During a complete history the pa- The newest guidelines divide those patients who tient should be asked about anything that would are at low risk of developing hepatic fibrosis from increase their risk of nephrotoxcity, such as obesity, those who are at highest risk. Patients are consid- diabetes mellitus, advanced age, and concomitant 52 ered to have hepatic fibrosis risk factors if they have use of nephrotoxic drugs. Exercise caution when diabetes mellitus type 2, are obese, consume excess dealing with patients taking multiple drugs because alcohol, have hepatitis B or hepatitis C virus, CsA has numerous drug-drug interactions due to and/or are exposed to hepatotoxic drugs.33 In these its metabolism by the cytochrome p450 34A system patients pretreatment biopsies may be warranted or when administering with foods like grapefruit 33,76 and may be repeated after the patient has reached a juice. During the complete physical examina- 1.0-g total cumulative dose.41 Its important to ob- tion at baseline and at each monthly visit, patients tain the blood sample at least 5 days after the last should be evaluated for skin neoplasms or infections because CsA increases the risk for developing dose of MTX because the drug can erroneously 52 49 squamous and basal cell carcinomas. In addition, elevate the results of liver function tests. Liver at baseline, all patients initiating CsA should un- function tests showing minor elevations (less than dergo routine age-appropriate cancer screening.52 twice the upper limit of normal) can be repeated in Testing for tuberculosis and hepatitis C at baseline 2 to 4 weeks.49 Any abnormality (Ͼ3-fold the upper is advisable.52 Because CsA is immunosuppressive, limit of normal) in liver function testing necessi- copyright. vaccines may be helpful, and booster vaccination tates a temporary reduction of MTX and repeat of may be necessary; however, live vaccines are con- tests within 2 to 4 weeks.49 If there are persistent traindicated with use of CsA.52 elevations in serum aspartate aminotranferase and hypoalbuminemia for 12 months, a liver biopsy Monitoring should be considered before the patient reaches the Before starting a patient on CsA, 2 confirmed nor- 1.5- to 2.0-g cumulative dose mark.41,49 Whether mal values for serum creatinine and blood pressure MTX treatment should be initiated in high-risk should be documented in addition to complete patients or those with any of the risk factors for

metabolic panels, including liver function testing, http://www.jabfm.org/ hepatic fibrosis should be decided on a case-by-case bilirubin, potassium, blood urea nitrogen, creati- 49 basis. If MTX is considered in these patients, a nine, complete blood counts, serum magnesium baseline liver biopsy is advisable; however, because (which may decease while taking CsA), uric acid some of these patients will discontinue MTX after (which is relevant for those at risk for gout), and 2 to 6 months because of adverse events or lack of fasting serum lipids.52 Despite the recommenda- efficacy, delaying a liver biopsy may also be advis- tions on the package insert, the current consensus 49 able. Low-risk patients require a liver biopsy ev- now requires monthly monitoring of renal function on 30 September 2021 by guest. Protected ery time they reach the 1.5- to 2.0-g total cumula- (creatinine clearance), blood pressure, physical ex- 41 tive dose. Recommendations to continue or aminations, adverse events, and a basic metabolic discontinue MTX based on liver biopsy are based panel, including creatinine, blood urea nitrogen, 74 on the results of Roenigk et al. Whereas liver potassium, complete blood count, and magne- biopsy remains the gold standard, it is fraught with sium.52 It is recommended that the Modification of risk; a liver ultrasound (transient elastography) of- Diet in Renal Disease formula rather than the fers the ability to determine whether the liver is Cockcroft-Gault equation be used for overweight fibrosed, but studies can be limited, especially if the patients and those Ͼ50 years old.18 After checking patient is overweight, has increased abdominal fasting serum lipids at the initiation of therapy, girth, or has a diagnosis of nonalcoholic steato- these levels can be tested at least every 6 months for hepatitis.75 evidence of hypercholesterolemia or hypertriglyc- doi: 10.3122/jabfm.2013.06.130055 Psoriasis Vulgaris 797 J Am Board Fam Med: first published as 10.3122/jabfm.2013.06.130055 on 7 November 2013. Downloaded from eridemia.52 Because of the monthly monitoring or and the large number of patients to be seen, it is laboratory tests and examinations, obtaining a CsA important that PCPs are equipped with the tools level is generally not necessary.52 necessary to understand, manage, and effectively Treating patients for more than 1 to 2 years treat psoriasis in a short amount of time. Dealing without nephrology consultation is not recom- with psoriasis as a complex systemic disease benefits mended because of CsA-associated risk of nephro- both the provider and the patient. In general, top- toxicity.17,52 Patients taking long-term therapy are ical therapies can be used for mild psoriasis. For also at risk of gingival hyperplasia, so yearly dental moderate to severe psoriasis, a combination of top- examinations are advised.52 The current recom- ical and light or topical and systemic (oral or bio- mendations for managing nephrotoxicity are re- logicals) can be used. In these cases, the decision of ducing the dose of CsA by 25% to 50% (equivalent whether to start oral versus biological therapy may to 0.5 to 1.0 mg/kg/day) if serum creatinine levels be personal and possibly guided by the patient’s increase more than 25% to 30% above baseline on finances if the drug is not covered by a patient’s 2 occasions (repeated measurements separated by 2 insurance. Payment assistance programs such as those weeks).52 If serum creatinine fails to return to 10% provided by the manufacturer for patients taking Enbrel of the patient’s baseline after checking the levels (http://www.enbrel.com/pay-for-ENBREL.jspx) and every other week for 1 month, the dose of CsA Humira (https://www.pparx.org/supporters/View should be reduced even further by 25% to 50%.52 Program.php?program_idϭ526) are available. Early Discontinuation of CsA should be considered if intervention and a multidisciplinary approach, man- serum creatinine remains Ͼ10% above the pa- aging all aspects of the patient’s care and comorbidi- tient’s baseline.52 ties, can be the focus of the PCP dealing with this For patients with no pre-existing hypertension challenging disease. but who developed hypertension while taking CsA as measured on 2 separate occasions, the PCP can

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