To test or not to test? An evidence-based assessment ofthe value of screening and monitoring tests whenusing systemic biologic agents to treat psoriasis

William Huang, MD, MPH,a Kelly M. Cordoro, MD,d Sarah L. Taylor, MD, PhD,a

and Steven R. Feldman, MD, PhDa,b,c

Winston-Salem, North Carolina, and Charlottesville, Virginia

The development of new treatments for psoriasis provides dermatologists novel ways to help control thedisease but raises questions about what laboratory screening tests are required. As of yet, no consensus orguidelines exist for dermatologists to follow and there may be misconceptions about the relative need forscreening and monitoring tests in patients treated with biologic agents. Current practice ranges from notesting to blanket screening panels. The purposes of this review are to (1) systematically review theliterature on the use of screening and monitoring tests when initiating and continuing biologic treatments(adalimumab, alefacept, efalizumab, etanercept, infliximab) for moderate to severe psoriasis or psoriaticarthritis; and (2) suggest practical guidelines for dermatologists on which to base such testing. We searchedthe Cochrane Collaborative Database (including the Cochrane Database of Systematic Reviews [CochraneReviews] and the Cochrane Central Register of Controlled Trials [Clinical Trials]) and the MEDLINE databaseusing medical subject headings as search terms when available or key words when appropriate. Wecompiled published data on risk and risk assessment related to systemic psoriasis treatments, used expertopinion where appropriate when published clinical data were not adequately informative, and assignedevidence grades for various screening tests based on standard methods of the US Preventive Services TaskForce. Finally, we developed a table of evidence grades for tests used to monitor different systemicmedications. There is not strong evidence to recommend most screening tests for monitoring biologicaltreatments. Neither is there strong evidence not to do such testing. Ultimately, from a practical standpoint, itis incumbent on the clinician to consider each patient independently and determine what screening testsare most appropriate for each individual patient. ( J Am Acad Dermatol 2008;58:970-7.)

Systemic biologic agents (alefacept, efalizumab,etanercept, infliximab, adalimumab) providevaluable options for patients with moderate

to severe psoriasis. The availability of these newtreatments raises the question of what laboratory

screening tests are required for initiating treatmentand monitoring patients on treatment. Although theFood and Drug Administration (FDA) of the UnitedStates sets forth recommendations for laboratorymonitoring when starting and continuing systemictreatments, those recommendations are closelybased on clinical trials done for registration. In lightof postmarketing reports of adverse events, thecurrent FDA-recommended screening and monitor-ing parameters are insufficient. Currently, clinicalpractice varies widely from no testing to blanketscreening panels.

As of yet, there is no consensus or guideline fordermatologists to follow and recommendations forscreening tests vary greatly among different organi-zations. The purposes of this review are to: (1)systematically review the literature for the level of

Abbreviations used:

FDA: Food and Drug AdministrationPPD: purified protein derivativeTB: tuberculosis

From the Center for Dermatology Research, Departments of

Dermatology,a Pathology,b and Public Health Sciences,c Wake

Forest University School of Medicine, Winston-Salem; and

Department of Dermatology, University of Virginia.d

The Center for Dermatology Research is supported by an educa-

tional grant from Galderma Laboratories LP. This study was

funded by a grant from Abbott Laboratories.

Disclosure: Dr Feldman serves as a consultant for the following

companies: Abbott, Amgen, Centocor, Astellas, Genentech,

Galderma, Warner Chilcott, and Stiefel. Drs Huang, Cordoro,

and Taylor have no conflicts of interest to declare.

Accepted for publication March 4, 2008.

Reprint requests: Steven R. Feldman, MD, PhD, Department of

Dermatology, Wake Forest University School of Medicine,

Medical Center Blvd, Winston-Salem, NC 27157-1071. E-mail:

sfeldman@wfubmc.edu.

Published online April 3, 2008.

0190-9622/$34.00

ª 2008 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2008.03.004

970

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evidence regarding the use of screening tests wheninitiating newer systemic biologic agents (alefacept,efalizumab, etanercept, infliximab, adalimumab) formoderate to severe psoriasis and psoriatic arthritis;and (2) suggest practical guidelines for dermatolo-gists on which to base screening tests performed forthese systemic biologic treatments.

METHODSLiterature search methods

We searched the Cochrane Collaborative andMEDLINE databases to identify any potential reviewsor abstracts of randomized controlled trials per-formed in the area of systemic biologic treatmentsfor psoriasis and screening tests (Table I). In addi-tion, we searched reference lists of reviewed articlesand referrals from specialists in the field to find anyother articles not found in the MEDLINE or CochraneCollaborative databases.

Evidence gradingWe reviewed full articles and graded evidence

based on standardized methods developed by the USPreventive Services Task Force1 (Table II). Excludedarticles included use of systemic biologic therapy inchildren or for indications other than psoriasis orpsoriatic arthritis, investigation of the use of multiplesystemic biologic therapies simultaneously, and useof systemic biologic therapies in erythrodermic andpustular psoriasis. Single case reports and data fromanimal testing were also excluded. Finally, wesought expert opinion from other specialties, whereappropriate, when published clinical data provedequivocal or not adequately informative.

RESULTSDespite various recommendations from the FDA

and other published consensus statements, noscreening test received greater than a B recommen-dation (n = 3) with most screening tests receiving C

(n = 8), D (n = 10), or I (n = 11) recommendations(Tables III and IV).

The evidence is good that monitoring of CD41 Tlymphocytes every 2 weeks can potentially assist inmonitoring the safety of alefacept, as the circulatingCD41 T lymphocytes in the blood decrease in adose-dependent manner.2,3 However, results fromclinical trials show that the incidence of infectionappears to be unrelated to the CD41 T-lymphocytecounts.4-7 In addition, investigators did not reportany cases of opportunistic infection. Clinical trialssubstituted placebo for active drug in any patientwho exhibited CD41 counts less than 250 cells/�L,so the evidence is insufficient to determine the actualeffect of keeping patients on alefacept with CD41

counts lower than this level. The potential risks ofCD41 T-cell monitoring are small and include excessburden on the patient (eg, travel costs, time, multipleblood draws) and having to stop a treatment regimenwithout adequate evidence that continuing willresult in adverse effects. The potential benefit andharm in unstudied populations cannot be deter-mined from existing data and, at this time, themagnitude of benefit remains unclear. A reasonable

Table I. Literature search methods

Database Search terms

Cochrane Collaborative* Psoriasis, psoriatic arthritis, screening test, systemic treatment, alefacept, Amevive,etanercept, Enbrel, efalizumab, Raptiva, adalimumab, Humira, infliximab, andRemicade

MEDLINEy Psoriasis (psoriasis OR psoriatic arthritis), safety and screening tests (screening test ORscreening tests OR screen OR screens OR test OR tests OR screening OR safety ORtolerability OR risk OR risk assessment), and biologic treatments (alefacept OR AmeviveOR etanercept OR Enbrel OR efalizumab OR Raptiva OR adalimumab OR Humira ORinfliximab OR Remicade)

*Cochrane Collaborative database (including the Cochrane Database of Systematic Reviews [Cochrane Reviews] and the Cochrane Central

Register of Controlled Trials [Clinical Trials]).yMEDLINE database using medical subject headings. Studies must have been in the English language, involve human subjects, and fall

between the dates of January 1, 1950, and July 1, 2006.

Table II. Recommendation grid1

Quality of

evidence

Net benefit

Substantial Moderate Small Zero/negative

Good A B C DFair B B C DPoor = I

Evidence grades: A, strongly recommend (quality of evidence is

good and magnitude of benefit is substantial); B, recommend (either

quality of evidence or magnitude of benefit or both is less than

needed for A recommendation); C, make no recommendation for or

against service (quality of evidence is either good or fair, but

magnitude of benefit is small); D, recommend against (Quality of

evidence is good or fair that magnitude of benefit is either zero or

negative); I, insufficient evidence (studies are lacking or of poor

quality, or produce conflicting results).

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972 Huang et al

practical approach is to check T-lymphocyte countsat a less frequent interval, perhaps monthly.

There is good evidence that routine laboratorymonitoring of platelets can lead to early detection ofasymptomatic thrombocytopenia with efalizumab.Of the 8 cases of immune-mediated thrombocytope-nia reported, 3 patients were hospitalized includingone for heavy uterine bleeding.8 Evidence to deter-mine whether early and periodic screening leads toimproved patient outcomes remains unclear as nodata exist on patients who developed thrombocyto-penia and continued to receive treatment. Althoughit is reasonable to assume that patients with

efalizumab-related thrombocytopenia who continueon the medication may eventually develop unneces-sary hemorrhage and bleeding, the evidence from theclinical trials does not allow for ascertainment of thisrisk. The evidence is good that patients who dodevelop efalizumab-related thrombocytopenia havea return to normal platelet counts after discontinua-tion of the medication and administration of systemiccorticosteroids or Rhesus factor immune globulinand platelet transfusion.

Among the biologic therapies for psoriasis andpsoriatic arthritis, etanercept has a favorable safetyprofile with long-term safety data available from its

Table III. Summary of evidence

Treatment Screening test

Current

recommendations Evidence grade

Alefacept CD41 lymphocyte count2,3,4-7,10-15 X82,83 CLFTs4-7,10,11,14,15 X84 DHIV ELISA4-7,10,11,14,15 1/e84 IHepatitis B and C4-7,10,11,16 X84 IOther (CBC, BMP, UA,

CXR, PPD)4-7,10,11,14,15X83,84 D

Efalizumab Blood platelets8,17-25 X82-84 BWBCs8,17-25 X83,84 DHemoglobin and hematocrit8,17-25 X83,84 ILFTs8,17-25 X84 DCRP8,17-25 None COther (BMP, UA, CXR, PPD, HIV ELISA,

hepatitis B and C)8,17-24X83,84; 1/e84(HIV) D

Etanercept PPD26-35 X82-84 CCBC26-29,36-38 X83,84 CLFTs26-29,34,35,38 X84 DANA and anti-dsDNA2,26-29,37,38 X84 CHepatitis B and C26-29,38-42 X84 IHIV ELISA26-29,43 1/e84 IOther (BMP, UA, CXR)26-43 X83,84 D

Infliximab PPD9,44-62 X83,84 BLFTs9,44-61 X84 CANA and anti-dsDNA9,44-61 X84 CHepatitis B and C44-61,63-74 X84 IHIV ELISA44-51,75,76 1/e84 ICBC9,44-61 X83,84 IOther (BMP, UA, CXR)44-61 X83,84 D

Adalimumab PPD77-81 X82-84 BHepatitis B and C77-81 X84 IHIV ELISA77-81 1/e84 ILFTs77-81 X84 ICBC77-81 X83,84 CANA and anti-dsDNA77-81 X84 COther (BMP, UA, CXR)77-81 X83,84 D

ANA, Antinuclear antibody; BMP, basic metabolic panel; CBC, complete blood cell count; CRP, C-reactive protein; CXR, chest radiograph; ds,

double-stranded; ELISA, enzyme-linked immunosorbent assay; LFT, liver function test; PPD, purified protein derivative; UA, urinalysis; WBC,

white blood cell count; X, recommended; 1/e, recommended/not recommended.

Evidence grades: A, strongly recommend (quality of evidence is good and magnitude of benefit is substantial); B, recommend (either quality

of evidence or magnitude of benefit or both is less than needed for A recommendation); C, make no recommendation for or against service

(quality of evidence is either good or fair, but magnitude of benefit is small); D, recommend against (Quality of evidence is good or fair that

magnitude of benefit is either zero or negative); I, insufficient evidence (studies are lacking or of poor quality, or produce conflicting results).

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use in other patient populations and postmarketingsurveillance. The evidence from clinical trials is goodto recommend against the routine screening of allpatients who are about to begin etanercept with apurified protein derivative (PPD) skin test for latentor active tuberculosis (TB). No cases of TB appear inany of the reviewed studies of etanercept in patientswith psoriatic arthritis and psoriasis, but there havebeen postmarketing reports of disseminated TBinfection. Although reported cases of TB are higherwith other tumor necrosis factor-a blockers and rarereports of TB in patients on etanercept exist, the netbenefit of screening every patient with a PPD skintest is small.

The evidence is good that patients taking inflix-imab, either as monotherapy or in conjunction withother agents, are at an increased risk for elevations inliver function tests including alanine aminotransfer-ase and aspartate aminotransferase. Patients oninfliximab experienced elevated liver transaminasesat a greater frequency than those on placebo inrheumatoid arthritis, ankylosing spondylitis, Crohn’sdisease, ulcerative colitis, psoriatic arthritis, andpsoriasis clinical trials. Generally this elevation wastransient and asymptomatic. However, rare cases ofsevere liver injury including acute liver failure andautoimmune hepatitis exist for patients taking

infliximab during postmarketing surveillance.9 Thenet benefit of screening is unclear as the vast majorityof patients who experience elevated liver enzymesare asymptomatic and have a return to normal levels,whereas those at increased risk of developing hepa-tic injury cannot be determined. A reasonable ap-proach is to consider interval screening in patients atrisk for liver injury. Therapy should be discontinueduntil further evaluation rules out liver injury in thosewho develop elevated liver enzymes or show signsand symptoms of liver dysfunction.

Caution, screening, and close follow-up are ad-vised inpatients about tobegin therapywith anyof theantitumor necrosis factor agents (adalimumab, inflix-imab, etanercept) who have a history or risk ofdeveloping congestive heart failure, demyelinatingdisorders, seizure disorders, and malignancies. Goodevidence from clinical trials and postmarketingsurveillance do not support routine pretreatmentscreening with urinalysis, chest radiograph, and met-abolic panels before initiation of any of the biologicagents.

On the whole, the most reasonable approach toscreening in addition to the aforementioned tests isbest based on careful clinical history and physicalexamination, which will allow tailored and targetedscreening.

Table IV. Biologic agents for psoriasis

Biologic agent Description Mechanism of action FDA approval FDA indications

FDA screening

recommendations

Alefacept14

(Amevive)Dimeric fusion protein

composed of LFA-3and IgG1

Inhibits interactionbetween the CD-2receptor of Tlymphocytes and itsligand, LFA-3

January2003

Plaquepsoriasis

CD41 T lymphocytesevery 2 wk

Efalizumab8

(Raptiva)Humanized monoclonal

IgG1 antibodyTargeted against

CD11a, a crucialsubunit of LFA-1

October2003

Plaquepsoriasis

Platelet count monthlyinitially then every 3mo

Etanercept37

(Enbrel)Fusion protein of

the p75 TNF receptorwith the Fc domainof immunoglobulin

Blocks binding ofTNF to cellsurfacereceptors

January2002

Psoriaticarthritis

Pretreatment PPDscreening

April 2004 Plaque psoriasis

Infliximab9

(Remicade)Chimeric

monoclonal antibodycomprised of a humanIgG1 constant regionattached toa murine antigen-binding region

Binds to andneutralizeshuman TNF-a.

May 2005 Psoriaticarthritis

Pretreatment PPDscreening

September2006

Plaquepsoriasis

Adalimumab78

(Humira)Recombinant, fully

human IgG1monoclonal antibodythat binds specificallyto TNF-a

Blocks interaction withp55 and p75 cellsurface receptors

October 2003 Psoriaticarthritis

Pretreatment PPDscreening

FDA, Food and Drug Administration; LFA, leukocyte function-associated antigen; PPD, purified protein derivative; TNF, tumor necrosis factor.

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DISCUSSIONBiologic medications provide patients much

needed options for the treatment of psoriasis andpsoriatic arthritis. How patients on these drugsshould be monitored is not yet well characterized.Clinical practice varies widely from no testing toblanket screening panels, and expert recommenda-tions vary significantly between organizations. Usinga systematic approach to search and review theliterature, and taking into account both the quality ofthe evidence and the magnitude of effect of screen-ing interventions, we find it difficult to make specificrecommendations. On the one hand, there is notstrong evidence to recommend most screening testsfor monitoring biological treatments. On the otherhand, there is not strong evidence not to do suchscreening laboratory tests.

From a practical standpoint, it is left to the clini-cian to decide what screening tests are most appro-priate for each of their patients. Although the netbenefit of screening in most cases cannot be deter-mined from the available data, from a purely clinicaland practical standpoint, without baseline screeninglaboratory test results, later abnormal laboratory testresults detected during monitoring have little mean-ing and their significance or causality cannot bereliably interpreted. Caution is needed when initiat-ing these medications with regard to the need for athorough risk assessment such that the appropriatetargeted baseline and monitoring tests can be used.Treatment must be individualized for each patient, asblanket recommendations for all patients are neitherclinically sound nor cost-effective. Screening for TBis important for all patients in endemic areas, inimmigrants from endemic areas, and anyone withrisk factors such as foreign travel, exposure, andequivocal PPD in the past. Although the evidence fordoing so is not strong, based on mechanism of actionand postmarketing reports, and in light of theCenters for Disease Control and Prevention andAmerican Thoracic Society recommendations, webelieve pretreatment PPD screening should be donefor all patients before starting an antitumor necrosisfactor agent.

Ideally, controlled trials of screening tests wouldprovide evidence needed to develop guidelines.Such studies had not been done at the time of ourreview. To obtain evidence on screening tests, weused data from randomized controlled trials thatassessed efficacy and safety of medications. We alsoincluded data from other types of research trials withthe exception of single case reports and animalstudies. In addition, many of the reported adverseoutcomes have occurred during postmarketing

surveillance. Unfortunately, the relationship be-tween adverse events and the medication used isdifficult (if not impossible) to assess from spontane-ous case reports.

A major limitation to this study and to the overallevidence for or against screening interventions forpatients about to begin systemic biologic therapy fortheir psoriasis or psoriatic arthritis is the data avail-able on this issue. Although the FDA recommendscertain screening tests before beginning biologictherapy, much of the evidence comes from singleor multiple clinical trials looking at the overall safetyand efficacy of the medication, rather than theappropriateness of screening. Therefore, difficultiesarise in forming strong, evidence-based guidelinesfor the use of screening tests.

Even without clear evidence on what screeningtests to perform when starting a patient on biologictherapy, providers must make a decision on whichscreening tests are appropriate for their patient.When deciding on treatment strategies, it is essentialto discuss with the patient the potential risks, ben-efits, side effects, and chance for resolution from thetherapy. Combined with an appropriate history andphysical examination, this discussion will assist inusing good clinical judgment to determine risk andany special considerations needed before startingtreatment. For instance, taking into account theprevalence of a particular disease in a communityor for a specific population would affect a provider’spretest probability and threshold for screening.Similarly, looking at a patient’s risk factors for diseasemay cause clinicians to be more inclined to screen.

The purpose of screening is to assess risk such thatour primary question becomes ‘‘Does screeningallow us to treat earlier and, if so, does this earliertreatment reduce the number of adverse healthevents?’’ In considering screening tests for patientsbeginning systemic biologic therapy for psoriasis orpsoriatic arthritis, we must acknowledge the fact thatscreening is not an entirely benign process. Thepossibility of false-positives and false-negative find-ings and the potential resultant psychologic, medical,and financial damage of inaccurate labeling andfurther evaluation and treatment is not a trivial issue.By seeking to address issues of net benefit (harm vsbenefit) and cost-effectiveness (cost of screening vsnot screening), future studies will direct us towardevidence-based guidelines. Although the data arecurrently lacking in this regard, the results of thisstudy should encourage future researchers to exam-ine the appropriateness of various screening inter-ventions and to ask the question for differentpopulations, as patients vary greatly in level of risk.

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