To test or not to test? An updated evidence-based assessment of the value of screening and monitoring tests when using systemic biologic agents to treat psoriasis and psoriatic arthritis

ORIGINAL

ARTICLE

To test or not to test? An updated evidence-based assessment of the value of screening and monitoring tests when using systemic biologic agents to treat psoriasis and psoriatic arthritis Christine S. Ahn, MD,a Emily H. Dothard, BA,a Michael L. Garner, BA,d Steven R. Feldman, MD, PhD,a,b,c and William W. Huang, MD, MPHa Winston-Salem and Chapel Hill, North Carolina Background: Safety profiles of systemic biologic agents for the treatment of psoriasis and psoriatic arthritis (PsA) encompass a wide spectrum of adverse events. To date, no uniform evidence-based guidelines exist regarding screening and monitoring patients who are undergoing biologic therapy. Objective: We sought to identify studies evaluating screening and monitoring tests in the treatment of psoriasis and PsA with systemic biologic agents, and to propose evidence-based practical guidelines. Methods: The MEDLINE database was searched to identify data on risks associated with adalimumab, etanercept, infliximab, and ustekinumab. Articles were reviewed and graded according to methods developed by the US Preventative Services Task Force. Results: Evidence was strongest (grade B) for tuberculosis screening. Interferon-gamma release assay was preferable to tuberculin skin testing. Among known hepatitis B virus carriers, the evidence grade was C for monitoring liver function tests and viral load. Limitations: This study was limited by the lack of high-quality controlled trials evaluating screening and monitoring tests in patients treated with biologic agents. Conclusions: Baseline tuberculosis testing remains the only screening test with strong evidence to support its practice. Other screening and monitoring tests commonly performed in patients who are taking biologic agents are supported only in certain clinical settings or lack evidence to support or recommend against their practice. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2015.06.004.) Key words: adalimumab; biologics; etanercept; infliximab; monitoring; psoriasis; psoriatic arthritis; safety; screening; ustekinumab.

S

ince the introduction of biologic agents in dermatology in 2002, they have become one of the most frequently used systemic

treatments for moderate to severe plaque psoriasis and psoriatic arthritis (PsA).1 As clinicians have gained experience using biologics, the knowledge

From the Departments of Dermatology, Center for Dermatology Research,a Pathology,b and Public Health Sciences,c Wake Forest School of Medicine, Winston-Salem, and the University of North Carolina School of Medicine,d Chapel Hill. The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, LP. Dr Feldman is a consultant and speaker for Galderma, Stiefel/GlaxoSmithKline, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, and Bristol Myers Squibb, has received grants from Galderma, Astellas, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, Biogen Idec, Coria/ Valeant, Pharmaderm, Ortho Pharmaceuticals, Aventis Pharmaceuticals, LaRoche Dermatology, 3M, Bristol-Myers Squibb, Stiefel/GlaxoSmithKline, Novartis, Medicis, Leo, HanAll Pharmaceuticals, Celgene, Basilea, and Anacor, and has received stock options from Photomedex. Dr Feldman is the founder and holds

stock in Causa Research. Drs Huang and Ahn, Ms Dothard, and Mr Garner have no conflicts of interest to declare. Funding sources: None. Presented in poster form at the 73rd Annual Meeting of the American Academy of Dermatology, San Francisco, CA, March 20-24, 2015. Accepted for publication June 3, 2015. Reprints not available from the authors. Correspondence to: William W. Huang, MD, MPH, Department of Dermatology, Wake Forest School of Medicine, 4618 Country Club Rd, Winston-Salem, NC 27104. E-mail: whuang@ wakehealth.edu. Published online July 14, 2015. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.06.004

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of potential adverse effects has expanded. Safety psoriatic arthritis, safety, screening tests, and bioprofiles of biologics include a wide spectrum of logic treatments (etanercept OR Enbrel OR adalievents, including opportunistic infections, the reacmumab OR Humira OR infliximab OR Remicade tivation of infections, malignancy, hepatotoxicity, OR ustekinumab OR Stelara). The search was and the exacerbation of comorbidities. limited to English articles published between July Antietumor necrosis factor-alfa (TNF-a) 1, 2006 and June 1, 2014. Case reports, data agents that have been approved by the US Food from animal studies, and studies involving and Drug Administration multiple systemic agents (FDA) for the treatment of used simultaneously or biCAPSULE SUMMARY psoriasis and PsA include ologics used for indications infliximab, etanercept, and other than psoriasis or PsA There are no evidence-based guidelines adalimumab. Ustekinumab, were excluded. Screening for screening and monitoring patients an interleukin-12/23 monoand monitoring tests in who are receiving biologic therapy for clonal antibody, was apotherwise healthy patients psoriasis and psoriatic arthritis. proved by the FDA in 2009. without known comorbidWe found that evidence was strongest Based on trials conducted for ities were distinguished (grade B) for tuberculosis screening registration, the FDA recomfrom testing in patients with in patients treated with biologic mends screening and monipreexisting comorbidities. agents. toring in patients treated with Articles were reviewed systemic biologic agents.2 and graded according to High-grade evidence is lacking to standardized methods develAs new adverse effects support other routine testing; therefore, oped by the US Preventative have emerged, professional physicians should use their clinical Services Task Force (USPSTF). dermatologic associations, judgement when screening and Grades of evidence were like the American Academy monitoring patients who are taking determined using current of Dermatology (AAD), biologic agents. guidelines of the USPSTF the Japanese Dermatology and correlated to practice Association (JDA), the suggestions (Appendices A British Association of Derand B, available at http://www.jaad.org). matologists (BAD), and the European Academy of Dermatology and Venereology (EADV) have attempted to provide guidance for screening and RESULTS monitoring tests (Table I).3-10 A total of 1039 articles were identified. Screening In 2006, a previous systematic literature review for relevant articles yielded 145 records. After articles sought to develop evidence-based guidelines for were assessed for content and eligibility, 26 were screening tests in the use of biologics.11 Alefacept included in the qualitative analysis (Fig 1). Among and efalizumab were discontinued in the United these, 16 studied screening tests in patients without States and European Union in 2006, and ustekinucomorbidities3,12-26 and 13 studied monitoring tests mab has been introduced. The purpose of this in patients with hepatitis C virus (HCV) infection, study is to review the literature supporting the hepatitis B virus (HBV) infection, and congestive current recommendations for screening and moniheart failure (CHF).3,17,19,27-36 toring with the use of currently available biologics. This study will highlight changes in screening and Screening and monitoring tests monitoring guidelines that have been recommenAntieTNF-a agents were studied in HBV and ded since our previous report and synthesize HCV, tuberculosis, and human immunodeficiency evidence-based guidelines for clinicians using bivirus (HIV) screening, skin cancer screening, renal, ologics for the treatment of plaque psoriasis and hepatocellular, and biliary liver function, complete PsA. blood cell counts (CBCs), urine studies, pregnancy tests, antinuclear antibody (ANA) and doublestranded DNA (dsDNA), and C-reactive protein METHODS (CRP). Ustekinumab was studied with regard to The MEDLINE database was searched for studies tuberculosis and skin cancer screening (Table II). pertaining to systemic biologic treatments and The highest evidence grade for screening studies screening tests in the context of psoriasis and PsA. was B, seen in the use of tuberculin skin testing (TST) Additional articles not contained in the MEDLINE and interferon-gamma release assay (IGRA; Table II). database were identified from citations within reBased on the USPSTF grading system, it is viewed articles.11 Search terms included: psoriasis or d

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Abbreviations used: AAD: ALP: ALT: ANA: AST: BAD: BMP: CBC: CHF: CMP: CRP: DB: dsDNA: EADV: FDA: HBcAb: HBV: HCV: HBsAb: HBsAg: HIV: IGRA: JDA: LFT: NMSC: PsA: TB: TNF: TST: USPSTF:

American Academy of Dermatology alkaline phosphatase alanine transaminase antinuclear antibody aspartate transaminase British Association of Dermatologists basic metabolic panel complete blood cell count congestive heart failure comprehensive metabolic panel C-reactive protein direct bilirubin double-stranded DNA European Academy of Dermatology and Venereology US Food and Drug Administration hepatitis B core antibody hepatitis B virus hepatitis C virus hepatitis B surface antibody hepatitis B surface antigen human immunodeficiency virus interferon-gamma release assay Japanese Dermatology Association liver function test nonmelanoma skin cancer psoriatic arthritis total bilirubin tumor necrosis factor tuberculin skin testing US Preventative Services Task Force

recommended this screen be provided because there is high certainty that the net benefit is moderate, or medium certainty that the net benefit is moderate to substantial (Appendix A). In studies comparing the 2 methods of tuberculosis screening, IGRA was preferred and had higher sensitivity and specificity.15 Three studies discussed screening for HBV with triple serology, which includes hepatitis surface antigen (HBsAg), hepatitis surface antibody (HBsAb), and hepatitis core antibody (HBcAb). Although screening for HBV is recommended because of the concern for viral reactivation, this is supported only by grade C evidence. Similarly, the evidence supporting HCV screening is grade C, indicating that there is moderate certainty that the net benefit of routine screening for HBV and HCV is small. Therefore, selective screening for HBV or HCV can be performed based on professional judgment and/or patient preference. There is insufficient evidence to recommend routine HIV screening, and screening should be based on clinical context. In reports evaluating the risk of HIV progression during biologic treatment, there were no notable increases in viral load, decreases in CD4 T cell counts, or opportunistic infections while being treated with antieTNF-a therapy. However, there is a general lack of evidence for HIV screening because HIV1 patients were excluded from most trials of biologic agents.19

Ahn et al 3

For general laboratory monitoring, a prospective cohort study including psoriasis patients who were taking etanercept or adalimumab was performed over 5 years.18 In this study, 9% of patients developed hematologic abnormalities, including lymphocytosis, thrombocytosis, thrombocytopenia, and neutropenia. Although none of these led to permanent discontinuation of biologic therapy, there was temporary interruption in patients with laboratory abnormalities or elevated infection parameters. Treatment was restarted once the hematologic abnormalities normalized.18 Abnormal laboratory values can therefore be seen, but they seem transient and with unknown consequence once cell counts are allowed to recover. However, because biologic therapy was suspended until abnormalities resolved, the consequences of continuing therapy with ongoing hematologic abnormalities remains unknown. Therefore, there is insufficient evidence to support screening CBCs. In the analysis of other laboratory findings, no renal impairment or changes in creatinine or creatinine clearance was observed. In liver function studies, an overall mean decrease in alkaline phosphatase (ALP) levels and increase in alanine transaminase (ALT) levels were observed; however, laboratory parameters that changed from pretreatment levels were still within normal reference ranges.18 In data from the Italian Psocare Registry, mean transaminases were evaluated in patients treated with TNF-a agents. Treatment with infliximab was associated with an increased risk of more than doubling aspartate transaminase (AST) and ALT levels above the upper limit of the normal by week 16. No change in level of serum AST and ALT were noted among patients at baseline or weeks 8 or 16 during treatment with adalimumab or etanercept.21 Based on these findings, monitoring hepatic function may be performed at the clinician’s discretion based on grade C evidence, and may be relevant among patients treated with infliximab. Compared to pretreatment levels, CRP typically decreases during biologic treatment.18 Although the decline correlates with disease improvement, the relevance of lowering CRP is not well characterized, and following CRP levels is not recommended because there is moderate or high certainty it does not offer any benefit. Development of ANA positivity has been observed in #4% of patients treated with etanercept or adalimumab and enhancement of positivity in 2%. In almost all cases, there were no clinical signs or symptoms of autoimmune disease.18 Based on this evidence, routine screening and monitoring of ANA is not recommended. In the Italian Psocare Registry, serum lipid levels were evaluated in patients who were treated with

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Table I. Current guidelines for screening and monitoring tests recommended by organizations Test

Screening tests TST or IGRA HBV serology HCV serology HIV CBC with differential BMP only (electrolytes and creatinine) CMP CRP b-D-glucan KL-6 HTLV-1 antibody ANA Lipid profile Chest radiograph CT scan of the chest Urinalysis Pregnancy test TTE Monitoring tests TST or IGRA HBV, HCV HIV CBC with differential BMP (electrolytes and creatinine) CMP CRP b-D-glucan KL-6 ANA Anti-dsDNA (if positive ANA) LFTs in HBV HBsAg and HBeAg HBV viral load LFTs in HCV Viral load in HCV TBSE Urinalysis Pregnancy test Chest radiograph TTE

AAD3,9,10

JDA4

EADV5,8

BAD6,7

d

d

d

d

d

d

d

d

d

d

d

d

d

d

/

d

d

d

d

d

d

d

d

d

d

d d d d

d

d

*

d

d

d

d

d

d

d

d

z

d

d d d

d

d

y

d

/ /

d

d

d

dy

d

d

d

d

d

d

d d d d d d

d

d

d

d

d d

d

d d

/

d d

y

A dot (d) indicates that the test is ‘‘recommended,’’ and a slash (/) indicates that the test should be ‘‘considered based on risk factors.’’ If blank, the organization either does not recommend the corresponding screening/monitoring test or does not specifically comment on this test. AAD, American Academy of Dermatology; ANA, antinuclear antibody; anti-dsDNA, antiedouble-stranded DNA; BAD, British Association of Dermatologists; BMP, basic metabolic panel; CBC, complete blood cell count; CMP, comprehensive metabolic panel; CRP, C-reactive protein; EADV, European Academy of Dermatology and Venereology; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B extracellular antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HTLV-1, human T-lymphotropic virus 1; IGRA, interferon-gamma release assay; JDA, Japanese Dermatology Association; TBSE, total body skin examination; TST, tuberculin skin test; TTE, transthoracic echocardiogram. *Applies to infliximab only. y Applies to antieTNF-a agents (ie, etanercept, adalimumab, and infliximab). z Applies to patients with New York Heart Association Class I or II.

etanercept or infliximab. Although significant changes in cholesterol levels were not observed, an isolated increase in triglyceride levels was seen in some patients who were taking etanercept.21 In a smaller cohort study, lipid levels were monitored in

15 patients with PsA treated with TNF-a agents without history of dyslipidemia or drugs that interfere with lipid levels. There were no changes in total cholesterol levels, but there were increases in triglyceride and very low density lipoprotein

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Fig 1. Flow sheet of literature search. The PubMed database was searched for reviews or abstracts of randomized controlled trials pertaining to systemic biologic treatments for screening tests in the context of psoriasis and psoriatic arthritis. All resulting records were then screened. Full-text records which passed screening were then assessed for eligibility, yielding the final records included in the qualitative synthesis. Records were excluded if they studied the simultaneous use of multiple systemic biologic agents, or if they studied systemic biologics for indications other than psoriasis vulgaris or psoriatic arthritis. Single case reports and data from animal studies were also excluded.

cholesterol levels. There are no outcome studies describing if the dyslipidemia developed while taking TNF-a agents required cessation of the biologic or hypertriglyceridemia treatment, and therefore screening and monitoring serum lipids in patients without underlying dyslipidemia is recommended on an evidence grade C basis, indicating moderate certainty that the net benefit is small. Evidence is sparse and controversial regarding serum pregnancy testing, with few reports associating antieTNF-a agents with vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula and/or esophageal atresia, renal and radial anomalies, and limb defects (VACTERL), and others reporting no complications in women who received biologic agents throughout pregnancy. However, ethical concerns prevent trials from evaluating the true potential risk or harm to the fetus while taking

biologics. The evidence is insufficient to support or refute serum pregnancy testing. Few reports have suggested that the use of a biologic therapy may predispose patients to higher rates of malignancies, such as lymphomas, nonmelanoma skin cancer (NMSC), and melanoma.25 In a report of 2 patients who developed multiple squamous cell carcinomas while taking ustekinumab, Young and Czarnecki25 suggest that ustekinumab promotes the development of multiple NMSCs in patients with an underlying genetic predisposition. However, in a study of long-term safety in patients treated with ustekinumab, rates of malignancy were comparable between ustekinumab- and placebo-treated individuals for both NMSC and all other malignancies throughout 3 years of follow-up.26 Based on this long-term study and limited evidence, skin examinations for the purpose

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Table II. Screening tests for biologics in psoriasis and psoriatic arthritis Screening test

TST IGRA Hepatitis B triple serology (HBsAg, HBsAb, and HBcAb) Hepatitis C serology HIV CBC with differential CMP (TB, DB, ALT, and ALP) LFTs Cr/CrCl CRP ANA and anti-dsDNA Lipid profile Serum pregnancy test TBSE

Biologic agent(s) studied

Evidence grade

Infliximab,12,13 adalimumab,12,13 and etanercept12,13 Infliximab,13,14 adalimumab,13,14,16 etanercept,13,14,16 and ustekinumab13-15 Infliximab,3,17,19 adalimumab,3,17,18 and etanercept3,17-19 Adalimumab,18 etanercept,18,19 and infliximab19 Infliximab19 and etanercept19 Adalimumab,18,20 etanercept,18,20 and infliximab20 Adalimumab18 and etanercept18 Infliximab,17,19,21 adalimumab,17,18,21 and etanercept17-19,21 Infliximab,21,22 adalimumab,18,21,22 and etanercept18,21,22 Adalimumab18 and etanercept18 Infliximab,23 adalimumab,18 and etanercept18 Infliximab,21,24 adalimumab,18,21 and etanercept18,21,24 Adalimumab18 and etanercept18 Ustekinumab25,26

B B C C I I D C D D D C I I

ALP, Alkaline phosphatase; ALT, alanine transaminase; ANA, antinuclear antibody; anti-dsDNA, anti-double-stranded DNA; AST, aspartate transaminase; CBC, complete blood count; CMP, comprehensive metabolic panel; Cr, creatinine; CrCl, creatinine clearance; CRP, C-reactive protein; DB, direct bilirubin; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; IGRA, interferon-gamma release assay; LFT, liver function test (includes AST and ALT); TB, total bilirubin; TBSE, total body skin examination; TST, tuberculin skin test; UA, urinalysis.

Table III. Monitoring tests for biologics in psoriasis and psoriatic arthritis Preexisting comorbidity

Hepatitis B

Hepatitis C

CHF

Monitoring test

LFTs Viral load

Biologic agent(s) studied 3,17,27,28

3,17,27-31

Evidence grade 3,17,27-31

Infliximab, adalimumab and etanercept Infliximab,3,19,27,29,33 adalimumab,3,27-33 etanercept,3,19,27-33 and ustekinumab33 LFTs Infliximab,33,34 adalimumab,33,34 and etanercept33,34 Viral load Infliximab,19,33 adalimumab,33 etanercept,19,33 and ustekinumab19 Liver biopsy Etanercept35 Baseline assessment Infliximab,36 adalimumab,36 etanercept,36 and ustekinumab36

C C I I I I

CHF, Congestive heart failure; LFT, liver function test.

of screening every 6 months during biologic therapy is not recommended. Screening and monitoring tests in special populations In the evaluation of safety and monitoring tests in patients with comorbidities, 13 studies were identified, and populations studied included patients with HBV, HCV, and CHF (Table III). Worldwide, an estimated 400 million people have HBV infection, and 1.6 billion people have had HBV exposure. Based on serologic categories, the risk of disease reactivation is variable. Active and inactive carriers are carriers of HBsAg, but distinguished by viral loads [2000 IU/mL in active carriers. An occult

carrier is HBsAg and HBcAb1. Patients with previous HBV infections are HBsAg and HBcAb1/ HBsAb1.32 Reactivation can be seen in chronic active and inactive carriers, with 1 study reporting a 4-year cumulative probability ranging from 6% to 15%.37 In contrast, HBV reactivation can occur in up to 48% of patients with chronic HBV after the cessation of chemotherapy or immunosuppression.3 Treatment with TNF-a inhibitors leads to increased HBV replication and reactivation in animal studies, likely because of TNF’s role in clearing HBV and suppressing viral replication.34 In clinical practice, there are few large-scale studies evaluating the risk of reactivation in active, inactive, and occult HBV carriers, and small case series have conflicting results. In a

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retrospective study of 257 patients treated with infliximab for inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, and psoriasis, 39% of HBsAg carriers developed HBV reactivation, compared to 5% of patients positive for HBcAb.17,38 In a small case series, 3 of 7 patients with inactive HBV treated with adalimumab or etanercept without antiviral prophylaxis met the criteria for HBV reactivation during treatment. Although none developed HBV reactivationerelated hepatitis, 1 patient required antiviral treatment.29 In another case series, 7 inactive HBsAg carriers received lamivudine prophylaxis before and during TNF-a inhibitor treatment, and none developed HBV reactivation during treatment or up to 24 months follow-up.27 In a study of 5 patients with inactive HBV receiving antiviral therapy during ustekinumab, etanercept, or infliximab treatment, there were no signs of HBV reactivation or increase in viral load.33 In a study of inactive and occult HBV carriers, 1 inactive HBV carrier received antiviral treatment with biologic treatment, while occult HBV carriers received biologic therapy without antiviral treatment, and no patients experienced reactivation.31 Among occult HBV carriers, 17 patients received etanercept without antiviral treatment, and no signs of reactivation or changes in AST, ALT, or viral load were seen through an average treatment of 7.8 months.30 Based on limited evidence from small study populations, the evidence for monitoring liver function and HBV viral loads in patients with HBV is grade C. Current guidelines suggest performing a hepatitis panel before treatment with biologics and treating according to serologic status. In na€ıve patients at risk for HBV, vaccination should be considered. In inactive carriers, antiviral prophylaxis is recommended before therapy and up to 6 to 12 months after treatment discontinuation because of the risk of reactivation after treatment. In occult carriers, antiviral prophylaxis is not necessary, although monitoring of liver function tests (LFTs) and HBsAg serology is needed for conversion monitoring. In patients with HCV, the impact of TNF-a inhibitors is not well understood. Although there are anecdotal reports of an association between HCV progression and certain immunosuppressed states like concomitant HIV infection, postebone marrow transplantation, or posteliver transplantation, other circumstances, such as chemotherapy, do not impact HCV disease course.34 In a review of 216 patients with HCV treated with antieTNF-a agents, there were only 3 cases of drug withdrawal because of suspicion of worsening HCV. The viral load in most cases remained stable or decreased.34 In a series of 5 patients with psoriasis and chronic HCV treated with

etanercept or adalimumab, no change was observed in LFTs. HCV RNA levels were undetectable in all patients throughout a mean treatment of 11 months.30 However, these anecdotal reports and small-scale studies are insufficient to support or refute the utility of monitoring LFTs and HCV viral load during biologic therapy. In 2 patients with HCV and PsA, the safety of etanercept was evaluated based on liver biopsy specimens obtained at baseline and 12 months of treatment. No evidence of worsening liver injury was associated with etanercept. However, only 2 patients were included, and this evidence is insufficient to support recommendations for or against obtaining liver biopsy specimens— although it is likely that the harm outweighs the benefit of this invasive procedure. There are reports of exacerbation of CHF linked to anti-TNF agents in rheumatoid arthritis treatment, and high doses of infliximab were associated with worsening cardiac events.39 The incidence is reported to be low, with only 7 cases identified across [4000 patients with psoriasis and/or PsA. The current evidence is insufficient to comment on the benefits and harms of CHF screening.40,41

DISCUSSION The evaluation of biologics-associated complications is challenging because of the inherent difficulty of assessing low-frequency events occurring over long periods of time. In addition, it is difficult to make well-founded recommendations regarding the utility of screening and monitoring in preventing uncommon events when data to support or refute these tests is sparse. Based on a 5-year prospective cohort of 162 patients who were taking antieTNF-a agents, routine testing is largely unsupported, because the laboratory abnormalities detected were not clinically meaningful.18 Despite the lack of evidence to support routine monitoring, current guidelines by professional organizations recommend routine testing; for example, the JDA recommends monitoring studies every 6 months, including a chest X-ray, CRP, white blood cell count, LFTs, ANA, and urinalysis.4 Although testing may seem innocuous, there are risks associated with detecting false-positives, leading to additional testing, morbidity, and additional health care cost and resources. In the context of widely variable recommendations, a systemic approach to this literature to develop evidence-based guidelines for screening and monitoring in different biologic agents is imperative. This study is limited by the lack of standardized controlled trials evaluating the use of screening and monitoring tests in patients undergoing biologic

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therapy. However, compared to previous evaluation of this literature, there is increasing evidence to support HBV screening in psoriasis and PsA patients and further refinement of management options based on specific HBV serology.11 The results of this study indicate areas of routine testing that remain unfounded in high-grade clinical evidence, provide evidence-based screening and monitoring guidelines in both healthy individuals and those with underlying comorbidities, and ultimately conclude that—given the limitations of the evidence—physicians must use their judgment when screening and monitoring patients who are undergoing therapy with biologic agents. REFERENCES 1. Shaw MK, Davis SA, Feldman SR, et al. Trends in systemic psoriasis treatment therapies from 1993 through 2010. J Drugs Dermatol. 2014;13:917-920. 2. FDA. What’s new for biologics. http://www.fda.gov/Biologics BloodVaccines/NewsEvents/WhatsNewforBiologics/default. htm. Accessed September 12, 2014. 3. Motaparthi K, Stanisic V, Van Voorhees AS, et al. From the Medical Board of the National Psoriasis Foundation: Recommendations for screening for hepatitis B infection prior to initiating anti-tumor necrosis factor-alfa inhibitors or other immunosuppressive agents in patients with psoriasis. J Am Acad Dermatol. 2014;70(1):178-186. 4. Ohtsuki M, Terui T, Ozawa A, et al. Japanese guidance for use of biologics for psoriasis (the 2013 version). J Dermatol. 2013; 40(9):683-695. 5. Pathirana D, Ormerod AD, Saiag P, et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol. 2009;23(Suppl 2):1-70. 6. Smith CH, Anstey AV, Barker JN, et al. British Association of Dermatologists guidelines for use of biological interventions in psoriasis. Br J Dermatol. 2005;153(3):486-497. 7. Smith CH, Anstey AV, Barker JN, et al. British Association of Dermatologists’ guidelines for biologic interventions for psoriasis. Br J Dermatol. 2009;161(5):987-1019. 8. Nast A, Spuls PH, Ormerod AD, et al. A critical appraisal of evidence-based guidelines for the treatment of psoriasis vulgaris: ‘AGREE-ing’ on a common base for European evidence-based psoriasis treatment guidelines. J Eur Acad Dermatol Venereol. 2009;23(7):782-787. 9. Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008;58(5):851-864. 10. Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58(5): 826-850. 11. Huang W, Cordoro KM, Taylor SL, et al. To test or not to test? An evidence-based assessment of the value of screening and monitoring tests when using systemic biologic agents to treat psoriasis. J Am Acad Dermatol. 2008;58(6):970-977. 12. Sanchez-Moya AI, Dauden E. Incidence of tuberculosis infection in psoriatic patients on anti-TNF therapy: report of a case

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Appendix A. Grade definitions by the US Preventive Services Task Force Grade

A B

C

D

I

Definition

The USPSTF recommends the service. There is high certainty that the net benefit is substantial. The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small. The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.

Suggestions for practice

Offer or provide this service Offer or provide this service

Offer or provide this service for selected patients depending on individual circumstances

Discourage the use of this service

Read the clinical considerations section of USPSTF Recommendation Statement. If the service is offered, patients should understand the uncertainty about the balance of benefits and harms

Appendix B. Level of certainty regarding the net benefit US Preventive Services Task Force Level of certainty

High

Moderate

Description

The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies. The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by such factors as: B The number, size, or quality of individual studies B Inconsistency of findings across individual studies B Limited generalizability of findings to routine primary care practice B Lack of coherence in the chain of evidence

As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion. Low

The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of: B The limited number or size of studies B Important flaws in study design or methods B Inconsistency of findings across individual studies B Gaps in the chain of evidence B Findings not generalizable to routine primary care practice B Lack of information on important health outcomes

More information may allow estimation of effects on health outcomes.