- Email: [email protected]
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
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 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 the disease but raises questions about what laboratory screening tests are required. As of yet, no consensus or guidelines exist for dermatologists to follow and there may be misconceptions about the relative need for screening and monitoring tests in patients treated with biologic agents. Current practice ranges from no testing to blanket screening panels. The purposes of this review are to (1) systematically review the literature 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 psoriatic arthritis; and (2) suggest practical guidelines for dermatologists on which to base such testing. We searched the Cochrane Collaborative Database (including the Cochrane Database of Systematic Reviews [Cochrane Reviews] and the Cochrane Central Register of Controlled Trials [Clinical Trials]) and the MEDLINE database using medical subject headings as search terms when available or key words when appropriate. We compiled published data on risk and risk assessment related to systemic psoriasis treatments, used expert opinion where appropriate when published clinical data were not adequately informative, and assigned evidence grades for various screening tests based on standard methods of the US Preventive Services Task Force. Finally, we developed a table of evidence grades for tests used to monitor different systemic medications. There is not strong evidence to recommend most screening tests for monitoring biological treatments. Neither is there strong evidence not to do such testing. Ultimately, from a practical standpoint, it is incumbent on the clinician to consider each patient independently and determine what screening tests are most appropriate for each individual patient. ( J Am Acad Dermatol 2008;58:970-7.)
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ystemic biologic agents (alefacept, efalizumab, etanercept, infliximab, adalimumab) provide valuable options for patients with moderate to severe psoriasis. The availability of these new treatments raises the question of what laboratory 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 educational 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: [email protected]. 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
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Abbreviations used: FDA: PPD: TB:
Food and Drug Administration purified protein derivative tuberculosis
screening tests are required for initiating treatment and monitoring patients on treatment. Although the Food and Drug Administration (FDA) of the United States sets forth recommendations for laboratory monitoring when starting and continuing systemic treatments, those recommendations are closely based on clinical trials done for registration. In light of postmarketing reports of adverse events, the current FDA-recommended screening and monitoring parameters are insufficient. Currently, clinical practice varies widely from no testing to blanket screening panels. As of yet, there is no consensus or guideline for dermatologists to follow and recommendations for screening tests vary greatly among different organizations. The purposes of this review are to: (1) systematically review the literature for the level of
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Table I. Literature search methods Database
Cochrane Collaborative* MEDLINEy
Search terms
Psoriasis, psoriatic arthritis, screening test, systemic treatment, alefacept, Amevive, etanercept, Enbrel, efalizumab, Raptiva, adalimumab, Humira, infliximab, and Remicade Psoriasis (psoriasis OR psoriatic arthritis), safety and screening tests (screening test OR screening tests OR screen OR screens OR test OR tests OR screening OR safety OR tolerability OR risk OR risk assessment), and biologic treatments (alefacept OR Amevive OR etanercept OR Enbrel OR efalizumab OR Raptiva OR adalimumab OR Humira OR infliximab OR Remicade)
*Cochrane Collaborative database (including the Cochrane Database of Systematic Reviews [Cochrane Reviews] and the Cochrane Central Register of Controlled Trials [Clinical Trials]). y MEDLINE 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.
evidence regarding the use of screening tests when initiating newer systemic biologic agents (alefacept, efalizumab, etanercept, infliximab, adalimumab) for moderate to severe psoriasis and psoriatic arthritis; and (2) suggest practical guidelines for dermatologists on which to base screening tests performed for these systemic biologic treatments.
METHODS Literature search methods We searched the Cochrane Collaborative and MEDLINE databases to identify any potential reviews or abstracts of randomized controlled trials performed in the area of systemic biologic treatments for psoriasis and screening tests (Table I). In addition, we searched reference lists of reviewed articles and referrals from specialists in the field to find any other articles not found in the MEDLINE or Cochrane Collaborative databases. Evidence grading We reviewed full articles and graded evidence based on standardized methods developed by the US Preventive Services Task Force1 (Table II). Excluded articles included use of systemic biologic therapy in children or for indications other than psoriasis or psoriatic arthritis, investigation of the use of multiple systemic biologic therapies simultaneously, and use of systemic biologic therapies in erythrodermic and pustular psoriasis. Single case reports and data from animal testing were also excluded. Finally, we sought expert opinion from other specialties, where appropriate, when published clinical data proved equivocal or not adequately informative.
RESULTS Despite various recommendations from the FDA and other published consensus statements, no screening test received greater than a B recommendation (n = 3) with most screening tests receiving C
Table II. Recommendation grid1 Quality of evidence
Good Fair Poor = I
Net benefit Substantial
Moderate
Small
Zero/negative
A B
B B
C C
D D
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).
(n = 8), D (n = 10), or I (n = 11) recommendations (Tables III and IV). The evidence is good that monitoring of CD41 T lymphocytes every 2 weeks can potentially assist in monitoring the safety of alefacept, as the circulating CD41 T lymphocytes in the blood decrease in a dose-dependent manner.2,3 However, results from clinical trials show that the incidence of infection appears to be unrelated to the CD41 T-lymphocyte counts.4-7 In addition, investigators did not report any cases of opportunistic infection. Clinical trials substituted placebo for active drug in any patient who exhibited CD41 counts less than 250 cells/L, so the evidence is insufficient to determine the actual effect of keeping patients on alefacept with CD41 counts lower than this level. The potential risks of CD41 T-cell monitoring are small and include excess burden on the patient (eg, travel costs, time, multiple blood draws) and having to stop a treatment regimen without adequate evidence that continuing will result in adverse effects. The potential benefit and harm in unstudied populations cannot be determined from existing data and, at this time, the magnitude of benefit remains unclear. A reasonable
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Table III. Summary of evidence Treatment
Alefacept
Efalizumab
Etanercept
Infliximab
Adalimumab
Screening test
CD41 lymphocyte count2,3,4-7,10-15 LFTs4-7,10,11,14,15 HIV ELISA4-7,10,11,14,15 Hepatitis B and C4-7,10,11,16 Other (CBC, BMP, UA, CXR, PPD)4-7,10,11,14,15 Blood platelets8,17-25 WBCs8,17-25 Hemoglobin and hematocrit8,17-25 LFTs8,17-25 CRP8,17-25 Other (BMP, UA, CXR, PPD, HIV ELISA, hepatitis B and C)8,17-24 PPD26-35 CBC26-29,36-38 LFTs26-29,34,35,38 ANA and anti-dsDNA2,26-29,37,38 Hepatitis B and C26-29,38-42 HIV ELISA26-29,43 Other (BMP, UA, CXR)26-43 PPD9,44-62 LFTs9,44-61 ANA and anti-dsDNA9,44-61 Hepatitis B and C44-61,63-74 HIV ELISA44-51,75,76 CBC9,44-61 Other (BMP, UA, CXR)44-61 PPD77-81 Hepatitis B and C77-81 HIV ELISA77-81 LFTs77-81 CBC77-81 ANA and anti-dsDNA77-81 Other (BMP, UA, CXR)77-81
Current recommendations
Evidence grade
X82,83 X84 1/e84 X84 X83,84
C D I I D
X82-84 X83,84 X83,84 X84 None X83,84; 1/e84(HIV)
B D I D C D
X82-84 X83,84 X84 X84 X84 1/e84 X83,84 X83,84 X84 X84 X84 1/e84 X83,84 X83,84 X82-84 X84 1/e84 X84 X83,84 X84 X83,84
C C D C I I D B C C I I I D B I I I C C 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).
practical approach is to check T-lymphocyte counts at a less frequent interval, perhaps monthly. There is good evidence that routine laboratory monitoring of platelets can lead to early detection of asymptomatic thrombocytopenia with efalizumab. Of the 8 cases of immune-mediated thrombocytopenia reported, 3 patients were hospitalized including one for heavy uterine bleeding.8 Evidence to determine whether early and periodic screening leads to improved patient outcomes remains unclear as no data exist on patients who developed thrombocytopenia and continued to receive treatment. Although it is reasonable to assume that patients with
efalizumab-related thrombocytopenia who continue on the medication may eventually develop unnecessary hemorrhage and bleeding, the evidence from the clinical trials does not allow for ascertainment of this risk. The evidence is good that patients who do develop efalizumab-related thrombocytopenia have a return to normal platelet counts after discontinuation of the medication and administration of systemic corticosteroids or Rhesus factor immune globulin and platelet transfusion. Among the biologic therapies for psoriasis and psoriatic arthritis, etanercept has a favorable safety profile with long-term safety data available from its
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Table IV. Biologic agents for psoriasis Biologic agent
Description
Mechanism of action
Alefacept14 (Amevive)
Dimeric fusion protein composed of LFA-3 and IgG1
Efalizumab8 (Raptiva)
Humanized monoclonal IgG1 antibody
Etanercept37 (Enbrel)
Fusion protein of the p75 TNF receptor with the Fc domain of immunoglobulin Chimeric monoclonal antibody comprised of a human IgG1 constant region attached to a murine antigenbinding region Blocks interaction with Recombinant, fully p55 and p75 cell human IgG1 surface receptors monoclonal antibody that binds specifically to TNF-a
Infliximab9 (Remicade)
Adalimumab78 (Humira)
Inhibits interaction between the CD-2 receptor of T lymphocytes and its ligand, LFA-3 Targeted against CD11a, a crucial subunit of LFA-1 Blocks binding of TNF to cell surface receptors Binds to and neutralizes human TNF-a.
FDA approval
FDA indications
FDA screening recommendations
January 2003
Plaque psoriasis
CD41 T lymphocytes every 2 wk
October 2003
Plaque psoriasis
January 2002 April 2004
Psoriatic arthritis Plaque psoriasis
Platelet count monthly initially then every 3 mo Pretreatment PPD screening
May 2005
Psoriatic arthritis Plaque psoriasis
September 2006
October 2003 Psoriatic arthritis
Pretreatment PPD screening
Pretreatment PPD screening
FDA, Food and Drug Administration; LFA, leukocyte function-associated antigen; PPD, purified protein derivative; TNF, tumor necrosis factor.
use in other patient populations and postmarketing surveillance. The evidence from clinical trials is good to recommend against the routine screening of all patients who are about to begin etanercept with a purified protein derivative (PPD) skin test for latent or active tuberculosis (TB). No cases of TB appear in any of the reviewed studies of etanercept in patients with psoriatic arthritis and psoriasis, but there have been postmarketing reports of disseminated TB infection. Although reported cases of TB are higher with other tumor necrosis factor-a blockers and rare reports of TB in patients on etanercept exist, the net benefit of screening every patient with a PPD skin test is small. The evidence is good that patients taking infliximab, either as monotherapy or in conjunction with other agents, are at an increased risk for elevations in liver function tests including alanine aminotransferase and aspartate aminotransferase. Patients on infliximab experienced elevated liver transaminases at a greater frequency than those on placebo in rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriatic arthritis, and psoriasis clinical trials. Generally this elevation was transient and asymptomatic. However, rare cases of severe liver injury including acute liver failure and autoimmune hepatitis exist for patients taking
infliximab during postmarketing surveillance.9 The net benefit of screening is unclear as the vast majority of patients who experience elevated liver enzymes are asymptomatic and have a return to normal levels, whereas those at increased risk of developing hepatic injury cannot be determined. A reasonable approach is to consider interval screening in patients at risk for liver injury. Therapy should be discontinued until further evaluation rules out liver injury in those who develop elevated liver enzymes or show signs and symptoms of liver dysfunction. Caution, screening, and close follow-up are advised in patients about to begin therapy with any of the antitumor necrosis factor agents (adalimumab, infliximab, etanercept) who have a history or risk of developing congestive heart failure, demyelinating disorders, seizure disorders, and malignancies. Good evidence from clinical trials and postmarketing surveillance do not support routine pretreatment screening with urinalysis, chest radiograph, and metabolic panels before initiation of any of the biologic agents. On the whole, the most reasonable approach to screening in addition to the aforementioned tests is best based on careful clinical history and physical examination, which will allow tailored and targeted screening.
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DISCUSSION Biologic medications provide patients much needed options for the treatment of psoriasis and psoriatic arthritis. How patients on these drugs should be monitored is not yet well characterized. Clinical practice varies widely from no testing to blanket screening panels, and expert recommendations vary significantly between organizations. Using a systematic approach to search and review the literature, and taking into account both the quality of the evidence and the magnitude of effect of screening interventions, we find it difficult to make specific recommendations. On the one hand, there is not strong evidence to recommend most screening tests for monitoring biological treatments. On the other hand, there is not strong evidence not to do such screening laboratory tests. From a practical standpoint, it is left to the clinician to decide what screening tests are most appropriate for each of their patients. Although the net benefit of screening in most cases cannot be determined from the available data, from a purely clinical and practical standpoint, without baseline screening laboratory test results, later abnormal laboratory test results detected during monitoring have little meaning and their significance or causality cannot be reliably interpreted. Caution is needed when initiating these medications with regard to the need for a thorough risk assessment such that the appropriate targeted baseline and monitoring tests can be used. Treatment must be individualized for each patient, as blanket recommendations for all patients are neither clinically sound nor cost-effective. Screening for TB is important for all patients in endemic areas, in immigrants from endemic areas, and anyone with risk factors such as foreign travel, exposure, and equivocal PPD in the past. Although the evidence for doing so is not strong, based on mechanism of action and postmarketing reports, and in light of the Centers for Disease Control and Prevention and American Thoracic Society recommendations, we believe pretreatment PPD screening should be done for all patients before starting an antitumor necrosis factor agent. Ideally, controlled trials of screening tests would provide evidence needed to develop guidelines. Such studies had not been done at the time of our review. To obtain evidence on screening tests, we used data from randomized controlled trials that assessed efficacy and safety of medications. We also included data from other types of research trials with the exception of single case reports and animal studies. In addition, many of the reported adverse outcomes have occurred during postmarketing
surveillance. Unfortunately, the relationship between adverse events and the medication used is difficult (if not impossible) to assess from spontaneous case reports. A major limitation to this study and to the overall evidence for or against screening interventions for patients about to begin systemic biologic therapy for their psoriasis or psoriatic arthritis is the data available on this issue. Although the FDA recommends certain screening tests before beginning biologic therapy, much of the evidence comes from single or multiple clinical trials looking at the overall safety and efficacy of the medication, rather than the appropriateness of screening. Therefore, difficulties arise in forming strong, evidence-based guidelines for the use of screening tests. Even without clear evidence on what screening tests to perform when starting a patient on biologic therapy, providers must make a decision on which screening tests are appropriate for their patient. When deciding on treatment strategies, it is essential to discuss with the patient the potential risks, benefits, side effects, and chance for resolution from the therapy. Combined with an appropriate history and physical examination, this discussion will assist in using good clinical judgment to determine risk and any special considerations needed before starting treatment. For instance, taking into account the prevalence of a particular disease in a community or for a specific population would affect a provider’s pretest probability and threshold for screening. Similarly, looking at a patient’s risk factors for disease may cause clinicians to be more inclined to screen. The purpose of screening is to assess risk such that our primary question becomes ‘‘Does screening allow us to treat earlier and, if so, does this earlier treatment reduce the number of adverse health events?’’ In considering screening tests for patients beginning systemic biologic therapy for psoriasis or psoriatic arthritis, we must acknowledge the fact that screening is not an entirely benign process. The possibility of false-positives and false-negative findings and the potential resultant psychologic, medical, and financial damage of inaccurate labeling and further evaluation and treatment is not a trivial issue. By seeking to address issues of net benefit (harm vs benefit) and cost-effectiveness (cost of screening vs not screening), future studies will direct us toward evidence-based guidelines. Although the data are currently lacking in this regard, the results of this study should encourage future researchers to examine the appropriateness of various screening interventions and to ask the question for different populations, as patients vary greatly in level of risk.
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54. Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomized trial. Lancet 2001;357: 1842-7. 55. Gottlieb AB, Evans R, Li S, Dooley LT, Guzzo CA, Baker D, et al. Infliximab induction therapy for patients with severe plaquetype psoriasis: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol 2004;51:534-42. 56. Kalb RE, Gurske J. Infliximab for the treatment of psoriasis: clinical experience at the State University of New York at Buffalo. J Am Acad Dermatol 2005;53:616-22. 57. Krathen RA, Berthelot CN, Hsu S. Sustained efficacy and safety of infliximab in psoriasis: a retrospective study of 73 patients. J Drugs Dermatol 2006;5:251-4. 58. Reich K, Nestle FO, Papp K, Ortonne JP, Evans R, Guzzo C, et al. Infliximab induction and maintenance therapy for moderateto-severe psoriasis: a phase III, multicenter, double-blind trial. Lancet 2005;366:1367-74. 59. Reich K, Nestle FO, Papp K, Ortonne JP, Wu Y, Bala M, et al. Improvement in quality of life with infliximab induction and maintenance therapy in patients with moderate-to-severe psoriasis: a randomized controlled trial. Br J Dermatol 2006; 154:1161-8. 60. Schopf RE, Aust H, Knop J. Treatment of psoriasis with the chimeric monoclonal antibody against tumor necrosis factor alpha, infliximab. J Am Acad Dermatol 2002;46:886-91. 61. Smith CH, Jackson K, Bashir SJ, Perez A, Chew AL, Powell AM, et al. Infliximab for severe, treatment-resistant psoriasis: a prospective, open-label study. Br J Dermatol 2006;155:160-9. 62. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098-104. 63. Campbell S, Ghosh S. Infliximab therapy for Crohn’s disease in the presence of chronic hepatitis C infection. Eur J Gastroenterol Hepatol 2001;13:191-2. 64. del Valle Garcı´a-Sa´nchez M, Gomez-Camacho F, PoyatoGonzalez A, Iglesias-Flores EM, de Dios-Vega JF, SanchoZapatero R. Infliximab therapy in a patient with Crohn’s disease and chronic hepatitis B virus infection. Inflamm Bowel Dis 2004;10:701-2. 65. Esteve M, Saro C, Gonzalez-Huix F, Suarez F, Forne M, Viver JM. Chronic hepatitis B reactivation following infliximab therapy in Crohn’s disease patients: need for primary prophylaxis. Gut 2004;53:1363-5. 66. Magro F, Pereira P, Carneiro F, Veloso FT. Reactive hepatitis in a patient with Crohn’s disease successfully treated with infliximab: does tumor necrosis factor alpha play a role in reactive hepatitis? Inflamm Bowel Dis 2005;11:88-90. 67. Michel M, Duvoux C, Hezode C, Cherqui D. Fulminant hepatitis after infliximab in a patient with hepatitis B virus treated for an adult onset still’s disease. J Rheumatol 2003;30:1624-5. 68. Millonig G, Kern M, Ludwiczek O, Nachbaur K, Vogel W. Subfulminant hepatitis B after infliximab in Crohn’s disease: need for HBV-screening? World J Gastroenterol 2006;12: 974-6. 69. Oniankitan O, Duvoux C, Challine D, Mallat A, Chevalier X, Pawlotsky JM, et al. Infliximab therapy for rheumatic diseases in patients with chronic hepatitis B or C. J Rheumatol 2004;31:107-9. 70. Ostuni P, Botsios C, Punzi L, Sfriso P, Todesco S. Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis 2003;62:686-7. 71. Peterson JR, Hsu FC, Simkin PA, Wener MH. Effect of tumor necrosis factor alpha antagonists on serum transaminases and
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viremia in patients with rheumatoid arthritis and chronic hepatitis C infection. Ann Rheum Dis 2003;62:1078-82. Roux CH, Brocq O, Breuil V, Albert C, Euller-Ziegler L. Safety of anti-TNF-alpha therapy in rheumatoid arthritis and spondylarthropathies with concurrent B or C chronic hepatitis. Rheumatology (Oxford) 2006;45:1294-7. Ueno Y, Tanaka S, Shimamoto M, Miyanaka Y, Hiyama T, Ito M, et al. Infliximab therapy for Crohn’s disease in a patient with chronic hepatitis B. Dig Dis Sci 2005;50:163-6. Wendling D, Auge B, Bettinger D, Lohse A, Le HG, BressonHadni S, et al. Reactivation of a latent precore mutant hepatitis B virus related chronic hepatitis during infliximab treatment for severe spondyloarthropathy. Ann Rheum Dis 2005;64:788-9. Bartke U, Venten I, Kreuter A, Gubbay S, Altmeyer P, Brockmeyer NH. Human immunodeficiency virus-associated psoriasis and psoriatic arthritis treated with infliximab. Br J Dermatol 2004;150:784-6. Gaylis N. Infliximab in the treatment of an HIV positive patient with Reiter’s syndrome. J Rheumatol 2003;30:407-11. Mease PJ, Gladman DD, Ritchlin CT, Ruderman EM, Steinfeld SD, Choy EH, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52:3279-89. Adalimumab (Humira) [package insert]. North Chicago (IL): Abbott Laboratories; 2004. Gordon KB, Langley RG, Leonardi C, Toth D, Menter MA, Kang S, et al. Clinical response to adalimumab treatment in patients
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with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol 2006;55:598-606. Furst DE, Schiff MH, Fleischmann RM, Strand V, Birbara CA, Compagnone D, et al. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (safety trial of adalimumab in rheumatoid arthritis). J Rheumatol 2003;30: 2563-71. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003;48: 35-45. Sterry W, Barker J, Boehncke WH, Bos JD, Chimenti S, Christophers E, et al. Biological therapies in the systemic management of psoriasis: international consensus conference. Br J Dermatol 2004;151(Suppl):3-17. Routhouska SB, Korman NJ. Initiating and monitoring patients on biologic therapy for psoriasis beyond the FDA: our more cautious approach. Psoriasis Forum. J Nat Psoriasis Found 2006;12:12-5. Smith CH, Anstey AV, Barker JN, Burden AD, Chalmers RJ, Chandler D, et al. British Association of Dermatologists guidelines for use of biological interventions in psoriasis 2005. Br J Dermatol 2005;153:486-97.
S
ystemic biologic agents (alefacept, efalizumab, etanercept, infliximab, adalimumab) provide valuable options for patients with moderate to severe psoriasis. The availability of these new treatments raises the question of what laboratory 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 educational 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: [email protected]. 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
Abbreviations used: FDA: PPD: TB:
Food and Drug Administration purified protein derivative tuberculosis
screening tests are required for initiating treatment and monitoring patients on treatment. Although the Food and Drug Administration (FDA) of the United States sets forth recommendations for laboratory monitoring when starting and continuing systemic treatments, those recommendations are closely based on clinical trials done for registration. In light of postmarketing reports of adverse events, the current FDA-recommended screening and monitoring parameters are insufficient. Currently, clinical practice varies widely from no testing to blanket screening panels. As of yet, there is no consensus or guideline for dermatologists to follow and recommendations for screening tests vary greatly among different organizations. The purposes of this review are to: (1) systematically review the literature for the level of
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Table I. Literature search methods Database
Cochrane Collaborative* MEDLINEy
Search terms
Psoriasis, psoriatic arthritis, screening test, systemic treatment, alefacept, Amevive, etanercept, Enbrel, efalizumab, Raptiva, adalimumab, Humira, infliximab, and Remicade Psoriasis (psoriasis OR psoriatic arthritis), safety and screening tests (screening test OR screening tests OR screen OR screens OR test OR tests OR screening OR safety OR tolerability OR risk OR risk assessment), and biologic treatments (alefacept OR Amevive OR etanercept OR Enbrel OR efalizumab OR Raptiva OR adalimumab OR Humira OR infliximab OR Remicade)
*Cochrane Collaborative database (including the Cochrane Database of Systematic Reviews [Cochrane Reviews] and the Cochrane Central Register of Controlled Trials [Clinical Trials]). y MEDLINE 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.
evidence regarding the use of screening tests when initiating newer systemic biologic agents (alefacept, efalizumab, etanercept, infliximab, adalimumab) for moderate to severe psoriasis and psoriatic arthritis; and (2) suggest practical guidelines for dermatologists on which to base screening tests performed for these systemic biologic treatments.
METHODS Literature search methods We searched the Cochrane Collaborative and MEDLINE databases to identify any potential reviews or abstracts of randomized controlled trials performed in the area of systemic biologic treatments for psoriasis and screening tests (Table I). In addition, we searched reference lists of reviewed articles and referrals from specialists in the field to find any other articles not found in the MEDLINE or Cochrane Collaborative databases. Evidence grading We reviewed full articles and graded evidence based on standardized methods developed by the US Preventive Services Task Force1 (Table II). Excluded articles included use of systemic biologic therapy in children or for indications other than psoriasis or psoriatic arthritis, investigation of the use of multiple systemic biologic therapies simultaneously, and use of systemic biologic therapies in erythrodermic and pustular psoriasis. Single case reports and data from animal testing were also excluded. Finally, we sought expert opinion from other specialties, where appropriate, when published clinical data proved equivocal or not adequately informative.
RESULTS Despite various recommendations from the FDA and other published consensus statements, no screening test received greater than a B recommendation (n = 3) with most screening tests receiving C
Table II. Recommendation grid1 Quality of evidence
Good Fair Poor = I
Net benefit Substantial
Moderate
Small
Zero/negative
A B
B B
C C
D D
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).
(n = 8), D (n = 10), or I (n = 11) recommendations (Tables III and IV). The evidence is good that monitoring of CD41 T lymphocytes every 2 weeks can potentially assist in monitoring the safety of alefacept, as the circulating CD41 T lymphocytes in the blood decrease in a dose-dependent manner.2,3 However, results from clinical trials show that the incidence of infection appears to be unrelated to the CD41 T-lymphocyte counts.4-7 In addition, investigators did not report any cases of opportunistic infection. Clinical trials substituted placebo for active drug in any patient who exhibited CD41 counts less than 250 cells/L, so the evidence is insufficient to determine the actual effect of keeping patients on alefacept with CD41 counts lower than this level. The potential risks of CD41 T-cell monitoring are small and include excess burden on the patient (eg, travel costs, time, multiple blood draws) and having to stop a treatment regimen without adequate evidence that continuing will result in adverse effects. The potential benefit and harm in unstudied populations cannot be determined from existing data and, at this time, the magnitude of benefit remains unclear. A reasonable
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Table III. Summary of evidence Treatment
Alefacept
Efalizumab
Etanercept
Infliximab
Adalimumab
Screening test
CD41 lymphocyte count2,3,4-7,10-15 LFTs4-7,10,11,14,15 HIV ELISA4-7,10,11,14,15 Hepatitis B and C4-7,10,11,16 Other (CBC, BMP, UA, CXR, PPD)4-7,10,11,14,15 Blood platelets8,17-25 WBCs8,17-25 Hemoglobin and hematocrit8,17-25 LFTs8,17-25 CRP8,17-25 Other (BMP, UA, CXR, PPD, HIV ELISA, hepatitis B and C)8,17-24 PPD26-35 CBC26-29,36-38 LFTs26-29,34,35,38 ANA and anti-dsDNA2,26-29,37,38 Hepatitis B and C26-29,38-42 HIV ELISA26-29,43 Other (BMP, UA, CXR)26-43 PPD9,44-62 LFTs9,44-61 ANA and anti-dsDNA9,44-61 Hepatitis B and C44-61,63-74 HIV ELISA44-51,75,76 CBC9,44-61 Other (BMP, UA, CXR)44-61 PPD77-81 Hepatitis B and C77-81 HIV ELISA77-81 LFTs77-81 CBC77-81 ANA and anti-dsDNA77-81 Other (BMP, UA, CXR)77-81
Current recommendations
Evidence grade
X82,83 X84 1/e84 X84 X83,84
C D I I D
X82-84 X83,84 X83,84 X84 None X83,84; 1/e84(HIV)
B D I D C D
X82-84 X83,84 X84 X84 X84 1/e84 X83,84 X83,84 X84 X84 X84 1/e84 X83,84 X83,84 X82-84 X84 1/e84 X84 X83,84 X84 X83,84
C C D C I I D B C C I I I D B I I I C C 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).
practical approach is to check T-lymphocyte counts at a less frequent interval, perhaps monthly. There is good evidence that routine laboratory monitoring of platelets can lead to early detection of asymptomatic thrombocytopenia with efalizumab. Of the 8 cases of immune-mediated thrombocytopenia reported, 3 patients were hospitalized including one for heavy uterine bleeding.8 Evidence to determine whether early and periodic screening leads to improved patient outcomes remains unclear as no data exist on patients who developed thrombocytopenia and continued to receive treatment. Although it is reasonable to assume that patients with
efalizumab-related thrombocytopenia who continue on the medication may eventually develop unnecessary hemorrhage and bleeding, the evidence from the clinical trials does not allow for ascertainment of this risk. The evidence is good that patients who do develop efalizumab-related thrombocytopenia have a return to normal platelet counts after discontinuation of the medication and administration of systemic corticosteroids or Rhesus factor immune globulin and platelet transfusion. Among the biologic therapies for psoriasis and psoriatic arthritis, etanercept has a favorable safety profile with long-term safety data available from its
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Table IV. Biologic agents for psoriasis Biologic agent
Description
Mechanism of action
Alefacept14 (Amevive)
Dimeric fusion protein composed of LFA-3 and IgG1
Efalizumab8 (Raptiva)
Humanized monoclonal IgG1 antibody
Etanercept37 (Enbrel)
Fusion protein of the p75 TNF receptor with the Fc domain of immunoglobulin Chimeric monoclonal antibody comprised of a human IgG1 constant region attached to a murine antigenbinding region Blocks interaction with Recombinant, fully p55 and p75 cell human IgG1 surface receptors monoclonal antibody that binds specifically to TNF-a
Infliximab9 (Remicade)
Adalimumab78 (Humira)
Inhibits interaction between the CD-2 receptor of T lymphocytes and its ligand, LFA-3 Targeted against CD11a, a crucial subunit of LFA-1 Blocks binding of TNF to cell surface receptors Binds to and neutralizes human TNF-a.
FDA approval
FDA indications
FDA screening recommendations
January 2003
Plaque psoriasis
CD41 T lymphocytes every 2 wk
October 2003
Plaque psoriasis
January 2002 April 2004
Psoriatic arthritis Plaque psoriasis
Platelet count monthly initially then every 3 mo Pretreatment PPD screening
May 2005
Psoriatic arthritis Plaque psoriasis
September 2006
October 2003 Psoriatic arthritis
Pretreatment PPD screening
Pretreatment PPD screening
FDA, Food and Drug Administration; LFA, leukocyte function-associated antigen; PPD, purified protein derivative; TNF, tumor necrosis factor.
use in other patient populations and postmarketing surveillance. The evidence from clinical trials is good to recommend against the routine screening of all patients who are about to begin etanercept with a purified protein derivative (PPD) skin test for latent or active tuberculosis (TB). No cases of TB appear in any of the reviewed studies of etanercept in patients with psoriatic arthritis and psoriasis, but there have been postmarketing reports of disseminated TB infection. Although reported cases of TB are higher with other tumor necrosis factor-a blockers and rare reports of TB in patients on etanercept exist, the net benefit of screening every patient with a PPD skin test is small. The evidence is good that patients taking infliximab, either as monotherapy or in conjunction with other agents, are at an increased risk for elevations in liver function tests including alanine aminotransferase and aspartate aminotransferase. Patients on infliximab experienced elevated liver transaminases at a greater frequency than those on placebo in rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriatic arthritis, and psoriasis clinical trials. Generally this elevation was transient and asymptomatic. However, rare cases of severe liver injury including acute liver failure and autoimmune hepatitis exist for patients taking
infliximab during postmarketing surveillance.9 The net benefit of screening is unclear as the vast majority of patients who experience elevated liver enzymes are asymptomatic and have a return to normal levels, whereas those at increased risk of developing hepatic injury cannot be determined. A reasonable approach is to consider interval screening in patients at risk for liver injury. Therapy should be discontinued until further evaluation rules out liver injury in those who develop elevated liver enzymes or show signs and symptoms of liver dysfunction. Caution, screening, and close follow-up are advised in patients about to begin therapy with any of the antitumor necrosis factor agents (adalimumab, infliximab, etanercept) who have a history or risk of developing congestive heart failure, demyelinating disorders, seizure disorders, and malignancies. Good evidence from clinical trials and postmarketing surveillance do not support routine pretreatment screening with urinalysis, chest radiograph, and metabolic panels before initiation of any of the biologic agents. On the whole, the most reasonable approach to screening in addition to the aforementioned tests is best based on careful clinical history and physical examination, which will allow tailored and targeted screening.
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DISCUSSION Biologic medications provide patients much needed options for the treatment of psoriasis and psoriatic arthritis. How patients on these drugs should be monitored is not yet well characterized. Clinical practice varies widely from no testing to blanket screening panels, and expert recommendations vary significantly between organizations. Using a systematic approach to search and review the literature, and taking into account both the quality of the evidence and the magnitude of effect of screening interventions, we find it difficult to make specific recommendations. On the one hand, there is not strong evidence to recommend most screening tests for monitoring biological treatments. On the other hand, there is not strong evidence not to do such screening laboratory tests. From a practical standpoint, it is left to the clinician to decide what screening tests are most appropriate for each of their patients. Although the net benefit of screening in most cases cannot be determined from the available data, from a purely clinical and practical standpoint, without baseline screening laboratory test results, later abnormal laboratory test results detected during monitoring have little meaning and their significance or causality cannot be reliably interpreted. Caution is needed when initiating these medications with regard to the need for a thorough risk assessment such that the appropriate targeted baseline and monitoring tests can be used. Treatment must be individualized for each patient, as blanket recommendations for all patients are neither clinically sound nor cost-effective. Screening for TB is important for all patients in endemic areas, in immigrants from endemic areas, and anyone with risk factors such as foreign travel, exposure, and equivocal PPD in the past. Although the evidence for doing so is not strong, based on mechanism of action and postmarketing reports, and in light of the Centers for Disease Control and Prevention and American Thoracic Society recommendations, we believe pretreatment PPD screening should be done for all patients before starting an antitumor necrosis factor agent. Ideally, controlled trials of screening tests would provide evidence needed to develop guidelines. Such studies had not been done at the time of our review. To obtain evidence on screening tests, we used data from randomized controlled trials that assessed efficacy and safety of medications. We also included data from other types of research trials with the exception of single case reports and animal studies. In addition, many of the reported adverse outcomes have occurred during postmarketing
surveillance. Unfortunately, the relationship between adverse events and the medication used is difficult (if not impossible) to assess from spontaneous case reports. A major limitation to this study and to the overall evidence for or against screening interventions for patients about to begin systemic biologic therapy for their psoriasis or psoriatic arthritis is the data available on this issue. Although the FDA recommends certain screening tests before beginning biologic therapy, much of the evidence comes from single or multiple clinical trials looking at the overall safety and efficacy of the medication, rather than the appropriateness of screening. Therefore, difficulties arise in forming strong, evidence-based guidelines for the use of screening tests. Even without clear evidence on what screening tests to perform when starting a patient on biologic therapy, providers must make a decision on which screening tests are appropriate for their patient. When deciding on treatment strategies, it is essential to discuss with the patient the potential risks, benefits, side effects, and chance for resolution from the therapy. Combined with an appropriate history and physical examination, this discussion will assist in using good clinical judgment to determine risk and any special considerations needed before starting treatment. For instance, taking into account the prevalence of a particular disease in a community or for a specific population would affect a provider’s pretest probability and threshold for screening. Similarly, looking at a patient’s risk factors for disease may cause clinicians to be more inclined to screen. The purpose of screening is to assess risk such that our primary question becomes ‘‘Does screening allow us to treat earlier and, if so, does this earlier treatment reduce the number of adverse health events?’’ In considering screening tests for patients beginning systemic biologic therapy for psoriasis or psoriatic arthritis, we must acknowledge the fact that screening is not an entirely benign process. The possibility of false-positives and false-negative findings and the potential resultant psychologic, medical, and financial damage of inaccurate labeling and further evaluation and treatment is not a trivial issue. By seeking to address issues of net benefit (harm vs benefit) and cost-effectiveness (cost of screening vs not screening), future studies will direct us toward evidence-based guidelines. Although the data are currently lacking in this regard, the results of this study should encourage future researchers to examine the appropriateness of various screening interventions and to ask the question for different populations, as patients vary greatly in level of risk.
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