Complications of Biologic Therapy for Psoriasis: Part II

Last year, biologic therapies came under the microscope for concerns over safety. After efalizumab (Raptiva, Genentech) was withdrawn from the market, the FDA issued new boxed warnings for many biologics.^1-4 In light of these warnings and heightened interest in safety data, this article series evaluates the wide-ranging complications and offers tips on how to prevent and manage these complications should they arise. In last month's article, we reviewed a number of complications, including malignant, neurologic, and infectious. Ahead, we will examine cardiac, hepatic, hematologic, immunologic, cutaneous, and injection/ infusion site complications.

Hepatic Complications
Hepatotoxicity has been reported with the use of alefacept (Amevive, Astellas), efalizumab, adalimumab (Humira, Abbott), etanercept (Enbrel, Amgen/Wyeth) and infliximab (Remicade, Centocor Ortho Biotech). Asymptomatic increases in alanine aminotransferase (ALT) and aspartate aminiotransferase (AST) are the most commonly reported hepatic finding.^14,61 These increases in liver enzymes rarely required discontinuation of the medication, however, the use of infliximab has been associated with greater liver complications than the other biologic agents listed.

The use of infliximab has been linked to acute liver failure, jaundice, hepatitis, cholestasis and autoimmune hepatitis. In some cases, elevations in the LFTs were not noted prior to recognition of liver injury.¹⁴ In studies where infliximab was used to treat psoriatic arthritis, 49 percent of patients experienced ALT elevations, compared to 16 percent on placebo. In two percent of the patients, ALT was greater than or equal to five times the upper limit of normal and in five percent of the patients, it was greater than or equal to three times the upper limit of normal.¹⁴ Patients who experience liver disease while taking the biologic agents have rarely required liver transplant and even died.

Current guidelines for monitoring liver function while taking any biologic agent include baseline chemistry screening and LFTs. Any abnormal results should prompt assessment for the underlying cause. During treatment with infliximab, some experts suggest LFTs should be repeated before each infusion.³⁴ If either AST or ALT rise to greater than five times the upper limit of normal, treatment should be withheld and any rise in liver enzymes should prompt repeating the test before the next infusion. A case report demonstrated that switching from one TNF inhibitor (adalimumab) to another (etanercept) because of liver dysfunction can be done safely in patients with psoriasis, ⁶¹ however, there is not enough evidence to state that this study can be repeated safely. Close monitoring and involvement of a specialist should be considered in switching biologic agents due to liver disease.

Cardiac Complications
Patients with psoriasis have an increased risk of cardiovascular disease.⁶² Comorbidities in patients with psoriasis include higher rates of diabetes, hypertension, obesity, and dyslipidemia, which are known to increase the incidence of myocardial infarction.^63,64 With these risk factors corrected for, patients continue to express a higher probability of myocardial infarction compared to controls. This is particularly true in younger patients with severe psoriasis.⁶² The increased predilection for cardiovascular disease in this patient population has caused debate over the use of potentially cardiotoxic drugs in patients with mild to severe heart failure.

Patients with congestive heart failure who were concurrently treated with TNF inhibitors were found to have worsening of heart failure in several reports. Patients with moderate to severe heart failure (NYHA Functional Class III/IV) treated with 10 mg/kg of infliximab were found to have higher rates of mortality than controls.^65,66 Patients treated with 10mg/kg and those with 5 mg/kg of infliximab were both shown to have increased rates of hospitalization due to worsening heart failure.^65,66 There have been post-marketing reports of worsening congestive heart failure (CHF) and new onset CHF in patients without preexisting cardiovascular disease in patients receiving infliximab or etanercept.^13,14 In the patients with new onset heart failure, an alarming 50 percent had no identifiable risk factors and 26 percent were younger than 50 years of age.⁶⁷

Two large studies have evaluated the use of etanercept in the treatment of mild to severe heart failure in patients that did not have other serious illnesses, being dosed at 25mg once, twice, and three times weekly. Both studies were terminated prematurely, owing to lack of benefit in heart failure patients. The pooled data was analyzed in the Randomized Etanercept Worldwide Evaluation (RENEWAL) analysis, which revealed no clinically relevant effect on mortality or chronic heart failure hospitalization.⁶⁸

Adalimumab and golimumab (Simponi, Centocor Ortho Biotech) are two TNF inhibitors that have little data on their safety in patients with congestive heart failure. At this time, it is recommended to approach the entire class of TNF inhibitors with caution in regards to cardiac complications until more studies are conducted and patient experiences can be reported. Treatment of patients with the Tcell inhibitors alefacept and efalizumab has resulted in few cases of cardiotoxicity or worsening of heart failure that could be associated with use of these agents.^69,70

Based on clinical trials, post-marketing experience and the FDA, TNF alpha inhibitors should not be used in patients with psoriasis who have moderate to severe heart failure (NYHA Class III/IV). In patients with well-compensated mild heart failure (NYHA Class I/II), data is not sufficient to determine the safety of TNF inhibitors. In this setting, physicians should obtain a baseline echocardiogram and those patients with an ejection fraction less than 50 percent should avoid treatment with TNF alpha inhibitors. If the ejection fraction is normal, then an informed discussion with the patient and close monitoring for signs or symptoms of worsening heart failure is appropriate.³⁷ Any of these biologic treatments should be stopped immediately in the setting of new symptoms or worsening of heart failure.⁶²

Hematological Complications
Alefacept is a recombinant fusion protein that works by binding to the T-cell lymphocyte antigen CD2. It is known to inhibit T lymphocyte activation and reduce the number of circulating CD4+ and CD8+ T-cells in a dose-dependent relationship.²⁶ For this reason, patients with below normal CD4+ Tcell counts should not be started on alefacept. It is also contraindicated for use in patients with human immunodeficiency virus (HIV).²⁶ In patients treated with alefacept, a baseline complete blood cell count should be obtained and CD4+ T-cell counts monitored every two weeks throughout the 12 week course of dosing. In the intramuscular study conducted, lymphocytopenia was more common after six to eight weeks of therapy.²⁶ During this study, 28 percent of patients had abnormally low CD4+ Tcell counts. If the CD4+ count falls below 250 cells/uL, dosing should be withheld and weekly monitoring initiated. Alefacept treatment should be discontinued if the CD4+ count does not normalize within a month.²⁶

The anti-TNF alpha agents have been rarely associated with anemia, leuokopenia, neutropenia, thrombocytopenia, pancytopenia and aplastic anemia. ^13-15,27 In some cases, the patients were also being treated with other medications and it is difficult to determine the causality of the hematologic disturbance.⁷¹ One recent study in rheumatoid arthritis patients actually showed a significant improvement in hemoglobin level while being treated with infliximab and methotrexate.⁷² Due to the current lack of evidence and possibly related fatalities following hematologic complications while being treated with TNF inhibitors, caution is advised.^13-15 Patients who develop easy bruising, prolonged bleeding, pallor or fever should be evaluated for a hematologic cause. Patients should have complete blood cell counts, including platelet counts, before starting therapy with these biologic agents an be appropriately monitored.

Immunologic Complications
The use of TNF alpha blocking agents has been associated with the development of auto-antibodies. Antinuclear antibodies (ANA) and anti-dsDNA antibodies were found at different prevalence rates among the various agents. Infliximab is associated with the highest occurrence rate of ANA with approximately 50 percent of patients treated testing positive.¹⁴ In comparison, only 12 percent and 11 percent of patients tested ANA positive that were treated with adalimumab and etanercept, respectively.^13,15 In all three medications, incidence of ANA or anti-dsDNA antibodies did not correlate with development of Lupus-like syndromes.

A retrospective review of all TNF inhibitor use in French hospitals found an incidence of lupuslike syndrome in a group of about 10,700 patients to be 0.19 percent for infliximab and 0.18 percent for etanercept.⁷³ In these patients all systemic lupus erythematosus symptoms resolved within 16 weeks of discontinuation of the drug. These patients most commonly present with rash, purpura, myalgia, serositis, and pneumonitis.⁷³

The monitoring of patients for ANA, antidsDNA antibodies and anticardiolipin antibodies while being treated with TNF inhibitors is not necessary. ³⁴ The correlation between development of auto-antibodies to signs and symptoms of lupus has not been shown, therefore, these nonspecific antibodies are not a contraindication to therapy with TNF inhibitors, nor do they necessitate discontinuation of therapy, should they develop.³⁴ If a patient develops signs or symptoms of lupus, the biologic agent should be withheld, and resolution of symptoms most often occurs.⁷⁴

Development of antibodies to alefacept has been reported to occur in 2.4 to three percent of patients treated and usually found at low titers.^26,69 The development of antibodies to etanercept was approximately six percent in clinical trials.¹³ The formation of antibodies to either of these medications has not been found to correlate with clinical response or adverse events. The long-term immunogenicity of these antibodies is currently unknown.

Clinical studies have shown that patients with psoriasis who are treated with infliximab are more likely to develop antibodies against infliximab at lower doses. One study showed that over a year 36 percent of patients receiving 5mg/kg compared to 51 percent of patients receiving 3mg/kg developed antibodies to infliximab.¹⁴ It has also been demonstrated that low dose methotrexate can lower the percentage of patients who develop these antibodies. Patients who develop antibodies to infliximab were more likely to have increased clearance rates, reduced efficacy and more infusion reactions.¹⁴ Approximately one percent of patients treated with infliximab will experience a serum sickness reaction that can occur as early as the second infusion and will recur if treatment is reinitiated.¹⁴ Clinical findings include fever, rash, myalgia, arthralgia, headache, facial edema, and/or dysphagia.⁷⁵ Prior to treatment, antihistamines, corticosteroids, and epinephrine should be available and used promptly, if a reaction occurs. Use of infliximab should not be continued in that patient.

The formation of antibodies to adalimumab has also been shown to result in neutralization of the medication and likely decreased efficacy. In contrast to infliximab, there have been no adverse reactions associated with these antibodies.¹⁵ In the three controlled trials reviewed, antibodies against adalimumab were detected in 12 percent of patients treated for rheumatoid arthritis.¹⁵ The use of methotrexate concomitantly with adalimumab resulted in only one percent of patients developing antibodies to adalimumab. The studies revealed that more frequent dosing was associated with fewer patients developing these antibodies, as well.¹⁵

Infusion/Injection Site Complications
The most common adverse events associated with infliximab are infusion reactions. Approximately 20 percent of patients in clinical studies experienced an infusion reaction.¹⁴ Patients had various presentations such as chills, fevers, pruritis, urticaria, irregularities in blood pressure and changes in heart rate. Serious infusion reactions occurred in less than one percent of patients and included anaphylaxis, convulsions and erythematous rash. Interestingly, patients who developed antibodies to infliximab were two to three times more likely to develop an infusion reaction than those who did not.^14,76 During the event of an infusion reaction, the symptoms should be treated appropriately and the infusion rate should be decreased or stopped based on the severity of the reaction.⁷⁷ Various pre-treatment regimens including corticosteroids and antihistamines have inconsistently been shown to reduce the risk of infusion reactions.^77-80 It has also been reported that maintaining a regular dosing regimen may result in fewer infusion reactions.⁶² Most importantly, patients who experience a severe infusion reaction should discontinue therapy with infliximab indefinitely, as future reactions may occur if treatment is resumed.⁸¹

Adalimumab, etanercept, and golimumab have all been associated with injection site reactions. The most common reactions are mild to moderate in severity and include erythema, itching, hemorrhage, pain or swelling at the injection site. These adverse events rarely necessitate discontinuing the TNF inhibitor, and they often decrease in severity and frequency following the first month of therapy. ^82,83 In order to decrease the likelihood of injection site reactions, one should vary the site of injection.

Etanercept treatment for plaque psoriasis was associated with 14 percent of patients developing injection site reactions compared to 37 percent of all patients treated for a rheumatologic disease in clinical trials.¹³ The increased frequency of injection site reactions during treatment of rheumatologic diseases other than psoriasis was seen with all the TNF inhibitors. In clinical trials, adalimumab was associated with 20 percent of patients experiencing injection site reactions.¹⁵ There was also a one percent incidence of hypersensitivity reactions, including allergic rash, anaphylactoid reactions, fixed drug reaction or urticaria. Treatment should be discontinued in patients who experience serious allergic reactions. Clinical trial data indicates that golimumab may have the lowest rate of injection site reactions among the TNF inhibitors at six percent of patients.²⁷

Alefacept is associated with injection site reactions as well. These reactions occurred in 16 percent of patients during clinical trials and remained constant throughout all courses of treatment. The most common injection site reactions include inflammation, bleeding, edema, and non-specific reactions.²⁶

Cutaneous Complications
The TNF alpha inhibitors approved for treatment of psoriasis have paradoxically been reported in numerous case studies to be associated with new onset or exacerbation of cutaneous psoriasis. The Tcell inhibitor alefacept has not been associated with these same complications. The FDA reviewed 69 cases in which patients receiving TNF inhibitor therapy for various rheumatologic conditions developed new onset psoriasis.¹⁷ The overall prevalence of induced psoriasiform lesions is estimated by several authors to be about 1.0-5.3 percent in various rheumatologic diseases.^84-86 The most common presentations have been development of pustular and palmoplantar forms of psoriasis. In a large review of 120 cases, there were 25 patients whose psoriasis worsened and several other cases in which psoriasis shifted in type during treatment with a TNF inhibitor.⁸⁷ The time from induction of therapy to exacerbation or new onset of psoriasis varied considerably, but occurred at a mean 9.5 months in these cases.⁸⁷ After discontinuation of the TNF inhibitor alone or in association with other psoriatic therapy, the majority of patients experience complete or partial improvement.^17,87 Prior to treatment, patients should be counseled on these risks and advised to report any changes or new onset of lesions as hospitalization has been necessary in some cases.¹⁷

An association between TNF inhibitors and vasculitis has been established during the post-marketing marketing experience with infliximab, etanercept and adalimumab. ^88-90 One group reviewed the Adverse Events Reporting System of the US Food and Drug Administration and found only 35 patients in approximately four years who were treated with infliximab or etanercept experienced a leukocytoclastic vasculitis (LCV).⁸⁸ Another group identified 113 cases of vasculitis in patients treated with TNF inhibitors between 1990 and 2006 with the majority (63 percent) having a LCV histology.⁸⁹ Both studies revealed that the majority of cases occurred in the treatment of rheumatoid arthritis and presented with cutaneous manifestations. These cutaneous lesions included purpura, petechiae, nodules, bullae and urticarial wheals.^88,89 Although rheumatoid arthritis and other autoimmune disorders are known to be associated with vasculitis, the temporal relationship between cutaneous lesion onset with initiation of anti-TNF therapy and the resolution with discontinuation gives strong evidence that the drug is at fault. This is also supported by the reoccurrence of LCV in five patients who were retried on etanercept after initially experiencing a vasculitis.⁸⁸

Although cutaneous manifestations represent a majority of the vasculitis presentations, involvement of the peripheral nervous system, kidney, central nervous system, pleura, heart and lung have also been reported.^88,89,91 These presentations have been seen in association with cutaneous lesions and as separate vasculitides. Patients developing systemic vasculitis have reported arthralgias, myalgias, fever, fatigue, edema, peripheral neuropathy, abdominal pain, pleuritic pain, pericardial effusion and hematuria.⁸⁸ The development of vasculitis with TNF inhibitor therapy is rare, but several steps should be taken when it is suspected. In the presentation of cutaneous symptoms, a thorough examination for any systemic involvement of vasculitis is necessary to ensure patient safety. The diagnosis can be confirmed by skin biopsy and one may possibly wish to culture as well to exclude infectious agents.⁸⁸ Discontinuation of the drug was shown to result in resolution of the vasculitis in 18 of 33 patients in one study.⁹¹ The remaining 14 required high-dose glucocorticoids and/or immunosuppressants for symptom resolution over several weeks.

Dr. Bechtel is on the Speaker's Bureau for Centocor, Amgen, and Abbott. Mr. Bauer has no conflicts.

1. 1. FDA: Manufacturers of TNF Blockers Must Highlight Risk of Fungal Infections. Available at http://www.fda.gov/News Events/Newsroom/Press Announcements (Sept 2008) UMC116942.htm.
2. Raptiva (PML)Dear Healthcare Provider letter 10/2008. Available at http://www.gene.com/gene/products/information/immunologic/raptiva.
3. FDA: Cancer Warning for TNF Blockers. Available at http://www.fda.gov/newsevents/newsroom/pressannoucejments/Aug2009/ucm175803.ht m.
4. Raptiva (Genentech Announces Voluntary Withdrawal of Raptiva from U.S. Market) 4- 2009. Available at http://www.gene.com/gene/products/information/immunologic/raptiva.
5. Gordon KB, Vaishnaw AK, O'Gorman J et al. Treatment of psoriasis with alefecept: correlation of clinical improvement with reductions of memory T-cell counts. Arch Dermatol. 2003;139:1563-1570.
6. Alwawi EA, Krulig E, Gordon KB. Long-term efficacy of biologics in treatment of psoriasis: What do we really know? Dermatologic Therapy. 2009; 22: 431-440.
7. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007; 356: 580-592.
8. Gelfand JM, BerlinJ, VanVoorhees, et al. Lymphoma rates are low but increased in patients with psoriasis. Arch Dermatol. 2003;139:1425-1429.
9. Gelfand JM, Shin DB, Neimann AL, et al. The risk of lymphoma in patients with psoriasis. J Invest Dermatol. 2006; 126:2194-2201.
10. Patel RV, Clark LN, Lebwohl, et al. Treatments for psoriasis and the risk of malignancy. J Am Acad Dermatol. 2009; 60: 1001-1017.
11. Krell J. Bagel J, Coynik D. Assessment and tracking of long-term alefacept safety (ATLAS): analysis of data from approximately 1,200 patients (abstract). J Am Acad Dermatol. 2007; 56 (supp 12): AB191.
12. Leonardi C, Toth D, Cather JC, et al. A review of malignancies observed during efalizumab clinical trials for plaque psoriasis. Dermatology. 2006; 213: 204-214.
13. Enbrel® (etanercept) prescribing information, Immunex Corporation, Thousand Oaks, CA.
14. Remicade® (infliximab) prescribing information, Centocor, Inc., Malverna, PA.
15. Humira® (adalimumab) prescribing information, Abbott Laboratories, North Chicago, IL.
16. Dommasch E, Gelfand JM. Is there truly a risk of lymphoma from biologic therapies? Dermatologic Therapy. 2009; 22: 418-430.
17. Information for Healthcare Professionals: Tumor necrosis factor (TNF) blockers (marketed as Remicade®, Enbrel®, Humira®, Cimzia®, and Simpori®). Available at http:www.fda.gov/drugs/drugSafetyInformationforPatients/Providers/Drug safetyInformationforHealthcareProfessionals/ucm174474.htm.
18. Stelara® (ustekinumab) prescribing information, Centocor, Inc., Malvern, PA.
19. Weber T. Progressive multifocal leukoencephalopathy. Neurol.Clin. 2008. Aug; 26 (3); 833-854.
20. Raptiva (PML 2nd case) Dear Healthcare Provider letter 11-2008. Available at http://www.gene.com/gene/products/information/immunologic/raptiva.
21. Raptiva (PML 3rd case) Dear Healthcare provider Letter 2-2009. Available at http://www.gene.com/gene/products/information/immunologic/raptiva.
22. CarsonKR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the research on adverse drug events and reports (RADAR) project. Blood. May 14; 113 (20): 4834-4840.
23. Ruiz-Jimeno T, Carvajal A, Mata L, et al. Demyelinating diseases in a patient with psoriatic arthritis and family history of multiple sclerosis treated with infliximab. J Rheumatol.2006; 33 (7): 1457-1458.
24. Hoffman FM, Hinton DR, Johnson K, et al. Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med. 1989 Aug 1; 170 (2): 607-612.
25. Robinson WH, Genovese MC, Moreland LW. Demyelinating and neurologic events reported in association with tumor necrosis factor · antagonism: by what mechanisms could tumor necrosis factor · antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? Arthritis Rheum. 2001 Sept; 44 (9): 1977-1983.
26. Amevive® (alefacept) prescribing information, Astellas Pharma US, Inc., Deerfield, IL.
27. Simponi® (golimumab) prescribing information, Centocor Ortho Biotech Inc., Horsham, PA.
28. Flynn JL, Chan J. Immunology of tuberculosis. Annu Rev Immunol 2001; 19: 93-129.
29. Mohan VP, Scanga CA, Yu K, et al. Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis: possible role for limiting pathology. Infection and Immunity 2001; 69: 1847-1855.
30. Wallis RS, Broder MS, Wong JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004; 38: 1261-1265.
31. Raviglione MC, O'Brien RJ. Harison's Principles of Internal Medicine. 17th Ed. McGraw- Hill Co Inc. 2008; Ch158.
32. Wolfe F, Michaud K, Anderson J, et al. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis and Rheumatism 2004; 50: 372- 379.
33. Mohan AK, Cote TR, Block JA, et al. Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor. Clin Infect Dis 2004; 39: 295-299.
34. Lebwohl M, Bagel J, Gelfand J, et al. From the Medical Board of the National Psoriasis Foundation: monitoring and vaccinations in patients treated with biologics for psoriasis. J Am Acad Dermatol 2008; 58(1): 94-105.
35. Laffitte E, Janssens J, Roux-Lombard P, et al. Tuberculosis screening in patients with psoriasis before antitumour necrosis factor therapy: comparison of an interferon-gamma release assay vs. tuberculin skin test. Br J Deratol Journal of Dermatology 2009; 161(4): 797-800.
36. FDA Alert 9/4/2008: Information for healthcare professionals: Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab). Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationfor PatientsandProviders/ucm124185.htm
37. Desai SB, Furst DE. Problems encountered during anti-tumor necrosis factor therapy. Best Pract Res 2006; 20: 757-790.
38. Deepe GS Jr. Tumor necrosis factor-alpha and host resistance to the pathogenic fungus, Histoplasma capsulatum. J Investig Dermatol Symp Proc 2007; 12(1): 34-37.
39. Uicker WC, Doyle HA, McCracken JP, et al. Cytokine and chemokine expression in the central nervous system associated with protective cell-mediated immunity against Cryptococcus neoformans. Med Mycol 2005; 43(1): 27-38.
40. Beaman L. Effects of recombinant gamma interferon and tumor necrosis factor on in vitro interactions of human mononuclear phagocytes with Coccidioides immitis. Infection and Immunity 1991; 59: 4227-4229.
41. Mehrad B, Strieter RM, Standiford TJ. Role of TNF alpha in pulmonary host defense in murine invasive aspergillosis. The Journal of Immunology 1999; 162: 1633-1640.
42. Kolls JK, Beck JM, Nelson S, et al. Alveolar macrophage release of tumor necrosis factor during murine Pneumocystis carinii pneumonia. Am J Respir Cell Mol Biol 1993; 8(4): 370- 376.
43. Algood HM, Lin PL, Flynn JL. Tumore necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis. Clin Infect Dis 2005; 41(Suppl 3): S189-193.
44. Arnold T, Sears C, Hage C. Invasive fungal infections in the era of biologics. Clinics in Chest Medicine 2009; 30(2): 279-86.
45. Kauffman CA. Histoplasmosis: A clinical and laboratory update. Clin Microbiol Rev 2007; 20(1): 115-132.
46. Bergstrom L, Yocum DE, Ampel NM, et al. Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor alpha antagonists. Arthritis Rheum 2004; 50: 1956-1966.
47. Tsiodras S, Samois G, Boumpas DT, et al. Fungal infections complicating tumor necrosis factor alpha blockade therapy. Mayo Clinic Proceedings. Mayo Clinic 2008; 83(2): 181- 194.
48. Kauffman, Carol A. Diagnosis of histoplasmosis in immunosuppressed patients. Current Opinion in Infectious Diseases. 2008; 21: 421-425.
49. Wheat, L. Approach to the diagnosis of the endemic mycoses. Clinics in Chest Medicine 2009; 30(2): 379-89.
50. Michel M, Duvous C, Hezode C, et al. Fulminant hepatitis after infliximab in a patient with hepatitis B virus treated for an adult onset still's disease. Rheumatol 2003; 30: 1624- 1625.
51. Esteve M, Saro C, Gonzalez-Huix F, et al. Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis. Gut 2004; 53: 1363-5.
52. Aslanidisa S, Vassiliadis T, Pyrpasopoulou A, et al. Inhibition of TNFalpha does not induce viral reactivation in patients with chronic hepatitis C infection: two cases. Clin Rheumatol 2007; 26: 261-264.
53. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345: 1098-1103.
54. Giles JT, Bathon JM. Serious infections associated with anticytokine therapies in the rheumatic diseases. J Intensive Care Med 2004; 19: 320-334.
55. Nathan DM, Angus PW, Gibson PR. Hepatitis B and C virus infections and anti-tumor necrosis factor-alpha therapy: Guidelines for clinical approach. J Gastroenterol Hepatol 2006; 21: 1366-1371.
56. Frankel AJ, Van Voorhees AS, Hsu S, Korman, et al. Treatment of psoriasis in patients with hepatitis C: From the medical board of the national psoriasis foundation. Journal of the American Academy of Dermatology 2009; October [Epub Ahead of Print].
57. Magliocco MA, Gottlieb AB. Etanercept therapy for patients with psoriatic arthritis and concurrent hepatitis C virus infection: report of 3 cases. J Am Acad Dermatol 2004; 51: 580- 584.
58. De Simone C, Paradisi A, Capizzi R, et al. Etanercept therapy in two patients with psoriasis and concomitant hepatitis C. J Am Acad Dermatol 2006; 54: 1102-1104.
59. Niewold TB, Gibofsky A. Concomitant interferon-alpha therapy and tumor necrosis factor alpha inhibition for rheumatoid arthritis and hepatitis C. Arthritis Rheum 2006; 54: 2335-2337.
60. Peterson JR, Hsu FC, Simkin PA, et al. Effect of tumor necrosis factor alpha antagonists on serum transaminases and viremia in patients with rheumatoid arthritis and chronic hepatitis C infection. Ann Rhem Dis 2003; 62: 1078-1082.
61. Massarotti M, Marasini B. Successful treatment with etanercept of a patient with psoriatic arthritis after adalimumab related hepatotoxicity. Int J Immunopathol Pharmacol 2009; 22: 547-549.
62. Menter, Alan. Gottliieb, Alice, Feldman, Steven R. 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: 826-850.
63. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA 2006; 296: 1735-1741.
64. Mallbris L, Granath F, Hamsten A, et al. Psoriasis is associated with lipid abnormalities at the onset of skin disease. J Am Acad Dermatol 2006; 54: 614-621.
65. Chung ES, Packer M, Lo KD, et al. Anti-TNF Therapy Against Congestive Heart Failure Investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderateto- severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial. Circulation 2003; 107(25): 3133-3140.
66. Packer M, Chung E, Batra S, et al. Randomized placebo-controlled dose-ranging trial of infliximab, a monoclonal antibody to tumor necrosis factor-alpha, in moderate to severe heart failure. Paper presented at: Annual Meeting of the Heart Failure Society of America; September 25, 2002; Boca Raton, Fla.
67. Kwon HJ, Cote TR, Cuffe MS, et al. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med. 2003; 138: 807–811.
68. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept World Evaluation (RENEWAL). Circulation 2004; 109: 1594-1602.
69. Goffe, B, Papp K, Gratton D, et al. (2005). An integrated analysis of thirteen trials summarizing the long-term safety of alefacept in psoriasis patients who have received up to nine courses of therapy. Clinical Therapeutics 2005; 27(12): 1912-1921.
70. Leonardi C, Menter A, Hamilton T, et al. Efalizumab: results of a 3-year continuous dosing study for the long-term control of psoriasis. Br J Dermatol 2008; 158(5): 1107-1116.
71. Theodoridou A, Kartsios C, Yiannaki E, et al. Reversible T-Large granular lymphocyte expansion and neutropenia associated with adalimumab therapy. Rheumatol Int 2006; 27: 201-202.
72. Doyle MK, Rahman MU, Han C, et al. Treatment with infliximab plus methotrexate improves anemia in patients with rheumatoid arthritis independent of improvement in other clinical outcome measures – a pooled analysis from three large, multicenter, doubleblind, randomized clinical trials. Semin Arthritis Rheum 2009; 39(2): 123-131.
73. De Bandt M, Sibilia J, Le Loet X, et al. Systemic lupus erythematosus induced by antitumor necrosis factor alpha therapy: a French national survey. Arthritis Research & Therapy 2005; 7: R545-R551.
74. Ramos-Casals M, Brito-Zeron P, Munoz S, et al. Autoimmune diseases induced by TNF targeted therapies: analysis of 233 cases. Medicine (Baltimore) 2007; 86:2 42-251.
75. Gamarra RM, McGraw SD, Drelichman VS, et al. Serum sickness-like reactions in patients receiving intravenous infliximab. J Emerg Med 2006; 30: 41-44.
76. Cheifetz A, Mayer L. Monoclonal antibodies, immunogenicity, and associated infusion reactions. Mt Sinai J Med 2005; 72: 250-256.
77. Lequerre T, Vittecoq O, Klemmer N, et al. Management of infusion reactions to infliximab in patients with rheumatoid arthritis or spondyloarthritis: experience from an immunotherapy unit of rheumatology. J Rheumatol 2006; 33: 1307-1314.
78. Farrell RJ, Alsahli M, Jeen YT, et al. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: a randomized controlled trial. Gastroenterology 2003; 124: 917-924.
79. Wasserman MJ, Weber DA, Guthrie JA, et al. Infusion-related reactions to infliximab in patients with rheumatoid arthritis in a clinical practice setting: relationship to dose, antihistamine pretreatment, and infusion number. J Rheumatol 2004; 31: 1912-1917.
80. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. New England Journal of Medicine 2003; 348: 601- 608.
81. Segiura F, Kojima T, Oba M, et al. Anaphylactic reaction to infliximab in two rheumatoid arthritis patients who had previously received infliximab and resumed. Mod Rheumatol 2005; 15: 201-203.
82. Khanna D, McMahon M, Furst DE. Safety of tumour necorsis factor-alpha antagonists. Drug Safety 2004; 27: 307-324.
83. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999; 130: 478-486.
84. Wendling D, Balblanc J, Briancon D, et al. Onset or exacerbation of cutaneous psoriasis during TNFalpha antagonist therapy. Joint Bone Spine 2008; 75: 315-318.
85. Bremmer M, Deng A, Gaspari AA. A mechanism-based classification of dermatologic reactions to biologic agents used in the treatment of cutaneous disease: Part 2. Dermatitis 2009; 20(5): 243-256.
86. Lee HH, Song IH, Friedrich M, et al. Cutaneous side-effects in patients with rheumatic diseases during application of tumor necrosis factor-alpha antagonists. Br J Dermatol 2007; 156: 486-491.
87. Wollina U, Hansel G, Koch A, et al. Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata: first 120 cases from the literature including a series of six new patients. Am. J. Clin. Dermatol 2008; 9(1): 1-14.
88. Mohan N, Edwards ET, Cupps TR, et al. Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents. J Rheumatol 2004; 31: 1955-1958.
89. Ramos-Casals M, Brito-Zeron P, Munoz S, et al. Autoimmune diseases induced by TNFtargeted therapies: analysis of 233 cases. Medicine (Baltimore) 2007; 86(4): 242-251.
90. Misery L, Perrot JL, Gentil-Perret A, et al. Dermatological complications of etanercept therapy for rheumatoid arthritis. Br J Dermatol 2002; 146: 334-335.
91. Marcous BS, De Bandt M. Vasculitides induced by TNF-alpha antagonists: a study in 39 patients in France. Joint Bone Spine 2006; 73: 710-713.