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Use of tumor necrosis factor alpha (TNF α) antagonists in a patient with psoriasis and Chagas disease* * Work performed at the Department of Dermatology, Facultad de Medicina, Pontificia Universidad Católica de Chile - Santiago, Chile.

Abstract

There are several studies on the benefits of using TNFα antagonists in the treatment of psoriasis, but few studies addressing the interaction of these drugs with chronic infections. We report the case of a 52-year-old patient diagnosed with psoriasis refractory to traditional systemic agents, who was treated with biologic therapies. After one year of treatment with biologic agents, the patient was diagnosed with Chagas Disease.

Keywords:
Biological agents; Chagas disease; Psoriasis; Tumor necrosis factor-alpha

INTRODUCTION

Long-term safety data on the use of TNF-α antagonists in psoriasis, as well as their interaction with concurrent comorbidities are still to be properly evaluated. TNF-α agents have been associated with increased risk of serious infections and reactivation of tuberculosis.1Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, 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;58:826-50.Increased incidence of opportunistic infections such as cerebral toxoplasmosis and toxoplasmic chorioretinitis have also been reported secondary to the use of Infliximab.2Lassoued S, Zabraniecki L, Marin F, Billey T. Toxoplasmic chorioretinitis and antitumor necrosis factor treatment in rheumatoid arthritis. Semin Arthritis Rheum. 2007;36:262-3.Interactions with chronic infectious illnesses such as Chagas disease (CD) have not been previously assessed.

CASE REPORT

A 52-year-old man from a rural-zone in northern Chile sought our clinic in December 2007 with a diagnosis of psoriasis established when he was 14-yearsold. He had over 80% of cutaneous involvement (PASI 20.6, (Figure 1). He had been treated with methotrexate, PUVA and acitretin with limited response. Chest radiography and PPD test were both within normal limits and we decided to start Etanercept 25 mg twice a week, subsequently titrated to 50 mg achieving only partial response. After five months, the patient was switched to adalimumab with significant improvement.

FIGURE 1
A: Patient before treatment with adalimumab. B: after treatment with adalimumab

Additionally, he referred a 5-year history of progressive constipation with poor response to laxatives. In August 2009 he underwent surgery due to megacolon (Figure 2). Histology was consistent with chagasic megacolon. The patient had not been previously diagnosed with Chagas disease (CD), but he most likely had it since childhood. Biologic therapy was subsequently discontinued while the extent of CD was assessed.

FIGURE 2
Abdominal X-ray examination with Barium enema. Note the dilatation of the sigmoid colon

Indirect immunofluorescence (IIF) IgG, qualitative polymerase chain reaction (qPCR), and real-time polymerase chain reaction (rtPCR,Chart 1) were performed in order to investigate Trypanosoma cruzi. Esophageal involvement was evaluated with barium swallow and cardiac involvement was explored with electrocardiogram and echocardiogram, all of which were normal. Specific therapy for CD was initiated with 5-nitrofuran 5 mg/kg/day and increased to 7 mg/kg/day for a 60-day-regimen on two occasions (August 2009 and May 2010 due to an alteration in the parasitemia dynamics).

CHART 1
Parasitological study and follow-up of the patient

Meanwhile, the patient's psoriatic lesions recurred, dramatically affecting his quality of life. The patient requested to have biologic therapy restarted. Potential adverse effects were carefully explained and discussed with him.

The patient was prescribed adalimumab 40 mg twice a month with excellent response (PASI 2.1,Figure 1) without evidence of CD reactivation as indicated by a non-reactive rtPCR after one-year follow-up.

DISCUSSION

Trypanosoma cruzi infection is a vectorial parasitic zoonosis caused by a hemoflagellate organism.3Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet. 2010;375:1388-402The infection, known to be highly burdensome, is classified as a Neglected Tropical Disease that affects people in extreme poverty and helps to perpetuate their impoverishment.4Hotez PJ, Fenwick A, Savioli L, Molyneux DH. Rescuing the bottom billion through control of neglected tropical diseases. Lancet. 2009;373:1570-5.

Twenty-percent of Latin American inhabitants (109 million individuals) are at risk of acquiring the infection, with 7.7 million individuals infected in 2005.3Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet. 2010;375:1388-402,5Aguilar V HM, Abad-Franch F, Racines VJ, Paucar CA. Epidemiology of Chagas disease in Ecuador. A brief review. Mem Inst Oswaldo Cruz. 1999;94:387-93.,6Organización Panamericana de la Salud. Estimación cuantitativa de la enfermedad de Chagas en las Américas. Montevideo, Uruguay: Organización Panamericana de la Salud; 2006.In Chile, there isn't enough information on the disease, however 0.4 - 0.7% of blood donors test positive for T. cruzi.7Guidelines for Chagas disease. 2006. Part I. Introduction and epidemiology. Rev Chilena Infectol. 2008;25:189-93.

With the advent of traveling and migration, the disease is not only restricted to endemic areas but it is spread worldwide, making the knowledge on CD mandatory to all physicians and not only those living in the Americas.3Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet. 2010;375:1388-402

The effects of immunomodulatory drugs on T. cruzi parasitemia dynamics and CD course in humans are not known, with only experimental evidence available from animal models with contradictory results.8Bilate AM, Salemi VM, Ramires FJ, de Brito T, Russo M, Fonseca SG, et al. TNF blockade aggravates experimental chronic Chagas disease cardiomyopathy. Microbes Infect. 2007;9:1104-13.

Kroll-Palhares K, Silvério JC, Silva AA, Michailowsky V, Marino AP, Silva NM, et al. TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-a blockade. Mem Inst Oswaldo Cruz. 2008;103:375-85.
-1010 Pérez AR, Fontanella GH, Nocito AL, Revelli S, Bottasso OA. Short treatment with the tumour necrosis factor-alpha blocker infliximab diminishes chronic chagasic myocarditis in rats without evidence of Trypanosoma cruzi reactivation. Clin Exp Immunol. 2009;157:291-9.Some studies demonstrated myocardial tissue alteration in Chagasic hamsters, with decrease in left ventricular systolic function, increase in IL-10-mRNA expression and an increase in the subendocardium inflammatory foci.8Bilate AM, Salemi VM, Ramires FJ, de Brito T, Russo M, Fonseca SG, et al. TNF blockade aggravates experimental chronic Chagas disease cardiomyopathy. Microbes Infect. 2007;9:1104-13.Other reports have shown even a decrease in the myocardial inflammatory foci and myocarditis in animals treated with TNFα antagonists and a down regulation of CD4+ and CD8+ T cells in cardiac tissue, keeping the expression of normal cardiac proteins like connexin-43, which is reduced and disorganized in untreated infected mice.9Kroll-Palhares K, Silvério JC, Silva AA, Michailowsky V, Marino AP, Silva NM, et al. TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-a blockade. Mem Inst Oswaldo Cruz. 2008;103:375-85.,1010 Pérez AR, Fontanella GH, Nocito AL, Revelli S, Bottasso OA. Short treatment with the tumour necrosis factor-alpha blocker infliximab diminishes chronic chagasic myocarditis in rats without evidence of Trypanosoma cruzi reactivation. Clin Exp Immunol. 2009;157:291-9.The most likely explanation is that TNFα in CD may act as a pro-inflammatory cytokine, inducing target-organ damage secondary to the recruitment and chemotaxis of neutrophils, lymphocytes and macrophages, thereby maintaining tissue inflammation.8Bilate AM, Salemi VM, Ramires FJ, de Brito T, Russo M, Fonseca SG, et al. TNF blockade aggravates experimental chronic Chagas disease cardiomyopathy. Microbes Infect. 2007;9:1104-13.

Kroll-Palhares K, Silvério JC, Silva AA, Michailowsky V, Marino AP, Silva NM, et al. TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-a blockade. Mem Inst Oswaldo Cruz. 2008;103:375-85.
-1010 Pérez AR, Fontanella GH, Nocito AL, Revelli S, Bottasso OA. Short treatment with the tumour necrosis factor-alpha blocker infliximab diminishes chronic chagasic myocarditis in rats without evidence of Trypanosoma cruzi reactivation. Clin Exp Immunol. 2009;157:291-9.

Conversely, TNFα may aid in containing T. cruzi infection and thus help maintaining low serologic levels of the hemoflagellate organism, leading to a complex interaction between the host and the agent. T. cruzi parasitemia did not change subsequent to anti-TNF administration in any of these studies.8Bilate AM, Salemi VM, Ramires FJ, de Brito T, Russo M, Fonseca SG, et al. TNF blockade aggravates experimental chronic Chagas disease cardiomyopathy. Microbes Infect. 2007;9:1104-13.

Kroll-Palhares K, Silvério JC, Silva AA, Michailowsky V, Marino AP, Silva NM, et al. TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-a blockade. Mem Inst Oswaldo Cruz. 2008;103:375-85.
-1010 Pérez AR, Fontanella GH, Nocito AL, Revelli S, Bottasso OA. Short treatment with the tumour necrosis factor-alpha blocker infliximab diminishes chronic chagasic myocarditis in rats without evidence of Trypanosoma cruzi reactivation. Clin Exp Immunol. 2009;157:291-9.Similarly, strict follow-up with rtPCR studies did not show any evidence of reactivation of CD with the use of etanercept or adalimumab in our patient. The detection of 1000 copies of T.cruzi DNA in the rtP-CR performed in May 2010 represents a very low level and could be explained by the natural fluctuation of T. cruzi parasitemia (or parasitemia dynamics)1111 Bua J, Volta BJ, Perrone AE, Scollo K, Velázquez EB, Ruiz AM, et al. How to improve the early diagnosis of Trypanosoma cruzi infection: relationship between validated conventional diagnosis and quantitative DNA amplification in congenitally infected children. PLoS Negl Trop Dis. 2013;7:e2476.since this change occurred while the patient was off biologic therapies. This alteration in parasitemia responded well to an additional course of 5-nitrofuran, and the rtPCRs performed in December 2010 and May 2011 were negative for T.cruzi DNA despite the patient being on anti-TNF therapy since May 2010.

The possibility that Chagas megacolon was triggered in our patient by our initial TNFα-antagonist therapy seems very unlikely, as the mean time of development of this chronic complication is namely 20 - 30 years.

Anti-TNF drugs' safety profiles and their use in patients with chronic infections such as CD are still undergoing long-term evaluation. This issue is of particular concern given the increasing prevalence of biologic therapy for multiple inflammatory disorders worldwide and the potential for their use in patients with unknown concurrent chronic infections such as CD.3Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet. 2010;375:1388-402

Screening recommendations for certain chronic infections prior to biologic therapy initiation have already been published and they include testing for hepatitis and tuberculosis at baseline.1Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, 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;58:826-50.Screening for additional infectious diseases are not included in these guidelines.

Lassoued et al postulated performing Toxoplasma serology as an initial workup, prior to the starting of anti-TNFα therapy.2Lassoued S, Zabraniecki L, Marin F, Billey T. Toxoplasmic chorioretinitis and antitumor necrosis factor treatment in rheumatoid arthritis. Semin Arthritis Rheum. 2007;36:262-3.Screening for hepatitis B virus is also part of the initial workup due to known cases of HBV reactivation and even death secondary to anti-TNF therapy.1212 Ramos-Casals M. Therapy: Are TNF blockers safe for patients with hepatitis B virus infection? Nat Rev Rheumatol. 2010;6:618-20.

Furthermore, we suggest adding CD serology to initial screening studies1Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, 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;58:826-50.before starting biologic therapies in CD endemic areas. This would allow a full treatment course with 5-nitrofuran prior to anti-TNF therapy, similar to concurrent HBV infection or TB infection. It would reduce and prevent an unknown but potential risk of CD reactivation, as occurs in 20% of HIV patients with severe meningoencephalitis, myocarditis, high parasitemia levels and even death (work up is listed inchart 2).1313 Ferreira MS, Nishioka Sde A, Silvestre MT, Borges AS, Nunes-Araújo FR, Rocha A. Reactivation of Chagas' disease in patients with AIDS: report of three new cases and review of the literature. Clin Infect Dis. 1997;25:1397-400.,1414 de Freitas VL, da Silva SC, Sartori AM, Bezerra RC, Westphalen EV, Molina TD, et al. Real-time PCR in HIV/Trypanosoma cruzi coinfection with and without Chagas disease reactivation: association with HIV viral load and CD4 level. PLoS Negl Trop Dis. 2011;5:e1277.

CHART 2
Suggested work-up for patients in endemic areas (or who are traveling/ have traveled to them) planning to start biologic therapies. Treatment could be performed with Nifurtimox or Benzimidazole but not with both. Captions: IIF: indirect immunofluorescence

Recently, T. cruzi serology was added as a screening tool in all patients who are candidates to solid organ transplants (unpublished data, observation of MT).

A consensus on guidelines for biologic therapy in the presence of CD has yet to be established and it would aid physicians in the initial workup of patients, in order to offer the highest safety and risk-benefit profiles to patients.

  • Financial Support: None.
  • How to cite this article: Navarrete-Dechent C, Majerson D, Torres M, Armijo D, Patel M, Menter A, de la Cruz C. Use of tumor necrosis factor alpha (TNFα) antagonists in a patient with psoriasis and Chagas disease. An Bras Dermatol. 2015;90(3 Supl 1):S171-4.
  • *
    Work performed at the Department of Dermatology, Facultad de Medicina, Pontificia Universidad Católica de Chile - Santiago, Chile.

References

  • 1
    Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, 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;58:826-50.
  • 2
    Lassoued S, Zabraniecki L, Marin F, Billey T. Toxoplasmic chorioretinitis and antitumor necrosis factor treatment in rheumatoid arthritis. Semin Arthritis Rheum. 2007;36:262-3.
  • 3
    Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet. 2010;375:1388-402
  • 4
    Hotez PJ, Fenwick A, Savioli L, Molyneux DH. Rescuing the bottom billion through control of neglected tropical diseases. Lancet. 2009;373:1570-5.
  • 5
    Aguilar V HM, Abad-Franch F, Racines VJ, Paucar CA. Epidemiology of Chagas disease in Ecuador. A brief review. Mem Inst Oswaldo Cruz. 1999;94:387-93.
  • 6
    Organización Panamericana de la Salud. Estimación cuantitativa de la enfermedad de Chagas en las Américas. Montevideo, Uruguay: Organización Panamericana de la Salud; 2006.
  • 7
    Guidelines for Chagas disease. 2006. Part I. Introduction and epidemiology. Rev Chilena Infectol. 2008;25:189-93.
  • 8
    Bilate AM, Salemi VM, Ramires FJ, de Brito T, Russo M, Fonseca SG, et al. TNF blockade aggravates experimental chronic Chagas disease cardiomyopathy. Microbes Infect. 2007;9:1104-13.
  • 9
    Kroll-Palhares K, Silvério JC, Silva AA, Michailowsky V, Marino AP, Silva NM, et al. TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-a blockade. Mem Inst Oswaldo Cruz. 2008;103:375-85.
  • 10
    Pérez AR, Fontanella GH, Nocito AL, Revelli S, Bottasso OA. Short treatment with the tumour necrosis factor-alpha blocker infliximab diminishes chronic chagasic myocarditis in rats without evidence of Trypanosoma cruzi reactivation. Clin Exp Immunol. 2009;157:291-9.
  • 11
    Bua J, Volta BJ, Perrone AE, Scollo K, Velázquez EB, Ruiz AM, et al. How to improve the early diagnosis of Trypanosoma cruzi infection: relationship between validated conventional diagnosis and quantitative DNA amplification in congenitally infected children. PLoS Negl Trop Dis. 2013;7:e2476.
  • 12
    Ramos-Casals M. Therapy: Are TNF blockers safe for patients with hepatitis B virus infection? Nat Rev Rheumatol. 2010;6:618-20.
  • 13
    Ferreira MS, Nishioka Sde A, Silvestre MT, Borges AS, Nunes-Araújo FR, Rocha A. Reactivation of Chagas' disease in patients with AIDS: report of three new cases and review of the literature. Clin Infect Dis. 1997;25:1397-400.
  • 14
    de Freitas VL, da Silva SC, Sartori AM, Bezerra RC, Westphalen EV, Molina TD, et al. Real-time PCR in HIV/Trypanosoma cruzi coinfection with and without Chagas disease reactivation: association with HIV viral load and CD4 level. PLoS Negl Trop Dis. 2011;5:e1277.

Publication Dates

  • Publication in this collection
    June 2015

History

  • Received
    18 Mar 2014
  • Accepted
    28 May 2014
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