Dermatology Online Journal

Letter: Human papilloma virus and molluscum contagiosum lesions related to infliximab therapy for psoriasis: A case series
S Georgala¹, AC Katoulis², A Kanelleas¹, A Befon¹, C Georgala¹
Dermatology Online Journal 18 (4): 9

1. First Department of Dermatology, “A. Sygros” Hospital, University of Athens, Greece.
2. Second Department of Dermatology, “Attikon” General University Hospital, University of Athens, Greece

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Abstract

INTRODUCTION: Biological therapy for psoriasis exerts its action via an immunomodulatory and eventually immunosuppressive mode. Immunosuppression is linked to HPV flares. Our purpose is to investigate a possible relationship between infliximab therapy for psoriasis and human papilloma virus and molluscum (HPV/MC) infections. METHODS: We report a case series of three patients with psoriasis on infliximab, who developed HPV/MC lesions following their treatment. RESULTS: Our patients developed HPV/MC lesions within a few months after the initiation of infliximab infusions for psoriasis. DISCUSSION: Immunosuppresion is related to HPV/MC flares. Biological therapy and in particular infliximab treatment acts by immunomodulation and eventually a degree of immunosuppression. CONCLUSIONS: Anti-TNF treatment could be associated with HPV and/or MC flares. For this reason, we suggest the consideration of obtaining a routine cervical PAP smear before the commencement and during treatment with anti-TNF agents for psoriasis.

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Introduction

Biological therapy for psoriasis is now well established. Its efficacy is proven. However, careful screening and monitoring are essential for all patients on biologics. Infliximab is a TNF-α inhibitor, which is considered a recommended medication for induction therapy for moderate to severe plaque psoriasis. Anti TNF-α therapy in general is associated with an increased risk of infections, especially of mycobacterial origin. Little is known regarding viral infections and their possible association with biological therapy. We report a case series of two cases of human papilloma virus (HPV) infection and one case of human papilloma virus and molluscum contagiosum (MC) infection developing after treatment with infliximab.

Case report 1

A 22-year-old man, without risk factors for HIV disease, presented to our clinic with multiple HPV and MC lesions on his lips, nose, abdomen, genital, and perianal areas. The patient had a 3-year history of psoriasis and was previously treated with topical corticosteroids and emollients without benefit. Nine months prior to presentation, treatment with infliximab 5 mg/kg was initiated and his psoriasis improved greatly. However, after the fourth infusion the above-mentioned lesions appeared and the patient presented to our clinic. He and his constant partner had no previous history of clinical HPV or MC infection. A PAP smear obtained from his partner was normal. The patient was HIV negative and his laboratory assessment was normal. Infliximab was discontinued and his psoriasis was treated with topical therapy. The HPV lesions were treated with three sessions of cryotherapy and the MC lesions with manual extractions.

Case report 2

A 25-year-old man with a 6-year history of psoriasis was started on infliximab 5 mg/kg. The clinical response was very good. The patient had been previously treated with topical corticosteroids and emollients and 3 years previously with cyclosporine 3 mg/kg daily for 5 months with moderate clinical response. He presented to us 2 weeks after the fourth infliximab infusion because he developed HPV lesions of the abdomen and genital areas. The patient was HIV negative and his laboratory tests were unremarkable. He had no history of HPV infection. He had a constant partner for the prior two years who had no clinical HPV infection and a negative PAP smear. Infliximab was discontinued and HPV lesions were treated with three sessions of cryotherapy. Psoriasis was treated with topical corticosteroids and emollients.

Case report 3

A 26-year-old woman presented to our department with numerous HPV lesions of the genital and perianal areas. The patient had a history of psoriasis diagnosed 4 years earlier and was previously treated with topical corticosteroids and emollients. Two years prior, cyclosporine 3.5 mg/kg was added with moderate clinical response. Cyclosporine was interrupted and infliximab 5 mg/kg was initiated. Three weeks after the fifth infliximab infusion the patient developed condylomata acuminata and presented to our clinic. The patient was HIV negative. A PAP smear, proctoscopy, and laboratory examination were normal. Her partner had no clinical HPV infection. Infliximab was discontinued and psoriasis was treated with methotrexate 15 mg/week. HPV lesions were treated with 3 sessions of cryotherapy.

Discussion

Biological therapy plays a central role in the treatment of psoriasis, mainly as a second line option in moderate to severe plaque psoriasis recalcitrant to previous topical or conventional systemic treatment. The family of biological drugs targeting tumor necrosis factor α (TNF-α) is comprised of etanercept, infliximab, and adalimumab. TNF-α is a pro-inflammatory cytokine with a complex role in innate immunity and host defense, particularly against mycobacterial infections. It acts principally by up-regulating the expression of an array of leukocyte-derived cytokines (interleukin-1, -6, -8, -18, granulocyte macrophage-colony stimulating factor), which orchestrate the aggregation of inflammatory cells at the site of infection [1, 2, 3]. The above-mentioned drugs block TNF-α. In this way they inhibit T-lymphocyte activation, which plays a pivotal role in psoriasis pathogenesis, thus exerting an immunomodulatory and eventually immunosuppressive action. Their main side effects include injection site and infusion reactions. The total incidence of infections in patients treated with biological therapy may be slightly elevated, which does not seem to apply for serious infections (those requiring antibiotic treatment or/and hospitalization). Opportunistic infections may occur [4]. In particular, regarding viral infections, reactivation of hepatitis B virus infection is common with the use of TNF-α blockers, unless anti-viral prophylaxis is used. Reactivation of herpes zoster virus is the most common problem associated with anti-TNF treatment. Also, primary varicella infection may present with atypical features in patients on anti-TNF treatment. Tuberculosis reactivation poses a significant threat related to biological therapy. Because of that, appropriate screening is advised before commencement of biological treatment. A potential risk of developing lymphoma or other malignancies cannot be excluded based on current knowledge, although it seems that in most cases the risk-benefit ratio is in the patients’ favor [4].

Infliximab is a chimeric monoclonal antibody against TNF-α. It binds with high affinity, avidity, and specificity to TNF-α. It is administered at a dose of 5 mg/kg as an intravenous infusion. Within the maintenance regimen, it is given at weeks 2 and 6 weeks, and thereafter every 8 weeks. It has the fastest response among the group of TNF-α blockers, producing a clinically significant response within 1-2 weeks [4].

Both HPV and MC virus infections occur worldwide. The latter presents mainly in childhood, whereas the former affects both children and adults. Both viruses usually have a mild to moderate clinical course in hosts with normal immune status, although immunosuppression, if present, seems to be an aggravating factor. Widespread lesions have been reported in immunocompromised patients with HIV or those receiving immunosuppressive therapy, suggesting that cell-mediated immunity is important in controlling the infection. Despite the severe immunosuppression following organ transplantation, the incidence of MC lesions is not greatly increased in this group, as opposed to other infections such as HPV and HSV lesions [5, 6, 7, 8]. Immune deficiencies, especially in cell-mediated immunity, predispose to clinically evident HPV lesions, either by reactivation of previously latent virus or by acquisition of new strains. The same applies for solid organ transplant recipients, HIV patients and patients with hematological malignancies [9, 10, 11]. Papillomas caused by HPVs are usually benign. However, a small fraction can progress to dysplasia or neoplasia. This is true for certain “high-risk” types (HPV 16, 18) and under specific predisposing genetic and environmental circumstances, which are incompletely understood.

The effect of anti-TNF therapy on HPV-associated diseases and MC occurrence remains largely unknown. TNF-α has a strong antiviral and antitumor action. It restricts the expression of E6/E7 genes in the cells infected by HPV 16 or 18 that have not yet progressed to dysplasia or neoplasia. However, during tumor progression HPV infected cells become insensitive to TNF-α [12]. E6 protein of HPV 16 binds directly to the TNF-α receptor 1 inhibiting TNF- induced apoptosis of the host cell [13]. MC viral proteins seem to interfere also with the TNF-α apoptotic pathway of the infected cells [14]. In our case, infliximab blocks TNF-α directly, allowing the expression of E6 protein. The balance is disturbed so TNF-α no longer exerts its antiviral properties. Subsequently, HPV and MC lesions develop or flare. There are very few case reports in the literature that suggest an increased risk of developing such lesions during anti-TNF therapy. Patients with inflammatory bowel disease receiving biological therapy including infliximab have been reported to show increased rates of PAP smear abnormalities, although these findings have not been universally confirmed [15, 16, 17]. There are also reports of anogenital condylomata in patients being treated with etanercept or infliximab for Crohn disease or psoriasis [7, 18].

It is logical for one to assume that anti-TNF treatment could be associated with HPV and/or MC flares. Viral reactivation is promoted by immunosuppression, which is established by the biological therapy itself. The exact mechanism is unknown. Such an assumption is strengthened by the temporal relationship between the beginning of biological treatment and onset of lesions. Our case series highlights the possible causal association between infliximab treatment and HPV/MC flares. To the best of our knowledge, it is the first case series published with three cases of confirmed lesions during infliximab treatment.

This is an observation, which needs to be confirmed by large scale studies. However, we believe that physicians should be aware of such a possibility and retain a high level of suspicion for the development of early lesions, especially in the anogenital area. We suggest the inclusion of PAP smear test to the array of screening laboratory tests for all female patients who are are candidates for psoriasis biological treatment. We also recommend its addition to the monitoring tests during treatment and for a few months afterwards. Furthermore, the consideration of administering the available HPV vaccine before anti-TNF therapy should be discussed between the patient and his/her physician as a measure of prophylaxis.

References

1. Tracey D, Lareskog L, Sasso E, et al. Tumour necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008; 117: 244-79. [PubMed]

2. Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nature Immunol 2007; 8: 950-7. [PubMed]

3. Blauvelt A. T-helper 17 cells in psoriatic plaques and additional genetic links between IL-23 and psoriasis. J Invest Dermatol 2008; 128: 1064-7. [PubMed]

4. Panthirana D, Ormerod AD, Saiag P, et al. European S3-Guidelines on the systemic treatment of psoriasis vulgaris. J Europ Acad Dermatol Venereol 2009; 23 (suppl 2): S5-70. [PubMed]

5. Rosenberg EW, Yusk JW. Molluscum contagiosum. Eruption following treatment with prednisone and methotrexate. Arch Dermatol 1970; 101: 439-41. [PubMed]

6. Cotton DW, Cooper C, Barrett DF, et al. Severe atypical molluscum contagiosum infection in an immunocompromised host. Br J Dermatol 1987; 116: 871-6. [PubMed]

7. Antoniou C, Kosmadaki MG, Stratigos AJ, et al. Genital HPV lesions and molluscum contagiosum occurring in patients receiving anti-TNF-alpha therapy. Dermatology 2008; 216: 364-5. [PubMed]

8. Euvrard S, Kanitakis J, Cochat P, et al. Skin diseases in children with organ transplants. J Am Acad Dermatol 2001; 44: 932-9. [PubMed]

9. Gentile G, Formelli G, Orsoni G, et al. Immunosuppression and human genital papillomavirus infection. Eur J Gynaecol Oncol 1991; 12: 79-81. [PubMed]

10. Rudlinger R, Grob R, Buchmann P, et al. Anogenital warts of the condyloma acuminatum type in HIV-positive patients. Dermatologica 1988; 176: 277-81. [PubMed]

11. Morison WL. Viral warts, herpes simplex and herpes zoster in patients with secondary immune deficiencies and neoplasms. Br J Dermatol 1975; 92: 625-30 [PubMed]

12. Herrero R. Human papillomavirus and cancer of the upper aerodigestive tract. J Natl Cancer Inst Monogr. 2003; 31: 47-51. [PubMed]

13. Fillipova M., Song H., Connolly JL., et al. The human papillomavirus 16 E16 protein binds to tumor necrosis factor receptor (TNF) R1 and protects cells from TNF-induced apoptosis. J Biol Chem 2002; 277: 21730-9. [PubMed]

14. Hu S., Vincenz C., Buller M., et al.: A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-1-induced apoptosis. J Biol Chem 1997; 272: 9621-4. [PubMed]

15. Kane S, Khatibi B, Reddy D. Higher incidence of abnormal pap smears in women with inflammatory bowel disease. Am J Gastroenterol 2008; 103: 631-63. [PubMed]

16. Singh H, Demers AA, Nugent Z, et al. Risk of cervical abnormalities in women with inflammatory bowel disease: a population-based nested case control study. Gastroenterology 2009; 136: 451-8. [PubMed]

17. Fireman B, Kane S, Herrinton LJ. Screening differences and risk of cervical cancer in inflammatory bowel disease. Aliment Pharmacol Ther 2008; 28: 598-605. [PubMed]

18. Somasekar A, Alcolado R. Genital condylomata in a patient receiving infliximab for Crohn’s disease. Postgrad Med J 2004; 80: 358-9. [PubMed]

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