The role of immunosuppressive agents in increased risk of viral infections in organ transplant recipients is widely recognized.1 Among the latter, infection with human papillomavirus (HPV) is responsible for the development of viral warts which may cause significant morbidity in individuals unable to mount an adequate T-helper-1-cell-mediated immune response. Moreover, some of these viral warts may have atypical histological features and therefore may progress to squamous cell carcinoma.2 Current therapies for HPV-associated warts mainly depend on the destruction of affected skin areas. But these treatments are of limited efficacy when the disease is diffused and, most importantly, are often painful for patients.3
New immunosuppressive drugs belonging to the target-of-rapamycin (TOR) inhibitors family (sirolimus, everolimus) have been successfully developed for the prevention of organ rejection after transplantation.4–8 They have also demonstrated a specific cytostatic effect on proliferating cells in vitro and in vivo, currently leading to a number of clinical trials in malignancies.9–15 Maintenance immunosuppression with TOR inhibitors has been associated with a significantly reduced incidence of de novo malignancies after renal transplantation16 and recent reports support the hypothesis that TOR inhibitors may also actually interfere with virus replication in the host.17–22 We report here the case of a young liver transplant recipient in whom sirolimus monotherapy conversion was followed by a rapid improvement in cutaneous warts. This case provides preliminary evidence that TOR inhibitors may be beneficial in immunosuppressed patients with recalcitrant severe cutaneous HPV-induced warts.
HPV, human papillomavirus; TOR, target of-rapamycin; OLT, orthotopic liver transplantation.
A 17-year-old girl was referred to our institution for screening prior to orthotopic liver transplantation (OLT) in July 2002. Her past medical history was noteworthy for type 1 autoimmune hepatitis diagnosed in February 1999 on a combination of suggestive features associating a marked elevation in serum γ-globulins at 26 g/L, seropositivity for anti-smooth muscle (1:200) and antinuclear (1:640) antibodies and histological features including periportal hepatitis with lymphocytic infiltrates and plasma cells. At that time, initial presentation associated hepatocellular failure (INR at 1.6, factor V 57% and albumin 26 g/L), jaundice (total bilirubin at 48 μmol/L) and increase aminotransferases level (over 5-fold the normal value). Primary therapeutic management consisted of an association of corticosteroids (prednisolone at 2 mg/kg/day) and azathioprine (2 mg/kg/day), leading to a significant favourable response in terms of clinical status and biochemical parameters. The progressive development of steroid-induced side effects led to their progressive decrease and replacement by oral cyclosporine 50 mg twice per day (SANDIMMUN® 100mg/mL) in August 1999 (Fig. 1). Clinical evolution and biological parameters enabled prednisolone withdrawal in May 2000, without any sign of relapse of the underlying liver disease and treatment consisted in a combination of cyclosporine and azathioprine.
A few months after the start of cyclosporine treatment, the patient developed warts, first on the finger extremities, involving the periungual region and the back of the hands. A clinical diagnosis of cutaneous HPV-induced warts with classical and limited features was made and dermatological specific treatment was initiated using local applications of keratolytic agents (salicylic acid 20%). Azathioprine was also withdrawn in November 2001 and the patient remained under cyclosporine monotherapy because of the normalization of functional liver tests, the absence of hypergammaglobuminemia and antibodies directed against smooth muscle. However, evidence for cirrhotic progression appeared in April 2002 with the development of cirrhotic decompensation with ascites leading to diuretic therapy. During this period, the numbers of warts increased progressively, reaching the soles of the feet and to a lesser extent, the legs and arms. A local first line of treatment remained unsuccessful. Pre-OLT screening showed Child Pugh B9 cirrhosis, upper digestive endoscopy showed portal hypertension with grade 3 esophageal varices and portal hypertension gastropathy. The patient was put on the waiting list on August 1, 2002 and OLT occurred on August 18, 2002. The postoperative course was uneventful, and histological examination of explanted liver confirmed diagnose of autoimmune cirrhosis. She was discharged from the hospital on day 17 with normal laboratory tests and the following immunosuppressive regimen: prednisolone (15 mg/day), tacrolimus (4 mg × 2/day) and mycophenolate mofetil (500 mg × 3/day).
In September 2002, carbon dioxide laser therapy was considered, but was not performed because of a high infectious hazard in this setting of immunosuppression, and also because of the extent of lesions. A combination of salicylate derivatives and cryotherapy was continued regularly in November 2002. The overall benefits were weak, as warts remained resistant to this therapeutic approach. Tacrolimus doses increased in March 2003 to 5 mg × 2/day because of suspicion of underimmunosuppression. In July 2003 a new localization appeared on the face, and was viewed as psychologically and socially unacceptable for the patient. Despite the potential risk of liver graft dysfunction, local application of imiquimod on the fingers was attempted for several weeks in October 2004, with no positive results. Due to the extent of the lesions with multiple localisations (hands, Fig. 2a; face, Fig. 2b; legs, arms, and feet, Fig. 2c) despite the use of the local and specific therapies, the immunosuppressive regimen was modified in June 2005, with an increase in mycophenolate mofetil to 1 g × 2 in order to decrease the dose of tacrolimus to 2 mg × 2/day, and then 1 mg × 2/day. These new regimens led to biopsy-proven grade 2 acute rejection according to Banff's classification in July 2005. Three consecutive corticosteroid boluses did not have a clear influence on biochemical abnormalities, and sirolimus 5 mg/day was introduced on July 25, 2005. At the end of August, warts exhibited inflammation and a focal area of hemorrhagic crust, followed by a modification in their thickness under sirolimus monotherapy. In September 2005, a significant improvement was seen, with a decrease in wart number first on the hands and then on the feet. Aminotransferase levels returned to normal in October 2005. Four months later, there was a dramatic improvement in the warts (Fig. 2d-2f). Sirolimus blood levels ranged between 8.1 and 11.5 ng/mL during the resolution of the warts. She remained well when last seen in June 2006.
The role of calcineurin inhibitors (cyclosporine, tacrolimus), widely used following organ transplantation, in the genesis of viral diseases, and notably HPV-associated warts, is well established.1, 23 In European populations, these warts are generally induced by HPV-2, HPV-27 and HPV-57, as observed in immunocompetent populations.24 They occur more often in patients with autoimmune disease such as lupus erythematosus suggesting a primary immunological defect among these patients.25, 26 Dermatological complications following transplantation are very common and 80% of transplant recipients will develop some warts. In this setting, the two most common treatments are patient-applied salicylic acid and physician-administered destruction methods (cryotherapy or laser therapy).3 Nevertheless, in a minority of cases, warts may be painful depending on their location (e.g., soles of the feet and near the nails), and are viewed as socially unacceptable when extended and/or located on visible areas (e.g., hands and face) as in our case. In this setting of transplantation, therapeutic management of warts may be disappointing because of the extent of the lesions in patients unable to develop a sufficient immune response directed against HPV. Moreover, although warts remain benign in nature, their potential progression to squamous cell carcinoma has been widely evoked.2
In our case, first-line treatments failed, and the psychological repercussions on daily life were high, i.e., our patient was unable to develop social relationships and she had not returned to school since the time of transplantation. Few publications have documented the effect of post-transplant dermatological complications on the quality of life, but female gender and young age are known to be independent predictive factors of impaired quality of life for dermatological complications following transplantation.27 Taking into account the fact that clinical efficacy of imiquimod has been observed for certain skin lesions, including viral warts in both immunocompetent and immunosuppressed patients,28, 29 we tested whether this new drug may be useful, safe and efficient in our case. Imiquimod is the leading member of a new class of immune response modifiers initially developed for topical treatment of external genital and perianal warts, and it is also effective in superficial and nodular basal cell carcinomas in non-immunosuppressed patients, and for treating squamous cell carcinomas in situ in transplant patients.30, 31 It enhances both the production and activity of antiviral cytokines such as interferon-γ.32, 33 Cytokines trigger the host's immune system to recognize and eradicate the skin lesion. This mechanism of action is thought to be harmful because of the increase in the T-helper-1-cell-mediated immune response which is also involved in the acute allograft rejection process. When this second approach failed, as a last resort, we significantly modified the immunosuppressive regimen with a decrease in the calcineurin inhibitor. The course which followed was noteworthy, with steroid-resistant acute rejection. A sparing strategy in case of autoimmune disease was not a good choice. Taking into account the properties of TOR inhibitors, we successfully tempted sirolimus conversion. TOR inhibitors are currently used in the prevention of rejection following kidney6, 7, 34 and more recently liver transplantation.4, 5 Several lines of evidence suggested that these drugs may be useful in the prevention of de novo tumors and the treatment of malignancies because of antiproliferative and cytostatic properties.9, 11, 12, 14–16 Recent studies have suggested that TOR inhibitors may interfere with the replication of different types of herpes viruses (cytomegalovirus, herpes virus 8, Epstein-Barr virus)18, 19, 35 and retroviruses (human immunodeficiency virus).21 Indeed, clinical trials showed significant lower incidence of cytomegalovirus infection following heart,17 liver,22 and kidney transplantations,20 while in vitro experiments showed that this effect was at least in part mediated through inhibition of the phosphatidylinositol-3-kinase (PI3k)/protein kinase B (Akt) pathway, an upstream activator of TOR which plays a key role in viral replication.36, 37 Since HPV activates the PI3k/Akt pathway,38–40 it is tempting to hypothesize that TOR inhibitors may alter HPV pathogenesis and thereby improve the course of warts.
After conversion to sirolimus and calcineurin inhibitor withdrawal, aminostransferase levels returned to normal and the cosmetic benefit appeared after a few weeks: initially with significant modifications in the thickness and color of the warts, followed by a reduction in their number, leading to overall improvement in this dermatological complication. To our knowledge, the successful use of TOR inhibitors in multitreatment-resistant HPV-induced warts has not been previously reported after OLT.
In summary, conversion to TOR inhibitors may be of benefit in immunosuppressed patients with recalcitrant severe cutaneous HPV-induced warts. Early dermatological referral and a careful choice of immunosuppressive therapy may enhance the quality of life, particularly in young female recipients with HPV-induced warts.