Secondary Prophylaxis with Liposomal Amphotericin B in a Patient with Mucosal Leishmaniasis Undergoing Immunobiological Therapy for Active Ankylosing Spondylitis

Abstract.

Immunosuppressive treatments for rheumatic diseases present special problems in areas endemic for chronic infectious diseases because of the possibility of reactivation. Leishmaniasis is a significant neglected tropical disease caused by different species of protozoan parasites within the genus Leishmania. Amastigotes live as intracellular parasites in a variety of mammalian cells, most notably within phagocytes such as macrophages, and residual parasites can persist even after treatment and healing of the lesions. We herein report a case of relapsing mucosal leishmaniasis after aggressive immunotherapy for ankylosing spondylitis, with requirement for secondary prophylaxis with amphotericin B to prevent reactivation. This approach can be necessary for patients from endemic areas of tegumentary leishmaniasis, who will undergo aggressive immunotherapy.

INTRODUCTION

Leishmaniasis is an anthropozoonosis caused by different flagellated protozoan species of the genus Leishmania transmitted by the bite of phlebotomine insects. The clinical manifestation of the disease depends not only on the Leishmania species involved but also on the patient’s immune status.¹

In humans, disease can manifest as tegumentary leishmaniasis (TL), affecting both cutaneous (cutaneous leishmaniasis) and mucosal tissue (mucosal leishmaniasis), or as visceral leishmaniasis, affecting visceral organs. Tegumentary leishmaniasis is a granulomatous disease of the skin and/or mucosa, most commonly manifesting as localized or disseminated cutaneous ulcers, diffusely scattered papules, mucosal lesions, or even atypical lesions.² Visceral leishmaniasis is the most severe form of the disease, which can be fatal if untreated.³ However, subclinical infection without progression to disease also occurs.

The host’s pattern of immune response plays an important role and can determine the evolution of leishmaniasis, leading to either disease or control. Even in the presence of immune control, residual parasites can cause chronic reactivation of disease. The pathogenesis of mucosal tissue has been associated with a hyperactive T-cell–mediated immune response, often resulting in progressive granulomatous inflammatory response with extensive destruction of the mucosal tissue.^4,5 These patterns show different profiles of preferential cytokine production as well as other cell products involved in the final activation of effector cells and tissue lesion, especially tumor necrosis factor (TNF) alpha.⁶

Liposomal amphotericin B is an efficient drug in the treatment of all forms of leishmaniasis.^7–9 Although some patients achieve clinical cure of leishmaniasis, the need for longer duration of treatment in addition to the risk of reactivation and relapse makes the clinical form of mucosal tissue difficult to treat and control. This situation becomes critical in the presence of comorbidities such as HIV infection, immunosuppressive therapy for cancer and autoimmune disorders, and immunosuppression following organ transplantation that alter the patient’s immune response, thereby compromising therapeutic response and evolution of mucosal tissue.^10,11

Tumor necrosis factor inhibitors have revolutionized the treatment of ankylosing spondylitis (AS), and five of them have been shown to be useful in the control of AS, namely, infliximab, etanercept, adalimumab, certolizumab, and golimumab. All these TNF inhibitors can significantly improve function, spinal mobility, peripheral synovitis, enthesitis, and quality of life scores. Despite their efficacy, their use can increase the risk of severe infections, mainly by opportunistic intracellular agents, such as Leishmania.¹² Thus, leishmaniasis in patients treated with anti–TNF-alpha therapy should be added to the list of opportunistic infections associated with biological treatments.

The main objective of this work was to draw clinicians’ attention to the risk of reactivation of latent infections in patients undergoing immunosuppressive anti-TNF therapy and raise awareness of secondary prophylaxis in cases of mucosal tissue to prevent relapses and destructive lesions.

Case report.

A 38-year-old man living in the Brazilian states of Minas Gerais and Roraima, both endemic for leishmaniasis, was diagnosed with AS in 2005 and had undergone several therapeutic approaches since then without effective response. In 2015, adalimumab was initiated, but the treatment was interrupted after 5 months because of a crusted lesion in the nasal septum. The lesion was biopsied and immunohistochemical analysis initially suggested the presence of NK/T lymphoma. However, further investigation confirmed a diagnosis of leishmaniasis based on strongly positive serological tests (indirect immunofluorescence 1:80 and ELISA 1:1,280) and a positive polymerase chain reaction (PCR) of mucosal biopsy. The PCR method was according to previous publication.¹³ Nasal endoscopy revealed granulomatous tissue after crust removal, suggesting active disease. The patient was treated with liposomal amphotericin B at a total dose of 35 mg/kg,^7–9 with clinical improvement.

In December 2015, adalimumab treatment was resumed because of AS activity, but the nasal lesion relapsed and adalimumab was interrupted again. The patient was hospitalized for retreatment with liposomal amphotericin B at the same dose. Afterward, adalimumab treatment was resumed. Since September 2016, this patient has been receiving secondary prophylaxis with liposomal amphotericin B at 3 mg/kg every 3 weeks without mucosal tissue relapses.

DISCUSSION

Some infectious agents are capable of residual survival within the host following clinical cure—a phenomenon called parasite persistence.¹⁴ This latency can be maintained for long periods, sometimes persisting for the host’s entire life. In our clinical case, the patient lived in endemic regions for leishmaniasis and had no previous history of cutaneous or mucosal lesions, thus suggesting that he had latent Leishmania infection, which became manifest after immunosuppression by adalimumab. The role played by the parasite–host interaction in the phenomenon of parasite persistence is not completely clarified,^1,14 but there are some reports demonstrating that Leishmania species are capable of modulating the host’s immune response, hence allowing them to survive within the host without causing significant harm.

We use liposomal amphotericin B at a total dose of 35 mg/kg in our clinic based on previous reports of good clinical response and healing of the lesion.^7–9 Secondary prophylaxis with amphotericin B has already been described for cases of Leishmania infantum/HIV coinfection,^15,16 but the prophylactic use of this drug in mucosal tissue is not common and requires additional assessment in controlled studies, including large numbers of patients with long-term follow-up.

Evolutionary control of leishmaniasis has been directly related to the presence of type 1 immune response, with production of cytokines such as IFN-gamma and TNF-alpha.¹⁷ Physiologically, TNF-alpha plays an important role in the host’s defense regarding formation and maintenance of granuloma and control of the disease. Anti-TNF monoclonal antibodies can reactivate chronic granulomatous diseases; therefore, timely screening for latent infections and prophylactic treatment for positive cases is necessary. Current recommendations do not include screening and prophylaxis for leishmaniasis before or during anti-TNF-alpha therapy.

In the present article, we described the case of a patient who lived in endemic regions for leishmaniasis in whom anti-TNF therapy for AS led to a relapse of mucosal tissue, which was clinically cured after specific treatment. Afterward, we successfully managed to prevent mucosal tissue relapse after initiating secondary prophylaxis with liposomal amphotericin B at a dosage of 3 mg/kg every 3 weeks, whereas AS remission was maintained by adalimumab therapy. Therefore, we emphasize the need to include TL in the investigation and differential diagnosis of mucocutaneous lesions in patients undergoing immunosuppressive therapy by monoclonal antibodies, mainly in individuals living in endemic areas. The present case report suggests that secondary prophylaxis with liposomal amphotericin B can be useful for the prevention of leishmaniasis relapse in patients undergoing immunobiological therapy with anti-TNF-alpha antibodies for the control of AS.