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On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.84 no.4 Rio de Janeiro July/Aug. 2009
Gleyce Tavares de Melo FortalezaI; Maria de Fátima de Medeiros BritoII; Josemir Belo dos SantosIII; Ana Roberta FigueiredoIV; Perla GomesV
studies under course, Service of Dermatology, Hospital das Clínicas de
Pernambuco Universidade Federal de Pernambuco (HC-UFPE) Recife
IIPh.D. and Master in Dermatology, Universidade Federal de Pernambuco (HC-UFPE) Recife (PE), Brazil
IIIHead of the Department of Tropical Medicine and Service of Dermatology, Hospital das Clínicas de Pernambuco Universidade Federal de Pernambuco (HC-UFPE) Recife (PE), Brazil
IVResident Physician, Service of Dermatology, Hospital das Clínicas de Pernambuco Universidade Federal de Pernambuco (HC-UFPE) Recife (PE), Brazil
VResident Physician, Service of Dermatology, Hospital das Clínicas de Pernambuco Universidade Federal de Pernambuco (HC-UFPE) Recife (PE), Brazil
Psoriasis is a chronic inflammatory disease affecting the skin and occasionally the joints. The biological agents have been engineered to target a specific step in the inflammatory cascade that leads to psoriasis, including tumor necrosis factor, which has a central role in the host defense against Mycobacterium tuberculosis. This is a case report about a psoriatic patient who presented splenic tuberculosis during treatment with infliximab.
Keywords: Psoriasis; Biological therapy; Tuberculosis
Psoriasis is a chronic disease of intermittent course that affects the skin and in some cases the joints as well. Severity of the disease is highly variable and in severe forms there is compromise of patients' quality of life. To present, there is no definite cure for psoriasis, and the objective of treatment is to quickly control the disease and provide prolonged remission.
Mild forms may be treated with topical agents, whereas moderate and severe forms normally require phototherapy or systemic treatment, including drugs such as methotrexate, acitretine, cyclosporine or biological agents.1
Biological agents represent major acquisitions in the therapeutic arsenal of psoriasis. These drugs were developed to reach the specific goals in the inflammatory cascade that leads to the disease. They may be subcategorized as T-cell inhibitors or cytokine antagonists 2,3. Among the cytokine antagonists, we can include infliximab, an inhibitor of alpha tumor necrosis factor (TNF-α). Even though biological therapy is considered safe and effective, it is important to be on the watch for potential risks associated with its use.
Caucasian 43-year-old man, holder of psoriasis for nine years, no joint impairment. Upon examination, we observed erythematous-desquamative plaques on the trunk, lower limbs and scalp (Figures 1 and 2). The disease did not respond to topical therapy and the patient presented intolerance to treatment with acitretine and methotrexate, which led to the indication of infliximab use. There was indication of phototherapy, but it was not available in our Center. All initial lab tests were normal, including anergy tuberculin test (zero) and chest x-rays without any abnormalities. Induction regimen with infliximab was started infusion of 50mg/Kg weight in weeks zero, two and six, associated with the use of methotrexate, 5 mg/week PO, to inhibit the production of antibodies. The patient progressed without significant improvement of skin lesions (Figure 3 and 4), but one month after the 3rd dose of infliximab he presented daily daytime fever, asthenia and weight loss. Complete blood count, cultures, urinalysis, urine culture, chest and paranasal sinus x-ray, abdominal ultrasound and sputum bacilloscopy were performed and did not show any abnormal results. Chest Computed Tomography Scan (CT scan) showed pleural effusion on the left, associated with passive atelectasia of basal segments of lower lobe, in addition to subtle nodular opacities of ground glass appearance on the right upper lobe (Figure 5). Pleural fluid analysis showed exsudate pattern, adenosine deaminase dosing = 34 U/L; the other parameters were nonspecific. CT scan of the abdomen showed increase in spleen volume, which presented heterogeneous aspect, with multiple and small isoattenuating images on the parenchyma, hypodense areas on contrasted phase and nonspecific character, in addition to intensification of mesenteric fat, of reticular aspect, suggestive of inflammatory affection (Figure 6). Splenic puncture with culture for bacteria, fungi and Kock bacilli (KB) was performed, which were all negative. Polymerase chain reaction for KB in blood and urine were also negative. Serology for paracoccidioidomycosis and histoplasmosis were not reagent. Histopathological tests of splenic fragments showed granulomatous splenitis of undetermined nature. Ziehl-Nielsen staining and PAS did not reveal alcohol-acid-resistant bacilli or fungi. An empirical treatment with regimen I for tuberculosis (rifampicin, isoniazid and pyrazinamide) was started, leading to total regression of symptoms and splenic lesions. Cutaneous lesions of psoriasis have not shown recurrence to present.
Psoriasis is a chronic dermatosis of universal occurrence characterized by the presence of erythematous-cutaneous lesions. In its pathogenesis there is acceleration of epidermal germ cycle, with marked shortening of the time of cell renovation in the epidermis of lesions. It is a condition mediated by activated T cells, showing a cytokine pattern of Th1, especially interleukin 2 and TNF-α. 4
Studies of quality of life in psoriasis revealed a similar impact to that observed in cancer, cardiopathy and arthritis 5. Patients with severe disease comprise approximately 20-30% of the cases and frequently require systemic treatment. All systemic therapy for psoriasis are associated with long term toxicity potential, in addition to high cost and possibility of failure. Biological therapy comprises a group of drugs designed to block specific stages of the inflammatory cascade implied in psoriasis pathogenesis. Currently, biological therapy is divided into two groups: (1) antagonists agents of TNF-α (ex. infliximab, etanercept, adalimumab), and (2) agents against T cells or antigen-presenting cells (ex. efalizumab, alefacept).6
Infliximab is a chimeric monoclonal antibody that competitively inhibits the soluble TNF-α and the forms linked with the cell membrane. It is indicated in psoriasis in plaques, psoriatic arthritis, Chrohn's disease, ankylosing spondilitis and rheumatoid arthritis, administered by intravenous infusion. Given that it is an immune suppressant agent, the occurrence of infections is a major concern in patients taking infliximab, as well as any other anti- TNF-α agent. In our country, there is special concern with tuberculosis (TB) 1.
TNF-α is a proinflammatory cytokine produced by lymphocyte T, macrophages and keratinocytes, found in high levels on the skin of psoriasis patients. It stimulates the production of other cytokines, including interleukins 1 (IL-1), IL-6 and IL-8 in addition to promoting proliferation of keratinocytes. All these signs may lead to inflammation in many organs, such as the skin and the joints. With neutralization of this cytokine by anti- TNF-α medication, there is interruption of the essential inflammatory cascade in the pathophysiology of psoriasis and psoriatic arthritis 7.
TNF-α effects are important not only in inflammation disorders, but they also have a crucial role in the defense of the host against Mycobacterium tuberculosis. The human immune response is highly efficient in containing the primary infection resulting from KB exposure, but not all viable microorganism are eliminated in some subjects. The bacillus may remain latent, period in which the infected subject is asymptomatic, but he has M. tuberculosis organism and at any time can trigger the disease 8. This condition is known as latent tuberculosis. TNF-α is involved in the destruction of bacilli through activation of macrophages and in preventing dissemination of infection by stimulating granuloma formation. Given that TNFκ is implied both in the protection against infection by mycobacteria and in the pathogenesis of tuberculosis, it is not surprising that the use of anti-TNF-α is associated with increase in incidence of TB 9. Even though in some cases there is new infection by M. tuberculosis, most result in reactivation of latent TB 10. Moreover, atypical presentations of TB such as extrapulmonary and disseminated forms are more frequent during treatment with any other anti- TNF-α agents 11.
The Disease Prevention and Control Center (CDC) recommends the performance of tuberculin test in all patients treated with TNF-a inhibitors. 12 Induration equal or greater to 5mm after 48 to 72 hours is considered positive for any patient candidate for use of anti TNF-α. Many immunocompromised subjects show anergy to tuberculin test; consequently, induration below 5mm should not definitely exclude the possibility of infection by M. tuberculosis. Even though it has immunosuppressant effect, anti-TNF treatment does not modify the response to tuberculin test 11.
The positivity of tuberculin test may mean latent infection by M. tuberculosis or active disease. Chest x-ray is an important screening test to try to differentiate the two conditions and should be performed in all patients with positive tuberculin test in programming treatment with biological agents 11. Suspicions findings in x-ray should lead to progression of investigation with sputum test or other tests that are necessary, and once TB diagnosis is confirmed, treatment with triple regimen should be started. Subjects with positive tuberculin test, but without radiological findings suggestive of TB, should be considered as holders of latent TB and receive prophylactic treatment before the beginning of anti-TNF agents 13.
Latent TB treatment proved to be efficient in preventing the development of active TB in 60% to 70% of patients, but even with good compliance to prophylactic treatment, some cases of TB may occur 14. In addition to prophylaxis, it is extremely important to maintain the surveillance of cases of active TB and atypical manifestations of tuberculosis in all patients using anti-TNF-α agents. In these cases, biological therapy is suspended and the triple regimen is started. 13
The biological therapy proved to be effective in the treatment of psoriasis. It represents an effective therapeutic option for those that do not tolerate conventional treatment or those in which it is not enough. However, as TNF-α is also a significant cytokine to fight infections, especially tuberculosis, the use of anti-TNF-α is associated with the risk of developing active TB.
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Gleyce Tavares de Melo Fortaleza
Rua dos Navegantes, nº 541, ap. 301, Boa Viagem,
CEP: 51021-010 - Recife - PE
Tel./Fax: 81 3326-6304/81 9212-6702/81 8818-0101
Conflict of interest:
Financial funding: None
How to cite this article: Fortaleza GTM, Brito MFM, Santos JB, Figueiredo AR, Gomes P. Tuberculose esplênica durante tratamento de psoríase com infliximabe. An Bras Dermatol. 2009;84(4):420-4.