RESUMEN
Short-term (26 weeks) Tg.rasH2 mouse carcinogenicity studies have been conducted as an alternative model to the conventional 2-year mouse carcinogenicity studies, using urethane as a positive control material. In these studies, urethane was used at a dose of 1,000 mg/kg/dose, administered intraperitoneally on days 1, 3, and 5. Urethane consistently produces lung adenomas and carcinomas and hemangiosarcomas of the spleen, proving validity of the assay. We conducted 3 pilot studies at 3 different sites of Charles River Laboratories using a lower dose of urethane (500 mg/kg/dose), administered on days 1, 3, and 5, followed by a 12-week observation period. Our results demonstrate that a lower dose can be used successfully with fewer number of animals per sex to prove the validity of the assay. However, based on our cumulative experience with this model, we propose to eliminate positive control dose groups in future Tg.rasH2 carcinogenicity studies.
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Experimentación Animal , Pruebas de Carcinogenicidad/métodos , Carcinógenos/toxicidad , Neoplasias Pulmonares/inducido químicamente , Neoplasias del Bazo/inducido químicamente , Uretano/toxicidad , Animales , Femenino , Neoplasias Pulmonares/fisiopatología , Masculino , Ratones , Ratones Transgénicos , Neoplasias del Bazo/fisiopatologíaAsunto(s)
Enfermedad de Crohn/tratamiento farmacológico , Inmunosupresores/efectos adversos , Neoplasias Hepáticas/inducido químicamente , Linfoma de Células T/inducido químicamente , Pancitopenia/etiología , Neoplasias del Bazo/inducido químicamente , Biopsia , Examen de la Médula Ósea , Colonoscopía , Enfermedad de Crohn/diagnóstico , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Linfoma de Células T/diagnóstico , Linfoma de Células T/terapia , Masculino , Valor Predictivo de las Pruebas , Factores de Riesgo , Neoplasias del Bazo/diagnóstico , Neoplasias del Bazo/terapia , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL) is a rare, poorly treatable malignancy associated with therapy for IBD. Current knowledge of HSTCL risk in IBD comes from an era of step-up therapy, before earlier use of biologics or combination therapy was advocated to achieve deep mucosal healing. HSTCL risk among newer biologic classes has also not been evaluated. AIMS: To systematically characterise the association of HSTCL with biologic therapy for IBD. METHODS: We conducted a literature search and query of the Food and Drug Administration Adverse Event Reporting System to summarise HSTCL cases among IBD patients with prior biologic exposure. Demographics and immunosuppression exposure were extracted. Patients were stratified by current regimen (combination therapy, biologic monotherapy or no biologic), and biologic class (anti-TNF, anti-integrin, anti-interleukin 12/23). RESULTS: Sixty-two cases of HSTCL were identified from 2486 abstracts and 181 FDA Adverse Events Reporting System reports. The median age of affected patients was 28 years (range 12-81), and 83.6% were male, 84.7% had Crohn's disease. Five of 62 patients had no reported azathioprine/mercaptopurine exposure. Three patients within the cohort developed HSTCL after exposure to natalizumab, vedolizumab or ustekinumab; all three also had anti-TNF and azathioprine/mercaptopurine exposure. Forty-three of 49 (87.8%) patients with known outcomes died with a median survival of 5 months. CONCLUSIONS: Consistent with existing data, almost all identified HSTCL cases among IBD patients on biologic therapy had azathioprine/mercaptopurine exposure, and all cases on patients exposed to biologics had anti-TNF exposure. These data suggest initiating a patient-centred discussion before starting anti-TNF therapy or other biologics.
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Productos Biológicos/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/epidemiología , Neoplasias Hepáticas/epidemiología , Linfoma de Células T/epidemiología , Neoplasias del Bazo/epidemiología , Adolescente , Adulto , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Neoplasias Hepáticas/inducido químicamente , Linfoma de Células T/inducido químicamente , Masculino , Persona de Mediana Edad , Neoplasias del Bazo/inducido químicamente , Estados Unidos/epidemiología , United States Food and Drug Administration , Adulto JovenRESUMEN
We report the first 2 cases of hepatosplenic T-cell lymphoma in adolescents diagnosed with autoimmune hepatitis under long-term treatment with azathioprine. Patients presented with fatigue, hepatosplenomegaly, and pancytopenia. The diagnosis could be confirmed performing biopsies of liver and spleen or bone marrow, which demonstrated infiltration of neoplastic T lymphocytes with the typical phenotype with both markers, CD56(+) and TCRγδ(+) Thus, these cases emphasize the need to constantly reevaluate the administered dose and duration of thiopurines for autoimmune hepatitis, especially in adolescents.
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Azatioprina/efectos adversos , Hepatitis Autoinmune/tratamiento farmacológico , Inmunosupresores/efectos adversos , Neoplasias Hepáticas/inducido químicamente , Linfoma de Células T/inducido químicamente , Neoplasias del Bazo/inducido químicamente , Adolescente , Azatioprina/uso terapéutico , Femenino , Hepatitis Autoinmune/complicaciones , Humanos , Inmunosupresores/uso terapéutico , Neoplasias Hepáticas/diagnóstico , Linfoma de Células T/diagnóstico , Masculino , Neoplasias del Bazo/diagnósticoRESUMEN
Hepatosplenic T-cell lymphoma (HSTCL) is a rare non-Hodgkin lymphoma with a high mortality rate. Higher incidence is reported in patients with inflammatory bowel disease, specifically in male patients that are younger than 35 years, and have been treated with thiopurine and tumor necrosis factor (TNF)-α inhibitor combination therapy for over 2 years. In this case report we describe a 47-year-old patient with Crohn's disease (CD) who developed HSTCL after having been treated with thiopurine monotherapy for 14 years. To our best knowledge, only eleven cases exist of patients with CD who developed HSTCL while on thiopurine monotherapy. We report the first patient with CD, older than 35 years, who developed HSTCL while on thiopurine monotherapy. This emphasizes that HSTCL risk is not limited to young men receiving both thiopurines and TNF-α inhibitors.
Asunto(s)
Azatioprina/efectos adversos , Enfermedad de Crohn/tratamiento farmacológico , Inmunosupresores/efectos adversos , Neoplasias Hepáticas/inducido químicamente , Linfoma de Células T/inducido químicamente , Neoplasias del Bazo/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azatioprina/administración & dosificación , Biopsia , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/inmunología , Esquema de Medicación , Resultado Fatal , Hemorragia Gastrointestinal/inducido químicamente , Humanos , Huésped Inmunocomprometido , Inmunohistoquímica , Inmunosupresores/administración & dosificación , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Linfoma de Células T/diagnóstico , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/inmunología , Masculino , Persona de Mediana Edad , Mucositis/inducido químicamente , Tomografía de Emisión de Positrones , Factores de Riesgo , Neoplasias del Bazo/diagnóstico , Neoplasias del Bazo/tratamiento farmacológico , Neoplasias del Bazo/inmunología , Factores de TiempoAsunto(s)
Hemangiosarcoma/inducido químicamente , Neoplasias Hepáticas/inducido químicamente , Neoplasias del Bazo/inducido químicamente , Dióxido de Torio/efectos adversos , Anciano , Carcinógenos , Medios de Contraste , Resultado Fatal , Hemangiosarcoma/diagnóstico por imagen , Humanos , Hígado/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Masculino , Intensificación de Imagen Radiográfica , Bazo/diagnóstico por imagen , Neoplasias del Bazo/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
AIM: To investigate if azathioprine could reduce adenoma formation in Apc(Min/+) , a mouse model of sporadic intestinal tumorigenesis. METHODS: Azathioprine was administered via drinking water (estimated 6-20 mg/kg body weight per day) to Apc(Min/+) and wildtype mice. Control animals received vehicle only (DMSO) dissolved in drinking water. At 15 wk of age all mice were sacrificed and intestines of Apc(Min/+) were harvested for evaluation of polyp number. Azathioprine induced toxicity was investigated by immunohistochemical analysis on spleens. RESULTS: All azathioprine treated mice showed signs of drug-associated toxicity such as weight loss and development of splenic T-cell lymphomas. Although this suggests that the thiopurine concentration was clearly in the therapeutic range, it did not reduce tumor formation (48 ± 3.1 adenomas vs 59 ± 5.7 adenomas, P = 0.148). CONCLUSION: We conclude that in the absence of inflammation, azathioprine does not affect intestinal tumorigenesis.
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Poliposis Adenomatosa del Colon/prevención & control , Anticarcinógenos/farmacología , Azatioprina/farmacología , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/metabolismo , Poliposis Adenomatosa del Colon/patología , Animales , Anticarcinógenos/toxicidad , Azatioprina/toxicidad , Femenino , Genes APC , Linfoma de Células T/inducido químicamente , Linfoma de Células T/patología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias del Bazo/inducido químicamente , Neoplasias del Bazo/patología , Factores de TiempoAsunto(s)
Azatioprina/efectos adversos , Inmunosupresores/efectos adversos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Mercaptopurina/efectos adversos , Canadá , Gastroenterología , Humanos , Enfermedades Inflamatorias del Intestino/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/prevención & control , Linfoma de Células T/inducido químicamente , Linfoma de Células T/prevención & control , Sociedades Médicas , Neoplasias del Bazo/inducido químicamente , Neoplasias del Bazo/prevención & controlRESUMEN
We present three cases of the rare hepatosplenic T-cell lymphoma (HSTCL); two patients suffering from Crohn disease who developed HSTCL on azathioprine without exposure to biologicals, and a third patient who had psoriasis treated using etanercept, cyclosporine and methotrexate. The evidence for an association between HSTCL and immunosuppressive drugs and biologicals is reviewed. We argue for improved pharmacovigilance processes to help determine the benefit to risk ratios for the use of these and other new agents.
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Productos Biológicos/efectos adversos , Inmunosupresores/efectos adversos , Neoplasias Hepáticas/diagnóstico , Linfoma de Células T/diagnóstico , Neoplasias del Bazo/diagnóstico , Adulto , Humanos , Neoplasias Hepáticas/inducido químicamente , Linfoma de Células T/inducido químicamente , Masculino , Factores de Riesgo , Neoplasias del Bazo/inducido químicamenteAsunto(s)
Ácidos Aristolóquicos/efectos adversos , Medicamentos Herbarios Chinos/efectos adversos , Linfoma de Células B/inducido químicamente , Neoplasias del Bazo/inducido químicamente , Quimioterapia Adyuvante , Femenino , Humanos , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/inducido químicamente , Fallo Renal Crónico/cirugía , Linfoma de Células B/diagnóstico , Linfoma de Células B/cirugía , Persona de Mediana Edad , Nefrectomía , Esplenectomía , Neoplasias del Bazo/diagnóstico , Neoplasias del Bazo/cirugía , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: To identify demographic and clinical characteristics associated with cases of hepatosplenic T-cell lymphoma (HSTCL) in patients with Crohn's disease, and to assess strength of evidence for a causal relationship between medications and HSTCL in Crohn's disease. METHODS: We identified cases of HSTCL in Crohn's disease in studies included in a comparative effectiveness review of Crohn's disease medications, through a separate search of PubMed and Embase for published case reports, and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS). We used three causality assessment tools to evaluate the relationship between medication exposure and HSTCL. RESULTS: We found 37 unique cases of HSTCL in patients with Crohn's disease. Six cases were unique to the published literature and nine were unique to AERS. Cases were typically young (<40 years of age) and male (86%). The most commonly reported medications were anti-metabolites (97%) and anti-tumor necrosis factor alpha (anti-TNFa) medications (76%). Dose and duration of therapy were not consistently reported. Use of aminosalicylates and corticosteroids were rarely reported, despite the high prevalence of these medications in routine treatment. Using the causality assessment tools, it could only be determined that anti-metabolite and anti-TNFa therapies were possible causes of HSTCL in Crohn's disease based on the data contained in the case reports. CONCLUSION: Systematic reviews that incorporate case reports of rare lethal events should search both published literature and AERS, but consideration should be given to the limitations of case reports. In this study, establishing a causative effect other than 'possible' between anti-metabolite or anti-TNFa therapies and HSTCL was not feasible because case reports lacked data required by the causality assessments, and because of the limited applicability of causality assessment tools for rare irreversible events. We recommend minimum reporting requirements for case reports to improve causality assessment and routine reporting of rare life-threatening events, including their absence, in clinical trials to help clinicians determine whether rare adverse events are causally related to a medication.
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Antimetabolitos/efectos adversos , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/efectos adversos , Neoplasias Hepáticas/inducido químicamente , Linfoma de Células T/inducido químicamente , Neoplasias del Bazo/inducido químicamente , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Antiinflamatorios/efectos adversos , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antimetabolitos/uso terapéutico , Niño , Recolección de Datos/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Fármacos Gastrointestinales/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Carcinogenicity of 1,1,1-trichloroethane (TCE) was examined by an inhalation exposure of F344 rats and BDF1 mice of both sexes to TCE at 0, 200, 800 or 3200 ppm for 6 h/d, 5 d/week for 104 weeks. In male rats, the incidences of bronchiolo-alveolar adenomas and peritoneal mesotheliomas were significantly increased in the 800 and 3200 ppm-exposed groups, respectively. The incidence of bronchiolo-alveolar adenomas in the 3200 ppm-exposed groups exceeded the range of historical control data in the Japan Bioassay Research Center. In female rats, the tumor incidences were not increased in any organs of the TCE-exposed groups. In male mice, a significant positive trend with dose was shown for incidences of bronchiolo-alveolar carcinomas, combined incidences of bronchiolo-alveolar adenomas/carcinomas and hepatocellular adenomas. The incidence of Harderian gland adenomas was significantly increased in the 3200 ppm-exposed group, and malignant lymphomas of spleen at this highest dose exceeded the range of historical control data. In female mice, the combined incidence of bronchiolo-alveolar adenomas/carcinomas was significantly increased in the 3200 ppm-exposed group, and the incidences of hepatocellular adenomas and combined incidences of hepatocellular adenomas/carcinomas were significantly increased in the 200, 800 and 3200 ppm-exposed groups with dose dependence except the combined incidence of hepatocellular adenomas/carcinomas in the 200 ppm-exposed group. The incidences of bronchiolo-alveolar adenomas in the 3200 ppm-exposed group and combined incidences of hepatocellular adenomas/carcinomas in the 200 ppm-exposed groups exceeded the ranges of historical control data. Thus, this study provided clear evidence of inhalation carcinogenicity for TCE in both rats and mice.
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Carcinógenos/toxicidad , Carcinoma/inducido químicamente , Neoplasias Hepáticas/inducido químicamente , Neoplasias Pulmonares/inducido químicamente , Neoplasias del Bazo/inducido químicamente , Tricloroetanos/toxicidad , Adenoma/inducido químicamente , Adenoma/patología , Administración por Inhalación , Animales , Carcinógenos/administración & dosificación , Carcinoma/patología , Femenino , Glándula de Harder/efectos de los fármacos , Glándula de Harder/patología , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/patología , Linfoma/inducido químicamente , Linfoma/patología , Masculino , Ratones , Ratas , Ratas Endogámicas F344 , Neoplasias del Bazo/patología , Pruebas de Toxicidad Crónica , Tricloroetanos/administración & dosificaciónAsunto(s)
Azatioprina/efectos adversos , Trasplante de Médula Ósea , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/terapia , Linfoma de Células T/inducido químicamente , Linfoma de Células T/terapia , Neoplasias del Bazo/inducido químicamente , Neoplasias del Bazo/terapia , Azatioprina/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Neoplasias Hepáticas/diagnóstico , Linfoma de Células T/diagnóstico , Neoplasias del Bazo/diagnóstico , Trasplante HomólogoRESUMEN
The lack of a clear guidance on the adequate number of animals used for positive controls in the short-term (26-weeks) transgenic mouse carcinogenicity studies has resulted in the use of high number of animals. In our earlier Tg.rasH2 studies, 25 mice/sex were used in the urethane-positive control dose groups that were sacrificed by 18 weeks. Based on a robust response, several of our protocols for Tg.rasH2 studies with 15 mice/sex and terminal sacrifice at 17 ± 1 weeks were submitted and accepted by the Carcinogenicity Assessment Committee of the US Food and Drug Administration since we demonstrated close to 100% response for the development of lung and splenic tumors (target organs) in 500 mice/sex. These 500 mice/sex included 17 groups of 25 mice/sex and 5 groups of 15 mice/sex. The objective of this investigation was to determine whether the number of animals can be further reduced along with the shortened duration of exposure to urethane. Accordingly, 10 Tg.rasH2 mice/sex/group were administered a total of 3 intraperitoneal (IP) injections of urethane (1000 mg/kg per day) on study days 1, 3, and 5, and the presence of tumors in the lungs and spleen was evaluated after 8, 10, 12, 14, or 16 weeks. Our results demonstrate that 100% of the mice at 8 weeks had developed lung tumors, whereas close to 100% of the mice at 14 weeks had developed splenic tumors. Based on the development of lung tumors alone in 100% of the mice, we recommend that 10 mice/sex are sufficient and that these mice can also be sacrificed as early as 10 ± 1 weeks following the administration of urethane.
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Alternativas al Uso de Animales , Pruebas de Carcinogenicidad/métodos , Carcinógenos/toxicidad , Uretano/toxicidad , Animales , Grupos Control , Femenino , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Transgénicos , Neoplasias del Bazo/inducido químicamente , Neoplasias del Bazo/patologíaRESUMEN
PURPOSE: To evaluate the antitumor activity of alcoholic extracts of green tea (Camella sinensis). METHODS: Four groups of six Wistar rats were inoculated intramuscularly with 10(6) Walker tumor cells/mL. During 10 days, the animals received by gavage either 0.9% saline solution (Group I; negative control), solution containing 20 mg/Kg of tamoxifen (Group II; positive control), solution containing 0.07 g/Kg alcoholic extract of C. sinensis (Group III), or solution containing 0.14 g/Kg alcoholic extract of C. sinensis (Group IV). Following euthanasia on the tenth day, the tumor, liver, kidneys and spleen were excised and weighed, and tumor volume and tumor growth inhibition were quantified. RESULTS: The average weight of the animals was greater in Group IV than in Group II (p=0.0107). Tumor weight was smaller in Group IV than in Group I (p=0.0062), but did not differ from Group II. Tumor volume was smaller in Groups II and IV than in Group I (p=0.0131). Tumor growth inhibition was observed in Groups II (44.67% ± 32.47), III (16.83% ± 53.02) and IV (66.4% ± 25.82) (p>0.05). The groups did not differ with regard to the weight of the excised organs. CONCLUSION: Alcoholic extracts of green tea have antitumor activity.
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Camellia sinensis/química , Carcinoma 256 de Walker/tratamiento farmacológico , Catequina/farmacología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/farmacología , Neoplasias del Bazo/tratamiento farmacológico , Animales , Carcinoma 256 de Walker/inducido químicamente , Neoplasias Renales/inducido químicamente , Neoplasias Hepáticas/inducido químicamente , Masculino , Ratas , Ratas Wistar , Neoplasias del Bazo/inducido químicamente , Té/químicaRESUMEN
PURPOSE: To evaluate the antitumor activity of alcoholic extracts of green tea (Camella sinensis). METHODS: Four groups of six Wistar rats were inoculated intramuscularly with 10(6) Walker tumor cells/mL. During 10 days, the animals received by gavage either 0.9% saline solution (Group I; negative control), solution containing 20 mg/Kg of tamoxifen (Group II; positive control), solution containing 0.07 g/Kg alcoholic extract of C. sinensis (Group III), or solution containing 0.14 g/Kg alcoholic extract of C. sinensis (Group IV). Following euthanasia on the tenth day, the tumor, liver, kidneys and spleen were excised and weighed, and tumor volume and tumor growth inhibition were quantified. RESULTS: The average weight of the animals was greater in Group IV than in Group II (p=0.0107). Tumor weight was smaller in Group IV than in Group I (p=0.0062), but did not differ from Group II. Tumor volume was smaller in Groups II and IV than in Group I (p=0.0131). Tumor growth inhibition was observed in Groups II (44.67% ± 32.47), III (16.83% ± 53.02) and IV (66.4% ± 25.82) (p>0.05). The groups did not differ with regard to the weight of the excised organs. CONCLUSION: Alcoholic extracts of green tea have antitumor activity.
OBJETIVO: Avaliar a atividade antitumoral do extrato alcoólico do chá verde (C. sinensis). MÉTODOS: Quatro grupos de seis ratos Wistar foram inoculados com 1x10(6) células/mL do tumor de Walker por via intramuscular. Os grupos foram tratados durante 10 dias, por gavagem, com salina 0,9 % (Grupo I, controle negativo), 20 mg/Kg de tamoxifeno (Grupo II, controle positivo) e extrato alcoólico de C. sinensis nas doses de 0,07 g/Kg (Grupo III) ou 0,14 g/Kg (Grupo IV). O volume e a inibição do crescimento tumoral foram calculados. RESULTADOS: A média dos pesos dos animais foi maior no Grupo IV do que no Grupo II (p=0,0107). O peso tumoral do Grupo IV foi menor do que o Grupo I (p=0,0062), mas não houve diferença quando comparado ao Grupo II. O volume tumoral foi menor nos grupos II e IV quando comparados ao Grupo I (p=0,0131). Inibição tumoral foi observada nos Grupos II = 44,67 ± 32,47, III = 16,83 ± 53,02 e IV = 66,4 ± 25,82 (p>0,05). Não houve diferença no peso dos órgãos entre os grupos. CONCLUSÃO: O extrato alcoólico do chá verde possui ação antitumoral.
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Animales , Masculino , Ratas , Camellia sinensis/química , /tratamiento farmacológico , Catequina/farmacología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/farmacología , Neoplasias del Bazo/tratamiento farmacológico , /inducido químicamente , Neoplasias Renales/inducido químicamente , Neoplasias Hepáticas/inducido químicamente , Ratas Wistar , Neoplasias del Bazo/inducido químicamente , Té/químicaAsunto(s)
Azatioprina/efectos adversos , Inmunosupresores/efectos adversos , Neoplasias Hepáticas/inducido químicamente , Lupus Eritematoso Sistémico/tratamiento farmacológico , Linfoma de Células T/inducido químicamente , Neoplasias del Bazo/inducido químicamente , Azatioprina/uso terapéutico , Femenino , Humanos , Inmunosupresores/uso terapéutico , Neoplasias Hepáticas/patología , Lupus Eritematoso Sistémico/complicaciones , Linfoma de Células T/patología , Persona de Mediana Edad , Neoplasias del Bazo/patologíaRESUMEN
BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL) is a rare, lethal disease generally seen in young male patients with inflammatory bowel disease. The study of biologic and immunomodulator naive patients in Crohn's disease (SONIC), advocates combining infliximab with an immunomodulator in moderate-to-severe Crohn's disease. Unfortunately, combined immunosuppression increases risk for HSTCL. We herein review all cases of HSTCL reported to the Food and Drug Administration (FDA) in patients receiving TNF-α inhibitors. METHODS: Individual reports from the FDA Adverse Event Reporting System database for lymphomas from the biological agents - infliximab, adalimumab, certolizumab, natalizumab, and etanercept were downloaded and analyzed with Microsoft Access. Full reports for all identified HSTCL cases were obtained from the FDA. RESULTS: Twenty-five cases of HSTCL were identified. Twenty-two (88%) patients had inflammatory bowel disease and three had rheumatoid arthritis. Four cases (16%) were in women and four patients were above 65 years of age. Twenty-four cases (96%) also received an immunomodulator (azathioprine, 6-mercaptopurine, or methotrexate). Two patients received adalimumab alone. CONCLUSION: HSTCL is no longer restricted to the previously identified risk group of young male patients, but can also occur in patients with rheumatoid arthritis, females and older adults receiving TNF-α inhibitors and immunomodulators. Improved disease outcomes using combination therapy should be tempered by the risk of developing HSTCL.