Chronic osteo-articular changes in patients with sickle cell disease

Abstract Background: Sickle cell disease (SCD) is an autosomal recessive genetic disease in which a mutation occurs in the β-globin chain gene, resulting in abnormal hemoglobin levels. In an environment with reduced oxygen concentration, red blood cells change their conformation, resulting in chronic hemolysis and consequent anemia and vaso-occlusive crises with injuries to several organs, with a significant impairment of the osteoarticular system. This study aimed to verify the chronic osteoarticular alterations and their association with clinical and laboratory characteristics of patients with SCD with a more severe phenotype (SS and Sβ0), on a steady-state fasis. Methods: Fifty-five patients were referred to a medical consultation with a specialized assessment of the locomotor system, followed by laboratory tests and radiographic examinations. Results: In total, 74.5% patients had hemoglobinopathy SS; 67.3% were female; and 78.2% were non-whites. The mean patient age was 30.5 years. Most patients (61.8%) reported up to three crises per year, with a predominance of high-intensity pain (65.5%). Radiographic alterations were present in 80% patients. A total of 140 lesions were identified, most which were located in the spine, femur, and shoulders. Most lesions were osteonecrosis and osteoarthritis and were statistically associated with the non-use of hydroxyurea. Conclusions: There was a high prevalence of chronic osteoarticular alterations, which was statistically associated only with the non-regular use of hydroxyurea.(AU)

Evaluation of hydroxyurea genotoxicity in patients with sickle cell disease / Avaliação da indução de genotoxicidade pela hidroxiureia em pacientes com doença falciforme

ABSTRACT Objective To evaluate the induction of DNA damage in peripheral blood mononuclear cells of patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea. Methods The study subjects were divided into two groups: one group of 22 patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea, and a Control Group composed of 24 patients with sickle cell disease who were not treated with hydroxyurea. Peripheral blood samples were submitted to peripheral blood mononuclear cell isolation to assess genotoxicity by the cytokinesis-block micronucleus cytome assay, in which DNA damage biomarkers - micronuclei, nucleoplasmic bridges and nuclear buds - were counted. Results Patients with sickle cell disease treated with hydroxyurea had a mean age of 25.4 years, whereas patients with sickle cell disease not treated with hydroxyurea had a mean age of 17.6 years. The mean dose of hydroxyurea used by the patients was 12.8mg/kg/day, for a mean period of 44 months. The mean micronucleus frequency per 1,000 cells of 8.591±1.568 was observed in the Hydroxyurea Group and 10.040±1.003 in the Control Group. The mean frequency of nucleoplasmic bridges per 1,000 cells and nuclear buds per 1,000 cells for the hydroxyurea and Control Groups were 0.4545±0.1707 versus 0.5833±0.2078, and 0.8182±0.2430 versus 0.9583±0.1853, respectively. There was no statistically significant difference between groups. Conclusion In the study population, patients with sickle cell disease treated with the standard dose of hydroxyurea treatment did not show evidence of DNA damage induction.

RESUMO Objetivo Avaliar o efeito da indução de danos ao DNA em células monocelulares do sangue periférico de pacientes com doença falciforme, genótipos SS e SC, tratados com hidroxiureia. Métodos Os sujeitos da pesquisa foram divididos em dois grupos: um de 22 pacientes com doença falciforme genótipos SS e SC tratados com hidroxiureia, e o outro controle, composto por 24 pacientes com doença falciforme que não eram tratados com o fármaco. As amostras de sangue periférico foram submetidas ao isolamento de células mononucleares do sangue periférico para avaliação da genotoxicidade pelo ensaio de micronúcleo citoma com bloqueio da citocinese, tendo sido quantificados os biomarcadores de danos ao DNA - micronúcleos, pontes nucleoplasmáticas e brotamento nuclear. Resultados Os pacientes com doença falciforme tratados com hidroxiureia apresentaram média de idade de 25,4 anos, enquanto aqueles com doença falciforme não tratados com hidroxiureia tiveram média de idade de 17,6 anos. A dose média de hidroxiureia utilizada pelos pacientes foi de 12,8mg/kg/dia, por período médio de 44 meses. A frequência média de micronúcleos por 1.000 células de 8,591±1,568 foi observada no Grupo Hidroxiureia e de 10,040±1,003 no Grupo Controle. Adicionalmente, a frequência média de pontes nucleoplasmáticas por 1.000 células e brotamento nuclear por 1.000 células para o Grupo Hidroxiureia e Controle foi de 0,4545±0,1707 versus 0,5833±0,2078, e de 0,8182±0,2430 versus 0,9583±0,1853, respectivamente. Não houve diferença estatisticamente significativa entre os grupos. Conclusão Na população estudada de pacientes com doença falciforme com tratamento em dose padrão de hidroxiureia, não houve evidência de indução de danos ao DNA.

Úlceras por hidroxiurea en paciente con policitemia vera / Ulcers to hydroxyurea in a patient with polycythemia vera

La hidroxiurea es un agente citostático que inhibe la síntesis de ADN. Se considera el tratamiento de primera línea para algunos trastornos mieloproliferativos, enfermedad de células falciformes, casos severos de psoriasis refractaria y como adyuvante en la terapia de VIH. Se ha informado de que algunos pacientes tratados con hidroxiurea pueden tener úlceras en las extremidades inferiores. Paciente femenino de 67 años de edad con antecedentes de policitemia vera tratada con hidroxiurea durante un año, se deriva a dermatología por presentar úlceras bilaterales en extremidades inferiores. Al examen físico se evidencian dos lesiones ulceradas en la región calcánea. Se realiza una biopsia de piel, y muestra signos no específicos de inflamación. Se decide la interrupción de la hidroxiurea y se inicia la terapia adyuvante con pentoxifilina. Las lesiones se resolvieron en dos meses, dejando una pequeña cicatriz residual. Es importante recordar esta rara complicación inducida por el uso prolongado de la hidroxiurea y, de esta manera, realizar un diagnóstico precoz y tratamiento adecuado, que hasta el momento es básicamente la suspensión de la hidroxiurea.

Hydroxyurea is a cytostatic agent that inhibits DNA synthesis. It is considered the first line treatment for some myeloproliferative disorders, sickle cell disease, severe cases of refractory psoriasis and as adjuvant in VIH therapy. It has been reported that some patients treated with hydroxyurea may have leg ulcers. A 67 year old female patient with a history of polycythemia vera treated with hydroxyurea for a year, is derived to dermatology for presenting bilateral lower extremity ulcers. Physical examination demonstrated two ulcerated lesions in the calcaneal region. A skin biopsy is performed, and it shows non-specific signs of inflammation. Discontinuation of hydroxyurea is decided and initiate adjuvant therapy with pentoxifylline. These ulcerative lesions were resolved within two months, leaving a small residual scar. It is important to remember this rare complication induced by prolonged use of hydroxyurea and thus, early diagnosis and appropriate treatment can be made, which so far is basically the suspension of hydroxyurea.

Ocorrência de múltiplas neoplasias em paciente portador de leucemia mieloide crônica: relato de caso / Occurence of multiple neoplasms in patient with chronic myeloid leukemia: case report

Introdução: A leucemia mieloide crônica é um distúrbio mieloproliferativo clonal com uma anormalidade citogenética específica, resultante da translocação entre os cromossomos 9 e 22 com consequente produção de uma proteína com atividade tirosina quinase alterada. Tratamentos históricos com drogas como bussulfan, hidroxiureia e interferon passaram a ser pouco utilizados devido ao surgimento dos inibidores de tirosina quinase, cujo principal representante é o mesilato de imatinibe. Esse fármaco é a terapia de primeira linha, sendo bem tolerado pelos pacientes e com baixo risco de eventos adversos severos. Entretanto, com cerca de dez anos de uso, ainda há preocupação com efeitos colaterais em longo prazo, tais como o desenvolvimento de segunda neoplasia. Objetivo: Descrever a ocorrência de múltiplas neoplasias em um portador de leucemia mieloide crônica. Método: Relata-se o caso de um paciente com leucemia mieloide crônica há 13 anos, tendo utilizado hidroxiureia e interferon como terapias prévias e em uso de mesilato de imatinibe há nove anos. Resultados: Há dois anos, o paciente apresentou dois nódulos em coxa esquerda que foram totalmente ressecados. Diagnosticou-se lipossarcoma mixoide e o paciente foi submetido à radioterapia. A tomografia computadorizada do abdomên de controle aos seis meses detectou nódulo espiculado na gordura mesenquimal adjacente ao jejuno/íleo. Feita laparotomia exploradora e ressecção, o anatomopatológico demonstrou fibromatose desmoide. Conclusão: O portador de tumor maligno tem risco aumentado de desenvolver uma segunda neoplasia, que pode dessa forma ocorrer nos portadores de leucemia mieloide crônica. Essa associação pode estar relacionada aos fármacos usados no tratamento da mesma.

Oral lesions associated with hydroxyurea treatment.

Hydroxyurea (HU) is an antimetabolic agent commonly used in myeloproliferative disorders and hematological diseases as well as in severe psoriasis. Despite of usually be well tolerated, sometimes it can induce immunosuppression and mucocutaneous adverse effects associated with discomfort or pain. Nevertheless, oral mucosal adverse reactions are extremely uncommon and present as ulcers, tongue depapilation and dyschromia. Complete remission of adverse effects is usually observed after withdrawal of the medication. The aim of this paper is to report two patients with oral lesions related to HU treatment. T0 he patients were adequately managed by changing hydroxyurea with imatinib mesilate. Oral lesions are rare complications of long-term hydroxyurea treatment and may be an indication of stopping therapy and substitution with imatinib mesilate.

Manifestações retinianas em pacientes portadores de anemia de células falciformes / Retinal sings in patients with sickle cell disease

A Organização Mundial de Saúde estima que mais de 5 por cento da população mundial seja portadora de algum tipo de hemoglobinopatia. Dentre essas encontramos a anemia de células falciformes, que tem seu principal efeito lesivo sobre a vasculatura periférica. Na retina, as lesões falciformes possuem fisiopatologia e classificação bem definidas. O objetivo é identificar as manifestações retinianas à anemia falciforme em pacientes encaminhados ao Hospital Bettina Ferro de Souza a partir do Hemocentro do Estado do Pará - HEMOPA. MÉTODOS: No Serviço de Oftalmologia do Hospital Universitário Bettina Ferro de Souza realizou-se em cinquenta pacientes portadores de anemia de células falciformes, sendo 37 genótipo SS e 13 genótipo SC, foram acompanhados pelo ambulatório de anemia falciforme do HEMOPA e selecionados aleatoriamente, sendo submetidos à entrevista para registro de sexo; idade; cor; genótipo; alterações oculares; medicamentos utilizados. exame oftalmológico, incluindo angiofluoresceínografia nos casos com alteração retiniana. RESULTADOS: Registro em protocolo de pesquisa e posteriormente submetidos à análise estatística utilizando o teste estatístico Qui-quadrado e p<0,05. Oitenta e oito por cento dos pacientes estudados não possuíam qualquer lesão retiniana falciforme, 3 por cento apresentaram oclusão vascular periférica, em 2 por cento evidenciou-se placa pigmentada, e 7 por cento apresentaram lesões não compatíveis com a doença falciforme; quanto ao sexo houve proporcionalidade de 50 por cento para ambos; faixa etária de maior predominância foi a de 11 e 15 anos com 38 por cento, 74 por cento enquandraram-se no genótipo SS e 26 por cento no SC. Em relação ao uso de medicamentos, notou-se maior prevalência de alterações oculares nos pacientes que faziam uso do ácido fólico isolado com 5 por cento, em contraste com aqueles em uso da associação hidróxiuréia e ácido fólico em que todos (27 por cento) possuíam exame fundoscópico normal. Todos os pacientes (29 por cento) com hemoglobina fetal acima de 10 por cento possuíam retina sem alterações. CONCLUSÃO: Poucos casos de lesões retinianas foram observados no grupo estudado, ainda assim esta pesquisa reafirma a importância da realização do exame oftalmológico de maneira precoce e periódica, visto que, a retinopatia falciforme é fato bem documentado e suas complicações podem resultar em amaurose.

The World Health Organization counts that more than 5 percent of the world's population carry some type of hemoglobinopathy. Among them we find the sickle cell aneamia that presents its main harmful effect on the peripheral vasculature. In the retina, the falciform lesions have a well defined physiopathology and classification. To identify the retinal manifestations caused by the falciform aneamia in patients directed to the Bettina Ferro de Souza Hospital from the Hemocenter of the State of Pará - HEMOPA, in the months of September through December of 2006. METHODS: Ophthalmologic examination was performed in the Department of Ophthalmology of the Bettina Ferro de Souza Hospital. and fifty patients with sickle cell aneamia (SS or SC) followed by the department of falciform aneamia of the Hematologia e Hemoterapia do Pará - HEMOPA have been randomly selected and submitted to interview in order to register their: sex; age; color; genotype; ocular alterations; medicines taken. Ophthalmologic examination was performed in the Department of Ophthalmology of the Bettina Ferro de Souza Hospital. It consisted of: evaluation of the acuity of vision with and without correction, indirect biomicroscopy, indirect binocular ophthalmoscopy, and, in case the latter presented alterations, a complementary study with angiofluoresceinography would be carried through. RESULTS: The outcomes have been registered in research protocol and later submitted to the statistic analysis using the Qui-square test, adopting, as level of significance, p<0,05. Eighty-eight percent of the patients did not present any falciform retinal sign, 3 percent presented peripheral vascular occlusion; in 2 percent, pigmented plate was shown, and 7 percent presented injuries which were not compatible with the falciform disease; there was a proportionality of 50 percent for males and females; there was a higher predominance (38 percent) of people aged from 11 and 15; 74 percent had SS genotype and 26 percent SC genotype; in relation to the use of medicines there was a higher prevalence of ocular alterations in patients who had made use of the folic acid isolated, with 5 percent, in contrast with those who had used the hidroxyurea association and folic acid, when all (27 percent) presented normal fundoscopic examination; all the patients (29 percent) that showed fetal hemoglobin rate above 10 percent had retina without alterations. CONCLUSION: Few cases of retinal signs have been observed in the studied group, however this research does not diminish the importance of early and periodic ophthalmologic examination, since falciform retinopathy is largely registered and its complications can lead to amaurosis.

Efeitos colaterais cutâneos após uso prolongado de hidroxiuréia na Policitemia Vera / Cutaneous effects after prolongaded use of hydroxyurea in Polycythemia Vera

A hidroxiureia é um derivado hidroxilado da ureia utilizado em diversas desordens hematológicas. Inúmeras alterações cutâneas, porém raras, são relatadas após seu uso prolongado. A patogênese das mesmas não está bem esclarecida, porém, sugere-se que a droga tenha uma ação tóxica direta sobre a pele. Descrevemos um homem de 75 anos, branco, com diagnóstico de Policitemia Vera que, ao longo de 11 anos de tratamento com hidroxiureia, evoluiu com várias lesões cutâneas: hiperpigmentação da pele, lesões atróficas em antebraços, melanoníquia longitudinal das 20 unhas, úlcera em antebraço direito, xerose cutânea, ictiose em pernas e carcinoma espinocelular no pavilhão auricular direito. Até o momento, os relatos na literatura descrevem pouca diversidade de lesões nos pacientes acometidos.

Hydroxyurea is an hydroxylated urea derivative used in many myeloproliferative disorders. Many, but unusual cutaneous disorders are related after its prolonged use. Their pathogenesis is not clear, but it is suggested that there is direct toxicity of the drug on the skin. We described a white, 75-year old man with diagnosis of Polycythemia Vera that in 11 years of treatment developed many cutaneous lesions: skin hyperpigmentation, atrophic lesions on forearms, longitudinal melanonychia of 20 nails, right forearm ulcer, cutaneous xerosis, ichthyosis and auricular spinocellular carcinoma. At this moment, the literature reports describe little diversity of lesions in affected patients.

Úlceras acrales por hidroxiurea en paciente con policitemia vera: comunicación de un caso / Acral ulcers associated with hydroxyurea therapy in a patient with polycythemia vera

La hidroxiurea (HU) es una droga antitumoral utilizada principalmente en enfermedades hematológicas. Es generalmente bien tolerada; sin embargo, puede asociarse a efectos adversos mucocutáneos severos, como úlceras acrales. La patogenia de estas úlceras es desconocida, y su aparición se relaciona a la patología de base, tiempo y dosis administrada. Son muy dolorosas, frecuentemente múltiples y por lo general revierten en forma espontánea al suspender el medicamento. La región maleolar es la más comúnmente comprometida. Presentamos el caso de una paciente de sexo femenino, de 64 años, en tratamiento con HU por policitemia vera, que presentó úlceras acrales a los tres años de tratamiento, con excelente evolución tras la suspensión del fármaco. Es fundamental conocer la existencia de estos efectos adversos para sospecharlos precozmente y realizar un oportuno diagnóstico y tratamiento.

Hydroxyurea (HU) is an antitumor drug commonly used in haematological diseases. It is usually well tolerated, however, it may be associated with severe muco-cutaneous side effects such as acral ulcers. The pathogenesis of these ulcers is unknown, and their appearance is related to the main disease, time and dosage. They are very painful, often multiple, an spontenous resolution after drug suspension is observed. The malleolus region is the most common site affected. We present the case of a 64-year-old woman with polycythemia vera treated with HU who developed acral ulcers after 3 years of treatment, with excellent response after drug discontinuation. For an opportune diagnosis and treatment of these side effects, it is very important to know of their existence and suspect that they may appear in advance.

Effect of hydroxyurea in children with sickle cell disease in Saudi Arabia

The objective of this study is to demonstrate the effects of hydroxyurea in children with sickle cell disease at Madina Maternity and Children's Hospital and to evaluate its short term safety. This was a retrospective review over two years period from 2004 - 2006. The inclusion criteria were: Children with sickle cell disease who had three or more attacks of painful crisis per year Children with sickle cell disease who had two or more episodes of acute chest syndrome per year. The dose range of Hydroxyurea was 15 - 30 mg/kg/day. The clinical episodes and the laboratory investigations were monitored monthly. The total patients included initially were 14; 4 patients were excluded because of poor compliance to treatment. 10 patients were eligible for the study. 6 were male and 4 were female. 8 patients were Saudi and 2 patients were non Saudis. The age range was 5 - 15 years. The attacks of painful crisis and acute chest syndrome were significantly reduced after Hydroxyurea treatment, also laboratory investigation showed significant increase in MCV and Hemoglobin F values after Hydroxyurea. We conclude that Hydroxyurea is effective in children with sickle cell disease and had no major short term adverse effect. However long terms follow up is required to evaluate long term adverse effect

Relationship between use of hydroxyurea and cholelithiasis in patients with major and intermediate beta-thalassemia

Cholelithiasis is a common problem among patients with homozygous major and intermediate beta-thalassemia due to chronic hemolysis, ineffective erythropoesis and other factors that causes variety of side effects. Hydroxyurea [HU] decreases hemolysis by increasing HbF production in homozygous beta-thalassemia patients. Up to now, there have not been evidences about relationship between use of Hydroxyurea and cholelithiasis in the patients. The aim of this study was to determine the relationship between use of HU and incidence of cholelithiasis in patients with major and intermediate beta-thalassemia referred to thalassemia research center of Mazandaran University of medical sciences at Boo-Ali Sina hospital of Sari, IRAN. This historical cohort study was performed in 2006. Study population was major and intermediate beta-thalassemia patients referred to Boo-Ali Sina Hospital of Sari, IRAN. The patients were divided to two groups: case and control groups. The case group [36 patients] was consisted of major or intermediate beta -thalassemia patients using hydroxyurea at least for one year, and the control group were: non-hydroxyurea user patients or beginning to use the drug less than 3 months. The groups were matched on order to age, gender and severity of the disease. Severity of the disease was determined according to grading, clinical and laboratory characteristics of the patients. Data about demographic information, severity of the disease and results of hepatobiliary ultrasound were recorded in a questionnaire. The data was analyzed using SPSS [11] software and t-test, Chi-square test and fisher exact test. Thirty-six [20 women [55.6%]] patients in case group and 36 [19 women [52.8%]] patients in control group were studied. The mean duration of use of hydroxyurea was 67.9 +/- 25.5 months with maximum 108 months [9 year]. The mean dosage of the drug was 14.9 +/- 5.9 mg/kg with maximum dosage 34 mg/kg. Thirteen [48.1%] patients in control group [12 cholelithiasis, 1 sludge] and 6 [19.4%] patients in case group [5 cholelithiasis, 1 sludge] had abnormal hepatobiliary sonography. The difference between two groups was significant statistically [P<0.02]. Among the different variables, a significant relationship was detected between gender of the patients and effect of HU on cholelithiasis. This study showed that the incidence of cholelithiasis in major and intermediate beta-thalassemia patients using hydroxyurea was less than non-hydroxyurea user patients did. As a result, it seems that there was a preventive effect of hydroxyurea in incidence of cholelithiasis in major and intermediate beta-thalassemia patients

Hydroxyurea Induced Perimalleolar Ulcers

Hydroxyurea (HU) is an antineoplastic drug commonly used to treat chronic myeloproliferative disorders. Common dermatological side effects include hyperpigmentation, scaling, erythema, alopecia, desquamation of face and hands. Leg ulceration following HU therapy is less common and very few cases have been reported so far. Objective of this paper is to increase the awareness of hydroxyurea induced leg ulcers which will aid in the early diagnosis and appropriate treatment. The first case was a chronic myeloid leukemia (CML) patient on HU 1.5 g/day for 5 yr, who had bilateral painful perimalleolar ulcers for 6 months. The second case was a CML patient on HU 1.5 g/day for 3 yr who developed bilateral lateral malleolar ulcers. Third case was a polycythemia vera (PV) patient on HU 1 g/day for 5 yr who presented with painful medial malleolar ulcer of 2 months. The last case of our report was an elderly PV patient on HU 1.5 g/day for 2 yr and presented with lateral malleolar ulcer which persisted on reducing the dose of HU. In all the 4 cases the ulcers healed on stopping HU. Our report confirms the association of chronic hydroxyurea therapy and perimalleolar ulcers which respond promptly after discontinuation of the drug. The heightened awareness among the physicians will promote early diagnosis and prompt relief from the agonizing ulcers.

Gamna Gandy bodies of spleen seen in CML: a causal association--a case report.

Gamna Gandy bodies are usually seen in spleen in cases of chronic venous congestion. We present a case of CML showing gamna gandy bodies. These may have occurred as a part of evolving portal hypertension which maybe due to antileukemic therapy or CML per se or due to a combination of both factors.

Reversible leg ulcer due to hydroxyurea in a case of chronic myeloid leukemia.

The cutaneous side effects of hydroxyurea are lesser known complication of long term hydroxyurea therapy in myeloproliferative disorders. We report a non-diabetic patient, who developed hydroxyurea dermopathy (leg ulcers) during long-term treatment with hydroxyurea for chronic myeloid leukemia (CML). The time course of the development of ulcers and its healing suggests that these resulted from the direct toxicity of hydroxyurea. We aim to increase clinical awareness of this problem.

Hydroxyurea induced leg ulcers.

A 34 years non diabetic lady with chronic myeloid leukaemia (CML) was treated with hydroxyurea and interferon. She developed leg ulcers. First time on left toe and three months later on right foot, a rare complication of hydroxyurea. Both were treated with local wound care and antibiotics. First time dose of hydroxyurea was reduced and second time drug was discontinued.

Psoriasis en pacientes con infeccion por el virus de lainmunodefiencia humana / Psoriasis in patients with human immunodeficiency virus infection

Se presenta el estudio de 9 pacientes que padecen psoriasis con serologia positiva para HIV.Entre tres de ellos la aparicion de la psoriasis fue previa al dignostico del HIV+, en los restantes posterior. Las formas clinicas de psoriasis halladas fueron: vulgar en tres, invertida en tres, pustulosa en dos y con compromiso de pequeños pliegues en uno. Los antecedentes familiares de psoriasis estuvieron presentes en uno, no se consignaron en dos y estuvieron ausentes en seis. El estadio clinico de la infeccion por HIV fue C3 en cinco, B2 en tres y en uno B3. La psoriasis se caracterizo por ser mas severa y, en dos casos, acompañada de sepsis estafilococcica. El tratamiento con medidas locales(cremas con corticoides, queratoliticos y balneoterapia) obtuvo resultados variables y la antibioticoterapia endovenosa instituida por la sepsis mejoro notablemente las lesiones cutaneas.