Polimorfismo do gene timidilato sintase e nível plasmático total de homocisteína em um grupo de pacientes turcos com artrite reumatoide: relação com a atividade da doença e toxicidade ao metotrexato / Thymidylate synthase genetic polymorphism and plasma total homocysteine level in a group of Turkish patients with rheumatoid arthritis: relationship with disease activity and methotrexate toxicity

Resumo Introdução: Relata-se que o polimorfismo do gene timidilato sintase (TS) e a homocisteína têm relação com o metabolismo do metotrexato (MTX), com achados conflitantes. O objetivo deste estudo foi determinar os níveis de homocisteína e a frequência de polimorfismos de repetição tripla (TS3R) e dupla (TS2R) do gene TS em um grupo de pacientes turcos com AR e avaliar sua associação com a toxicidade ao MTX e a atividade da doença. Métodos: Foram incluídos no estudo 64 pacientes com AR e 31 indivíduos no grupo controle, com média de 48,7 ± 12,5 e 46,2 ± 13,4 anos. Foram obtidas as características demográficas e foi registrado o número de pacientes que relataram efeitos adversos ao MTX no grupo AR. Foram analisados os níveis de homocisteína e os polimorfismos TS2R/TS3R. Foi determinada a distribuição de genótipos de acordo com a toxicidade ao MTX e a atividade da doença. Resultados: Os dados demográficos foram semelhantes entre os pacientes e controles. Todos faziam suplementação de ácido fólico a uma dose média de 5 mg/semana. Dos 64 pacientes, 36 apresentaram efeitos adversos ao tratamento com MTX. Encontrou-se uma frequência de polimorfismos TS2R e TS3R semelhante nos grupos AR e controle. Encontrou-se que os polimorfismos TS2R e TS3R eram semelhantes em pacientes com e sem eventos adversos relacionados com o MTX. O nível médio de homocisteína também foi similar em pacientes com e sem polimorfismo do gene TS, mas era mais elevado (12,45 μmol/L vs. 10,7 μmol/L) em pacientes com do que sem efeitos adversos relacionados com o MTX. O nível médio de homocisteína se correlacionou com o VHS no grupo AR. Conclusões: Os níveis de homocisteína podem afetar a atividade da doença e a toxicidade ao MTX, mas os polimorfismos 2 R e 3 R no gene TS não se correlacionaram com a toxicidade ao MTX em pacientes com AR que recebem suplementação de ácido fólico. São necessários mais estudos para esclarecer os polimorfismos em outras enzimas que podem ser responsáveis pela toxicidade ao MTX em pacientes com AR.

Abstract Background: The polymorphism of thymidylate synthase (TS) gene and homocysteine are reported to have a relationship to methotrexate (MTX) metabolism, with conflicting results. The aim of this study was to determine homocysteine levels and the frequency of TS gene triple repeat (TS3R) and double repeat (TS2R) polymorphisms in a group of Turkish RA patients and evaluate its association with MTX toxicity and disease activity. Methods: Sixty-four patients with RA and 31 control subjects with a mean age of 48.7 ± 12.5 and 46.2 ± 13.4 years were enrolled for the study. Demographic characteristics were obtained and a number of patients with MTX-related adverse affects were recorded in the patient group. The homocysteine levels and TS2R/TS3R polymorphisms of the TS gene were analyzed and the distribution of genotypes according to MTX toxicity and disease activity was determined. Results: The demographic properties were similar between the patient and control subjects. Folic acid supplementation with a mean dose of 5 mg folic acid/week was present in all patients. Thirty-six of the 64 patients showed adverse effects to MTX treatment. The respective frequency of TS2R and TS3R polymorphisms was found to be similar in the patient and control groups. TS2R and TS3R gene polymorphisms were found to be similar in patients with and without MTX-related adverse events. The mean homocysteine level was also similar in patients with and without TS gene polymorphism, but was found to be higher (12.45 μmol/L vs 10.7 μmol/L) in patients with MTX-related side effects than in patients without side effects. The mean level of homocysteine was correlated with levels of ESR in the patient group. Conclusions: In conclusion, homocysteine levels might affect the disease activity and toxicity of MTX but 2R and 3R polymorphisms in the TS gene were not related with MTX-related toxicity in RA patients receiving folate supplementation. Further studies are needed to illuminate the polymorphisms in other enzymes that might be responsible for the MTX toxicity in patients suffering from RA.

Thymidylate synthase genetic polymorphism and plasma total homocysteine level in a group of Turkish patients with rheumatoid arthritis: relationship with disease activity and methotrexate toxicity.

BACKGROUND: The polymorphism of thymidylate synthase (TS) gene and homocysteine are reported to have a relationship to methotrexate (MTX) metabolism, with conflicting results. The aim of this study was to determine homocysteine levels and the frequency of TS gene triple repeat (TS3R) and double repeat (TS2R) polymorphisms in a group of Turkish RA patients and evaluate its association with MTX toxicity and disease activity. METHODS: Sixty-four patients with RA and 31 control subjects with a mean age of 48.7 ± 12.5 and 46.2 ± 13.4 years, were enrolled to the study. Demographic characteristics were obtained and number of patients with MTX-related adverse affects, were recorded in the patient group. The homocysteine levels and TS2R/TS3R polymorphisms of the TS gene were analyzed and the distribution of genotypes according to MTX toxicity and disease activity, were determined. RESULTS: The demographic properties were similar between the patient and control subjects. Folic acid supplementation with a mean dose of 5mg folic acid/week, was present in all patients. Thirty-six of the 64 patients showed adverse effects to MTX treatment. The frequency of TS2R and TS3R polymorphisms were found to be similar in the patient and control groups. TS2R and TS3R gene polymorphisms were found to be similar in patients with and without MTX-related adverse events. The mean homocysteine level was also similar in patients with and without TS gene polymorphism, but was found to be higher (12.45µmol/L vs 10.7µmol/L) in patients with MTX-related side effects than in patients without side effects. The mean level of homocysteine was correlated with levels of ESR in the patient group. CONCLUSIONS: In conclusion, homocysteine levels might effect the disease activity and toxicity of MTX but 2R and 3R polymorphisms in the TS gene, were not related with MTX-related toxicity in RA patients receiving folate supplementation. Further studies are needed to illuminate the polymorphisms in other enzymes that might be responsible from the MTX toxicity in patients suffering from RA.

Fibromyalgia syndrome: is it related to vitamin D deficiency in premenopausal female patients?

There are a number of studies that have evaluated the relationship between fibromyalgia (FM) and vitamin D deficiency with conflicting results. The aim of this study was to assess vitamin D deficiency in patients with FM and to evaluate the relationship with the common symptoms of FM and levels of serum vitamin D. Forty premenopausal female fibromyalgia patients and 40 age- and sex-matched control subjects were included in the study. The demographic characteristics of all subjects, including age, sex, and body mass index, were recorded. The number of tender points was recorded, and the intensity of the widespread pain of the subjects was measured by the visual analog scale. The activities of daily living component of the Fibromyalgia Impact Questionnaire (FIQ-ADL), was used to assess physical functional capacity. Serum vitamin D was measured in both groups, and vitamin D levels <37.5 nmol/L were accepted as vitamin D deficiency. The vitamin D levels and clinical and laboratory characteristics of the patient and control groups were comparatively analyzed. The relationship between vitamin D levels and clinical findings of the FM patients were also determined. The mean age was 41.23 ± 4.8 and 39.48 ± 4.08 years for the patient and control groups, respectively. The pain intensity, number of tender points, and FIQ-ADL scores were higher in FM patients than in control subjects. The mean levels of vitamin D in the patient and control groups were determined to be 31.97 ± 15.50 and 28.97 ± 13.31 nmol/L, respectively (p > .05). The incidence of vitamin D deficiency was similar between the patient and control groups (67.5% vs. 70%). Vitamin D levels significantly correlated with pain intensity (r = -0.653; p = .001) and FIQ-ADL scores in the FM group (r = -0.344; p = .030). In conclusion, the results of this study indicate that deficiency of vitamin D is not more common in premenopausal female patients with FM than in control subjects without FM. However, the association between pain and vitamin D levels in FM patients emphasizes that hypovitaminosis of vitamin D in the FM syndrome may have an augmenting impact on pain intensity and functional status. Future studies are needed to show the effect of vitamin D supplementation in the reduction of pain intensity and disability in patients suffering from this chronic condition.

The Frequency of A1298C and C677T Polymorphisms of the Methylentetrahydrofolate Gene in Turkish Patients with Rheumatoid Arthritis: Relationship with Methotrexate Toxicity.

The C677T and A1298C polymorphisms of methylenetatrahydrofolate reductase (MTHFR) gene are reported to have a relationship to methotrexate (MTX) metabolism, with conflicting results. The aim of this study was to determine the frequency of MTHFR C677 T and A1298C gene polymorphisms in a group of Turkish RA patients and evaluate its association with MTX toxicity.Sixty-four patients with RA and 31 control subjects with a mean age of 48.7 ±12.5 and 46.2 ± 13.4 years, were enrolled to the study. Demographic characteristics were obtained and MTX-related adverse effects were recorded in the patient group. The A1298C and C677T polymorphisms of the MTHFR gene were analyzed and the distribution of genotypes according side effects, were determined.The frequency of MTHFR C677T and A1298C polymorphisms were similar in the patient and control groups. Folic acid supplementation with a mean dose of 5mg folic acid/week, was present in all patients. Thirty-six of the 64 patients showed adverse effects to MTX treatment, and MTX had been discontinued in 12 (18.8%) patients due to side effects and/or inefficacy. MTHFR C677T and A1298C gene polymorphisms were found to be similar in patients with and without MTX-related adverse events.In conclusion, A1298C and C677T polymorphisms in the MTHFR gene, were not related with MTX-related toxicity in RA patients receiving folate supplementation. Further studies are needed to illuminate the polymorphisms in other enzymes that might be responsible from the MTX toxicity in patients suffering from RA.

Factors associated with functional disability in patients with rheumatoid arthritis.

To determine factors associated with functional disability in patients with rheumatoid arthritis (RA). A total of 100 RA patients were reviewed retrospectively. Multiple regression analysis was used to investigate associations between the dependent variable (health assessment questionnaire) and independent variables (age, disease duration, hand grip strength values, VAS and DAS-28 scores). Main factors associated with functional disability were disease activity score as reflected in a high score on the DAS-28 (r=0.68, p<0.001) and disease duration (r=0.23, p<0.05). Increased age, decreased grip strength and high pain level were associated with lower functional ability, but none of these was a predictor of disability in the regression model. The results indicate that age, disease duration, disease activity, pain intensity and hand grip strength are related to physical disability in patients with RA. However, only disease activity has an impact on physical function. Thus, treatment of RA patients should focus on early inhibition of disease activity in order to achieve a good functional outcome.

Decreased handgrip strength and increased hip osteoporosis in patients with Alzheimer`s disease.

OBJECTIVE: To evaluate the causes of disability in the musculoskeletal system, and depression in patients with Alzheimer`s disease (AD) and healthy controls. METHODS: A case-controlled study in which healthy elderly patients (n=56) and patients with AD (n=75) attending the Geriatric Rehabilitation Unit of Ankara Education and Research Hospital, Department of Physical Medicine and Rehabilitation were compared on several measures of disability including handgrip strength, knee x-rays graded for osteoarthritis, dual-energy x-ray absorptiometry results for osteoporosis, and depression scores in the training period of 2003-2004. RESULTS: Handgrip strength values were significantly lower in patients with AD compared to the controls (19.4 versus 37 pounds force). Osteoporosis in the femoral neck was also more prominent in patients with AD compared to controls (T-scores: -2.1 versus -1.2). Handgrip strength was moderately correlated with femoral neck T-scores (r=0.6, p=0.001). CONCLUSION: Strategies should be developed to protect patients with AD from osteoporosis and reduced muscle strength.