چاپ صفحه |  صفحه نخست سامانه |  نویسندگان |  اطلاعات تفضیلی |  دانلود مقاله | علوم پزشکی کرمانشاه |
| کد مقاله | 8761 |
| عنوان فارسی مقاله | |
| عنوان لاتین مقاله | Leading cause of important DMARDs` discontinuation in Rheumatoid Arthritis |
| نوع ارائه | پوستر |
| عنوان کنگره / همایش | 24 امین کنگره سالیانه جامعه پزشکان متخصص داخلی ایران |
| نوع کنگره / همایش | داخلی |
| کشور محل برگزاری کنگره/ همایش | ایران |
| شهر محل برگزاری کنگره/ همایش | تهران |
| سال انتشار/ ارائه شمسی | 1392 |
| سال انتشار/ارائه میلادی | 2013 |
| تاریخ شمسی شروع و خاتمه کنگره/همایش | 1392/02/24 الی 1392/02/27 |
| آدرس لینک مقاله/ همایش در شبکه اینترنت | 24th annual congress of iranian society of Internal Medicine |
| آدرس علمی (Affiliation) نویسنده متقاضی | 1.0000 |
| نویسنده | نفر چندم مقاله |
|---|---|
| بیتا انوری | اول |
| عنوان | متن |
|---|---|
| کلمات کلیدی | methotrexate, chloroquine, hydroxychloroquine, rheumatoid arthritis |
| چکیده | Background: Methotrexate (MTX) and anti-malarial drugs are widely prescribed in Rheumatoid Arthritis as Disease-Modifying Anti Rheumatic drugs (DMARDs). Some patients discontinue treatment due to adverse effect that may influence disease reactivation. Objective: to evaluate more common causes of important DMARDs withdrawal including methotrexate, chloroquine or hydroxychloroquine in patients with Rheumatoid Arthritis Methods: Retrospective chart review of patients with Rheumatoid Arthritis that were selected in Rheumatologic Clinic of Shariati Hospital in 2006. Patients who received at least one month methotrexate (MTX) (with or without chloroquine or hydroxychloroquine consumption) were included to determine frequency and more prevalent causes of drug discontinuation. Also duration of treatment, creatinine clearance and mean MTX dose per month were included and comparison between two groups (those who did not stop drugs and those who stopped them) was performed. Results: Among 295 patients with Rheumatoid Arthritis, 84 patients (28.5%) discontinued MTX. Adverse drug effect was found in 27.4% of them but no one has developed serious adverse outcome like cirrhosis. Among 271 patients who received antimalarial agents, 117 patients (41.3%) discontinued treatment. 51.3% of these interruptions were due to ophthalmological consultation and presence of retinopathy, macular pigmentation and keratopathy, without any persistent or serious ocular complication like blindness. Age, gender, Cr Cl. and duration of treatment had no significant effect on drug withdrawal. Only, patients who interrupted treatment due to retinopathy were significantly older than the others (53.9 ± 12.2 versus 48.1 ± 12.6 years, P=0.003). Conclusion: MTX has low rate of discontinuation especially due to adverse effects. Rate of ocular toxicity was relatively high among patients who received anti-malarial drugs in spite of no serious adverse effect. It may be due to close observation and serial annual eye examination to detect “earlier stage” of ocular toxicity. Key words: methotrexate, chloroquine, hydroxychloroquine, rheumatoid arthritis. |
| متن مقاله | Introduction The widespread prescription of Disease Modifying Anti Rheumatoid Drugs (DMARDs) in the most prevalent rheumatoid disease “Rheumatoid Arthritis (RA)”, requires more attention to adverse drug effects especially those lead to discontinue drugs. It is in order to avoid any harm to the patients and design better practical guideline for routine medical practice. Also sudden DMARDs withdrawal may precipitate disease reactivation after remitting disease. Common DMARD examples are methotrexate (as the most common prescribed DMARD in Rheumatoid Arthritis) and antimalarial agents such as chloroquine or hydroxychloroquine (as anti-inflammatory agents). In a retrospective multicenter study of 760 patients to analyze reasons for DMARD discontinuation, 47.1 % of patients interrupted therapy because lack of efficacy, 43.2 % because of adverse events, and 9 % for undefined reasons. The most serious toxicities of MTX include hepatic fibrosis (rare) and cirrhosis (rare), pneumonitis (uncommon), and myelosuppression which require monitoring with serial control of CBC, platelet count, AST, albumin and creatinine every 4-8 weeks. Antimalarial drug therapy still requires intensive monitoring to avoid severe retinal damage that can lead to legal blindness. Appropriate examinations should be performed regularly in order to decide whether to taper or stop when damage is still mild, preclinical, or reversible. Some believed that follow-up eye examinations should be performed at 6- to 12 months intervals , but other suggested routine ophthalmic screening is not indicated in hydroxychloroquine-treated patients whose renal function is normal, if the daily dosage is <6.5 mg/kg. A multi centric research on 1162 patients to evaluate the causes of DMARDs discontinuation demonstrated that antimalarial agents was the second DMARD which was stopped (after gold). Our study was focused on causes of these DMARDs discontinuation and final prognosis of drug interruption due to adverse effects. Patients and Methods Data were obtained among 295 Rheumatoid Arthritis patients who received ≥ 7.5 mg methotrexate (MTX) weekly for at least one month, during their follow up, in academic rheumatology clinic of Shariati Hospital. Samples were collected among patients who were visited in The Rheumatology Clinic of Shariati Hospital in 2006. All of the patients were under regular follow up and serial laboratory findings were documented in their charts. These charts were reviewed retrospectively for finding any evidence of MTX prescription and those who received it for at least one month were included and their charts reviewed for chloroquine or hydroxychloroquine prescription. Then any discontinuation (temporary or permanent discontinuation until data gathering time on 2006) were noted and finally the patients were divided into two groups: those interrupted the drugs and the others who continued them (for each drug group). Our form for collecting data was consisted of demographic features about age, gender in addition to disease activity, and any concurrent DMARDs` consumption such as chloroquine or hydroxychloroquine, their doses and duration, dose and duration of prednisolone consumption, weekly MTX dose, its duration and cumulative dose and results of serial laboratory tests at each visit such as complete blood cells count (CBC), blood urea nitrogen (BUN), creatinin, mean creatinine clearance (Cr Cl). (calculated by Cockroft-Gault equation), aspartate aminotransferase(AST), alanine aminotransferase(ALT), alkaline phosphatase, serum albumin, prothrombin time and bilirubin and liver sonography (if present). Also serial ophthalmologic consultations were obtained from the charts of patients who received chloroquine or hydroxychloroquine to evaluate ophthalmic complications leading to drug discontinuation. Any cause of drug discontinuation was identified as regards to the patients` charts and was added to the form. Finally, initiation of the same drug (against persistent drug discontinuation) was noticed in the form and their follow-up such as their laboratory findings was collected to evaluate another adverse drug reaction. According to evidence of drug discontinuation, the above parameters were analyzed using SPSS-12 and t-test was used to compare the two groups. Categorical variables are compared using the chi-square test. Variables are expressed as mean ± SD, and P <0.05 was considered to be statistically significant. Results Among 295 RA patients who received at least one month MTX, 271 patients (91.9%) were received chloroquine or hydroxychloroquine during their course of follow-up in Rheumatologic Clinic of Shariati Hospital from 1991- 2006. Flowchart of research tree is seen. (Figure 1) Mean age of the patients was 49.4 (±12.8) years and 84.4% was female. Mean creatinine clearance was 105.2 (± 36.6) cc/min/1.73m² and none of them had evidence of severe renal insufficiency (Cr Cl. < 30 cc/min/1.73m²). Mean duration of MTX treatment was 40.5 (± 34.6) months and mean MTX dose per month was 35.7 (±11.4) mg. 84 patients (28.5%) discontinued MTX but only 23 patients (7.8%) discontinued it permanently. None of them developed severe or irreversible clinical or laboratory complication such as cirrhosis or pulmonary fibrosis. We did not found any exact recorded reason for MTX discontinuation by the patients as the most common cause (36.9%) and other causes in descending values consisted of: controlled disease and discontinuation by the physicians (26.2%), abnormal LFT (liver function test) in 11.9%, pregnancy (8.3%), nausea and vomiting (6%), neutropnea or pancytpnea (3.6%), dyspnea due to suspected pulmonary adverse effect in one patient, and blurred vision, epigastric pain, urticaria and unknown hyper sensitivity each one in one patient (Adverse events contained 27.4% of causes). There was no significant difference in age, gender, Cr Cl. and duration of treatment with MTX between patients who discontinued MTX due to adverse effect and those who didn’t (Table 1). However, mean MTX dose per month among patients who discontinued MTX was lower than the others (33.3 ± 9.7 mg/ month versus 36.6 ± 11.8 with P =0.02). Chloroquine or hydroxychloroquine was consumed for 4.6 (±3.9) years by the patients with doses of 150 and 200-400 mg daily respectively. Among 271 patients who received chloroquine or hydroxychloroquine, 117 patients (43.1%) discontinued treatment during their course of follow up and permanent discontinuation was seen among 102 patients (37.6%). So, its frequency was higher than MTX discontinuation rate; however duration of treatment was significantly higher than MTX as well (P<0.0001). After adjustment of treatment duration, 61.8% of patients who was treated with antimalarial agents less than 3.5 years continued to take it, in comparison to 69.9% among MTX group (P=0.38). Therefore, no significant difference was present between MTX and chloroquine or hydroxychloroquine discontinuation rate. 60 patients (51.3%) discontinued chloroquine or hydroxychloroquine because of ocular adverse effect revealed by ophthalmological consultation. 55 patients (91.6% of all patients with eye involvement) stopped it permanently. These complications were defined as retinopathy, macular pigmentation and keratopathy but none of them developed blindness or severe irreversible adverse outcome. In descending values, after oculopathy, the reason for discontinuation of chloroquine or hydroxychloroquine was not found among 22 patients (18.8%), discontinuation by the physicians due to controlled disease or changing chloroquine to hydroxychloroquine or other DMARDs by 18.8% and pregnancy in 5.1%. Tinnitus, myopathy, unknown hypersensitivity and oral intolerance were the other reasons, each one in one patient. In comparison between MTX and antimalarial agents, there was no significant difference in drug discontinuation due to adverse effect. Like MTX, there was no significant difference in age, gender, Cr Cl and duration of treatment with antimalarial agents between patients who stopped drug consumption and those who did not. Retinopathy was seen among patients whose treatment duration was >3.5 years by 24.3% and those <3.5 years by 31.4% (P=0.28). Only, patients who interrupted treatment due to retinopathy were significantly older than the others (53.9 ± 12.2 versus 48.1 ± 12.6 year old with P=0.003). Discussion Permanent discontinuation of MTX and antimalarial drugs were seen among 7.8% and 37.6% of patients, respectively. Most common cause of MTX discontinuation could not be found and adverse effect contained 27.4% with dominancy of abnormal LFT. Most common cause in antimalarial drugs was ocular complication without any permanent ocular sequel. Guidelines for the monitoring of disease-modifying agents have been developed to reduce risk of harm to the patients. Anti-malarial agents had relatively low rates of toxicity. , , Their most serious and dreaded side effect “retinopathy” could be prevented by adjusting drug dosage to the weight of the patients. The recommended 'safe' daily dose for hydroxychloroquine is 6.5 mg/kg of body weight and for chloroquine 4 mg/kg. In our study in spite of no serious adverse outcome (like the studies of Pareek A and others and Richard I Rynes and others 13), the frequency of drug discontinuation due to ocular toxicity was relatively high. It may the result of close observation by serial annual eye examination to detect “earlier stage” of ocular toxicity. In the later study , duration of treatment didn’t predispose patients to toxicity that is supported by our results. Discontinuation rate of MTX and aminoquinolines were reported in an article by 36.5% and 12.1% respectively because of unwanted effects opposite to our results. It is not clear whether these patients had serial ocular examination or not (because of Russian language of full article). So many other factors like performing routine laboratory tests, their intervals or serial eye examinations could affect revealing adverse drug effects. Some of these changes may be mild and subclinical but could change the treatment course and cause unnecessary drug corruption. Most of discontinuation causes in our study were the result of findings in serial screen. On the other hand it may cause the lower rate of severe adverse outcome that all patients and also physicians are worried about them. The findings of another study showed the reasons for MTX discontinuation were included adverse effects in 26 patients (56.5% of discontinuations), inefficacy in 15 (32.6%), improvement of status in three (6.5%), pregnancy in one (2.1%), and other disease (lung cancer) in one (2.1%). Those adverse effects consisted of gastrointestinal toxicity (6 patients), oral ulcers (3 patients), rash (3 patients), malaise (3 patients), pulmonary symptoms (3 patients), pneumonia (2 patients), nodules (2 patients), other side effects (2 patients), and abnormal laboratory data in two patients (neither of which was found in routine testing), so the most common causes of corruption were clinical adverse effects in contrast with our results. Another study showed toxic reactions leading to withdrawal were most common with gold (62.6 %) and methotrexate (62.5 %). Its frequency was similar to the result of article by Yasizi Y and others about toxicity of MTX. They defined adverse effects as the most common cause of MTX discontinuation. Our findings showed fewer frequency of MTX discontinuation due to toxicity, in spite of longer treatment duration than the former study. The lowest DMARDs’ discontinuation rate was reported by Chinas . An Egyptian Research showed 26% of patients stopped MTX. 56.5% of these patients stopped it due to gastric upset (nausea, gastritis and peptic ulcer), one patient due to pneumonitis, one due to leukopenia and two patients due to elevated liver enzyme. It may show better drug tolerance in Iranian patients that could help us continue the medications. In two other researches in RA: MTX is well tolerated over the longer term, so that over 50% of patients starting MTX continuing to take it 12 years later and in the another research among 273 patients with 437 person-years of MTX exposure, adverse effects were the reasons for discontinuation in 34 patients (12.5%). Also, in one study among 152 rheumatoid arthritis patients treated with MTX the overall probability of continuing to take MTX was 71.2% at 1 year, 55.5% at 3 years, 50% at 5 years, and 49% at 6 years. After multivariate analysis, younger age had no significant effect on the probability of continuing MTX therapy that was compatible with our results, however another study showed increasing age is associated with a greater tendency for methotrexate discontinuation in patients with newly diagnosed RA. In a previous retrospective multicenter study of 760 patients, DMARDs were discontinued by 9 % of patients for undefined reasons which is very lower than ours. High rate of MTX discontinuation without exact recorded reason in our study may be due to poor charts documentation and limitations due to retrospective pattern of our study. It seems to be very important that improving patient`s chart completion could help us to remove limitations and achieve better results. Based on our findings, there was no preference for older age to develop MTX toxicity that leads us to monitor all patients with no respect to their age. It is different with the antimalarial drugs discontinuation due to adverse effect that was increased with advanced age. Ultimately, due to some differences in published data from around the world, a systematic review with respect to different local confounding factors could reveal the effective factors properly. Safety profile of MTX with relatively low rate of corruption especially due to adverse effect is supported for long term use by our results and most previous researches, although close observation with the arm of evidenced based guidelines should be the governance. About antimalarial dugs, most of discontinuation causes in our study were the results of close observation and serial eye examination to detect “earlier stage” of ocular toxicity. But it could have a preventive effect in serious adverse outcome that has been reported in literature. Table 1: Comparison between two groups of patients with Rheumatoid Arthritis (those who interrupted taking DMARDs and those who continued) in Shariati Rheumatologic clinic, Tehran, Iran Drug groups Methotrexate consumption Aminoquinilin consumption Discontinuation Yes No P value Yes No P value Number of patients (%) 84 (28.5) 211 (71.5) 117 (43.2) 154 (56.8) Age(SD) 50.1(12.3) 49.2(13.1) 0.6 50.6(13.3) 48.1(12.6) 0.3 Gender (male) (female) 11(23.9%) 35(76.1%) 0.3 16(39%) 25(61%) 0.3 17(29.3%) 73(70.7%) 101(43.9%) 129(56.1%) Creatinine clearance(SD) 101.7(32.2) 106.6(38.2) 0.2 104.8(33.6) 107.1(39.7) 0.1 Duration of treatment(SD) 41.5(33.5) Months 40.1(35.1) Months 0.3 4.9(3.8) years 4.4(4.1) years 0.7 Cumulative dose(SD) 1325.3(1097.4) 1360.5(1190.2) 0.2 Mean dose per month(SD) 33.3(9.7) 36.6(11.8) 0.02 |
| نتیجه مقاله | Based on our findings, there was no preference for older age to develop MTX toxicity that leads us to monitor all patients with no respect to their age. It is different with the antimalarial drugs discontinuation due to adverse effect that was increased with advanced age. Ultimately, due to some differences in published data from around the world, a systematic review with respect to different local confounding factors could reveal the effective factors properly. Safety profile of MTX with relatively low rate of corruption especially due to adverse effect is supported for long term use by our results and most previous researches, although close observation with the arm of evidenced based guidelines should be the governance. About antimalarial dugs, most of discontinuation causes in our study were the results of close observation and serial eye examination to detect “earlier stage” of ocular toxicity. But it could have a preventive effect in serious adverse outcome that has been reported in literature. |
| نام فایل | تاریخ درج فایل | اندازه فایل | دانلود |
|---|---|---|---|
| 2016-07-09-0007.jpg | 1395/05/07 | 1040608 | دانلود |
| DMARD.docx | 1395/05/07 | 221221 | دانلود |
| 2016-07-09-0009.jpg | 1395/05/07 | 513365 | دانلود |
