Methotrexate for chronic non-necrotizing anterior scleritis in Chinese patients

INTRODUCTION

All eyes had active scleritis at the time when MTX was initiated. The proportion of eyes that achieved inflammation control was 59.4% (19/32), 65.6%(21/32) and 78.1% (25/32) 3mo, 6mo, and 12mo respectively after the addition of MTX (Figure 1). BCVA was found to be improved, unchanged, and decreased in 20 eyes (62.5%),9 eyes (28.1%) and 3 eyes (9.4%, 2 due to development of cataract) respectively.

SUBJECTS AND METHODS

This study complied with the Declaration of Helsinki and was approved by the Institutional Review Board of Peking Union Medical College Hospital (PUMCH;S-K1363-2). This was a single-center retrospective comparative study. Written and verbal consent for participation in the study was obtained from all participants.

運(yùn)輸采用的是卸料運(yùn)輸攪拌車，運(yùn)輸時間要控制合理，不能過長，在運(yùn)輸中若發(fā)生混凝土離析，則需要進(jìn)行二次攪拌。通常情況下，攪拌車運(yùn)輸時間要＜30min。

Uncontrolled non-necrotizing anterior scleritis usually causes protracted ocular redness and pain which may seriously affect the patient’s daily activities and quality of life. Due to its low prevalence, reports on anterior scleritis in the Chinese population were scarce, and most of the ophthalmologists in this country are unfamiliar with the diagnosis and longterm treatment of anterior scleritis. Oral corticosteroids are commonly used as the first-line treatment, but they may cause significant side effects as a long-term maintenance therapy including glaucoma, cataract, elevated blood pressure and blood sugar, gastric ulcers, psychiatric effects,osteoporosis,

. Disease recurrence during tapering of oral corticosteroids is also frequently encountered. IMT is an important complementary for oral corticosteroid and MTX is recommended to be the IMT agent of choice for anterior scleritis based on the number of reports from the western counties

. However, it is less well studied in the Chinese population, which highlights the value of the current study.Subsequent studies with different evaluation criteria, dosing regimens of MTX and accompanying treatments continued to reveal generally favorable effectiveness of MTX on nonnecrotizing anterior scleritis. In Jachens and Chu’s study

,64.7% of their scleritis patients achieved inflammation control which was defined as a resolution of inflammation in the affected eyes for 3mo or longer. In Wieringa

’s report

, however, only 47% (17/36) patients achieved disease quiescence for longer than 3mo with less than 10 mg daily oral prednisone with or without IMT. The maintenance doses of MTX in Jachens and Chu

and Wieringa

studies were 20 mg/wk, 30 mg/wk orally, respectively. More promising results were reported by David

with 90.5%and 92.3% of their patients achieved inflammation control and steroid-sparing success respectively at doses between 15 and 25 mg/wk, but 4 patients (5 eyes) also underwent periocular corticosteroid injections during the treatment period. In some studies, favorable responses were observed when a lower-dose of MTX (10 to 15 mg/wk) was adopted

.

Our study also revealed a lower rate (22.7%) of systemic comorbidities than previous studies, which were reported to range between 23.4% and 57.0%

. In addition, RP was found to be the most common associated systemic condition in our study, which was reported to be, as compared to RA

,a relatively minor cause of scleritis involving 0.96% to 6.39%of patients

. However, whether our study revealed a distinctive clinical profile of Chinese anterior scleritis patients or just an anecdotal finding requires further validation.

Complications were observed in 13(59.1%) patients. Interstitial keratitis was the most common complication and was observed in 6 patients (27.3%; 4 had keratitis before initiation of MTX); scleral thinning, anterior uveitis, elevated IOP, and development of cataract were observed in 4, 4, 3 and 2 patients during follow up, respectively.Temporary elevation of liver enzymes was observed in 1 patient(4.5%) which result in withdraw of MTX, and no other serious drug-related adverse event was documented.

The proportion of patients that achieved corticosteroid-sparing success was 50.0% (11/22), 77.3% (17/22), and 77.3% (17/22)3mo, 6mo, and 12mo respectively after MTX treatment, with 8 (36.4%) patients completely discontinued oral corticosteroid(Figure 2). After initiation of MTX, the average dose of systemic corticosteroid significantly decreased from 22.50 mg/d of prednisone or equivalent to 3.47 mg/d at 12mo observation period (

<0.01). The immunosuppression load was 5.14±0.87 and 2.76±2.34 (

<0.01) before and 12mo after MTX treatment respectively. Treatment failure occurred in 22.7% (

=5) of the patients, of whom 3 had stopped MTX and 2 were on MTX when the eye became re-inflamed. They required additional therapy, and cyclophosphamide (

=2) or tacrolimus (

=3) was administered to these patients.

RESULTS

Thirty-two affected eyes of 22 patients (16 females and 6 males) with a median age of 48.2±15.5y (range 20-80y) were included in this study. The demographic and clinical characteristics of the patients are summarized in Table 1. Sixteen patients were diagnosed with diffuse anterior scleritis and 6 patients with nodular anterior scleritis. The mean duration of active scleritis before starting MTX treatment was 2.3±1.7mo (range: 1 to 8mo). Systemic diseases were identified in 22.7% of the patients, among which 5 (22.7%) patients had an associated systemic disease with 3 patients had RP and 2 had RA, 3 (2 RP, 1 RA) had been on tacrolimus 1 or 2 mg/d without dose up-titration within 6mo before and during follow up after initiation of MTX. In total,59.1% of the patients were treated with topical corticosteroids.

Anterior scleritis, mostly mediated by autoimmune mechanisms, is an ocular inflammatory disease presented as redness and pain of the sclera. Persistent or recurrent non-infectious anterior scleritis may lead to visual threatening ocular complications including scleral thinning,keratitis, uveitis, glaucoma, and cataract

. An underlying systemic disease is frequently present in patients with anterior scleritis

. Reported comorbidities included rheumatoid arthritis(RA), ankylosing spondylitis (AS), relapsing polychondritis(RP), inflammatory bowel disease (IBD), granulomatosis with polyangiitis (GPA), and systemic lupus erythematosus (SLE)

.Anterior scleritis can be categorized into necrotizing, nodular,and diffuse subtypes. The necrotizing subtype is the most severe and destructive subtype which warrants aggressive immunosuppressive treatment, the non-necrotizing forms are usually less progressive.Treatment of acute anterior scleritis depends on the severity of the disease. While oral nonsteroidal anti-inflammatory drug (NSAID) is adequate for some mild patients, oral corticosteroid remains the mainstay treatment for more severe cases. Immunomodulatory treatment (IMT) is often considered to spare corticosteroid when long-term immunosuppression is required

. Methotrexate (MTX) is a folic acid analog and competitive inhibitor of dihydrofolate reductase. By blocking the conversion of dihydrofolate to tetrahydrofolate and inhibiting cell division, MTX has both antiproliferative and anti-inflammatory effects

. While MTX has been well known as the first-line corticosteroid-sparing agent for pediatric uveitis

. The promising effect of MTX on non-necrotizing anterior scleritis is suggested by studies from western countries

. However, only a few studies have demonstrated the use of immunosuppressive treatments for scleritis or other ocular inflammatory diseases in Asian populations

. To the best of our knowledge, this study is one of the first studies that reported the safety and efficacy of low-dose MTX in Chinese patients with non-necrotizing anterior scleritis.

The main outcomes were corticosteroidsparing success and inflammation control. Corticosteroidsparing success was defined as oral prednisone ≤10 mg/d for longer than 1mo with stable or continuously improving scleral inflammation. The active phase of scleritis was defined as≥1+ (mild scleral inflammation with diffuse mild dilation of deep episcleral vessels)

in at least one quadrant. Inflammatory control was defined as complete resolution of scleral redness and pain in the affected eye without recurrence. The calculation of immunosuppressive load was based on the scoring system proposed by Nussenblatt

, in which different immunosuppressive agents have scores ranging from 0-9 in each dose of the drug. And the amount of tacrolimus was converted to cyclosporine based on the literature to do the calculation

.The paired Student’s

-test was used for statistical analyses.

Before institution of IMT, history of recurrent or chronic infections was excluded, and blood cell count, liver functions, renal functions, hepatitis B virus, hepatitis C virus,blood T-SPOT. Tuberculosis (TB) antinuclear antibodies and chest X-rays were screened for baseline assessment and to exclude potential contraindications. MTX was considered for patients who required ≥3mo of systemic corticosteroids (≥10 mg/d) for inflammation control or when corticosteroids were not tolerated. In all patients, oral corticosteroid was given before or concomitantly with MTX, and the initial dose was prednisolone 10-40 mg/d or equivalent methylprednisolone.Corticosteroid was slowly tapered depending on disease severity and the patients’ responsiveness to treatment and stopped when scleritis had been quiescent for at least 3mo with minimal dose (≤5 mg/d prednisone or equivalent) of corticosteroid. Topical corticosteroid eye drops (1% prednisolone actate, 0.1% dexmathosone or 0.1% fluoromethalone) with proper tapering schedule were applied to control comorbid anterior uveitis in accordance with international consensus at presentation or during follow up

. Blood tests, including blood cell count, liver and kidney functions were obtained every 1 to 3mo to monitor potential side effects of MTX. The initial oral dose of MTX was 10-15 mg/wk, with 5 mg folic acid supplemented the next day after the MTX dose to lower the risk of gastrointestinal side effects. Follow-up visits were scheduled every 1-2wk at the active phase and every 1-3mo at the quiescent phase. A complete ophthalmic examination including best-corrected visual acuity (BCVA), intraocular pressure (IOP), slit-lamp examination of the sclera and anterior segment, and fundoscopy was performed at each visit. The data collected included the patients’ age, sex, follow-up period, topical and systemic treatments, ocular complications,associated systemic diseases, BCVA in the form of logarithm of the minimum angle of resolution (logMAR) units.

DISCUSSION

Patients who were diagnosed with non-necrotizing anterior scleritis and had received oral MTX to control active scleritis between January 2015 and June 2019 at the Department of Ophthalmology, PUMCH were retrospectively reviewed. The patients met any of the following criteria were excluded in this study: 1) allergy and intolerance to MTX; 2)duration of MTX was less than 3mo; 3) duration of followup after initiation of MTX was less than 1y; 4) the patient had been on MTX before the development of scleritis for comorbid systemic disease; 5) the patients had been on biologics(such as anti-tumor necrosis factor agents), or has increased the dose of other IMT agents (cyclosporin A, azathioprine,tacrolimus, mycophenolate,

.), or had undergone periocular corticosteroid injection or ocular surgery, within 6mo before initiation of MTX or during follow up; 6) had positive findings for any infectious etiology.

In our study, corticosteroid-sparing success was achieved in 77.3% of patients with sustained disease quiescence in 78.1%of the eyes 12mo after initiation of MTX. Of the 5 patients who underwent scleritis relapse, 3 had withdrawn MTX when inflammation recurred, disclosing a lower recurrence rate in patients maintained with MTX. In addition, the maximum dose of MTX was 15 mg/wk during the whole follow-up period and no periocular injections were used or has increased the dose of other IMT agents, suggesting the promising role to achieve treatment success of low dose MTX for Chinese patients with non-necrotizing anterior scleritis. Our study revealed also higher tolerability of long-term MTX than previous studies. Compared to 6%

to 11.8%

of intolerance observed in previous studies, serious side effects that result in discontinuation of MTX were only observed in 4.5% of patients, which indicates that monitoring the cumulative adverse effects of MTX is still important. Probably due to different pharmacogenetics in the East Asian population, the recommended dose of MTX is usually lower than the western countries

. The recommended dose for a particular patient in our study was based on disease severity and tolerance. The lower dosing regimen of MTX adopted might explain at least in part the better safety profile in our study.

應(yīng)用于分揀工位的機(jī)械手需要對產(chǎn)品的位置進(jìn)行定位，并能夠準(zhǔn)確地對產(chǎn)品進(jìn)行分揀和抓取，目前應(yīng)用比較多的分揀裝置主要是利用傳感器來進(jìn)行分揀，而這類分揀只能辨別出產(chǎn)品的形狀、大小和材質(zhì)，而不能準(zhǔn)確地對產(chǎn)品的位置進(jìn)行定位，所以產(chǎn)品在進(jìn)入分揀工位之前只能一字行拍好，然后才能進(jìn)行分揀和裝箱，增加了生產(chǎn)環(huán)節(jié)，降低了生產(chǎn)效率。因此本文中機(jī)械手的分揀采用視覺伺服系統(tǒng)，即模擬人的視覺系統(tǒng)，利用雙攝像頭成像交叉定位，并結(jié)合小孔成像技術(shù)模型，來實現(xiàn)對目標(biāo)物體的定位。

3.1 器械護(hù)士 ①準(zhǔn)備常規(guī)和特殊器械，檢查性能和潔凈度，備齊所需術(shù)中放療手術(shù)器械，使用前與巡回護(hù)士共同清點數(shù)目。②按常規(guī)配合手術(shù)，根據(jù)無瘤原則區(qū)分手術(shù)器械，備兩套吸引器。③切除腫瘤后，按醫(yī)師要求挑選出限光筒，固定卡托，協(xié)助醫(yī)師將限光筒對準(zhǔn)照射部位，并將其固定，用鉛塊屏蔽正常組織使之免受照射。④將加速器發(fā)射端套上無菌機(jī)罩，器械臺用雙層無菌中單覆蓋，并監(jiān)督臺上一切無菌操作。⑤為提高照射效果，要吸凈限光筒內(nèi)的滲液。⑥放射治療完畢，手術(shù)人員更換手術(shù)衣和手套;協(xié)助醫(yī)師取下限光筒，取出鉛塊，重新鋪單，更換清潔器械;沖洗，清點，關(guān)切口。

One should also keep in mind the limitations of our current study. Selection biases are inevitable due to the tertiary referral center-based, retrospective nature of the study. The sample size is also limited. Nevertheless, this study is one of the first pilot studies that evaluated low dose MTX for chronic,noninfectious, non-necrotizing anterior scleritis in the Chinese population thus may serve as a good reference.

In conclusion, low dose MTX appeared to be a well-tolerated and generally effective treatment in patients with nonnecrotizing anterior scleritis patients in the Chinese population.Multi-center studies with longer follow-up and larger sample sizes are needed in the future to validate our results.

3.2.2 分時段收取停車費(fèi)用。適當(dāng)調(diào)節(jié)停車需求，根據(jù)停車時間的長短進(jìn)行分時段、分地段收費(fèi)，可以實行彈性收費(fèi)制度，鼓勵短時停車以提高停車位的周轉(zhuǎn)率。在此基礎(chǔ)上，也可以對有不同需求的群體進(jìn)行不同的收費(fèi)標(biāo)準(zhǔn)，對長時間占用車位的人適當(dāng)提高收費(fèi)標(biāo)準(zhǔn)，從而確保停車場的利用處于相對均衡的狀態(tài)。

ACKNOWLEDGEMENTS

Supported by The Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2018PT32029).

在畜牧業(yè)養(yǎng)殖中，所產(chǎn)生的糞便、廢水等，除直接排放之外，還會供應(yīng)到農(nóng)業(yè)中，以此達(dá)到互利互惠的效果，在多數(shù)農(nóng)村養(yǎng)殖戶中，也多采用該種方式處理牲畜糞便。然而，事實上，畜禽糞便確實具有較多營養(yǎng)，是最佳的基肥，能夠為農(nóng)作物補(bǔ)充氮磷元素，但是，禽畜糞便的過度施灑，也會抑制農(nóng)作物生長，甚至導(dǎo)致其死亡。尤其是近幾年，畜牧業(yè)采用集約形式，養(yǎng)殖飼料與藥品中含有的工業(yè)化學(xué)成分越來越多，這些物質(zhì)進(jìn)入畜禽糞便中，直接為種植的土壤帶來污染。

Xiao JY, None; Liang AY, None; Gao F, None; Zhao C, None; Zhang MF, None.

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