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.

运输采用的是卸料运输搅拌车，运输时间要控制合理，不能过长，在运输中若发生混凝土离析，则需要进行二次搅拌。通常情况下，搅拌车运输时间要＜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.

应用于分拣工位的机械手需要对产品的位置进行定位，并能够准确地对产品进行分拣和抓取，目前应用比较多的分拣装置主要是利用传感器来进行分拣，而这类分拣只能辨别出产品的形状、大小和材质，而不能准确地对产品的位置进行定位，所以产品在进入分拣工位之前只能一字行拍好，然后才能进行分拣和装箱，增加了生产环节，降低了生产效率。因此本文中机械手的分拣采用视觉伺服系统，即模拟人的视觉系统，利用双摄像头成像交叉定位，并结合小孔成像技术模型，来实现对目标物体的定位。

3.1 器械护士 ①准备常规和特殊器械，检查性能和洁净度，备齐所需术中放疗手术器械，使用前与巡回护士共同清点数目。②按常规配合手术，根据无瘤原则区分手术器械，备两套吸引器。③切除肿瘤后，按医师要求挑选出限光筒，固定卡托，协助医师将限光筒对准照射部位，并将其固定，用铅块屏蔽正常组织使之免受照射。④将加速器发射端套上无菌机罩，器械台用双层无菌中单覆盖，并监督台上一切无菌操作。⑤为提高照射效果，要吸净限光筒内的渗液。⑥放射治疗完毕，手术人员更换手术衣和手套;协助医师取下限光筒，取出铅块，重新铺单，更换清洁器械;冲洗，清点，关切口。

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 分时段收取停车费用。适当调节停车需求，根据停车时间的长短进行分时段、分地段收费，可以实行弹性收费制度，鼓励短时停车以提高停车位的周转率。在此基础上，也可以对有不同需求的群体进行不同的收费标准，对长时间占用车位的人适当提高收费标准，从而确保停车场的利用处于相对均衡的状态。

ACKNOWLEDGEMENTS

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

在畜牧业养殖中，所产生的粪便、废水等，除直接排放之外，还会供应到农业中，以此达到互利互惠的效果，在多数农村养殖户中，也多采用该种方式处理牲畜粪便。然而，事实上，畜禽粪便确实具有较多营养，是最佳的基肥，能够为农作物补充氮磷元素，但是，禽畜粪便的过度施洒，也会抑制农作物生长，甚至导致其死亡。尤其是近几年，畜牧业采用集约形式，养殖饲料与药品中含有的工业化学成分越来越多，这些物质进入畜禽粪便中，直接为种植的土壤带来污染。

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

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