Efficacy and Safety of hydroxychloroquine sulphate in rheumatoid arthritis: a randomized,double-blind,placebo controlled clinical trial – an Indian experience

ABSTRACT

Objective: Hydroxychloroquine (HCQ) has been used for a long time worldwide as a therapy for rheumatoid arthritis (RA). This trial was designed to determine whether HCQ was efficacious and safe in Indian patients with RA.

Research design and methods: The trial was a multicentre, placebo controlled, randomized and double-blind study. One hundred and twenty-two patients with RA were enrolled in 3 different centres for the trial (26 males and 96 females in the age group of 18–60 years). Patients were randomized to receive either hydroxychloroquine tablets (n = 61) two tablets of 200?mg daily or placebo (n = 61) two tablets daily. After 8 weeks all patients received one tablet of hydroxychloroquine 200?mg daily for 4 weeks. Every patient also received one tablet of Nimesulide 100?mg twice daily.

Main outcome measures: Assessment of response at 12 weeks using modified ACR 20 (American College of Rheumatology 20) criteria where Health Assessment Questionnaire (HAQ) was replaced by ARA (American Rheumatology Association) functional class.

Results: 40.4% of patients on hydroxychloroquine showed improvement by modified ACR response criteria whereas only 20.7% (?p = 0.02) showed improvement in the placebo group. No significant side effects were observed in any of the patients. There were no ocular toxicities.

Conclusions: Hydroxychloroquine was found to be an effective and well-tolerated drug in rheumatoid arthritis in Indian patients.     

Adherence to treatment in systemic lupus erythematosus patients

Adherence is defined as “the extent to which a person's behaviour coincides with medical or health advice.” Poor adherence to therapeutic regimens is a common and expensive problem in patients with chronic diseases including systemic lupus erythematosus (SLE) and is associated with a higher risk of flares, morbidity, hospitalisations and poor renal outcome. Non-adherence to the treatment is multifactorial for most patients and varies according to unintentional or intentional patterns. The rates of non-adherence in SLE patients range from 3% to 76% depending on the assessment methods, which are all subject to limitations. Indeed, poor adherence to therapeutic regimens is difficult to evaluate. Two studies have shown that undetectable blood hydroxychloroquine (HCQ) concentration may be a simple, objective and reliable marker of non-adherence in SLE patients. The accurate diagnosis of non-adherence may prevent one from incorrectly interpreting disease manifestations as a lack of response. It may then avoid an unnecessary or even dangerous treatment escalation.     

羟氯喹治疗对视网膜电图的影响

[目的]通过观察视网膜电图(ERG)变化,评估羟氯喹(HCQ)对视网膜损害。[方法]对45例系统性红斑狼疮、类风湿性关节炎和原发性干燥综合症用HCQ治疗的患者进行为期1年的前瞻性研究。在服药前后分别进行视力、视野、眼底和ERG的检查并给予比较。[结果]治疗期间视力,眼底和视野的检查均无异常。但有3位患者分别在服药3个月和6个月时出现了ERG的a波和b波振幅下降。[结论]ERG能较早的观察到HCQ对视网膜的毒性,对视功能损伤有早期诊断价值。     

Is non-biological treatment of rheumatoid arthritis as good as biologics?

The management of rheumatoid arthritis (RA) in the past three decades has undergone a paradigm shift from symptomatic relief to a “treat-to-target” approach. This has been possible through use of various conventional and biologic disease modifying anti-rheumatic drugs (DMARDs) which target disease pathogenesis at a molecular level. Cost and infection risk preclude regular use of biologics in resource-constrained settings. In the recent years, evidence has emerged that combination therapy with conventional DMARDs is not inferior to biologics in the management of RA and is a feasible cost-effective option.     

硫酸羟氯喹治疗肺表面活性蛋白C基因突变致婴儿间质性肺病1例并文献复习

目的：报道硫酸羟氯喹治疗肺表面活性蛋白C基因（SFTPC）突变致婴儿间质性肺病的疗效,提高对该病诊断和治疗的认识。方法：总结分析1例SFTPC突变致婴儿间质性肺病的临床特点、诊断过程和硫酸羟氯喹的疗效,并进行文献复习。结果：患儿女,2月龄,因“生后反复咳嗽伴气促2个月”于2015年9月9日就诊。患儿在新生儿期即发生呼吸窘迫,持续无法离氧。影像学示肺部渗出,病原学检查均阴性,常规抗感染治疗无效,否认肺部疾病家族史。基因检测发现SFTPC基因外显子4有1个杂合错义突变位点（c.T337C:p.Y113H）,目前尚无报道。患儿13月龄时开始硫酸羟氯喹治疗,治疗6个月后,呼吸窘迫、生长发育情况和胸部CT影像学表现明显改善。在PubMed、Web of Science、中国知网、维普数据库和万方数据库中检索SFTPC基因突变的间质性肺病,检索时间均从建库至2016年12月1日,共检索到相关文献12篇,均为英文文献。总结包括本文1例患儿在内的51例SFTPC基因突变致间质性肺病病例使用硫酸羟氯喹的治疗情况,随访0.3~15.8年,其中单用硫酸羟氯喹治疗的有12例,均取得良好疗效,未提及或未发现药物不良反应;全身糖皮质激素合用硫酸羟氯喹治疗39例,33例（84.6%）有效,2例（5.1%）无改善,4例（10.3%）恶化（1例死亡）。结论：对于SFTPC基因突变的婴儿间质性肺病,早期发现和早期诊断很重要,及早使用硫酸羟氯喹治疗可以改善临床症状、体征和生长发育情况,减少终末肺的发生。     

A Case of Hydroxychloroquine Induced Acute Generalized Exanthematous Pustulosis Confirmed by Accidental Oral Provocation

Acute generalized exanthematous pustulosis (AGEP) is a clinical reaction pattern that is principally drug induced and this is characterized by acute, nonfollicular sterile pustules on a background of edematous erythema. Hydroxychloroquine (HCQ) has been widely used to treat rheumatic and dermatologic diseases and HCQ has been reported to be an uncommon cause of AGEP. A 38-year-old woman with a 1-year history of dermatomyositis and polyarthralgia was treated with HCQ due to a lack of response to a previous medication. Three weeks after starting HCQ therapy, the pustular skin lesion developed and then this resolved after the HCQ was withdrawn and steroid treatment was started. A similar pustular eruption developed after HCQ was accidentally readministered.     

Successful Treatment of Hydroxychloroquine-Induced Recalcitrant Acute Generalized Exanthematous Pustulosis with Cyclosporine: Case Report and Literature Review

Acute generalized exanthematous pustulosis (AGEP) is a cutaneous reaction principally induced by drugs. Spontaneous resolution is observed in most patients. However, severe cases required systemic corticosteroid administration. Hydroxychloroquine, which is used to treat some dermatologic and rheumatologic diseases because of its anti-inflammatory and immunosuppressive effects, is an uncommon cause of AGEP. A 67-year-old female patient presented with severe AGEP due to hydroxychloroquine treatment. She was recalcitrant to supportive care and systemic corticosteroid treatment butwas successfully treated with cyclosporine. Hydroxychloroquine-induced AGEP occurs in women with underlying rheumatologic diseases, has a longer latent period, and has a severe course usually requiring systemic treatment.     

Macular sensitivities measured by microperimetry in patients on hydroxychloroquine treatment

Purpose: To examine retinal sensitivity in patients on hydroxychloroquine (HCQ) with no evidence of retinopathy.

Materials and methods: Seventy patients on HCQ and 30 healthy control subjects were included prospectively. All subjects underwent complete ophthalmic examination including best corrected visual acuity, tonometry, colour vision testing, biomicroscopy of anterior segment, dilated fundoscopy, 10-2 visual field testing, and spectral domain optical coherence tomography. The patients and control subjects who met the inclusion criteria and had normal tests underwent microperimetry (MP) testing. First, all patients were compared with the control group. Secondly, patients were divided into three sets of groups based on (1) duration of use ≤5?years (DOU≤5) and?>5?years (DOU>5), (2) daily dose ≤5?mg/kg/day (DD≤?5) and >5?mg/kg/day (DD>5), and (3) a cumulative dose ≤1000?gr (CD≤?1000) and >1000?gr (CD>1000), and these groups were compared to each other and to the control group. A correlation analysis was also performed between MP sensitivity and DOU, DD, and CD.

Results: Seven patients on HCQ showing visual field abnormality were excluded which yielded 63 patients and 30 control subjects for the final analysis. We observed significant differences only in the central region but not in the paracentral or peripheral regions on MP in HCQ users. The median MP sensitivities in the central region were significantly lower in all the patients [84 (63–100) dB], and in subgroups of DOU >5 [84 (63–99) dB], DD >5 [82 (63–97) dB] and CD >1000 [82 (63–92) dB] when compared to controls [89.7 (83–98) dB]. A statistically significant correlation was found only between DD and MP sensitivity in the central region (r?=??0.263; p?=?0.02).

Conclusions: MP sensitivities in the central macula were significantly lower in patients taking HCQ for more than 5?years, at a daily dose more than 5?mg per day, and with a cumulative dose over 1000?gr. Further research investigating long-term follow-up changes in MP sensitivities is needed to determine cutoff values for early retinal toxicity.