High-dose Hydroxychloroquine Research Articles

The effect of oral hydroxychloroquine on chondral defect: An experimental study.

This study aims to evaluate the time- and dose-dependent effects of oral hydroxychloroquine (HCQ) on focal full-thickness knee chondral defect healing in a rabbit model. Cartilage defects of 4x4 mm2 were created on both medial femoral condyles of 24 New Zealand rabbits. The rabbits were divided into six groups (A-F) according to HCQ administration and sacrifice time: A (three-week control) and B (six-week control) received no additional interventions; C (20 mg/kg HCQ, three weeks); D (20 mg/kg HCQ, six weeks); E (40 mg/kg HCQ, three weeks); and F (40 mg/kg HCQ, six weeks). Osteochondral specimens were evaluated macroscopically, histologically, and immunohistochemically. The terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP nick end labeling (TUNEL) method was used to detect apoptotic cells. The International Cartilage Repair Society (ICRS) scores were significantly higher in the experimental groups than in the controls (p<0.001). The Wakitani scores in Group D showed a significant improvement compared to those in Group B (p<0.01). The 20 mg/kg HCQ treatment groups showed better recovery than the controls (p<0.01). High-dose HCQ (40 mg/kg) treatment significantly reduced the intensity of collagen type 2 immunoreactivity compared to that in the groups receiving 20 mg/kg of HCQ (p<0.01). Collagen type 2 expression in Group F was significantly lower than that in Group D (p<0.01). There were more TUNEL-positive cells in the repair sites of Groups E and F than in the lower-dose experimental groups and untreated experimental groups (p<0.001). A low dose of HCQ improved cartilage repair, while higher doses of HCQ exerted a negative effect on cartilage regeneration in rabbits. In the presence of defective cartilage, the use of HCQ at an appropriate dose and time is important for cartilage health.

Effects of hydroxychloroquine on atrial electrophysiology in in silico wild-type and PITX2+/- atrial cardiomyocytes.

Hydroxychloroquine (HCQ) is commonly used in the treatment of autoimmune diseases and increases the risk of QT interval prolongation. However, it is unclear how HCQ affects atrial electrophysiology and the risk of atrial fibrillation (AF). We quantitatively examined the potential atrial arrhythmogenic effects of HCQ on AF using acomputational model of human atrial cardiomyocytes. We measured atrial electrophysiological markers after systematically varying HCQ concentrations. The HCQ concentrations were positively correlated with the action potential duration (APD), resting membrane potential, refractory period, APD alternans threshold, and calcium transient alternans threshold (p < 0.05). By contrast, HCQ concentrations were inversely correlated with the maximum upstroke velocity and calcium transient amplitude (p < 0.05). When the therapeutic concentration (Cmax) of HCQ was applied, HCQ increased APD90 by 1.4% in normal sinus rhythm, 1.8% in wild-type AF, and 2.6% in paired-like homeodomain transcription factor2 (PITX2)+/- AF, but did not affect the alternans thresholds. The overall in silico results suggest no significant atrial arrhythmogenic effects of HCQ at Cmax, instead implying apotential antiarrhythmic role of low-dose HCQ in AF. However, at an HCQ concentration of fourfold Cmax, arapid pacing rate of 4 Hz induced prominent APD alternans, particularly in the PITX2+/- AF model. Our in silico analysis suggests a potential antiarrhythmic role of low-dose HCQ in AF. Concomitant PITX2 mutations and high-dose HCQ treatments may increase the risk of AF, and this potential genotype/dose-dependent arrhythmogenic effect of HCQ should be investigated further.

Successful Heart Transplantation in a Pan-Inflammatory Patient with Interstitial Lung Disease

Introduction We present a case with multiple comorbidities posing a dilemma regarding the need for multi-organ transplant or not being a candidate for any transplant. Case Report 58 year old Hispanic female was referred with decompensated heart failure (CHF), in cardiogenic shock. She had a history of nonischemic cardiomyopathy on home milrinone therapy. She had interstitial lung disease (ILD) on chronic therapy with high-dose hydroxychloroquine (HCQ), mycophenolate (MMF) and prednisone. She had an overlap syndrome consisting of inflammatory arthritis, ILD and myositis for four years, with a history of recurrent myositis flares treated with intravenous immunoglobulin. Presenting creatinine was impaired at 1.9mg/dL. Catheterization on milrinone 0.375mcg/kg/min showed RA 27, PA 60/41 (44), PCWP 33 with a Fick cardiac index 1.7, PAPi of 0.7 and SVR 23WU. Her initial response to diuresis was poor with worsening creatinine so she received an axillary intra-aortic balloon pump (IABP). Positive serologies included highly elevated Jo-1 antibody (185 AU/mL, reference 1000 U/L but repeat levels were normal. Endomyocardial biopsy showed inflammatory lymphocyte and macrophage infiltration. Following aggressive diuresis, HRCT chest showed persistent bilateral ground-glass opacities with interlobular thickening and lower lobe bronchiectasis consistent with ILD without honeycombing. Repeat PFT showed stable FVC of 41% predicted. After multidisciplinary discussion, she was listed status 2 for heart transplant only. Given the relative stability of her restrictive lung disease, concomitant lung transplant was not pursued. HCQ was stopped. She received a heart transplant the next day with basiliximab induction. She was extubated post-operative day 1 and on day 10 she is off inotropes and on tacrolimus, MMF and steroid taper, with no ongoing acute issues. Summary The patient's presentation was dramatic with cardiogenic shock and the decision was time-sensitive given the dependence on IABP. She was not an LVAD candidate given the RV failure (low PAPi). The transplant workup was done methodically yet urgently, with excellent multidisciplinary response, resulting in a successful heart transplant.

Hydroxychloroquine treatment in European patients with lupus erythematosus: dosing, retinopathy screening and adherence

BackgroundUse of hydroxychloroquine (HCQ) is common in patients with lupus erythematosus. Long-term use (ie, ≥5 years) and high-dose HCQ (ie, >5 mg/kg/day) are both risk factors for developing HCQ retinopathy....

SAT0169 HYDROXYCHLOROQUINE PRESCRIPTION PATTERNS IN EUROPE - THE EUROPEAN SURVEY FOR LUPUS PATIENTS (ESLP)

Background:Long-term use of hydroxychloroquine (HCQ) is very common in patients with lupus erythematosus. It has been associated with wide-ranging benefits and it is generally well tolerated1. However, long-term use (i.e. &gt; 5 years) and high-dose HCQ (i.e. &gt; 5 mg/kg/day) are both considered to be risk factors for developing HCQ retinopathy2.Advances in our understanding of HCQ retinopathy has led to changes in the recommendations for HCQ dosing and retinopathy screening1-3. The latest EULAR guidelines for the management of systemic lupus erythematosus (SLE)4recommend a maximum HCQ dose of 5 mg/kg/day and ophthalmological screening at baseline and annually after 5 years of HCQ treatment.Objectives:To assess whether recent EULAR guidelines regarding HCQ dosing and retinopathy screening are affecting prescription patterns and screening frequencies in Europe.Methods:Patients in Europe were given the opportunity to complete the online European Survey for Lupus Patients (ESLP) initiated by LUPUS EUROPE. The survey was promoted on social media from the 26thof June – 11thof July 2019. The survey consisted of 29 questions. Each participant was asked, among other things, to report their body weight (kg), daily HCQ dose and if they have received baseline screening and/or regular eye examinations.Results:The online survey was completed by 2938 lupus patients from 36 countries. The majority were female (86.5%) and diagnosed with SLE (85.7%). The daily HCQ dose (mg/kg) was available from 1678 patients (57.1%). The median ± IQR HCQ dose was 4.3 ± 2.5 mg/kg/day with a median treatment duration of 7 years (IQR: 3 – 14).The recommended daily HCQ dose of 5 mg/kg was exceeded by 618 patients (36.8%). Low HCQ dose (≤ 4 mg/kg) was reported by 769 patients (45.8%). In addition, 284 out of 1786 patients (15.9%) reported they skipped HCQ once a week or more often. Nevertheless, only 8.7% of patients reported that they were more likely to skip HCQ than other medication. Patients from Belgium, Israel, France and Portugal reported the highest HCQ dosages. In contrast, patients from Spain reported the lowest HCQ dosages (Figure 1).Figure 1.HCQ dose (mg/kg/day) reported by patients (• median HCQ dose). PRT: Portugal, POL: Poland, NLD: Netherlands, ITA: Italy, ISR: Israel, GRC: Greece, FRA: France, FIN: Finland, ESP: Spain, DEU: Germany, CHE: Switzerland, BEL: Belgium.Moreover, 935 out of 1137 patients diagnosed in the past 10 years (82.2%) reported that they have received an ophthalmological screening at baseline. Lastly, 1167 patients reported long-term use of HCQ (i.e. ≥ 5 years). Only about 64% of them (n=748) reported that they receive regular eye examinations (i.e. at least once every year).Conclusion:Studies have suggested that prescription patterns in the USA and UK were already affected by guidelines regarding HCQ dosing1. We show large inter- and intra-country variations of HCQ dosing in Europe. Additionally, most centers fail to follow recent recommendations4regarding annual screening of retinopathy in case of long-term HCQ use.More research is needed to assess the clinical efficacy of low-dose HCQ and to confirm whether proper screening modalities are being employed as recommended by recent guidelines2-4.

Immunosuppressive effects of hydroxychloroquine and artemisinin combination therapy via the nuclear factor-κB signaling pathway in lupus nephritis mice.

Lupus nephritis (LN) is one of the most common and severe manifestations of systemic lupus erythematosus, leading to permanent renal damage and chronic kidney disease. Hydroxychloroquine (HCQ) serves a protective role against lupus-associated clinical manifestations and medical complications; however, it results in numerous adverse reactions, limiting its long-term use. The aim of the present study was to investigate the combined effect of HCQ and artemisinin (ART) on LN, and to elucidate the underlying mechanisms. An in vivo LN mouse model was prepared, and the animals were administered prednisone (PDS; serving as a positive control), high-dose HCQ (H-HCQ) or low-dose HCQ combined with ART (L-HCQ + ART) once daily for 8 weeks. The body weight, serum biochemical parameters, immune and inflammatory indicators, renal and spleen histological alterations, and mRNA expression levels of Kruppel-like factor 15 (KLF15) and nuclear factor-κB (NF-κB) were analyzed. It was observed that L-HCQ + ART and H-HCQ ameliorated the LN-induced body weight decrease, and significantly decreased the levels of anti-double stranded DNA, antinuclear antibodies, immunoglobulin G, interferon γ, tumor necrosis factor-α and transforming growth factor-β1, as well as improved the kidney and spleen pathology, when compared with the model group. In addition, L-HCQ + ART and H-HCQ treatments induced KLF15 upregulation and NF-κB downregulation. These results indicated that treatment with L-HCQ + ART exerted renoprotective effects by regulating the expression levels of cytokines, KLF15 and NF-κB. This combination treatment may have a similar immunosuppressive effect as PDS and H-HCQ, and may be a promising alternative for LN treatment.

The effect of hydroxychloroquine on lupus erythematosus-like skin lesions in MRL/lpr mice

Objectives: To evaluate the effect and safety of hydroxychloroquine (HCQ) on lupus erythematosus (LE)-like skin lesions in the MRL/lpr mouse, a model for systemic LE (SLE).Methods: We divided the MRL/lpr mice into three groups that were given: (1) drinking water, (2) HCQ at a dose of 4 mg/kg/d, or (3) HCQ at a dose of 40 mg/kg/d. The HCQ was administered to examine the effect and safety of HCQ on skin lesions and the number of infiltrating cells including mast cells in the dermis.Results: Six of 13 mice in the group given drinking water, 3 of 11 mice in the group administered low-dose HCQ (4 mg/kg/d), and 1 of 10 mice in the group administered high-dose HCQ (40 mg/kg/d) presented the skin lesions. The average number of mast cells was 81, 50, and 12 (magnification, ×100), the mortality rate was 24%, 8%, and 9% and the mean body weight gain was 4.6 g, 8.0 g and 5.1 g, respectively.Conclusions: HCQ was demonstrated to decrease the appearance of LE-like lesions and the number of mast cells in the dermis. Furthermore, there were no obvious systemic adverse effects. This study provides evidence that suggests benefits in human patients.

Retinal toxicity of high-dose hydroxychloroquine in patients with chronic graft-versus-host disease

ObjectiveTo evaluate retinal toxicity in patients treated with high-dose hydroxychloroquine (HCQ) (Plaquenil, Sanofi Pharmaceuticals) for chronic graft-versus-host disease (GVHD). DesignCohort study. ParticipantsTwelve patients with chronic GVHD treated with 800 mg/day HCQ between June 2005 and December 2010. MethodsPatients in this study underwent ophthalmologic examination yearly and ancillary studies including colour vision, Amsler grid, fundus photographs, Humphrey 10-2 automated perimetry, spectral-domain optical coherence tomography (SD-OCT), and multifocal electroretinography (mfERG). Evidence of HCQ toxicity was determined by the presence of scotomas in the Amsler grid and Humphrey 10-2 automated perimetry, and confirmed by at least 1 objective test including SD-OCT or mfERG. ResultsOf the 12 patients, 7 were male and 5 were female. Mean age was 49 years. Mean best corrected visual acuity at baseline was 20/25 and remained 20/25 at final follow-up. Median duration of HCQ treatment was 22.8 months. Median adjusted daily dosage was 11.5 mg/kg/day. Seven patients developed vortex keratopathy. No signs of pigmentary retinopathy or bull’s-eye maculopathy were found in any of the patients. Three patients developed retinal toxicity with scotomas in the Amsler grid and Humphrey 10-2 automated perimetry, as well as abnormal mfERG. Retinal structure measured by SD-OCT was abnormal in 2 of the 3 patients with retinal toxicity. Colour vision measured by Ishihara plates, as well as by 100 Hue colour test, was abnormal in 2 of the 3 patients with retinal toxicity. ConclusionsHigh-dose HCQ in patients with GVHD was associated with higher incidence and earlier development of retinal toxicity.

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma

Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m2 daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.

Refractory subacute cutaneous lupus erythematosus successfully treated with rituximab

A 48-year-old woman presented with pruritic, scaly, annular plaques over her upper back and chest that were clinically, serologically and histologically characteristic of subacute cutaneous lupus erythematosus (SCLE). She failed to respond to conventional treatment, which included high-dose hydroxychloroquine, methotrexate, prednisolone, chloroquine, acitretin, thalidomide, dapsone and azathioprine. Subsequently treated with intravenous rituximab 375 mg/m(2) weekly for 4 weeks, she remained on adjuvant oral hydrochloroquine 600 mg daily and topical clobetasol propionate 0.05% ointment as required. Clearing of annular plaques was noted 8 weeks after the initial course of rituximab. By 12 weeks there were no new lesions and only post-inflammatory hyperpigmentation remained. Both hyper- and hypopigmentation, which is more common, are consistent with SCLE lesion regression. Skin lesions recurred 11 months later; however, no further lesions occurred after re-introduction of rituximab therapy. The treatment was well tolerated. A maintenance regimen of rituximab, 375 mg/m(2) every 8 weeks for 2 years, was commenced 3 months after completing the second course of treatment, with ongoing disease remission. Rituximab appears to have activity in refractory SCLE and clinical trials are required to further assess this potential therapy.

High-dose hydroxychloroquine treatment of porphyria cutane tarda

High-dose hydroxychloroquine is rarely used in the treatment of porphyria cutanea tarda (PCT). The purpose of this study was to evaluate the efficacy and safety of a novel high-dose hydroxychloroquine regimen in patients with PCT. Sixty-five first episodes and 28 recurrent episodes of PCT were treated with hydroxychloroquine, 250 mg three times daily, for 3 days. In patients with a high urine porphyrin concentration a single phlebotomy of 500 ml was performed before therapy of the first episode. Modified high-dose hydroxychloroquine regimens were used in patients with markedly elevated liver transaminases with or without associated chronic liver disease. Long-term follow-up data showed an overall relapse rate of 33%, significantly higher among male patients (45%) than among female patients (17%) (p less than 0.05). A transient hepatotoxic reaction occurred in the majority of patients. The reaction seemed to be especially severe among phlebotomized female patients. Hydroxychloroquine, 250 mg three times daily, is a rapid, efficacious, and safe treatment in patients with PCT.