To determine the relationship between current hydroxychloroquine (HCQ) use and 2 indicators of glycemic control, fasting glucose and insulin sensitivity, in nondiabetic women with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA).
Nondiabetic women with SLE (n = 149) or RA (n = 177) recruited between 2000 and 2005 for a cross-sectional evaluation of cardiovascular risk factors were characterized by HCQ usage status. Unadjusted and multivariately adjusted mean fasting glucose, median insulin, and insulin resistance [assessed by the homeostasis model assessment (HOMA-IR) calculation] were compared among HCQ users and nonusers for disease-specific groups.
More women with SLE were taking HCQ than those with RA (48% vs 18%; p < 0.0001; mean dose ~ 400 mg vs ~ 200 mg). For women with SLE or RA, after adjustment for age, waist circumference, disease duration, prednisone dosage, C-reactive protein, menopausal status, nonsteroidal antiinflammatory drugs, and disease-specific indicators, serum glucose was lower in HCQ users than in nonusers (SLE: 85.9 vs 89.3 mg/dl, p = 0.04; RA: 82.5 vs 86.6 mg/dl, p = 0.05). In women with SLE, HCQ use also was associated with lower logHOMA-IR (0.97 vs 1.12, p = 0.09); in those with RA, no differences in logHOMA-IR were seen. HCQ usage was not associated with fasting insulin levels in either patient group.
HCQ use was associated with lower fasting glucose in women with SLE or RA and also lower logHOMA-IR in the SLE group. The use of HCQ may be beneficial for reducing cardiovascu lar risk by improving glycemic control in these patients.
HYDROXYCHLOROQUINE; RHEUMATOID ARTHRITIS; SYSTEMIC LUPUS ERYTHEMATOSUS; HYPERGLYCEMIA; DIABETES MELLITUS
Hydroxychloroquine (HCQ) is an antimalarial drug used as chemoprophylaxis against malaria caused by Plasmodium vivax in the Republic of Korea Army (ROKA). In this study, we evaluated the pharmacokinetics (PK) of HCQ and its metabolites and the relationship between the PK of HCQ and the effect of treatment of HCQ on vivax malaria in South Koreans. Three PK studies of HCQ were conducted with 91 healthy subjects and patients with vivax malaria. Plasma concentrations were analyzed by noncompartmental and mixed-effect modeling approaches. A two-compartment model with first-order absorption best described the data. The clearance and the central and peripheral volumes of distribution were 15.5 liters/h, 733 liters, and 1,630 liters, respectively. We measured the plasma concentrations of HCQ in patients with prophylactic failure of HCQ and compared them with the prediction intervals of the simulated concentrations for HCQ from the final PK model built in this study. In 71% of the patients with prophylactic failure, the plasma concentrations of HCQ were below the lower bounds of the 95% prediction interval, while only 8% of them showed higher levels than the upper bounds of the 95% prediction interval. We report that a significant cause of prophylactic failure among the individuals in ROKA was ascribed to plasma concentrations of HCQ lower than those predicted by the PK model. However, prophylactic failure despite sufficient plasma concentrations of HCQ was confirmed in several individuals, warranting continued surveillance to monitor changes in the HCQ susceptibility of Plasmodium vivax in the Republic of Korea.
Hydroxychloroquine (HCQ) is an antimalarial agent that is commonly used to treat rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The present report documents a case of hypoglycaemia due to HCQ in a patient with SLE and diabetes mellitus type 2, in which the HCQ completely replaced the need for daily subcutaneous insulin.
In recent years hydroxychloroquine (HCQ) has emerged as a key therapy in systemic lupus erythematosus (SLE). We determined the rates of HCQ use in a diverse, community-based cohort of patients with SLE and identified predictors of current HCQ use.
Patients were participants in the University of California San Francisco (UCSF) Lupus Outcomes Study (LOS), an ongoing longitudinal study of patients with confirmed SLE. We examined the prevalence of HCQ use per person-year and compared baseline characteristics of users and non-users, including demographic, socioeconomic, clinical, and health-system use variables. Multiple logistic regression with generalized estimating equations was used to evaluate predictors of HCQ use.
Eight hundred and eighty one patients contributed 3095person-years of data over 4 interview cycles. The prevalence of HCQ use was 55 per 100 person-years and was constant throughout the observation period. In multivariate models, the odds of HCQ use were nearly doubled among patients receiving their SLE care from a rheumatologist compared to those identifying generalists or nephrologists as their primary sources of SLE care. In addition, patients with shorter disease duration were more likely to use HCQ, even after adjusting for age and other covariates.
In this community-based cohort of patients, HCQ use was suboptimal. Physician specialty and disease duration were the strongest predictors of HCQ use. Patients who are not using HCQ, those with longer disease duration, and those who see non-rheumatologists for their SLE care should be targeted for quality improvement.
OBJECTIVE—To investigate the therapeutic benefit of cyclosporin A (CSA) switching to hydroxychloroquine (HCQ) in patients with rheumatoid arthritis (RA).
METHODS—Thirty four patients with RA who displayed residual inflammation and disability despite partial responses to prior maximal tolerated doses of methotrexate, were included. All were treated with a staged approach using CSA for 24 weeks to induce clinical improvement, followed by HCQ for 16 weeks to maintain the improvement. Seven ACR core set measures were evaluated every four to eight weeks.
RESULTS—During a 40 week open trial, 27/34 patients completed the study. CSA treatment significantly reduced the tender joints score, swollen joints score, visual analogue pain scale, patient's or doctor's global assessment, patient's self assessed disability, and C reactive protein. Compared with the time of entry into the trial, patients who switched from CSA to HCQ still possessed significantly lower levels of most variables, determined at 28, 32, and 40 weeks. According to the ACR 20% improvement definition, 15/27 (56%) patients had improved at 24 weeks after CSA treatment, and 14/27 (52%) remained improved at 16 weeks after the change to HCQ. Frequent side effects, such as hypertrichosis, gastrointestinal trouble, and hypertension, were noted during CSA treatment, but most of these disappeared after switching to HCQ. The mean levels of blood pressure and serum creatinine were significantly increased during CSA treatment, but returned to normal after changing to HCQ.
CONCLUSIONS—The data suggest that CSA switching to HCQ treatment may be an effective strategy for patients with RA partially responding to methotrexate, particularly those with toxicity due to CSA.
Hand pain with stiffness is a common clinical presentation to early arthritis clinics, with outcome varying from resolution to the development of rheumatoid arthritis.
To assess the response and predictors of response to intramuscular methylprednisolone (MP) and hydroxychloroquine (HCQ) using a standardised treatment protocol.
Patients with inflammatory hand pain (IHP), defined as predominantly hand pain and morning stiffness of at least 30 min duration, received a standardised assessment prior to receiving intramuscular MP. Response (primary outcome) at 4 weeks was a 50% improvement in symptoms as perceived by the patient; responders who relapsed received repeat intramuscular MP and HCQ.
102 patients were recruited, of which 21% were rheumatoid factor (RF) positive, 23% had clinical synovitis, 25% had raised C‐reactive protein level and 55% had ultrasound‐detected synovitis. 73% responded, with associated significant reductions in morning stiffness, Health Assessment Questionnaire, painful and tender joint counts, and visual analogue scores (p⩽0.006 for all). Ultrasound‐detected synovitis (p<0.001) and RF (p = 0.04), but not clinical synovitis (p = 0.74), were significantly associated with response to intramuscular MP. 86% who remained on HCQ long term reported a benefit.
Patients with IHP have significant improvement in symptoms and function following intramuscular MP. Further placebo‐controlled trials are required to assess the role of intramuscular MP and ultrasonography in managing this patient group.
Prior research demonstrates that hydroxychloroquine (HCQ) lowers glycated hemoglobin (HbA1c) in non-rheumatic diabetic patients. We examined medical records of patients with diabetes mellitus (DM) and concomitant rheumatic illness to measure changes in HbA1c after starting HCQ or methotrexate (MTX).
We utilized electronic medical records to identify patients initiating either HCQ or MTX, with a diagnosis of DM or HbA1c ≥ 7%, and with at least one HbA1c measurement before and within 12 months after initiation. A structured medical record abstraction examined rheumatologic diagnosis, use of oral glucocorticoids, body mass index, age, gender. Adjusted linear regression models determined changes in HbA1c from pre-drug values to the lowest post-drug values within twelve months.
We identified 45 HCQ users and 37 MTX users who met inclusion criteria. Half in each group carried a rheumatoid arthritis diagnosis. Age, gender, and mean pre-drug HbA1c levels were similar across groups. Mean BMI for HCQ users (35.4 kg/m2) was slightly higher than MTX users (32.2 kg/m2) (p = 0.13). Glucocorticoid use appeared more common in MTX (46%) than HCQ (29%) users (p = 0.17). The mean reduction in HbA1c between pre- and post-HCQ was 0.66% (95% CI 0.26–1.05) versus 0.11% (95% CI −0.18 – 0.40) for MTX. In fully adjusted analyses, the reduction in HbA1c among HCQ users was 0.54% greater than the drop among MTX users (p = 0.041).
HCQ initiation was associated with a significantly greater reduction in HbA1c as compared to MTX initiation among diabetic patients with rheumatic disease.
Poor adherence to treatment is difficult to diagnose accurately. Hydroxychloroquine (HCQ) has a long elimination half‐life and its concentration in whole blood can be measured easily.
To evaluate the utility of a very low blood HCQ concentration as a marker of poor compliance in patients with systemic lupus erythematosus (SLE).
HCQ concentrations were determined on a blinded basis in 203 unselected patients with SLE. At the end of the study, the patients were informed of the results and retrospectively interviewed about their adherence to treatment.
14 (7%) patients said that they had stopped taking HCQ (n = 8) or had taken it no more than once or twice a week (n = 6). Their mean (SD) HCQ concentration was 26 (46) ng/ml. range (0–129 ng/ml) By contrast, the other patients had a mean HCQ concentration of 1079 ng/ml range (205–2629 ng/ml). The principal barriers to adherence were related to HCQ treatment characteristics. Adherence subsequently improved in 10 of the 12 patients whose blood HCQ concentrations were remeasured.
Very low whole‐blood HCQ concentrations are an objective marker of prolonged poor compliance in patients with SLE. Regular drug assays might help doctors in detect non‐compliance and serve as a basis for counselling and supporting these patients.
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.
Acute generalized exanthematous pustulosis; Adverse drug reactions; Hydroxychloroquine; Provocation test
This investigator-initiated study explores the safety, maximum tolerated dose (MTD), clinical response, and pharmacokinetics (PK) of hydroxychloroquine (HCQ) with and without erlotinib in patients with advanced non-small cell lung cancer (NSCLC).
Patients with prior clinical benefit from an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor were randomized to HCQ or HCQ plus erlotinib in a 3+3 dose escalation schema.
Twenty-seven patients were treated, 8 with HCQ (arm A) and 19 with HCQ plus erlotinib (arm B). EGFR mutations were detected in 74% of patients and 85% had received ≥2 prior therapies. Arm A had no dose-limiting toxicities (DLTs), but the MTD was not reached as this arm closed early to increase overall study accrual. In arm B, 1 patient each experienced grade 3 rash, nail changes, skin changes, nausea, dehydration, and neutropenia, 1 had grade 4 anemia, and 1 developed fatal pneumonitis, all considered unrelated to HCQ. There were no DLTs, therefore the highest tested dose for HCQ with erlotinib 150mg was 1000mg daily. One patient had a partial response (PR) to erlotinib/HCQ, for an overall response rate of 5% (95% CI, 1–25). This patient had an EGFR mutation and remained on therapy for 20 months. Administration of HCQ did not alter the PK of erlotinib.
HCQ with or without erlotinib was safe and well-tolerated. The recommended phase 2 dose of HCQ was 1000mg when given in combination with erlotinib 150mg.
Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) has been inducted as a mediator of inflammation in rheumatoid arthritis. Methotrexate combination therapy forms an important component of the treatment regimen in rheumatoid arthritis. The present study was undertaken to evaluate the influence of Methotrexate-Hydroxychloroquine (MTX-HCQ) combination and Sulfsalazine- Hydroxychloroquine (SSZ-HCQ) combination on the expression GM-CSFR in neutrophils isolated from synovial fluids. 15 cases of confirmed rheumatoid arthritis patients who presented at the hospital for surgical correction of joint deformities were selected for the study. Neutrophils isolated from the synovial fluids were used as the source of the receptor for quantitation on an enzyme immunoassay (EIA). The EIA was developed and standardized in our laboratory for quantification of the GM-CSF R. The findings are suggestive of the fact that the administration of MTX-HCQ combination has positive influence on the expression of the GM-CSF R on neutrophils as against SSZ-HCQ combination. The physiological basis of this increase needs further investigation.
Methotrexate; Rheumatoid arthritis; GM-CSF receptor; Synovial fluid
Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs) in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX, SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD.
To evaluate the effect of different concomitant disease modifying antirheumatic drugs (DMARDs) on the persistence with antitumour necrosis factor (anti-TNF) therapies in patients with rheumatoid arthritis (RA).
This analysis included 10 396 patients with RA registered with the British Society for Rheumatology Biologics Register, a prospective observational cohort study, who were starting their first anti-TNF therapy and were receiving one of the following DMARD treatments at baseline: no DMARD (n=3339), methotrexate (MTX) (n=4418), leflunomide (LEF) (n=610), sulfasalazine (SSZ) (n=308), MTX+SSZ (n=902), MTX+ hydroxychloroquine (HCQ) (n=401) or MTX+SSZ+HCQ (n=418). Kaplan–Meier survival analysis was used to study the persistence with anti-TNF therapy in each DMARD subgroup up to 5 years. Multivariate Cox proportional hazard models, stratified by anti-TNF used and start year and adjusted for a number of potential confounders, were used to compare treatment persistence overall and according to the reason for discontinuation between each of the DMARD subgroups, using MTX as reference.
One-year drug survival (95% CI) for the first anti-TNF therapy was 71% (71% to 72%) but this dropped to 42% (41% to 43%) at 5 years. Compared with MTX, patients receiving no DMARD, LEF or SSZ were more likely to discontinue their first anti-TNF therapy while patients receiving MTX in combination with other DMARDs showed better treatment persistence.
These results support the continued use of background DMARD combinations which include MTX. Consideration should be given to the discontinuation of LEF and SSZ monotherapy at the time anti-TNF therapies are started, with the possible exception of the SSZ+ETN combination.
OBJECTIVE—To determine the effect of intramuscular gold and oral hydroxychloroquine(HCQ) on the lipid profile of patients with rheumatoid arthritis (RA).
METHOD—A prospective randomised clinical trial of 12 months' duration was performed in 100 RA patients. Data on clinical and laboratory parameters of disease activity, and fasting serum lipid samples was collected at baseline and at three monthly intervals over one year.
RESULTS—The expected second line response was seen with no significant difference in efficacy between the groups at 12 months. The HCQ group had a significant overall improvement in their lipid profile while there was a trend for lipid profiles in the gold group to worsen.
CONCLUSIONS—HCQ is an effective second line agent that has beneficial effects on serum lipids. This should be taken into account when choosing a disease modifying anti-rheumatic drug in patients who suffer from RA and who have significant cardiovascular risk factors.
Low-dose hydroxychloroquine (HCQ) and ataxia-telangiectasia-mutated (ATM) protein kinase have recently been postulated to be beneficial for the prevention of the age-associated metabolic syndrome including hypertension, hypercholesterolemia and glucose intolerance; however, the effects of low-dose HCQ on the expression of ATM downstream phosphorylated Akt (protein kinase B) and p53 proteins and cardiomyocyte apoptosis in the peri-infarct myocardium remain unclear.
To explore the effects of low-dose HCQ on the expression of phosphorylated Akt and p53 proteins and cardiomyocyte apoptosis in the peri-infarct myocardium in a rat model.
Myocardial infarction (MI) was induced experimentally in a subset of rats, while others underwent sham operation (sham). Three days after operation, surviving Sprague-Dawley male rats were divided into MI+HCQ, MI, sham+HCQ and sham groups. MI+HCQ and sham + HCQ groups were treated with HCQ (3.4 mg/kg); and MI and sham groups were treated with phosphate buffered (ie, physiological) saline (10 mL/kg) by gavage every day for 12 weeks. The expression of phosphorylated Akt and p53 proteins and cardiomyocyte apoptosis in the peri-infarct myocardium was detected by Western blot and terminal deoxynucleotidyl transferase dUTP nick end labelling, respectively.
Twelve weeks after treatment, the expression of phosphorylated Akt protein was significantly increased (P<0.05). Expression of phosphorylated p53 protein was not significantly different (P>0.05) in the peri-infarct myocardium of the MI+HCQ group from that in the MI group. The cardiomyocyte apoptosis rate in the peri-infarct myocardium was significantly decreased in the MI+HCQ group compared with the MI group (P<0.05).
Low-dose HCQ can significantly increase the expression of phosphorylated Akt protein without significantly impacting expression of phosphorylated p53 protein in the peri-infarct myocardium. Accordingly, it can inhibit cardiomyocyte apoptosis in the peri-infarct myocardium.
Akt (protein kinase B); Cardiomyocyte apoptosis; Hydroxychloroquine (HCQ); Myocardial infarction (MI); P53 (protein 53)
To evaluate the antihyperglycemic activity of atorvastatin and hydroxychloroquine combination in alloxan-induced diabetic rats.
Materials and Methods:
Alloxan induced diabetic Wistar male rats were randomized into six groups of 6 rats each. (Normal rats, diabetic control, atorvastatin (ATV), hydroxychloroquine (HCQ), ATV 5 mg /kg + HCQ 100 mg/kg, and ATV 10 mg/kg + HCQ 200 mg/kg). The rats were treated for 9 days and blood samples were collected at baseline and end of therapy. These samples were analyzed for plasma glucose by autoanalyzer. Changes in body weight, water, food intakes and total protein content were also recorded.
Atorvastatin and hydroxychloroquine alone and in combination reported significant fall in blood glucose level from baseline. Fall in glucose level was significantly more in high dose combination of atorvastatin and hydroxychloroquine (ATV: 10 mg/kg + HCQ: 200 mg/kg) as compared to other study treatment groups (ATV: 17% Vs HCQ: 7% Vs ATV 5mg/kg + HCQ 100mg /kg: 14% Vs ATV 10mg/kg + HCQ 200mg /kg: 21%; p<0.01). ATV and HCQ individually and in combination also improved the body weight loss. The weight gain was significantly more in combination treated rats as compared to positive control group and greater than those who received atorvastatin and hydroxychloroquine alone. Rats treated with the combination also reported significant decrease in food intake and significant increase in total protein.
Increased hypoglycemic effect in combination may be due to potentiation or synergism between HCQ and ATV. Further studies are required to demonstrate clinically significant antidiabetic effect.
Antihyperglycemic activity; alloxan; atorvastatin; hydroxychloroquine; plasma glucose
We hypothesized that initiation of a new disease modifying anti-rheumatic drug DMARD) for rheumatoid arthritis (RA) treatment would decrease use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) and narcotics.
Using administrative databases we assembled 4 retrospective cohorts of RA patients (1998-2005), and identified 5 groups initiating DMARD regimens: methotrexate with (new MTX) or without (first MTX) use of other non-biologic DMARDs in the previous year; new hydroxychloroquine and/or sulfasalazine (new HCQ/SSZ) and new leflunomide (new LEF), both with previous use of MTX; and new TNF-α antagonists (new anti-TNF). We compared within-person differences in any use of co-therapies (≥1 prescription) between the 6 months before and the 6-12 months after DMARD initiation.
Among 32476 DMARD initiators, the prevalence of corticosteroids, NSAIDs and narcotics use increased by 15%, 5% and 6% respectively in the 6 months before initiation compared to the previous 6 months suggesting worsening of the disease. In the 6 to 12 months after initiation for most initiator groups, more patients stopped using corticosteroids and NSAIDs than started, with overall decreases of 8.9% [95%CI 8.4-9.4%] for corticosteroids and 12.9% [95%CI 12.3-13.4%] for NSAIDs. The proportion of narcotic users changed little (overall decrease of 2.5% [95%CI 1.9-3.0%]).
Use of all three co-therapies increased in the 6 months before initiation of new DMARD regimens for RA. Use of corticosteroids and NSAIDs decreased modestly 6-12 months fter initiation, but there was only a very small decrease in narcotic use. These differential changes require further study.
Chemoprophylaxis with hydroxychloroquine (HCQ) and primaquine has been used in the Republic of Korea (ROK) Army since 1997. It may facilitate the development of chloroquine (CQ)-resistant strains of Plasmodium vivax. We investigated the therapeutic efficacy of HCQ and the pvmdr1 gene polymorphisms in P. vivax. From June to September 2006, 102 soldiers with vivax malaria near the demilitarized zone in Gyeonggi-do, ROK, were enrolled in the study. We determined the status of compliance of chemoprophylaxis. In 85 patients, therapeutic efficacy was monitored 28 days after standard HCQ treatment; 66 (64.7%) of 102 malaria patients had taken all chemoprolaxis with HCQ. In all patients enrolled in the therapeutic efficacy monitoring, parasitemia had not been observed since 3 days after standard HCQ treatment. However, the ubiquitous presence of the F1076L mutation of the pvmdr1 was observed. There was no evidence that the F1076L mutation of pvmdr1 could contribute to failure of HCQ treatment.
To determine whether early toxic effects from hydroxychloroquine (HCQ) could be detected by spectral-domain optical coherence tomography (SD-OCT) before symtomatic visual loss occured.
Materials and Methods:
Fifteen subjects with a history of the chronic use of hydroxychloroquine monotherapy for less than five years without fundus changes (group 1) and 15 visually normal healthy subjects (group 2) were enrolled in this study. All participants underwent systemic and ocular examination, visual field testing, and macular scan imaging using SD-OCT.
There were no significant differences in sex and ages between the groups (P > 0.05). Mean duration of HCQ usage in group 1 was 2.5 ± 1.34 (range:1-5) years. Visual field testing with central 10-2 threshold program was normal in all subjects. Inner retinal thickness in parafoveal and perifoveal area were found to be significantly lower in group 1 compared to group 2 (P < 0.01 for perifoveal, P < 0.05 for parafoveal retinal measurements). However, significant thinning was demonstrated only in full retinal thickness of perifoveal area in group 1 compared to group 2 (P: 0.013). Parafoveal and perifoveal inner retinal thickness measurements of inferior quadrants were significantly reduced in group 1 compared to group 2 (P < 0.01).
Significant thinning of inner retinal layer especially in parafoveal and perifoveal areas in the absence of clinical fundus changes was observed in our study. We consider that SD-OCT may determine when inner retinal thinning starts in these patients and may contribute a quantitative approach to the early diagnosis and progression of retinal changes.
Hydroxychloroquine; optical coherence tomography; retinal toxicity; retinal thickness
A recent case control study suggested a benefit of hydroxychloroquine (HCQ) in lowering the risk of cardiac manifestations of neonatal lupus (cardiac-NL) in pregnancies of anti-SSA/Ro positive patients with Systemic Lupus Erythematosus (SLE). A historical cohort assembled from three international databases was used to evaluate whether HCQ reduces the nearly tenfold increase in risk of recurrence of cardiac-NL, independent of maternal health status.
Methods and Results
Two hundred fifty seven pregnancies of anti-SSA/Ro positive mothers (40 exposed and 217 unexposed to HCQ) subsequent to the birth of a child with cardiac-NL were identified from three databases (U.S., England, and France). Exposure was defined as the sustained use of HCQ throughout pregnancy with initiation prior to ten weeks of gestation. The recurrence rate of cardiac-NL in fetuses exposed to HCQ was 7.5% (3/40) compared to 21.2% (46/217) in the unexposed group (p=0.050). While there were no deaths in the exposed group, the overall case fatality rate of the cardiac-NL fetuses in the unexposed group was 22%. In a multivariable analysis which adjusted for database source, maternal race/ethnicity, and anti-SSB/La status, HCQ use remained significantly associated with a decreased risk of cardiac-NL (Odds Ratio=0.23; 95% CI: 0.06–0.92; p=0.037). Similar results were obtained with propensity score analysis, an alternative approach to adjust for possible confounding by indication.
Based on aggregate data from a multinational effort, in mothers at high risk of having a child with cardiac-NL, the use of HCQ may protect against recurrence of disease in a subsequent pregnancy.
heart block; antibodies; cardiomyopathy; prevention; hydroxychloroquine
To determine the prevalence of high-risk factors for hydroxychloroquine (HCQ) retinopathy and compliance with the American Academy of Ophthalmology (AAO) screening guidelines at the San Francisco Veterans Affairs Medical Center (VASF) and to develop an approach to improve the risk-benefit relationship and informed consent during HCQ treatment.
All medical records of patients receiving HCQ were reviewed, with special attention to high-risk factors for retinopathy. The results were used to develop a method of enhancing the risk-benefit relationship and improving informed consent at the VASF.
Of the 109 patients taking HCQ at the VASF, 87% had at least one high-risk factor for retinal toxicity and 47% had two or more risk factors. Thirty-four percent had no evidence of an eye examination having been performed. An approach has been developed to improve the risk-benefit and informed consent for patients using HCQ at the VASF.
A significant number of veterans taking HCQ may be at an increased risk for retinal toxicity. More than one-third of these patients may not be managed as recommended by the AAO. Methods to minimize these risks and improve informed consent are outlined.
OBJECTIVE: To study maternal and fetal outcome of pregnancy in patients with lupus who were exposed to hydroxychloroquine (HCQ). METHODS: The case records of women (n = 33) exposed to HCQ during their pregnancies (n = 36) and of 53 control patients from a single lupus pregnancy centre were reviewed to determine lupus activity, obstetric experience, and infant outcome. RESULTS: HCQ was not apparently teratogenic. Lupus activity and obstetric outcome in the two groups were similar. CONCLUSION: HCQ continuation is probably safe during pregnancy in patients with lupus, but there is no obvious advantage in commencing treatment.
Plasmacytoid dendritic cells (pDCs) constitutively express two members of the Toll-like receptor (TLR) family, TLR-9 and TLR-7, through which they can be stimulated to produce high levels of interferon (IFN)-α, a key mediator of the pathogenesis of systemic lupus erythematosus (SLE). Given the known efficacy of hydroxychloroquine (HCQ) in the treatment of SLE, we examined its ability to inhibit such pDC function in vivo.
Peripheral blood mononuclear cells (PBMCs) from SLE subjects treated or not with HCQ and from healthy controls were stimulated with the TLR-9 agonist, CpG oligodeoxynucleotides (CpG-A ODN)-2216, and the TLR-7 agonist, imiquimod. The proportion of monocytes, B cells, myeloid dendritic cells, pDCs, and natural killer (NK) cells producing IFN-α and tumor necrosis factor alpha (TNF-α) was then analyzed by multiparameter flow cytometry.
After TLR-9/7 stimulation in both SLE and healthy subjects, significant production of IFN-α and TNF-α was only observed in pDCs. TLR-7 and TLR-9 induced IFN-α and TNF-α production by pDCs from subjects with SLE was decreased relative to that found in controls (TLR-9/IFN-α, P < 0.0001; TLR-9/TNF-α P < 0.0001; TLR-7/TNF-α P = 0.01). TLR-9 and TLR-7 induced IFN-α and TNF-α production by pDCs was severely impaired in 36% (TLR-9) and 33% (TLR-7) of SLE subjects. In almost all cases, these subjects were being treated with HCQ (HCQ vs. no HCQ: impaired TLR-9/IFN-α, P = 0.0003; impaired TLR-7/IFN-α, P = 0.07; impaired TLR-9/TNF-α, P < 0.009; impaired TLR-7/TNF-α, P < 0.01).
Treatment with HCQ is associated with impaired ability of pDCs from subjects with SLE to produce IFN-α and TNF-α upon stimulation with TLR-9 and TLR-7 agonists.
Rheumatoid arthritis is one of the commonest autoimmune diseases. It is a chronic, progressive, systemic inflammatory disorder affecting the synovial joints and typically producing symmetrical arthritis. If left untreated, it leads to joint destruction and thus deformity and disability.
In the recent years, advances in molecular biology have led to a variety of new treatment approaches to rheumatoid arthritis and other systemic inflammatory diseases associated with autoimmunity. Anti tumor necrosis factor (TNF) agents are emerging in the frontline management of rheumatoid arthritis (RA) in the current era of biological treatment.
We presented a 46-year-old Chinese female with a history of seropositive RA for the past 22 years refractory and intolerant to multiple medications including sulphasalazine (SSZ), leflunomide, hydroxychloroquine (HCQ) and methotrexate (MTX), thus infliximab, a tumor necrosis factor (TNF) inhibitor was initiated. However, despite receiving 6 cycles of infliximab therapy, she still complained of persistent disabled multiple joint pain and swelling. This report will discuss about rheumatoid arthritis, which is refractory to infliximab (a TNF inhibitor) and its alternative.
Rheumatoid arthritis; Biologics treatment; Tumor-necrosis factor inhibitor; Infliximab
To determine the efficacy of subsequent disease modifying antirheumatic drug (DMARD) therapies after initial methotrexate (MTX) failure in patients with recent onset rheumatoid arthritis (RA), treated according to the DAS for 2 years.
In groups 1 and 2 of the BeSt study, 244 RA patients were initially treated with MTX 15–25 mg/week. Patients who discontinued MTX because of insufficient clinical response (disease activity score, DAS >2.4) or toxicity were classified as “MTX failures.” In group 1, these patients switched to sulfasalazine (SSA), then leflunomide and finally to MTX + infliximab (IFX). In group 2, “MTX failures” added SSA to MTX, then hydroxychloroquine (HCQ), then prednisone, and eventually switched to MTX + IFX. “MTX successes” were patients who achieved a DAS ⩽2.4 after 2 years while still on MTX monotherapy. Total Sharp/van der Heijde score (TSS) progression from 0–2 years was assessed in “MTX failures” versus “MTX successes.”
After 2 years, 162/244 patients (66%) had discontinued MTX because of insufficient response or toxicity. Of these, 78% also failed on SSA (adding or switching), 87% subsequently failed on leflunomide (in group 1), and 64% on MTX + SSA + HCQ (in group 2). 34 of 48 patients (71%) in groups 1 and 2 were successfully treated with MTX + IFX. After 2 years, regardless of the “success” on subsequent DMARDs, “ MTX failures” had a median TSS progression of 3 units (mean 9) versus 1 unit (mean 3) in “MTX successes” (p = 0.007).
After failure on initial MTX, treatment with subsequent conventional DMARDs is unlikely to result in a DAS ⩽2.4 and allows progression of joint damage.
rheumatoid arthritis; methotrexate; DMARDs; joint damage