Hydroxychloroquine

Autophagy is an evolutionarily conserved, intracellular self-defense mechanism where organelles and proteins are sequestered into autophagic vesicles (AVs) that are subsequently degraded through fusion with lysosomes. Cells thereby prevent the toxic accumulation of damaged or unnecessary components, but also recycle these components to sustain metabolic homoeostasis. Heightened autophagy is a mechanism of resistance for cancer cells faced with metabolic and therapeutic stress, revealing opportunities for exploitation as a therapeutic target in cancer. We summarize recent developments in the field of autophagy and cancer, and build upon the results presented at the Cancer Therapeutics and Evaluation Program (CTEP) Early Drug Development meeting in March, 2010. Herein, we describe our current understanding of the core components of the autophagy machinery, the functional relevance of autophagy within the tumor microenvironment and outline how this knowledge has informed preclinical investigations combining the autophagy inhibitor hydroxychloroquine (HCQ) with chemotherapy, targeted therapy and immunotherapy. Finally, we describe ongoing clinical trials involving HCQ as a first

Objectives. We aimed to establish the prevalence, predictors and clinical consequences of vitamin D deficiency in patients with SLE. Methods. Cross-sectional study including patients fulfilling ACR criteria for the classification of SLE. Serum 25(OH)D levels at 30 and 10 ng/ml were the cut-off values for vitamin D insufficiency and vitamin D deficiency, respectively. SLE activity was measured by SLEDAI and irreversible organ damage by the SLICC-ACR index. Fatigue was quantified using a 0-10 visual analogue scale (VAS). Results. Ninety-two patients (90% women, 98% white) were included in the study. Sixty-nine (75%) and 14 (15%) patients presented with vitamin D insufficiency and deficiency, respectively. Female sex (P ¼ 0.001), treatment with HCQ (P ¼ 0.014) and treatment with calcium and vitamin D (P ¼ 0.049) predicted higher levels of 25(OH)D. Photosensitivity [odds ratio (OR) 3.5] and photoprotection (OR 5.7) predicted vitamin D insufficiency and deficiency, respectively. Higher age (OR 0.95) and HCQ use (OR 0.29) protected against vitamin D deficiency. Patients with vitamin D deficiency had a higher degree of fatigue as quantified by a 0-10 VAS (mean 5.32 vs 4.03, P ¼ 0.08). No relation was seen between vitamin D insufficiency or deficiency and disease duration, SLEDAI or SLICC-ACR indexes. Conclusions. Vitamin D insufficiency and deficiency are common in patients with SLE and are associated with sun avoidance. HCQ prevented vitamin D deficiency. Vitamin D deficiency was related to a higher degree of fatigue. Vitamin D levels had no relation with SLE severity.

ObjectiveTo study the impacts of 1) the delay from the onset of symptoms to the institution of disease-modifying antirheumatic drug (DMARD) therapy, 2) two treatment strategies (treatment with a combination of DMARDs or with a single drug), and 3) the presence of HLA–DRB1 alleles (shared epitope) on the prediction of disease remission after 2 years in patients with early rheumatoid arthritis (RA).To study the impacts of 1) the delay from the onset of symptoms to the institution of disease-modifying antirheumatic drug (DMARD) therapy, 2) two treatment strategies (treatment with a combination of DMARDs or with a single drug), and 3) the presence of HLA–DRB1 alleles (shared epitope) on the prediction of disease remission after 2 years in patients with early rheumatoid arthritis (RA).MethodsIn the FIN-RACo (FINnish Rheumatoid Arthritis Combination therapy) trial, 195 patients with recent-onset RA (median duration 6 months) were randomly assigned to receive either 1) a combination of DMARDs (sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone) or 2) a single DMARD with or without prednisolone. The presence of a shared epitope was tested for in 165 of the 178 patients completing the study. The additional variables of age, sex, presence of rheumatoid factor, number of fulfilled American College of Rheumatology criteria for the classification of RA, and length of delay from onset of symptoms to institution of therapy were entered into a logistic regression model to determine the significant predictors for remission at 2 years.In the FIN-RACo (FINnish Rheumatoid Arthritis Combination therapy) trial, 195 patients with recent-onset RA (median duration 6 months) were randomly assigned to receive either 1) a combination of DMARDs (sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone) or 2) a single DMARD with or without prednisolone. The presence of a shared epitope was tested for in 165 of the 178 patients completing the study. The additional variables of age, sex, presence of rheumatoid factor, number of fulfilled American College of Rheumatology criteria for the classification of RA, and length of delay from onset of symptoms to institution of therapy were entered into a logistic regression model to determine the significant predictors for remission at 2 years.ResultsThe delay to therapy (cut point of 4 months) was the only significant predictor for remission in patients treated using the single-DMARD strategy, while no variable was a significant predictor for remission in those treated using the combination-DMARD strategy. The frequency of achieving remission in the combination-DMARD group after 2 years was similar in patients with short (0–4 months) and long (>4 months) delay periods (11 of 26 patients and 22 of 53 patients, respectively [∼42% in each group]), while the corresponding frequencies in the single-DMARD group were 8 of 23 patients (35%) and 7 of 63 patients (11%) (P = 0.021). The presence of a shared epitope was not related to the induction of remission.The delay to therapy (cut point of 4 months) was the only significant predictor for remission in patients treated using the single-DMARD strategy, while no variable was a significant predictor for remission in those treated using the combination-DMARD strategy. The frequency of achieving remission in the combination-DMARD group after 2 years was similar in patients with short (0–4 months) and long (>4 months) delay periods (11 of 26 patients and 22 of 53 patients, respectively [∼42% in each group]), while the corresponding frequencies in the single-DMARD group were 8 of 23 patients (35%) and 7 of 63 patients (11%) (P = 0.021). The presence of a shared epitope was not related to the induction of remission.ConclusionThe delay of a few months from the onset of symptoms to institution of therapy decreases the ability of the traditional single-drug strategy to induce remission in early RA.The delay of a few months from the onset of symptoms to institution of therapy decreases the ability of the traditional single-drug strategy to induce remission in early RA.

Objective. Hydroxychloroquine (HCQ) is often needed to manage disease activity in systemic lupus erythematosus (SLE) during pregnancy. The purpose of this study was to examine lupus activity and pregnancy outcomes in women with SLE treated or not treated with HCQ during pregnancy.

The objective was to determine whether the frequency of flare in systemic lupus erythematosus (SLE) patients is increased during pregnancy and the pucrpcrium. Seventy-eight pregnancies in 68 SLE patients attending the lupus pregnancy clinic, at St Thomas' Hospital, during the last 5 yr were included. The pregnancy period and 8 weeks post-delivery were considered. This group was compared with a control group of 50 consecutive, non-pregnant, age-matched SLE patients attending our weekly lupus clinic. Additionally, 43 of the pregnant patients carried on attending the lupus clinic for the year after puerperium, and their course was compared with themselves during pregnancy. SLE activity was assessed using the Lupus Activity Index (LAI) score. An increase St0.26 in the score was considered as a flare of the disease. Pregnancy and control groups were homogeneous for age, race, disease duration and distribution of autoantibodies. Sixty-five per cent of the patients flared during pregnancy and/or the puerperium and 42% flared in the control group {P = 0.015).The rates of flare per patient/month were 0.082 ± 0.004 for the pregnancy group and 0.039 ±0.003 for the control group (P < 0.001). The 43 patients whose course was controlled after the puerperium flared more frequently during pregnancy than thereafter (McNemar test, P = 0.003). The rates of flare per patient/month were 0.093 ± 0.006 during pregnancy and the puerperium, and 0.049 ± 0.004 after the puerperium (P «= 0.0015). Kidney and central nervous system involvement was not different between the pregnancy and control groups. In terms of frequency of flares, there was no difference in any of the groups between patients taking and not taking steroids. We conclude that SLE tends to flare during pregnancy. Flares are maximal during the second and third trimester and the puerperium. Flares are not more severe than in non-pregnant patients, and most of the flares can be managed conservatively. Prednisolone does not prevent flares.

Methods. SLE patients enrolled in a longitudinal study of outcome were analyzed (LUMINA; Lupus in Minorities: Nature versus nurture) for the manner in which ACR criteria manifestations occurred prior to the accrual of 4 of them. Time at which a criterion was said to be present was determined by review of all previously available medical records and interview. Univariable and multivariable Cox proportional hazard models were examined for the association with time to accrual of 4 ACR criteria; results were reported as hazard ratios.

We conducted a randomized, controlled study to assess the need for hydroxychloroquine (HCQ) during lupus pregnancy and to assess safety. Twenty consecutive pregnant patients with similar characteristics were enrolled. The HCQ group included eight patients with systemic lupus erythematosus (SLE) and two with discoid lupus erythematosus (DLE). The placebo (PL) group included nine patients with SLE and one with DLE. The HCQ group had no flare-ups. SLEPDAI scores were similar at study entry, and at conclusion the placebo group had significantly higher scores. One patient had improvement of skin lesions and another of arthritis, allowing a decrease of prednisone dose. There were no retinal effects. Three patients in the PL group flared up, two with skin rashes, one also with arthritis and uveitis, and one (previously in remission on HCQ) with hemolytic anemia, polyserositis and anti-dsDNA antibody. Toxemia was diagnosed in only three patients in the PL group (one fetal death). Comparing ...

ObjectiveThe use of hydroxychloroquine (HCQ) in pregnancy remains controversial. The recent demonstration that HCQ passes across the placenta, with cord blood concentrations nearly identical to those found in maternal blood, emphasizes the need for careful evaluation of pregnancies in women receiving HCQ. However, only small series of HCQ-treated pregnant women have been reported, and most of these studies had no control group. We now report our experience with 133 pregnancies in women being treated with HCQ, resulting in 117 live births. Results in the HCQ group are compared with those in a control group.The use of hydroxychloroquine (HCQ) in pregnancy remains controversial. The recent demonstration that HCQ passes across the placenta, with cord blood concentrations nearly identical to those found in maternal blood, emphasizes the need for careful evaluation of pregnancies in women receiving HCQ. However, only small series of HCQ-treated pregnant women have been reported, and most of these studies had no control group. We now report our experience with 133 pregnancies in women being treated with HCQ, resulting in 117 live births. Results in the HCQ group are compared with those in a control group.MethodsOne hundred thirty-three consecutive pregnancies in 90 women treated with 200 mg of HCQ either twice daily (122 pregnancies) or once daily (11 pregnancies) were studied. These pregnancies were compared with 70 consecutive pregnancies in 53 women with similar disorders who did not receive HCQ. Electrocardiography was performed in 47 children of mothers treated with HCQ and in 45 children in the control group.One hundred thirty-three consecutive pregnancies in 90 women treated with 200 mg of HCQ either twice daily (122 pregnancies) or once daily (11 pregnancies) were studied. These pregnancies were compared with 70 consecutive pregnancies in 53 women with similar disorders who did not receive HCQ. Electrocardiography was performed in 47 children of mothers treated with HCQ and in 45 children in the control group.ResultsEighty-eight percent of pregnancies in the HCQ group and 84% of those in the control group ended successfully with a live birth. The outcomes of pregnancy were not statistically different between groups. One child in each group died of causes related to prematurity. Three malformations were observed in the HCQ group (1 hypospadias, 1 craniostenosis, and 1 cardiac malformation) versus 4 in the control group. On the electrocardiograms, the PR interval and the corrected QT interval were not statistically different between groups. No visual, hearing, growth, or developmental abnormalities were reported in any of the children at the last follow-up (ages 12–108 months; mean age 26 months).Eighty-eight percent of pregnancies in the HCQ group and 84% of those in the control group ended successfully with a live birth. The outcomes of pregnancy were not statistically different between groups. One child in each group died of causes related to prematurity. Three malformations were observed in the HCQ group (1 hypospadias, 1 craniostenosis, and 1 cardiac malformation) versus 4 in the control group. On the electrocardiograms, the PR interval and the corrected QT interval were not statistically different between groups. No visual, hearing, growth, or developmental abnormalities were reported in any of the children at the last follow-up (ages 12–108 months; mean age 26 months).ConclusionOur findings support preliminary evidence for the safety of HCQ therapy during pregnancy. This treatment probably should be maintained throughout pregnancy in patients with systemic lupus erythematosus.Our findings support preliminary evidence for the safety of HCQ therapy during pregnancy. This treatment probably should be maintained throughout pregnancy in patients with systemic lupus erythematosus.

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): &#39;MTX only&#39;, 0.16 (0.04 to 0.66); &#39;MTX and SSZ ever&#39;, 0.20 (0.08 to 0.51...

Objective. The antimalarial medication hydroxychloroquine has been proposed as a thromboprotective agent in systemic lupus erythematosus (SLE), but studies thus far have been limited by the possibility of confounding by indication. This study was conducted to assess whether exposure to antimalarial drugs is associated with a decrease in thrombovascular events (TEs) in patients with SLE.

Background Results of epidemiological studies, neuropathological observations, and in-vitro experiments all suggest that inflammatory mechanisms contribute to the destructive lesions in Alzheimer's disease. We aimed to establish the effect of the anti-inflammatory drug hydroxychloroquine on the progression of dementia. Methods We did a double-blind, parallel-group, multicentre trial in which we randomly assigned 168 patients with early Alzheimer's disease to hydroxychloroquine (200 or 400 mg dependent on bodyweight), or placebo for 18 months. Outcome measures were related to activities of daily living, cognitive function, and behavioural abnormalities. Analysis was by intention to treat. Results At 18 months, mean scores for the interview for deterioration in daily life in dementia in patients on hydroxychloroquine (22•6 [SD 11•4]) did not differ from those for patients on placebo (21•3 [10•5]). Also, mean scores on the cognitive subscale of the Alzheimer's disease assessment scale were closely similar in hydroxychloroquine (26•4 [14•9]) and placebo (25•7 [14•3]) treated patients, as were behavioural changes, measured by the revised memory and behavioural problems checklist (36•3 [12•0] and 34•2 [12•4], respectively). Explorative analyses did not suggest any specific subgroup that benefited from hydroxychloroquine. The frequency and nature of serious adverse events and sideeffects were much the same in both groups. 155 (92%) patients completed all assessments over the entire study. Interpretation Anti-inflammatory treatment with hydroxychloroquine for 18 months does not slow the rate of decline in minimal or mild Alzheimer's disease.

Five healthy volunteers received, in a randomised crossover design study, a 155 mg oral tablet and an intravenous infusion of 155 mg racemic hydroxychloroquine (200 mg hydroxychloroquine sulphate) to assess the bioavailability of the commercially available tablet (Plaquenil, Winthrop Laboratories, Australia). 2 The terminal elimination half-life of hydroxychloroquine is more than 40 days, thus blood and urine samples were collected for 5 months following each dose to characterise adequately the terminal elimination phase and obtain accurate estimates of the areas under the concentration-time curves. 3 The mean (± s.d.) fraction of the oral dose absorbed, estimated from the blood and urine data, was 0.74 (±0.13). A wide range of estimates of the fraction of the oral dose absorbed was calculated from the plasma data (0.41-1.53), reflecting the difficulties of accurate measurement of hydroxychloroquine in plasma. 4 A period of 6 months is required to achieve 96% of steady-state levels of hydroxychloroquine with the usual once daily, oral dosage regimen. Pharmacokinetic factors may thus be partly responsible for the delayed action of the drug in rheumatic conditions. S Haemodialysis will not aid in the case of oral overdose with hydroxychloroquine. Although the proportionate increase in clearance may be large, the increase in the fraction of the dose excreted will be negligible. The extensive sequestration of the drug by tissues limits effectiveness of haemodialysis.

A dose-response relationship for hydroxychloroquine (HCQ), in terms of the proportion of patients achieving the Paulus 20% criteria for improvement, had previously been observed in patients with rheumatoid arthritis (RA) receiving a 6-week loading regimen of 400, 800, or 1,200 mg HCQ daily. This present retrospective analysis was performed to investigate possible relationships between the blood HCQ and HCQ-metabolite concentrations and measures of efficacy and toxicity. In addition, we sought to ascertain whether further investigation of HCQ/HCQ-metabolite levels might lead to testing of one of these substances as a new antirheumatic drug.

ObjectiveTo compare the efficacy of therapy with a combination of disease-modifying antirheumatic drugs (DMARDs) versus therapy with a single DMARD in the prevention of work disability in patients with early rheumatoid arthritis (RA).To compare the efficacy of therapy with a combination of disease-modifying antirheumatic drugs (DMARDs) versus therapy with a single DMARD in the prevention of work disability in patients with early rheumatoid arthritis (RA).MethodsIn the Finnish Rheumatoid Arthritis Combination Therapy trial, 195 patients with recent-onset RA were randomly assigned to receive either combination therapy with DMARDs (sulfasalazine, methotrexate, hydroxychloroquine) plus prednisolone or single therapy with a DMARD with or without prednisolone. After 2 years, the drug treatment strategy was no longer restricted. At baseline, 162 patients (80 in the combination-treatment group and 82 in the single-treatment group) were still working or at least available for work. After 5 years of followup, data on all sick leave and retirement were obtained from social insurance registers or case records. The main outcome for each patient was the cumulative duration of all sick leaves and RA-related disability pensions, divided by the observation period during which the patient was not retired because of another disease or because of age.In the Finnish Rheumatoid Arthritis Combination Therapy trial, 195 patients with recent-onset RA were randomly assigned to receive either combination therapy with DMARDs (sulfasalazine, methotrexate, hydroxychloroquine) plus prednisolone or single therapy with a DMARD with or without prednisolone. After 2 years, the drug treatment strategy was no longer restricted. At baseline, 162 patients (80 in the combination-treatment group and 82 in the single-treatment group) were still working or at least available for work. After 5 years of followup, data on all sick leave and retirement were obtained from social insurance registers or case records. The main outcome for each patient was the cumulative duration of all sick leaves and RA-related disability pensions, divided by the observation period during which the patient was not retired because of another disease or because of age.ResultsThe cumulative duration of work disability per patient-observation year was significantly lower in those randomized to combination therapy than in those randomized to single therapy: median 12.4 days (interquartile range [IQR] 0–54) versus 32.2 days (IQR 6–293) (P = 0.008, sex- and age-adjusted P = 0.009). This was mainly due to the difference in sick leaves (i.e., work disability periods ≤300 days): median 11.7 days (IQR 0–44) per patient-observation year in those treated with combination therapy and 30.0 days (IQR 6–68) in those treated with single therapy (P = 0.002). No statistically significant difference was seen in RA-related disability pensions.The cumulative duration of work disability per patient-observation year was significantly lower in those randomized to combination therapy than in those randomized to single therapy: median 12.4 days (interquartile range [IQR] 0–54) versus 32.2 days (IQR 6–293) (P = 0.008, sex- and age-adjusted P = 0.009). This was mainly due to the difference in sick leaves (i.e., work disability periods ≤300 days): median 11.7 days (IQR 0–44) per patient-observation year in those treated with combination therapy and 30.0 days (IQR 6–68) in those treated with single therapy (P = 0.002). No statistically significant difference was seen in RA-related disability pensions.ConclusionAggressive initial treatment of RA with a combination of DMARDs improves 5-year outcome in terms of lost productivity in patients with RA of recent onset.Aggressive initial treatment of RA with a combination of DMARDs improves 5-year outcome in terms of lost productivity in patients with RA of recent onset.

Study objectives: Previously, IPH patients have been reported to have an average survival of 2.5 years. However, at our institution, many IPH patients have survived longer than that. Therefore, we conducted this study to determine the clinical course and current mortality of pediatric IPH patients treated with immunosuppressants. Design: Retrospective chart review. Setting: Children's hospital. Participants: Seventeen patients in whom IPH was diagnosed between 1972 and 1998. Measurements and results: Mean age at diagnosis was 4.5 ؎ 3.5 years, and 12 patients were female. At diagnosis, all patients had anemia and pulmonary infiltrates; 85% had hypoxemia, 65% had hemoptysis, and 70% had fever. The diagnosis was made by open lung biopsy in 13 patients (76%), hemosiderin-laden macrophages in BAL fluid in 1 patient (6%), hemosiderin-laden macrophages in gastric aspirate in 2 patients (12%), or by clinical presentation alone in 1 patient (6%). The mean duration of follow-up for all patients was 3.6 ؎ 3.4 years (range, 0.7 to 10.2).

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 inflint outcome. Results-HCQ was not apparently teratogenic. Lupus activity and obstetric outcome in the two groups were similar.

derivatives, tropolones and diones, having pK,&'s in the range 3-7 uncouple oxidative phosphorylation in liver mitochondria. Many substituted resorcinols and tropolones are more potent uncouplers than the related phenols and it is possible to relate this enhanced potency to their lower pK,'s than those of the corresponding phenols.

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.

La fièvre Q est une zoonose ubiquitaire causée par l'agent pathogène Coxiella burnetii responsable de manifestations cliniques aiguës et chroniques. Sa prévalence géographique hétérogène semble surtout liée à la connaissance du clinicien et à la disponibilité d'un centre de référence. Son expression clinique polymorphe impose d'évoquer le diagnostic devant toute pneumopathie, hépatite, fièvre prolongée, endocardite n'ayant pas fait la preuve de son étiologie. Le diagnostic est surtout sérologique. Si la fièvre Q aiguë est le plus souvent d'évolution bénigne, l'endocardite est constamment fatale sans traitement. Le traitement est efficace et bien toléré, mais il doit être adapté à la forme aiguë ou chronique, à la présence d'une valvulopathie cardiaque, d'un anévrisme ou d'une prothèse vasculaire et d'une immunodépression, et à la situation particulière de la femme enceinte.

While serious infections are significant causes of morbidity and mortality in systemic lupus erythematosus (SLE), the epidemiology in a nationwide cohort of SLE and lupus nephritis (LN) patients has not been examined. Using the Medicaid Analytic eXtract (MAX) database, 2000-2006, we identified patients 18-64 years with SLE and a subset with LN. We ascertained hospitalized serious infections using validated algorithms, and 30-day mortality rates. We used Poisson regression to calculate infection incidence rates (IR), and multivariable Cox proportional hazards models to calculate hazard ratios (HR) for first infection, adjusted for sociodemographics, medication use, and a SLE-specific risk adjustment index. We identified 33,565 patients with SLE and 7,113 with LN. There were 9,078 serious infections in 5,078 SLE patients and 3,494 infections in 1,825 LN patients. The infection IR per 100 person-years was 10.8 in SLE and 23.9 in LN. In adjusted models, in SLE, we observed increased ris...

Objective: To assess the prevalence and factors associated with low bone mineral density (BMD) in HIVinfected adolescents. Methods: This was a cross-sectional study of a Brazilian cohort of vertically HIV-infected adolescents. Body composition and lumbar spine (LS) and total body (TB) BMD were estimated by dual-energy X-ray absorptiometry (DXA). Low BMD was considered for a Z-score À2 standard deviations. Pubertal development, anthropometric data, laboratory measurements, antiretroviral regimen, and time of immunological and virological recovery were evaluated as factors associated with a low BMD. Results: Seventy-four adolescents aged 17.3 AE 1.8 years were studied. Low BMD was present in 32.4% of them. LS and TB BMD Z-scores were positively correlated with weight, body mass index (BMI), BMI Z-score, total body fat, and nutritional status. Patients on tenofovir had lower LS and TB BMD Z-scores. Time on tenofovir was indirectly correlated with LS and TB BMD Z-scores. No difference was found regarding levels of calcium, parathyroid hormone, or 25-hydroxyvitamin D according to BMD status. Conclusions: Control of the HIV infection, especially before the initiation of puberty, might have a positive influence on bone gain. Body composition and nutritional status had a positive influence on BMD that was more evident in females, suggesting that nutritional intervention may have a positive impact on BMD.

Objective. To analyse therapeutic management of eosinophilic fasciitis (EF). Methods. We reviewed 34 adult patients with biopsy-proven EF. Analyses focused on the therapeutic management, including treatment modalities, responses and associated or predictive factors. Results. Thirty-four patients were included with a diagnosis age of 53 (15) years. They were featured by cutaneous manifestations (88%) including morphoea (41%), myalgia (86%) and hypereosinophilia (85%). Thirty-two patients (94%) were eligible for treatment evaluation and all received CSs as a first-line therapy. Fifteen patients (47%) received methylprednisolone pulses (MPPs) at treatment initiation and 14 patients (44%) received an immunosuppressive drug (ISD), usually MTX (86%), as a second-line therapy. Complete remission was achieved for 69% of patients, remission with disability 19% and failure 12%. A poor outcome was associated with a diagnosis time delay of >6 months [odds ratio (OR) = 14.7] and the lack of MPPs (OR = 12.9). Conclusion. Our study reports new insights into the therapeutic management of EF: (i) CS treatment remains the standard therapy for EF, taken alone or in association with an ISD; (ii) MPPs at initiation of treatment are associated with a better outcome and a lower need of ISD use; (iii) an ISD, usually MTX, might be useful as a second-line therapy, mainly in patients with morphoea-like lesions. Naturally, these practical conclusions should be confirmed by a prospective and multicentre study.

Objective.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).Methods.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.Results.More women with SLE were taking HCQ than those with RA (48% vs 18%; p &lt; 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 dru...

Introduction: Early treatment of rheumatoid arthritis (RA) has been shown to retard the development of joint damage for a period of up to 5 years. The aim of this study was to evaluate the radiologic progression beyond that time in patients with early RA initially treated with a combination of three disease-modifying antirheumatic drugs (DMARDs) or a single DMARD.

Lichen planopilaris (LPP) and its variant frontal fibrosing alopecia (FFA) are primary lymphocytic cicatricial alopecias for which there is no evidence-based therapy.We assessed the efficacy of hydroxychloroquine in active LPP and FFA using the LPP Activity Index (LPPAI), a numeric score that allows quantification of the symptoms and signs of the condition for statistical comparison. In addition, we determined with the LPPAI if any improvement (reduction) in the numeric score pretreatment and posttreatment reached statistical significance.This was a retrospective, single-center chart review of 40 adult patients with LPP, FFA, or both who were treated with hydroxychloroquine for up to 12 months from 2004 to 2007 at the University of California, San Francisco Hair Center. Symptoms, signs, activity, and spreading were scored at each visit in the standardized cicatricial alopecia flow chart. A numeric score was assigned to these markers of disease activity and a numeric score was calculated at each visit.There was significant reduction (P < .001) in the LPPAI at both 6 and 12 months. After 6 months, 69% had improved (reduced) symptoms and signs. At 12 months, 83% had improvement (reduction) in symptoms and signs.Retrospective analysis and uncontrolled study are limitations.Hydroxychloroquine is effective in decreasing symptoms and signs in LPP and FFA as shown by significant reduction in the LPPAI in 69% and 83% of patients after 6 and 12 months of treatment, respectively.

Introduction-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).

Objective. Rheumatoid arthritis (RA) is associated with increased risk for cardiovascular (CV) events through multiple factors. Fish oil has been shown to reduce symptoms in RA and to reduce CV risk. We assessed the effect of an antiinflammatory dose of fish oil on CV risk factors within a program of combination chemotherapy for patients with early RA. Methods. Patients who chose not to take fish oil (n = 13) were compared with patients who achieved a sustained elevation of eicosapentaenoic acid (EPA) in plasma phospholipid fatty acids (> 5% total fatty acids) while taking fish oil over a 3-year period (n = 18). We examined cellular content of arachidonic acid (AA), synthesis of thromboxane A 2 and prostaglandin E 2 , use of nonsteroidal antiinflammatory drugs (NSAID), traditional CV lipid risk factors, and disease activity at 3 years. Results. At 3 years, AA (as a proportion of AA plus long-chain n-3 fatty acids that can compete with AA for cyclooxygenase metabolism) was 30% lower in platelets and 40% lower in peripheral blood mononuclear cells in subjects taking fish oil. Serum thromboxane B 2 was 35% lower and lipopolysaccharide-stimulated whole-blood prostaglandin E 2 was 41% lower with fish oil ingestion compared to no fish oil. NSAID use was reduced by 75% from baseline with fish oil (p < 0.05) and by 37%

To compare 1-year clinical efficacy of (1) initial triple disease-modifying antirheumatic drug therapy (iTDT) with initial methotrexate (MTX) monotherapy (iMM) and (2) different glucocorticoid (GC) bridging therapies: oral versus a single intramuscular injection in early rheumatoid arthritis. In a single-blinded randomised clinical trial patients were randomised into three arms: (A) iTDT (methotrexate+sulfasalazine+hydroxychloroquine) with GCs intramuscularly; (B) iTDT with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. Primary outcomes were (1) area under the curve (AUC) of Health Assessment Questionnaire (HAQ) and Disease Activity Score (DAS) and (2) the proportion of patients with radiographic progression. 281 patients were randomly assigned to arms A (n=91), B (n=93) or C (n=97). The AUC DAS and HAQ were respectively -2.39 (95% CI -4.77 to -0.00) and -1.67 (95% CI -3.35 to 0.02) lower in patients receiving iTDT than in those receiving iMM. After 3 months, tre...

IMPORTANCE Given the infrequent occurrence of hydroxychloroquine toxic effects, few data are available about the presenting features and long-term follow-up of patients with hydroxychloroquine retinopathy, making it difficult to surmise the clinical course of patients after cessation of drug treatment. OBJECTIVE To report functional and structural findings of hydroxychloroquine retinal toxic effects after drug therapy discontinuation. DESIGN A retrospective medical record review was performed to identify patients taking hydroxychloroquine who were screened for toxic effects from PARTICIPANTS Seven consecutive patients diagnosed as having hydroxychloroquine retinal toxic effects.

Background: there is a dramatic need for drugs with anti-HIV-1 activity that are affordable for resource-poor countries. Chloroquine (CQ) is one such drug. Objecti6es: to review the data indicating that CQ has anti-HIV-1 activity. Results: chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) are endowed with a broad anti-HIV-1 activity inhibiting X4, R5, and X4/R5 stains in lymphocytic and monocytic cells. Interestingly, CQ is capable of inhibiting HIV-1 replication at concentrations within the range reported in plasma of individuals chronically treated with doses of the drug which have well-known and limited toxicity. These effects have been confirmed in vivo in two clinical trials. The principal mechanism of HIV-1 inhibition by CQ seems to be an effect on gp120 on a post-transcriptional level. Because CQ and HCQ appear to have a novel site of action (i.e. post-transcriptional inhibition of gp120), these drugs may be particularly useful in combination with other anti-retroviral agents (e.g. ZDV, ddI and HU). Conclusion: combining these drugs with other anti-HIV-1 agents, especially HU and ddI, may be an interesting option for the treatment for HIV-1 infected individuals in the developing world.

Introduction: Rheumatoid arthritis (RA) is associated with changes in body composition and bone mineral density (BMD). The purpose of the present study was to evaluate whether anti-TNF treatment in early RA has an impact on body composition and BMD besides that which could be achieved by intensive disease-modifying anti-rheumatic drug (DMARD) combination therapy. Methods: Forty patients with early RA who failed treatment with methotrexate up to 20 mg/week for 3 months were randomised to addition of sulphasalazine and hydroxychloroquine (treatment A) or addition of infliximab (treatment B). At 3, 12 and 24 months, body composition and BMD were assessed by total-body dual-energy X-ray absorptiometry. At the same time points, leptin, adiponectin, apolipoproteins, insulin-like growth factor-1 (IGF-1) and markers of bone remodelling were analysed. Compliance to treatment was considered in the analyses. Data were analysed with a mixed, linear model. Results: Patients treated with anti-TNF had a significant increase in fat mass at 2 years, 3.8 (1.6 to 5.9) kg, in contrast to patients in treatment A, 0.4 (-1.5 to 2.2) kg (P = 0.040), despite similar reduction in disease activity. Both treatment strategies prevented loss of muscle mass and bone. Leptin concentrations increased significantly in both groups at 2 years and adiponectin increased significantly at 2 years in treatment A and at 1 year in treatment B. There were no significant changes in apolipoproteins or IGF-1. The markers of bone resorption decreased at 12 months in both treatment groups with no significant difference between the treatment groups. Conclusions: Infliximab therapy increased body fat mass, an effect that was not achieved with the combination of DMARDs, despite a similar reduction in disease activity, and thus seemed to be drug specific. The increase of fat mass was not associated with an exacerbated atherogenic lipid profile. Leptin and adiponectin concentrations increased in both treatment groups. The increase of adiponectin may partially explain the reduced frequency of cardiovascular diseases found when disease activity is reduced in RA. Trial registration: ISRCTN39045408.

Objective-The purpose of this study was to compare the long term eVectiveness between chloroquine (CQ) and hydroxychloroquine (HCQ). Methods-Medical charts of all patients seen by eight rheumatologists practising in two tertiary care centres and starting antimalarial treatment between January 1985 and December 1993 were reviewed. Patient characteristics, disease, and treatment information were collected. The main outcome measures were the cause of and the time to the discontinuation of antimalarial drugs resulting from all causes, principally toxicity or ineYcacy, or both. Bivariate analysis including t tests and 2 tests were used to assess diVerences between means and proportions respectively. Survival curves were evaluated using the Kaplan-Meier method. Multivariate analysis (Cox regression) was used to adjust for potential confounders. Results-After all medical records were reviewed, 1042 eligible cases were identified. From these, 940 (90%) had usable information and they represent the cohort. Five hundred and fifty eight had rheumatoid arthritis, 178 had systemic lupus erythematosus, 127 had palindromic arthritis, and 77 had other diagnoses. Fifty seven per cent of the patients received CQ and 43% HCQ. The propor-

Objectives: Patients with classic Whipple's disease have a lifetime defect in immunity to Tropheryma whipplei and frequently develop treatment failures, relapses or reinfections. Empirical treatments were tested before culture was possible, but the only in vitro bactericidal treatment consists of a combination of doxycycline and hydroxychloroquine.

ObjectivePrior research demonstrates that hydroxychloroquine (HCQ) lowers glycosylated hemoglobin (HbA1c) in diabetes patients without rheumatic disease. 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).Prior research demonstrates that hydroxychloroquine (HCQ) lowers glycosylated hemoglobin (HbA1c) in diabetes patients without rheumatic disease. 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).MethodsWe used electronic medical records to identify patients beginning treatment with either HCQ or MTX who had a diagnosis of DM (or a pretreatment HbA1c value of ≥7%) and at least 1 HbA1c measurement both before and within 12 months after initiation of treatment. Using a structured medical record abstraction, we examined rheumatic disease diagnosis, cumulative steroid use, duration (months) between drug initiation and lowest HbA1c value, a change in DM medication, body mass index (BMI), age, and sex. Adjusted linear regression models determined changes in HbA1c from pretreatment values to the lowest posttreatment values within 12 months.We used electronic medical records to identify patients beginning treatment with either HCQ or MTX who had a diagnosis of DM (or a pretreatment HbA1c value of ≥7%) and at least 1 HbA1c measurement both before and within 12 months after initiation of treatment. Using a structured medical record abstraction, we examined rheumatic disease diagnosis, cumulative steroid use, duration (months) between drug initiation and lowest HbA1c value, a change in DM medication, body mass index (BMI), age, and sex. Adjusted linear regression models determined changes in HbA1c from pretreatment values to the lowest posttreatment values within 12 months.ResultsWe identified 45 patients taking HCQ and 37 patients taking MTX who met the inclusion criteria. Rheumatoid arthritis had been diagnosed in approximately half of the patients in each group. Age, sex, and mean pretreatment HbA1c levels were similar across groups. The mean BMI of those taking HCQ (35.4 kg/m2) was slightly higher than that of those taking MTX (32.2 kg/m2) (P = 0.13). Glucocorticoid use appeared more common in those taking MTX (46%) than in those taking HCQ (29%) (P = 0.17). The mean reduction in HbA1c from pretreatment values to the lowest posttreatment values was 0.66% (95% confidence interval [95% CI] 0.26, 1.05) in those taking HCQ compared with 0.11% (95% CI −0.18, 0.40) in those taking MTX. In fully adjusted analyses, the reduction in HbA1c among those taking HCQ was 0.54% greater than the reduction among those taking MTX (P = 0.041).We identified 45 patients taking HCQ and 37 patients taking MTX who met the inclusion criteria. Rheumatoid arthritis had been diagnosed in approximately half of the patients in each group. Age, sex, and mean pretreatment HbA1c levels were similar across groups. The mean BMI of those taking HCQ (35.4 kg/m2) was slightly higher than that of those taking MTX (32.2 kg/m2) (P = 0.13). Glucocorticoid use appeared more common in those taking MTX (46%) than in those taking HCQ (29%) (P = 0.17). The mean reduction in HbA1c from pretreatment values to the lowest posttreatment values was 0.66% (95% confidence interval [95% CI] 0.26, 1.05) in those taking HCQ compared with 0.11% (95% CI −0.18, 0.40) in those taking MTX. In fully adjusted analyses, the reduction in HbA1c among those taking HCQ was 0.54% greater than the reduction among those taking MTX (P = 0.041).ConclusionHCQ initiation was associated with a significantly greater reduction in HbA1c as compared with MTX initiation among diabetes patients with rheumatic disease.HCQ initiation was associated with a significantly greater reduction in HbA1c as compared with MTX initiation among diabetes patients with rheumatic disease.

Objective. Inflammatory arthritis of the hands is a frequent clinical presentation with a variable outcome. Patients not satisfying the classification criteria for recognized arthritides are described as having undifferentiated inflammatory arthritis, for which there are no accepted therapeutic algorithms. This study assessed the clinical outcome of patients with undifferentiated arthritis of the hands after use of a treatment algorithm, and evaluated the prognostic features in these patients. Methods. One hundred consecutive patients with undifferentiated arthritis of the hands were assessed following use of a pragmatic treatment algorithm that was based on clinical presentation and response to treatment. The following standard step-up treatment protocol was used: 1) nonsteroidal antiinflammatory drugs (NSAIDs), 2) a single dose of corticosteroid administered by either intramuscular or intraarticular injection, and 3) disease-modifying antirheumatic drugs (DMARDs). Patients with specific rheumatologic diagnoses were excluded. The primary outcome was persistence of synovitis at 12 months. Results. Seventy-eight percent of patients received NSAIDs, 72% received corticosteroids, and 30% received DMARD therapy. Among patients who had Dr. Conaghan's work was supported by the Arthritis Research Campaign (ARC). Dr. Emery is an ARC Professor of Rheumatology.

Aims Hydroxychloroquine (HCQ) is used widely in the treatment of chronic in¯ammatory diseases such as rheumatoid arthritis. Since there is great interindividual variability in the pharmacokinetics of HCQ and chloroquine is a potent inhibitor of CYP2D6-catalysed pathways in vitro, we wished to study the interaction of HCQ with CYP2D6-mediated metabolism of other drugs in vivo. Methods Metoprolol and dextromethorphan (DM) were selected as probe drugs because they are well-studied and widely used test substrates of CYP2D6. In this randomized, double-blind crossover study, seven healthy volunteers with extensive metabolizer phenotype for CYP2D6 ingested either 400 mg hydroxychloroquine or placebo daily for 8 days after which single oral dose pharmacokinetics of metoprolol were investigated. Dextromethorphan metabolic ratio (DM-MR) was also determined at baseline and after the ingestion of HCQ or placebo. Results Concomitant administration of HCQ increased the bioavailability of metoprolol, as indicated by signi®cant increases in the area under the plasma concentration-time curve (65t4.6%) and maximal plasma concentrations (72t6.9%) of metoprolol. While the DM-MR values were not signi®cantly changed, the phenotypic classi®cation of one individual, who was heterozygous for a mutant CYP2D6 allele, was converted to a poor metabolizer by HCQ administration. Conclusions HCQ inhibits metoprolol metabolism most probably by inhibiting its biotransformation by CYP2D6. The inhibitory effect of HCQ on dextromethorphan metabolism was not apparent when DM-MR was used as an indicator, except in an individual with limited CYP2D6 capacity.

Objective. To assess the reliability and concurrent validity of the Medication Adherence Self-report Inventory (MASRI) when used in systemic lupus erythematosus (SLE), to investigate the predictive validity of the MASRI using pharmacy refill information as the criterion standard, and to propose a sensible approach to the screening for nonadherence in a clinical setting. Methods. Adherence to 2 medications (hydroxychloroquine and prednisone) was measured in 55 patients using the MASRI, pill counts, and physician ratings (MD scale). Adherence based on pharmacy refill information served as a criterion standard with nonadherence defined as adherence rates <80%. To determine test-rest reliability of the MASRI, 20 patients completed the measure twice within a 2-week period. Results. Using pharmacy information, 39% of the patients were nonadherent to prednisone and 51% to hydroxychloroquine. The MASRI had acceptable internal consistency (Cronbach's ␣ 0.7) and good reliability. Irrespective of the drug assessed, MASRI ratings were moderately correlated with patient adherence (pharmacy), supporting the concurrent validity of the MASRI. The combination of adherence estimation by MD scale rating at <85% and by MASRI at <90% was 87% sensitive and 86% specific for identifying patients who were nonadherent to prednisone. These cutoff values also appeared suitable for identifying nonadherence to hydroxychloroquine. Conclusion. The MASRI is a reliable measure of adherence to medications in SLE. The measure has concurrent and predictive validity. When combined with the MD scale, the MASRI appears to be a useful screening tool for nonadherence in patients with SLE that could be suitable for clinical practice.

Multifocal ERG ring ratios provide a sensitive and objective method to detect ocular toxicity in patients taking hydroxychloroquine (Plaquenil). In order to measure ring ratios, the average mfERG amplitude was calculated for each of five concentric rings of a 61-hexagon mfERG. The age-corrected amplitude of the central hexagon (R 1 ) and the ratios of R 1 to each of the successive rings (R 1 /R 2 , R 1 /R 3 , etc.) were then computed. Normative values for ring ratios were established from a population of 67 normal controls. In the study population, a ring was considered abnormal if it was above the 99% confidence limits for the normal population. The technique was evaluated on 131 eyes of 62 patients taking Plaquenil for a variety of conditions including rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome. Patients who had taken Plaquenil for an extended period showed a higher incidence of retinal toxicity, regardless of the condition for which they were taking the drug. Among patients who had taken a cumulative dose of less than 1,250 g, 7 of 67 eyes (10%) showed a characteristic mfERG defect, while in patients with a cumulative dosage of 1,250 g or more, 26 of 64 eyes (41%) showed one of these defects. In at least one patient, the technique was able to detect the early onset of Plaquenil toxicity followed by reversal of the toxic effects after the medication was discontinued. It appears appropriate to recommend that mfERG testing be done on all patients on Plaquenil therapy.