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A woman with systemic lupus erythematosus developed severe myopathy after a septicemic episode, and her treatment before admission was hydroxychloroquine sulfate and prednisolone. A muscle biopsy revealed no evidence of vasculitis and creatine kinase was normal. She continued taking maintenance prednisolone and with intensive physiotherapy her muscle strength slowly returned. It is possible that the hydroxychloroquine was responsible for the myopathy.
The quinolines, hydroxychloroquine (Plaquenil) and chloroquine are used primarily for their anti-inflammatory effects in the treatment of auto-immune conditions such as rheumatoid arthritis. Another common use of these drugs is the prophylaxis and suppression of malaria. The use of quinolines may cause several ocular side-effects. The most significant complication is irreversible macular damage resulting in both visual acuity and visual field loss. However, the Royal College of Ophthalmologists, UK (RCO) recently recommended against the monitoring of patients receiving quinoline therapy as it was deemed to be too costly, given the low incidence of retinal complications. In this article, we present a case of hydroxychloroquine retinopathy, describe the ocular changes associated with quinoline therapy and recommend an optometric review schedule for patients who are currently taking these drugs. Furthermore, we recommend a proactive approach toward medical practitioners prescribing these drugs for optometric-based monitoring of these patients.
Ninety-nine patients were treated with hydroxychloroquine sulfate for connective tissue diseases during a seven year period. All patients received the medication for at least one year and most were treated with a daily dosage of 400 mg. Four patients experienced toxic effects, but no patient sustained permanent loss of visual acuity. Toxicity did not seem to represent a cumulative dosage effect. Funduscopic and visual field examinations at six-month intervals are sufficient to detect the occasional adverse reactions and prevent serious retinal toxic effects when a maximum daily dosage of 400 mg is maintained.
Seventeen patients (15 women, two men) with progressive, erosive seropositive rheumatoid arthritis (RA) refractory to conventional therapy were treated with cyclophosphamide, azathioprine, and hydroxychloroquine sulfate for an average of 27 +/- 19 months (mean +/- SD throughout) (range, five to 60 months). Disease suppression began in 14 patients within three to 16 months (mean, seven months). Five patients achieved complete remission, two had activity in a single joint only, seven had partial disease suppression, and three showed no response. Prednisone dosage was decreased or administration discontinued in nine of ten patients (5.8 +/- 1.2 to 2.7 +/- 3 mg/day). Serial hand roentgenograms showed recortication of erosions in nine patients, with "filling in" of some erosions in three of these. No change was seen in the roentgenograms of five patients, while progressive disease occurred in three instances. Combined therapy with small doses of three drugs, each with proved antirheumatic activity when used separately in larger doses, may provide satisfactory long-term disease control in patients with intractable RA. This regimen is experimental. Proof of efficacy requires a controlled study. Until such data are obtained, this drug combination is not recommended for general use.
OBJECTIVE: To investigate the usefulness of hydroxychloroquine (HCQ) dose-loading to increase the percentage of responders or rate of response in treating rheumatoid arthritis (RA). METHODS: Two hundred twelve patients with early RA (mean duration 1.5 years) were enrolled in a 24-week trial. Patients were stabilized with 1,000 mg naproxen/day and then began a 6-week, double-blind trial comparing treatment with HCQ at 400 mg/day (n = 71), 800 mg/day (n = 71), and 1,200 mg/day (n = 66), followed by 18 weeks of open-label HCQ treatment at 400 mg/day. RESULTS: All patients had mild, active disease at the time of initiation of HCQ treatment (31-43% rheumatoid factor positive; no previous disease-modifying antirheumatic drugs; mean swollen joint count 8.6-10.4). Based on the Paulus criteria, response during the 6-week double-blind portion of the study was 47.97%, 57.7%, and 63.6% in the 400 mg/day, 800 mg/day, and 1,200 mg/day groups, respectively (P = 0.052). Discontinuations for adverse events were dose related (3 in the 400 mg/day group, 5 in the 800 mg/day group, 6 in the 1,200 mg/day group). Most involved the gastrointestinal (GI) system, with the background naproxen treatment possibly contributing. Ocular abnormalities occurred in 17 of 212 patients (8%) but were not dose related. CONCLUSION: Dose-loading with HCQ increased the degree of response at 6 weeks in this group of patients with early, predominantly seronegative RA. Adverse GI events were dose related, while adverse ocular events were not.
This report describes the case of an appropriately dosed patient who developed maculopathy <8 years after starting hydroxychloroquine (HCQ) therapy for systemic lupus erythematosus. Risk factors and screening for HCQ-associated maculopathy are discussed.
A 51-year-old man developed progressive debilitating limb and respiratory muscle weakness while undergoing treatment for chronic graft-versus-host disease secondary to allogeneic bone marrow transplant for mantle cell lymphoma. He had a normal serum creatine kinase level and acetylcholine receptor antibodies were negative. Electromyography showed a severe, nonirritable myopathy and a sensory motor axonal polyneuropathy. A muscle biopsy showed a necrotizing, vacuolar myopathy with many fibers containing autophagic and red-rimmed vacuoles, suggestive of an amphiphilic drug myopathy. The patient's strength and function improved significantly after discontinuation of hydroxychloroquine.
OBJECTIVE: To compare the efficacy of combination therapy with methotrexate (MTX) and hydroxychloroquine (HCQ), MTX and sulfasalazine (SSZ), and MTX, HCQ, and SSZ in patients with rheumatoid arthritis (RA). METHODS: RA patients (n = 171) who had not previously been treated with combinations of the study medications were randomized to receive 1 of the 3 treatment combinations in this 2-year, double-blind, placebo-controlled protocol. HCQ was given at a dosage of 200 mg twice a day. The dosage of MTX was accelerated from 7.5 mg/week to 17.5 mg/week in all patients who were not in remission. Similarly, the dosage of SSZ was escalated from 500 mg twice a day to 1 gm twice a day in patients who were not in remission. The primary end point of the study was the percentage of patients who had a 20% response to therapy according to the American College of Rheumatology (ACR) criteria at 2 years. RESULTS: Intent-to-treat analysis revealed that patients receiving the triple combination responded best, with 78% achieving an ACR 20% response at 2 years, compared with 60% of those treated with MTX and HCQ (P = 0.05) and 49% of those treated with MTX and SSZ (P = 0.002). Similar trends were seen for the ACR 50% response, with 55%, 40%, and 29% of patients in the 3 treatment groups, respectively, achieving these results at 2 years (P = 0.005 for the triple combination group versus the MTX and SSZ group). All combination treatments were well-tolerated. Fourteen patients (evenly distributed among the 3 groups) withdrew from the protocol because of symptoms that were potentially related to the study medication. CONCLUSION: The triple combination of MTX, SSZ, and HCQ is well-tolerated, and its efficacy is superior to that of the double combination of MTX and SSZ and is marginally superior to that of the double combination of MTX and HCQ.
OBJECTIVE: 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. METHODS: Patients with active RA (n = 212) began a 6-week, double-blind trial comparing 3 different doses of HCQ at 400, 800, or 1,200 mg/day, followed by 18 weeks of open-label HCQ treatment at 400 mg/day. Patients were repeatedly evaluated for treatment efficacy and toxicity. Blood samples were available from 123 patients for analysis of HCQ, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ) levels using high-performance liquid chromatography. Achievement of the modified Paulus 20% improvement criteria for response in RA was used as the primary efficacy parameter. Spontaneously reported adverse events were categorized and analyzed as toxicity outcome variables. The relationship between response (efficacy and toxicity) and drug levels was evaluated using logistic regression analysis. RESULTS: The subset of patients with blood concentration data was equivalent to the larger study population in all demographic and outcome characteristics. The mean HCQ, DHCQ, and DCQ elimination half-lives were 123, 161, and 180 hours, respectively. There was a positive correlation between the Paulus 20% improvement criteria response and blood DHCQ concentrations during weeks 1-6 (P < 0.001). A potential relationship between ocular adverse events and BDCQ levels was found (P = 0.036). Logistic regression analysis of adverse events data showed that adverse gastrointestinal events were associated with higher HCQ levels (P = 0.001-0.021) during weeks 1, 2, and 3. CONCLUSION: There is a weak, but predictable, relationship between blood DHCQ concentrations and efficacy of treatment with HCQ. In addition, there is an association between gastrointestinal adverse events and elevated blood HCQ concentrations. Further investigation of these relationships is warranted to see if DHCQ may be introduced as a new antirheumatic drug.
OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Ocular toxicity of long-term hydroxychloroquine treatment was assessed by regular ophthalmologic examinations in 99 patients. No patient developed significant loss of vision or visual field constriction to a white test object. Three patients had evidence of toxicity, but the medication had to be permanently discontinued in only one who subsequently had regression of all abnormalities except visual field constriction to a red test object. Neither duration of treatment nor the diagnosis of systemic lupus erythematosus predisposed patients to toxicity.
Plasma levels of hydroxychloroquine (HCQ) and its metabolites were measured, by high performance liquid chromatography, in 37 rheumatoid arthritis patients who could be clearly distinguished as responders (n = 28) or nonresponders (n = 9) to HCQ, 400 mg/day. Efficacy in both groups was determined by the patients' erythrocyte sedimentation rates, joint counts, morning stiffness, global assessments, concurrent drug therapies, and grip strength. The response rate was 76%. Responders had a mean HCQ level of 213 ng/ml, versus 306 in nonresponders (P less than 0.05). The mean level of HCQ plus total metabolites in responders was 363 ng/ml, versus 554 in nonresponders (P less than 0.01). We conclude that monitoring plasma HCQ levels is unlikely to be helpful in individualizing effective drug dosage.
We calculated the time required for therapeutic benefit to become apparent following initiation of treatment with D-penicillamine (DP), hydroxychloroquine (HCQ), or placebo (each administered concomitantly with a nonsteroidal antiinflammatory drug) using data from a double-blind, randomized 12-month trial in 162 patients with juvenile rheumatoid arthritis. Using previously published criteria to classify the outcome, we found that 60% of the HCQ group, 46% of the DP group, and 39% of the placebo group responded favorably after 12 months of therapy. Data from examinations between the initial and final assessments were used to determine when the response first occurred. Approximately 50% of all patients who showed improvement at 12 months had already done so by 2 months. After 6 months, 96% of the DP group, 88% of the HCQ group, and 85% of the placebo group responders had met the criteria for response. The average time until response was attained was 105 days for the DP group, 129 days for the HCQ group, and 140 days for the placebo group. Our results indicate that a favorable response to these slow-acting antirheumatic drugs is unlikely if improvement has not occurred within the first 6 months of therapy.
OBJECTIVE: To report the antiinflammatory and antiviral effects of hydroxychloroquine (HCQ) treatment in 2 patients with AIDS and inflammatory arthritis. METHODS: Two patients with AIDS and inflammatory arthritis were treated with HCQ, which was given in a loading dose of 600 mg/day. The maintenance dosage was calculated to remain below 6.5 mg/kg/day. Both patients had initial T cell subset studies; 1 patient, had serum and plasma collected before and after 1 year of HCQ treatment. Assays were performed for T cell subsets, recoverable human immunodeficiency virus type 1 (HIV-1) RNA, mitogen- and antigen-specific proliferation, and interleukin-6 (IL-6) levels. New studies on the use of HCQ as an anti-HIV-1 agent are reviewed. RESULTS: Both patients had a dramatic decrease in their arthritis activity. Neither patient required immunosuppressive therapy or developed an opportunistic infection. In the patient who was studied after 1 year of therapy, there was a 1-log decrease in recoverable HIV-1 RNA, improved mitogen- and antigen-specific immune responses, and a large decrease in the IL-6 level while taking HCQ. Recent in vitro and in vivo assays in patients with HIV infection have shown similar antiviral and antiinflammatory effects from HCQ. CONCLUSION: HCQ may exert simultaneous anti-inflammatory and antiviral effects in patients with HIV infection and inflammatory arthritis. If larger studies confirm this observation, it may be the drug of choice in this population of patients.
OBJECTIVE: To define the true risk of hydroxychloroquine (HCQ) retinal toxicity by studying the largest single group yet evaluated. METHODS: Retrospective chart review of all patients in the Kaiser Permanente Medical Care Program, Southern California Region, who had HCQ prescriptions filled from 1991 through 1993 (1,556 patients in 11 medical centers). Of 1,207 charts of patients who took HCQ and had documented ophthalmologic examinations, initial screening identified 21 charts (1.7%) that indicated possible HCQ toxicity. RESULTS: We identified 1 patient with definite toxicity (1 of 1,207; 0.08%) and 5 other patients with indeterminate but probable toxicity (5 of 1,207; 0.4%). The incidence of definite HCQ retinal toxicity in patients treated with HCQ at <6.5 mg/kg/day was 0. CONCLUSION: In HCQ-treated patients whose renal function is normal, routine ophthalmic screening is not indicated if the daily dosage is <6.5 mg/kg. In patients whose daily dosage is >6.5 mg/kg or who have taken HCQ continuously for > 10 years, annual screening may be appropriate.
OBJECTIVE: To examine whether hydroxychloroquine (HCQ) usage is associated with a reduced risk of damage accrual in patients with systemic lupus erythematosus (SLE). METHODS: Patients (n = 518) meeting the American College of Rheumatology criteria for diagnosis of SLE and with </=5 years disease duration at study entry were followed up annually. Socioeconomic, demographic, clinical, and serologic manifestations as well as disease activity (by the Systemic Lupus Activity Measure [SLAM]) and damage (by the Systemic Lupus International Collaborating Clinics damage index [SDI]) were measured. Propensity scores were calculated to adjust for confounding factors affecting treatment assignment. A Cox proportional hazards model was used to compare the risk of developing new damage according to HCQ use at enrollment into the study. RESULTS: Fifty-six percent of the patients were treated with HCQ at the time of study enrollment. Patients who were not treated with HCQ on enrollment had higher SLAM and SDI scores than patients who were treated. Untreated patients were significantly more likely to have major organ involvement such as renal disease (P < 0.0001) or central nervous system disease (P < 0.0025). Results of unadjusted analysis suggested that treated patients were less likely to accrue damage (hazard ratio [HR] 0.68). With adjustment for differences in treatment assignment, HCQ usage was still associated with a reduced risk of developing new damage, with an HR of 0.68 (95% confidence interval [95% CI] 0.53-0.93) (P = 0.014). With adjustment for differences in treatment assignment, HCQ usage was still associated with a reduced risk of developing new damage (HR 0.73 [95% CI 0.52-1.00]) (P = 0.05). However, patients receiving HCQ who had no damage at study entry had a statistically significant decrease in the risk of damage accrual (HR 0.55 [95% CI 0.34-0.87]) (P = 0.0111), whereas those receiving HCQ who had damage at study entry did not (HR 1.106 [95% CI 0.70-1.74]) (P = 0.6630). CONCLUSION: These findings indicate that, after adjustment for propensity to receive HCQ, HCQ usage is independently associated with a reduced risk of damage accrual in SLE patients who had not yet accrued damage at the time of treatment initiation.
OBJECTIVE: To study the possible relationship between whole-blood hydroxychloroquine (HCQ) concentrations and clinical efficacy of HCQ in patients with systemic lupus erythematosus (SLE). METHODS: Whole-blood HCQ concentrations were measured, under blinded conditions, in 143 unselected patients with SLE who had been receiving HCQ 400 mg daily for at least 6 months. The relationship of these concentrations to current disease activity and to subsequent exacerbations during 6 months of followup was investigated. RESULTS: At baseline, 23 patients had active disease (mean +/- SD SLE Disease Activity Index 12.4 +/- 7.5). The mean whole-blood HCQ concentration in this group was significantly lower than that in the 120 patients with inactive disease (694 +/- 448 ng/ml versus 1,079 +/- 526 ng/ml; P = 0.001). Among the 120 patients who had inactive disease at baseline, the mean HCQ concentration at baseline in the 14 (12%) who had disease exacerbations during followup was significantly lower than that in the patients whose disease remained inactive. Multivariate logistic regression showed that the HCQ concentration was the only predictor of exacerbation (odds ratio 0.4 [95% confidence interval 0.18-0.85], P = 0.01). Receiver operating characteristic curve analysis showed that a whole-blood HCQ concentration cutoff of 1,000 ng/ml had a negative predictive value of 96% for exacerbation during followup. CONCLUSION: Low whole-blood HCQ concentrations are associated with SLE disease activity and are a strong predictor of disease exacerbation. Regular drug assaying and individual tailoring of treatment might help to improve the efficacy of HCQ treatment in patients with SLE.
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. METHODS: This was a prospective study of pregnancies in women with SLE who were evaluated between 1987 and 2002. The pregnancies were divided into 3 groups: no HCQ exposure during pregnancy (163 pregnancies), continuous use of HCQ during pregnancy (56 pregnancies), or cessation of HCQ treatment either in the 3 months prior to or during the first trimester of pregnancy (38 pregnancies). The pregnancy outcomes, fetal outcomes, and lupus activity during pregnancy were compared among these groups. RESULTS: The rates of miscarriage, stillbirth, pregnancy loss, and congenital abnormality were not statistically different among the 3 groups. The degree of lupus activity during pregnancy, however, was significantly higher in women who stopped taking HCQ. These women had a higher degree of lupus activity, as measured by the physician's estimate of lupus activity and the SLE Disease Activity Index, as well as an increased rate of flare, during pregnancy. More serious lupus complications, such as proteinuria and thrombocytopenia, were not significantly higher in women who stopped taking HCQ. Women who continued taking HCQ were maintained on a lower average dose of prednisone during pregnancy. CONCLUSION: We recommend the continuation of HCQ treatment during pregnancy. Our findings are consistent with prior reports of the absence of fetal toxicity. Similar to studies of nonpregnant women, the cessation of HCQ treatment during pregnancy increases the degree of lupus activity.