Action of chloroquine phosphate in rheumatoid arthritis. II. Chromosome damaging effect.

Neill, William A.; Panayi, G. S.; Duthie, J. J. R.; Prescott, R.

doi:10.1136/ard.32.6.547

Cited by 30 publications

(3 citation statements)

References 15 publications

(9 reference statements)

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“…This might be linked to the observations by Neill et al (1973) of chromosomal aberrations induced by CQ in PBMC of rheumatic patients since Lai et al (2001) have shown that HCQ 3.75 or 7.5 lM (in what is considered therapeutic concentrations) induces cell death in IL-2-stimulated and resting normal human PBMC and Jurkat T cells or other T cell lines in a time-dependent fashion by mechanisms involving DNA damage through caspase-3 as well as caspase-8 independent, by a Z-Asp-Glu-Val-Asp-fluoromethyl ketone-sensitive signalling pathway. There is no involvement of Fas in mediating the apoptosis induced by HCQ or other anti-rheumatic drugs.…”

Section: T Cell Responsesmentioning

confidence: 77%

Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases

et al. 2015

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HCQ and CQ have a good reputation for being effective and relatively safe treatments in SLE, mild-moderate RA and Sjøgren's syndrome. There is need for (a) more information on their mode of action in relation to the control of these diseases, (b) scope for developing formulations that have improved pharmacokinetic and therapeutic properties and safety, and (c) further exploring their use in drug combinations not only with other disease modifying agents but also with biologics.

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Section: T Cell Responsesmentioning

confidence: 77%

Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases

et al. 2015

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“…12 However, most of these studies were too small to assess the risk of major malformations, and many based their conclusion on the statistical significance of underpowered comparisons. 26 Given that HCQ crosses the placenta 21 and inhibits cell division and DNA synthesis 27 and that initial reports suggested an increased risk of chromosomal damage attributable to chloroquine, 28 concerns regarding effects on rapidly dividing embryonic cells remain. Specific malformations reported among exposed newborns included cleft lip and palate (1 of 79) 12 and pulmonary hypoplasia in a preterm infant (1 of 133).…”

Section: Contextmentioning

confidence: 99%

Hydroxychloroquine early in pregnancy and risk of birth defects

Huybrechts

Bateman

Zhu

et al. 2021

American Journal of Obstetrics and Gynecology

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Background Hydroxychloroquine (HCQ) is generally considered safe in pregnancy for the treatment of rheumatic conditions, but studies have been too small to evaluate teratogenicity. Quantifying the risk of congenital malformations associated with early pregnancy exposure to HCQ is important both in the context of its ongoing use for rheumatological disorders as well as its potential future use for COVID-19 prophylaxis, for which a number of clinical trials are ongoing despite initial trials for COVID-19 treatment having been negative. Objective The study objective was to evaluate the risk of major congenital malformations associated with exposure to HCQ during the first trimester, the period of organogenesis. Study Design We performed a population-based cohort study nested in the Medicaid Analytic eXtract (MAX, 2000-2014) and IBM MarketScan Research Database (MarketScan, 2003-2015). The source cohort included 2,045 HCQ exposed and 3,198,589 unexposed pregnancies continuously enrolled in their respective insurance program from 3 months before the last menstrual period through at least one month after delivery; infants were enrolled for at least 3 months after birth. We compared the risk of congenital malformations in women with HCQ use during the first trimester versus no use, restricting the cohort to women with rheumatic disorders and using propensity score matching to control for indication, demographics, medical comorbidities, and concomitant medications (N= 1,867 HCQ exposed; 19,080 unexposed pregnancies). The outcomes considered included major congenital malformations diagnosed during the first 90 days after delivery, and specific malformation types for which there were at least 5 exposed events: oral clefts, cardiac, respiratory, gastrointestinal, genital, urinary, musculoskeletal, and limb defects. Results Overall, 54.8 per 1,000 infants exposed to HCQ were born with a major congenital malformation versus 35.3 per 1,000 unexposed infants, corresponding to an unadjusted relative risk of 1.51 (95% CI, 1.27–1.81). Patient characteristics were balanced in the restricted, propensity score matched cohort. The adjusted relative risk was 1.26 (1.04–1.54); it was 1.33 (1.08-1.65) for a daily dose ≥400mg and 0.95 (0.60-1.50) for <400mg. Among the different malformation groups considered, more substantial increases in the risk for oral clefts, respiratory anomalies and urinary defects were observed, although estimates were imprecise. No pattern of malformations was identified. Conclusions Our findings suggest a small increase in the risk of malformations associated with first trimester HCQ use. For most patients with autoimmune rheumatic disorders, the benefits of treatment during pregnancy will likely outweigh this risk. If HCQ were shown to be effective for COVID-19 prophylaxis in ongoing trials, the risk of malformations would need to be balanced against such benefits.

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“…In vitro studies show that C causes chromosomal damage. 19 Our study documents fetal wastage in seven of 21 pregnancies. In the other 14 live birth babies, no congenital abnormalities were detected at ages between 9 months and 19 years.…”

Section: Discussionmentioning

confidence: 90%

Pregnancy Outcome Following First Trimester Exposure to Chloroquine

Levy¹,

Buskila²,

Gladman³

et al. 1991

Amer J Perinatol

111

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Although the use of chloroquine (C) and hydroxychloroquine (HC) in the treatment of malaria prophylaxis during pregnancy is probably safe, the use of much higher doses for treatment of systemic lupus erythematosus (SLE) and rheumatoid arthritis during pregnancy has been controversial. We analyzed the cases of 24 pregnant women with a total of 27 pregnancies who had taken these drugs during their first trimester of pregnancy. C and HC were given in 11 patients with SLE, three with rheumatoid arthritis, and four for malaria prophylaxis. Most of these women had already been on antimalarial drugs for 1 to 172 months prior to pregnancy (mean, 32.2 months). Of the 27 pregnancies, 14 resulted in normal full-term deliveries, six were aborted due to severe disease activity or social conditions, three were stillbirths, and four pregnancies resulted in spontaneous abortions. No congenital abnormalities were detected in the 14 live births at ages between 9 months and 19 years (mean, 5.3 years). All these children are physically and developmentally normal with no clinical evidence of eye or hearing defects. The seven pregnancies that were associated with fetal loss occurred particularly in patients who had active SLE, although stillbirth and spontaneous abortion occurred also in patients with rheumatoid arthritis and in two of the three patients who had been treated prophylactically for malaria. Although of the 215 reported pregnancies with C and HC exposure, including our study, only seven (3.3%) had congenital abnormalities, the risk associated with antimalarials may be cumulative and further studies are needed to elucidate the safety of this drug later in pregnancy.

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Action of chloroquine phosphate in rheumatoid arthritis. II. Chromosome damaging effect.

Cited by 30 publications

References 15 publications

Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases

Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases

Hydroxychloroquine early in pregnancy and risk of birth defects

Pregnancy Outcome Following First Trimester Exposure to Chloroquine

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