DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Overview

Hydroxychloroquine (HCQ) is commonly used to treat various rheumatic diseases, with its therapeutic effects often explained by theories based on in vitro studies.¹ These theories suggest that HCQ inhibits certain cellular functions and molecular pathways involved in immune activation, partly by accumulating in the lysosomes and autophagosomes of phagocytic cells and altering local pH concentrations.

In Malaysia, HCQ has been approved by the Drug Control Authority (DCA) for conditions such as rheumatoid arthritis, juvenile chronic arthritis, discoid and systemic lupus erythematosus (SLE), as well as dermatological conditions caused or aggravated by sunlight.² There are currently 4 HCQ products available, all in tablet form, registered with the DCA.³

Sweet’s syndrome, also known as acute febrile neutrophilic dermatosis, manifests as fever and erythematous papules, plaques, or nodules.⁴ Histopathologic examination typically reveals a dense neutrophilic dermal infiltrate without evidence of vasculitis.^4-5 Sweet syndrome can be divided into 3 subtypes: classic, malignancy-associated, and drug-induced.

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA), through its global safety signal monitoring, became aware that the European Medicines Agency (EMA) and the Japan Pharmaceuticals and Medical Devices Agency (PMDA) had requested updates to the hydroxychloroquine (HCQ) product information to include the risk of acute febrile neutrophilic dermatosis (Sweet’s syndrome).^6-7 The EMA’s decision was based on available data from the literature and spontaneous reports and in view of a plausible mechanism of action.⁶ The  PMDA reviewed 6 reports (1 locally and 5 globally) involving HCQ and the event. Although no direct causal link was established for the local case, 4 global cases indicated a reasonably possible association between HCQ and Sweet’s syndrome, which led to the PMDA’s decision to proceed with regulatory action.

While the pathogenesis of Sweet’s syndrome remains unclear, evidence points to cytokine dysregulation as a central factor in its clinical and pathological changes.⁸ Various cytokines, including IL-1, IL-3, IL-6, IL-8, G-CSF, GM-CSF, and interferon-gamma, have been implicated. Alternative theories suggest that a triggering factor, such as an antigen in individuals with genetic predispositions, may incite a pro-inflammatory response.⁵

According to literature reviews and global spontaneous report data, Sweet’s syndrome induced by HCQ may occur within 9 days to 1 month from administration.^5,9 The literature also documented a case demonstrating positive dechallenges along with prednisone therapy and a positive rechallenge.⁵

Adverse Drug Reaction Reports¹⁰

To date, the NPRA has received 242 reports documenting 446 adverse events suspected to be linked to HCQ. Among these, the most commonly reported adverse events include electrocardiogram QT prolonged (29 reports), pruritus (29), rash (28), and rash maculo-papular (15). Notably, there have been no reported local cases of Sweet’s syndrome associated with the administration of HCQ products.

Advice for Healthcare Professionals

• Be aware of the potential risk of Sweet’s syndrome associated with HCQ use.
• Advise patients to monitor for any skin reactions, such as plum-coloured, raised, and painful sores, especially on the arms, hands, fingers, face, and neck, accompanied by fever, following treatment with HCQ. Remind them to seek immediate medical attention if these symptoms occur.
• If signs and symptoms suggestive of Sweet’s syndrome develop, refer the patient to a dermatologist for diagnosis confirmation and further management. In cases where HCQ is the suspected culprit, immediately discontinue HCQ, and consider an alternative therapy.
• Report all suspected adverse events associated with HCQ-containing products to the NPRA.

Regulatory Actions

NPRA had completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13(45) Jld.1] had been issued for all registration holders of products containing hydroxychloroquine to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

As of the NPRA's current review, there is insufficient evidence to establish causal links between Sweet's syndrome and other aminoquinolines, such as chloroquine and primaquine. Up to the present, no local or global reports of Sweet’s syndrome events associated with these products have been recorded. Additionally, this information has not been reflected in the product information of Malaysia's reference countries.

References:

1. Schrezenmeier, E. and Dörner, T. Mechanisms of action of hydroxychloroquine and chloroquine: Implications for rheumatology’, Nature Reviews Rheumatology. 2020 Feb 7;16(3), pp. 155–166. Available from: https://doi.org/10.1038/s41584-020-0372-x
2. National Pharmaceutical Regulatory Agency (NPRA). Plaquenil 200mg Film-coated Tablets (hydroxychloroquine sulphate) [Package Insert]. QUEST3+ Product Search. 2024 June [cited 2024 June 7].Available from: https://www.npra.gov.my 
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [Cited 2024 Feb 9]. Available from: https://www.npra.gov.my
4. Nelson CA, Noe MH, McMahon CM, Gowda A, Wu B, Ashchyan HJ, et al. Sweet syndrome in patients with and without malignancy: A retrospective analysis of 83 patients from a tertiary academic referral center. Journal of the American Academy of Dermatology. 2018 Feb;78(2):303-309.e4. Available from: https://doi.org/10.1016/j.jaad.2017.09.013  
5. Manzo C, Pollio N, Natale M. Sweet’s Syndrome Following Therapy with Hydroxychloroquine in a Patient Affected with Elderly-Onset Primary Sjogren’s Syndrome. Medicines. 2019 Nov 15;6(4):111.Available from: https://doi.org/10.3390/medicines6040111
6. ‌European Medicines Agency (EMA). Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisation(s)-Annex I[Internet]. 2022 Jan 24 [cited 2024 June 7]. Available from: https://www.ema.europa.eu/en/medicines/psusa/psusa-00001693-202104 
7. Japan Pharmaceuticals and Medical Devices Agency (PMDA). Summary of Investigation Results (Hydroxychloroquine sulfate) [Internet]. 2012 Jun 26 [cited 2023 Feb 20]. Available from: https://www.pmda.go.jp/files/000249938.pdf 
8. Barton JL, Pincus L, Yazdany J, Richman N, McCalmont TH, Gensler L, et al. Association of Sweet’s Syndrome and Systemic Lupus Erythematosus. Case Reports in Rheumatology [Internet]. 2011 Nov 14 [cited 2024 June 7];2011:e242681. Available from: https://www.hindawi.com/journals/crirh/2011/242681/
9. ‌Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2024 [cited 2024June 7]. Available from: https://www.vigilyze.who-umc.org (access restricted)
10. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2024 [Cited on 2024 Apr 5]. Available from: https://www.npra.gov.my (access restricted)

Written by: Noor'ain Shamsuddin

Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Norleen Mohamed Ali