Abstract
Hydroxychloroquine is considered a relatively benign drug and is regularly used by rheumatologists and dermatologists. We highlight the severe adverse drug reaction potential of this commonly prescribed medication. We report the case of a 63-year-old male, who presented with widespread skin eruption following initiation of hydroxychloroquine two weeks earlier for an inflammatory arthritis. He had typical clinical, biochemical and histological features of the now recognised formal ‘diagnosis’ of severe cutaneous adverse drug reaction. The culprit drug was stopped and he responded to oral and topical steroids as well as supportive measures. Severe reactions to hydroxychloroquine are uncommon; however, as in this case, drug hypersensitivity reactions often manifest in skin. In a drug normally considered to be safe, these potential cutaneous side effects should be highlighted in information given to patients prior to commencement.
Keywords
Case presentation
A 63-year-old male presented to our emergency department (ED) with a widespread skin eruption that had continued to progress over the preceding 48 hours. He had a diagnosis of a seronegative inflammatory arthritis, treated over the previous year with simple therapies such as naproxen and co-codamol. Hydroxychloroquine (200 mg twice daily) was initiated three weeks prior to his presentation to ED by his rheumatology team. He noticed dusky discolouration of his feet and ankle areas after taking this drug for 15 days at which point he stopped. He was commenced on oral steroids but the rash quickly spread proximally to his hands and upper limbs and, shortly before acute presentation, to face and lips, with significant periorbital oedema.
Physical examination
He was hypertensive and pyrexial on admission. Examination found the rash to be non-blanching with areas of palpable purpura and vaguely targetoid annular areas on the ulnar surface of his forearms. There was confluent and diffuse erythema on the posterior trunk spreading to the upper buttocks (Figures 1 and 2). His face was significantly involved with prominent swelling of the lower eyelids. There was early haemorrhagic crusting of the lower mucosal lip and the patient complained of intraoral discomfort. Nikolsky sign on various sites was negative and he was haemodynamically stable. There was no lymphadenopathy or organomegaly.
(a) Striking symmetrical violaceous eruption on medial arches of feet. (b) Purpuric rash on dorsa of feet with a few intact blisters on right foot and haemorrhagic crusts overlying the toes. (a) Extensive non-blanching almost vasculitic type of rash on lower limbs. (b) Some targetoid lesions on ulnar aspect of forearms with palmar sparing and a few blisters on upper arms.
Investigations
Laboratory examinations revealed an elevated C-reactive protein (161 mg/L), hyponatremia (127 mmol/L) and leucocytosis (12.3 × 109/L) with a clear eosinophilia (2.2 × 109/L). Blood film revealed reactive lymphocytes. Urinalysis was normal. He had pre-existing weakly positive ANA of 1/160 (not repeated) and the remaining vasculitis screen was negative. A skin biopsy was performed which showed collection of neutrophils overlying a spongiotic epidermis and a mixed neutrophil and eosinophil infiltrate in the superficial dermis. There were a few atypical lymphocytes and scattered necrotic keratinocytes (Figure 3). Direct immunofluorescence was negative.
High power view demonstrating sub-corneal collection of neutrophils and epidermal spongiosis. The underlying dermis shows perivascular chronic inflammatory infiltrate with presence of atypical lymphocytes and red cell extravasation. There are a few scattered necrotic keratinocytes.
Differential diagnosis, treatment and outcome
Given the recent introduction of a new drug and the widespread progressive nature of the rash, this was felt to be a hydroxychloroquine-induced severe cutaneous adverse reaction (SCAR). Although all these clinical features confirm our diagnosis of cutaneous drug reaction, there can be several subtypes and clinicopathological features which will influence progression and prognosis. Considering the pyrexia, eosinophilia, presence of atypical lymphocytes, timeline of presentation and histology findings, a diagnosis of drug rash with eosinophilia and systemic symptoms (DRESS) was made.
Our patient was treated with oral prednisolone 30 mg daily, topical mometasone ointment and a greasy emollient. A strict fluid balance was kept. The culprit drug was indefinitely discontinued. After four days of treatment, the rash became less florid and started to desquamate with peeling and shearing of the skin on the soles of the feet, at which point he was discharged home. His blood test abnormalities had resolved, and his CRP was less than 10 mg/L.
Discussion
Hydroxychloroquine, an antimalarial drug, is used as a therapeutic option in various specialties for its immunosuppressive and anti-inflammatory properties.1,2 It generally has a low toxicity profile making it a desirable initial systemic therapy for rheumatologists and dermatologists. 3 The half-life is 30–60 days. Side effects include gastrointestinal and neurological symptoms. Its cutaneous side effects range from mild skin reactions such as alopecia, pruritus, angioedema, exanthems and pigmentation to serious life-threatening cutaneous drug eruptions.4–6 This medication has been reported to cause acute generalised exanthematous pustulosis (AGEP), DRESS syndrome, Stevens–Johnson syndrome and toxic epidermal necrolysis – collectively known as SCAR. 7 It is one of the seven drugs most strongly associated with AGEP. 8 Additionally, it is well known to occasionally exacerbate skin conditions such as psoriasis and porphyria. 9 A change in the drug’s formulation since 2000 has been followed by an apparent increased incidence of cutaneous reactions, although reasons for this remain unclear. 10
In conclusion, clinicians must bear in mind that one of the main differential diagnoses for patients presenting with acute cutaneous manifestations is a drug hypersensitivity reaction. These potentially severe side effects as seen in our case emphasise the need for clinicians to be wary when informing patients and prescribing hydroxychloroquine. This knowledge will also aid to detect and treat drug reactions at an early stage.
Drug rash with eosinophilia and systemic symptoms
DRESS also known as drug-induced hypersensitivity syndrome is a rare but potentially life-threatening adverse drug reaction. It is typically characterised by a severe exfoliative dermatitis, haematologic abnormalities (eosinophilia and atypical lymphocytosis), lymphadenopathy and internal organ involvement (liver, kidney and lung). This syndrome differs from other drug eruptions in that it has a delayed onset and clinical manifestations can persist for longer. Symptoms usually develop between three weeks and three months after commencing the drug. Common culprits include anticonvulsants, allopurinol and sulphonamides. The diagnosis of DRESS can be difficult due to the long latency period and broad spectrum of clinical features. A scoring system has been developed to aid diagnosis; the RegiSCAR scoring system. DRESS must be recognised promptly and culprit drug withdrawn. Treatment is mostly supportive and symptomatic. Use of corticosteroids and ciclosporin are sometimes required.11,12
Learning points
Severe cutaneous drug reactions to hydroxychloquine can present in many ways as it encompasses several subtypes. They can be florid and widespread. Patients may present out of hours in an acute setting, and may be systemically unwell. Even relatively safe drugs which have been initiated with in the last two to three months should be considered at an early stage in severe skin reactions. Suspect drugs should ideally be stopped immediately and treatment should be started promptly.
Footnotes
Authors’ contributions
All authors contributed equally and approved submission.
Patient’s consent
Written informed consent was obtained from the patient for the publication of information relevant to the case and for the anonymised pictures.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.