The quinacrine experience in a population of cutaneous lupus erythematosus and dermatomyositis patients

To the Editor

Quinacrine, a compounded antimalarial, has been used for patients intolerant or unresponsive to hydroxychloroquine. In March 2016 the Pharmacy Compounding Advisory Committee (PCAC) raised safety concerns about quinacrine-associated aplastic anemia. Additionally, the Office of New Drugs (OND) advised that although quinacrine may be safe at the 100 mg/day dose prescribed for rheumatic skin diseases, generalists might prescribe this drug at higher dosages and for alternative indications that have yet to be formally studied. Consequently, this orphan drug may no longer be compounded or might become effectively unavailable with prescription requiring an IND, IRB approval, patient consent, and toxicity reporting.¹

To evaluate the need for continued access, we surveyed providers at various institutions to determine their quinacrine prescribing practices. Two rheumatologic skin disease specialists (Drs. MC and CB) from Texas, estimated having seen 96 and 30 patients on quinacrine within the last year but could not provide exact figures. An academic dermatologist (Dr. RDS) from Utah, prescribed quinacrine to 98 patients over a 3-year period (see acknowledgements). We examine the extent of quinacrine use and its associated toxicities at the Hospital of the University of Pennsylvania (HUP).

Through an electronic search of HUP’s data stores from June 1^st, 2015–May 31^st, 2016, we found that out of 899,990 active patients 241 (0.027%) were prescribed quinacrine. Most prescriptions were ordered by dermatology (n=177) and rheumatology (n=75) with 18 individuals prescribed by multiple departments. Records from 111 patients who filled prescriptions at the hospital pharmacy indicate that quinacrine was prescribed to 63.1% (n=70) by dermatologists, 34.2% (n=38) by rheumatologists, and 2.7% (n=3) by internists. Although the OND stated that maintaining quinacrine availability would open access to “any prescriber…for any use…at any dose,” we found that quinacrine has almost exclusively been prescribed by rheumatic skin disease specialists at our center.¹

Secondly, we retrospectively analyzed two NIH-funded prospective longitudinal databases of cutaneous lupus erythematosus (CLE) (n=421) and dermatomyositis (DM) (n=215) initiated in 2007 by Dr. Victoria P. Werth’s research team. All patients were seen at HUP’s outpatient autoimmune skin disease clinic. Those without antimalarial history (n=73) or scant records (n=25) were excluded. Over half (58.7%, n=316) of the remaining 538 patients used quinacrine. Quinacrine users (n=314) were more likely to have smoking history (current=20.6%, past=28.8%, never=50%) than non-users (n=222, current=16.2%, past=19.4%, never=64.4%), χ² (2, N=536) =10.79, p=0.0045, likely representing treatment escalations required in smokers (Table 1).²

Table 1.

Demographics of all patients on antimalarials and subset on quinacrine

		Total on Antimalarials N = 538 N (%)	Quinacrine Users N = 316 N (%)	Percentage of Quinacrine Users per Demographic Category %
Mean Age		52.3	52.9
Gender
Female		458 (85.1)	273 (86.4)	59.6
Male		80 (14.9)	43 (13.6)	53.8
Race
Black		125 (23.2)	76 (24.1)	60.8
White		376 (69.9)	217 (68.7)	57.7
Asian		16 (3.0)	7 (2.2)	43.8
Other		18 (3.3)	14 (4.4)	77.8
Unknown		3 (0.6)	2 (0.6)	66.7
Ethnicity
Hispanic		15 (2.8)	10 (3.2)	66.7
Not-Hispanic		519 (96.5)	303 (95.9)	58.4
Unknown		4 (0.7)	3 (0.9)	75
Smoking History
Never		301 (55.9)	158 (50)	52.5
Current		101 (18.8)	65 (20.6)	64.4 *
Past		134 (24.9)	91 (28.8)	67.9 *
Unknown		2 (0.4)	2 (0.6)	100
Disease Type
CLE		368 (68.4)	222 (70.3)	60.3
Dermatomyositis		170 (31.6)	94 (29.7)	55.3
CLE subtype
Discoid Total		162 (30.1)	114 (21.2)	70.4
Discoid + SLE		64 (11.9)	53 (16.8)	84.7
Discoid + LP		6 (1.1)	6 (1.9)	100
LET Total		24 (4.5)	12 (3.8)	50
LET +SLE		1 (0.2)	1 (0.3)	100
LP		4 (0.7)	1 (0.3)	25
Hypertrophic		3 (0.6)	2 (0.6)	66.7
Chilblains		2 (0.4)	2 (0.6)	100
Lupus Pernio		1 (0.2)	1 (0.3)	100
SCLE Total		70 (16.9)	41 (12.9)	58.6
SCLE + SLE		19 (3.5)	10 (3.2)	52.6
ACLE Total		12 (2.2)	4 (1.3)	33.4
ACLE + SLE		11 (2.0)	4 (1.3)	36.7
Total SLE		64 (11.9)	41 (13.0)	64.1
History of HCQ a		534 (99.3)	312 (98.7)	58.4
History of CQ b		98 (18.2)	85 (26.9)	86.7

^*Quinacrine users are significantly more likely to have smoking history than non-users, p = 0.0045.

^aHCQ = hydroxychloroquine,

^bCQ = Chloroquine

Of the quinacrine users, 36 patients were started recently and details of the course are unavailable. Quinacrine was started in the majority (86.1%, n=241) of the remaining 280 due to hydroxychloroquine refractoriness, consistent with studies on its efficacy for recalcitrant disease.³ Following initiation, quinacrine was discontinued in 50.4% (n=141), hydroxychloroquine in 44.5% (n=237), and chloroquine in 62.2% (n=61). Patients on these medications are not mutually exclusive as most were on either hydroxychloroquine or chloroquine in combination with quinacrine. Notably, quinacrine was discontinued more often than other antimalarials due to cost and access barriers (quinacrine: 23.4%, n=33; hydroxychloroquine: 4.6%, n=11; chloroquine: 16.4%, n=10) rather than side effects (quinacrine: 30.5%, n=43; hydroxychloroquine: 42.6%, n=101; chloroquine: 49.2%, n=30) (Table 2).

Table 2.

Toxicities of quinacrine, hydroxychloroquine, and chloroquine

		Quinacrine N (%)	HCQ * N (%)	CQ ** N (%)
Total		43	101	30
Skin
Dyschromia		8 (18.6)	2 (2.0)	0
Pruritic Rash		11 (25.6)	36 (35.6)	7 (23.4)
Bullous Rash		0	2 (2.0)	0
CLE exacerbation		0	1 (1.0)	0
Alopecia		0	5 (5.0)	3 (10.0)
Gastrointestinal
N / V / D / C a		8 (18.6)	20 (19.8)	6 (20.0)
Transaminitis		2 (4.7) b	1 (1.0)	0
Dysgeusia		2 (4.7)	0	1 (3.4)
Neurologic
Headache / Dizziness		3 (7.0)	10 (9.9)	1 (3.4)
Tinnitus		1 (2.3)	2 (2.0)	0
Hearing Loss		0	1 (1.0)	0
Insomnia		1 (2.3)	0	1 (3.4)
Anxiety		1 (2.3)	0	0
Mental Fog		1 (2.3)	3 (3.0)	1 (3.4)
Auditory Hallucinations		0	1 (1.0) g	0
Nightmares		0	1 (1.0)	0
Ocular		0	18 (17.8)	10 (33.4)
Musculoskeletal
Myopathy		1 (2.3)	1 (1.0)	0
Muscle Cramps		0	1 (1.0)	0
Joint Pains		0	1 (1.0)	0
Shakes / Tremors		0	1 (1.0)	0
Hematologic / Oncologic
Thrombocytopenia		1 (2.3) c	0	0
Leukopenia		1 (2.3) d	0	0
Pancytopenia		1 (2.3) e	0	0
Other
Hypersensitivity		1 (2.3) f	0	0
Lethargy/Fatigue		4 (9.3)	1 (1.0)	1 (3.4)
Weight Gain		0	1 (1.0)	0
Palpitations		0	1 (1.0)	0

^aNausea / Vomiting / Diarrhea / Constipation

^bTransaminitis was mild. Lab values are available for one case: AST 47 ALT 85

^cLab values unclear from records

^dIn setting of lupus flare in patient with SLE-related leukopenia; unclear if drug induced

^eIn the setting of evolving MDS. WBC 2.9, Hematocrit 31.7, Platelets 130K

^fDyspnea, body cramping, fatigue, methemoglobinemia; similar reaction on dapsone

^gRelated to supratherapeutic plaquenil dose

^*HCQ = Hydroxychloroquine;

^**CQ = Chloroquine

Following side effects, quinacrine was restarted in 27.7% (n=13), hydroxychloroquine in 25.7% (n=26), and chloroquine in 16.7% (n=5). There were two instances of mild transaminitis and three of slight hematological disturbances not clearly attributable to quinacrine. In prior reports of WWII soldiers, 1/500,000 patients experienced aplastic anemia at dosages exceeding 100 mg/day.^4,5 Quinacrine’s safety is thus supported by our large experience.

Our study is limited by its retrospective methodology. It is crucial to continue to examine the repercussions of the loss of quinacrine availability considering the lack of suitable alternatives.

Abbreviations List

PCAC

Pharmacy Compounding Advisory Committee

OND

Office of New Drugs

IND

Investigational New Drug

IRB

Institutional Review Board

HUP

Hospital of the University of Pennsylvania

CLE

Cutaneous Lupus Erythematosus

SLE

Systemic Lupus Erythematosus

LP

Lupus Profundus

LET

Lupus Erythematosus Tumidus

SCLE

Subacute Cutaneous Lupus Erythematosus

ACLE

Acute Cutaneous Lupus Erythematosus

DM

Dermatomyositis

WWII

World War II

HCQ

Hydroxychloroquine

CQ

Chloroquine

N / V / D / C

Nausea / Vomiting / Diarrhea / Constipation

AST

Aspartate Aminotransferase

ALT

Alanine Aminotransferase

MDS

Myelodysplastic Syndrome