SHORT COMMUNICATION

Drug Invest. 7 (2): 1 13-116, 1994 0114-2402194/0002-0113/$02.00/0 © Adis International Lintited. All rights reserved.

Alopecia Associated with Sulfasalazine

Peter Ian Pillans l and David 1. Woods2

Centre for Adverse Reactions Monitoring and National Toxicology Group, University of Otago Medical School, Dunedin, New Zealand

2 Drug Information Service, Dunedin Hospital, Dunedin, New Zealand

A spontaneous notification of alopecia in a patient on sulfasalazine treatment received by the New Zealand Centre for Adverse Reactions Moni­toring (NZCARM) prompted a review of the liter­ature, and of cases reported to the World Health Organization (WHO) Collaborating Centre for International Drug Monitoring.

Methods, Case Histories and Results

Spontaneous reports of adverse reactions to medicines are sent on standard reporting cards from healthcare professionals throughout New Zealand to the NZCARM. Founded in 1965, there are now 24 784 adverse reaction reports in the database. Causality is assessed by a clinician ac­cording to guidelines set by the WHO Collaborat­ing Centre for International Drug Monitoring (Venulet 1992). A 'probable' causal relationship is assigned if there is a plausible temporal relation­ship, the event is unlikely to be attributed to con­current disease or other drugs, and there is im­provement of the reaction on drug withdrawal. 'Possible' causality also demands a reasonable time sequence, but the reaction might be con­founded by concurrent disease or other drugs, and information on drug withdrawal may be lacking or unclear.

The NZCARM received a report of diffuse hair loss from the scalp of a 33-year-old man on sul­fasalazine 2g daily for 24 months for ulcerative

colitis. The ulcerative colitis was well controlled, there were no other symptoms, and he was not receiving concomitant medication. There was no further hair loss after a reduction in the dosage of sulfasalazine to 1 g daily.

Communication with the WHO revealed a fur­ther 34 reports of alopecia associated with sul­fasalazine. This represents the total experience re­ported by 12 countries over 18 years. With the permission of the relevant national reporting cen­tres, individual case details were obtained and ex­amined. Two were duplicate reports, and in 7 inad­equate information was provided. Two further patients were on numerous confounding drugs and have also been omitted from further analysis. Case descriptions of the remaining 23 patients, plus the New Zealand patient (case 24) where causality seemed possible, are presented in table I. In 4 cases there was a probable causal association with sul­fasalazine, and in the remaining 20 a possible rela­tionship was considered.

Of the 24 patients, 18 were female. Age was recorded in 22 cases and ranged from 8 to 74 years (mean 36.8 years). The indication for sulfasalazine was given in l3 cases and included ulcerative colitis (n = 5), colitis (1), regional enteritis (2), ir­ritable colon (1), and rheumatoid arthritis (4). The dose of sulfasalazine was given in 15 cases and ranged from 1 to 8g (mean 2.4g) daily. Alopecia

...... Table I. Case descriptions of patients with alopecia associated with sulfasalazine ......

oj:>.

Case no. Age/gender Onset date Daily dose of Duration of Indication Other drugs Outcome of sulfasalazine

sulfasalazine treatment withdrawal

14/F Jan 1975 Unknown Unknown Ulcerative colitis Bismuth subgallate Unknown

2 74/F Dec 1977 Unknown 3mths Colitis Not recovered when

reported

3 43/M SeP.1981 3g 7mths Unknown Unknown

4 BlF Oct 1982 2g 9mths Irritable colon Unknown

5 301M 1983 500mg Unknown Unknown Prednisolone 5mg daily Unknown

6 18/F Oct 1983 8g Unknown Unknown Salbutamol, theophylline Not recovered when reported

7 ?/F Oct 1984 Unknown 7wks Unknown Not recovered when

reported

8 27/F Dec 1985 19 2mths Ulcerative colitis Recovered

9 17/F Jul 1985 3g 4 mths Ulcerative colitis Recovered

10 31/F Dec 1985 Unknown 27mths Unknown Hydrocortisone rectally in Not recovered when

1984 reported

11 28/F Jun 1986 Unknown 3.5 mths Unknown Prednisolone Feb-Mar 1986 Unknown

12 581F May 1986 Unknown 1 day (also rash) Unknown Aporex Not recovered when

(paracetamoVpropoxyphene) reported

Temazepam

Indomethacin

13 73/F Aug 1986 3g 4mths Rheumatoid arthritis Unknown

14 36/F Aug 1986 1.5g Unknown Ulcerative colitis Unknown t::::l

15 471M Dec 1987 Unknown 5mths Unknown Azathioprine since Sep 87 - Recovered i:! continued

0<:> ;;-

16 27/M Nov 1987 Unknown 4mths Unknown Recovered ~ ~ 'I --. tv '-'-'0

~

Sulfasalazine-Associated Alopecia 115

manifested after 2 to 6 months' therapy in 14 of the 20 patients where duration of therapy was stated.

Eleven patients were on concomitant medica-Ql tion (see table I). The outcome of sulfasalazine as Gi withdrawal was given in only 5 patients; partial :> c: c: C" Ql Ql Ql

recovery occurred in 1 and full recovery in 4. No U> .s:: .s::

€ ~ ~

~ "0 rechallenge data were provided. ~ !!! ~

Ql Ql c: c: > c: > c: c:

~ ~ Ql ~~ ~ ~al ~ ~ 0 i; 0 0 Discussion c: c: c: ~ 1: c: c:

"" "" &l - 8. "" - 8. "" "" c: c: o Ql c: o Ql c: c: => => a: z ~ => z ~ => =>

In the colon, the azo linkage of sulfasalazine is

Ql ~ split by bacteria liberating the 2 constituents of the

c: .2!0 molecule, 5-aminosalicylic acid (5-ASA) and sul-0 .~

:2 c: "0

«i as C> fapyridine (Sutherland et al. 1993). No association .s:: ..., E 1: 2l ~ ~ has been demonstrated between side effects and .2 c: I'-~ .s:: c: c: Ql 'iii ~ ,2 Ql c: c: ~ ~ serum concentrations of sulfasalazine or 5-ASA. c:t;;o 5l Ql 5l &l

However, elevated serum sulfapyridine concentra-~~8-:E 'c e 'c 0 c: E c: :> ~ Q. al..:. 88af~ :> tions have been demonstrated in patients with £a ~ :>

a. a....,

alopecia, and in association with other toxic man-U> ,!!l :2 ifestations, predominantly in slow acetylators ~ '1:' U> U> B (Taffet & Das 1982). .s:: .s::

~ :E as U> 1: 1: E

~ as as ~ ~ :> Of 6 other cases of alopecia associated with sul-:2 "0 Ql

B '0 Ql Ql -E Ql c: as c: (ij «i «i ~~

,~ fasalazine described in the literature, the age and ~ ~ E 0 E c: c: li! c: :> c: :> ,2 ,2 Ql ' C: Ql sex were noted in 4 of the patients and all were "" Ql "" Ql 2' 2' > .s:: c: .s:: c: .s:: :> 1: .2 => a: => a: a: a: ..., as => female, aged 29, 50, 51 and 68 years (Attar & An-

uras 1981; Codeluppi et al. 1987; Fich & Eliakim 1988; Taffet & Das 1982). All had ulcerative or

U> U> U> Crohn's colitis and the dosage of sulfasalazine was

U> U> U> U> U> ~ -= ~ 3 to 4g daily. Alopecia occurred after a few to 5 ~ ~ ~

.s:: .s:: E E E L() L() ~ months, and outcome was documented for 4 pa-N ~ '" <0 ~ M M N

~ tients. In 1 patient, hair loss stopped about 1 month after discontinuation of sulfasalazine. In a second

c: g>~ case, hair regrowth followed a few months after ~ ' C: "0 0 :> c: c:

C> C>~~ stopping sulfasalazine, but alopecia recurred on "" C> c: C> ~ C> C> N => N ~ N~U> N N rechallenge (Codeluppi et al. 1987). Substitution

of 5-ASA for sulfasalazine was accompanied by

l8 l8 co ~ Oi '"

hair regrowth. In a third case, massive hair loss co ~ Oi 0> occurred during treatment with sulfasalazine 4g ~ 0> 0> 0> ~

0> 0> ~ ~

~ ~ ~

>- C> i; &l a '0 >- .c daily, ceased with interruption of therapy, but did as :> as Ql ~ < z 0 < 0 ~ LL

not recur with sulfasalazine 2g daily (Codeluppi et al. 1987). The 29-year-old woman commenced sul-

LL LL ~ LL ~ LL ~ fasalazine treatment during pregnancy and was on

M 0 ia ~ C;; <i5 ~ M 2g daily when alopecia was noted 4 months after <0 I'- '" L() N {'o. '" delivery. Although hair regrowth occurred after stopping sulfasalazine, there was no recurrence 2

~ e? ~ 0 (;j N '" ~ months later on rechallenge with the same dose, N N N N

116

and the hair loss was attributed to postpartum alo­pecia (Fich & Eliakim 1988). The authors did not consider whether sulfasalazine may have been con­tributory in this predisposed individual. In com­mon with other autoimmune disorders, ulcerative colitis has rarely been associated with a distinct form of alopecia, alopecia areata (Treem et al. 1993).

Three of 4 cases where gender was stated in the literature and 75% of the patients in the present series were female, which is in keeping with drug­induced alopecia (Bork 1988). With the exception of cytotoxic agents, drug-induced alopecia does not usually begin until 2 to 5 months after starting treatment. Such alopecia is consistent with the telogen effluvium type where there is diffuse hair loss, mainly involving the scalp, and typically re­covers on cessation of therapy (Brodin 1987). The only patient in the present series with a reported onset of alopecia after 1 day of sulfasalazine treat­ment had an accompanying skin rash. Skin rash has been reported within 24 hours of taking sulfasalaz­ine, but was not associated with elevated serum sulfapyridine concentrations, and was thought to be due to hypersensitivity (Taffet & Das 1982).

The fact that 9 of 12 countries reported only 1 or 2 cases each over a period of 18 years not only reflects the rarity of this side effect, but may ex­plain the widespread lack of appreciation of the association. The remaining 3 countries notified 4 or more cases. Although it is not known whether alopecia may be due to the sulfapyridine or 5-ASA component of sulfasalazine, it may be reasonable to consider a trial of newer 5-ASA derivatives

Drug Invest. 7 (2) 1994

where treatment withdrawal or dose reduction are not possible.

The substantial case series presented here where more than half the patients were on sulfasalazine alone, the preponderance of females, interval to on­set, and recovery on drug withdrawal, strengthen a possible causal relationship between sulfasalazine and alopecia.

Acknowledgements

We thank Mr Sten Olsson for providing the details on cases reported to the WHO drug monitoring programme.

References

Attar A, Anuras S. Sulfasalazine and hair loss. Abstract. Gastroen­terology 80: 102, 1981

Bork K. Cutaneous side effects of drugs, p. 249, WB Saunders Com­pany, Philadelphia, 1988

Brodin MB. Drug-related alopecia. Dermatologic Clinics 5: 571-579, 1987

Codeluppi PL, Chahin NJ, Merighi A, Rigo G, Manenti F. A compli­cation of SASP (sulfasalazine) therapy: hair loss. Digestive Dis­eases and Sciences 32: 221-222,1987

Fich A, Eliakim R. Does sulfasalazine induce alopecia? (letter) Jour­nal of Clinical Gastroenterology 10: 466, 1988

Sutherland LR, May GR, Shaffer EA. Sulfasalazine revisited: a meta-analysis of 5-aminosalicylic acid in the treatment of ulcera­tive colitis. Annals of Internal Medicine 118: 540-549,1993

Taffet SL, Das KM. Desensitization of patients with inflammatory bowel disease to sulfasalazine. American Journal of Medicine 73: 520-524, 1982

Treem WR, Veligati LN, Rotter JI, Targan SR, Hyams JS. Ulcerative colitis and total alopecia in a mother and her son. Gastroenterology 104: 1187-1191, 1993

Venulet J. Role and place of causality assessment. Phar-macoepidemiology and Drug Safety I: 225-234, 1992

Correspondence and reprints: Dr Peter I. Pillans, National

Toxicology Group, Medical School, PO Box 913, Dunedin, New

Zealand.