1056 Brief communications
Journal of the American Academy of Dermatology
June 1995
Ranitidine treatment of hand eczema in patients with atopic dermatitis: A
double-blind, placebo-controlled trial
Niels K. Veien, MD, PhD,a Knud Kaaber, MD,b Poul 01holm Larsen, MD,C
Aksel Otkjaer Nielsen, MD, b and Kristian Thestrup-Pedersen, MD, PhDd
Aalborg, Herning, and Aarhus, Denmark
Atopic dermatitis is a major contributory factor
in chronic hand eczema.1 There is no uniformly successful
treatment of either chronic hand eczema or atopic
dermatitis.2
The histamine type 2 receptor antagonist, ranitidine,
possesses immunomodulating properties, possibly because of
its inhibition of histamine activity.3 We have seen alleviation
of chronic hand eczema in a few atopic patients treated with
ranitidine for gastric ulcer. This observation prompted a
placebo-controlled trial to determine whether ranitidine is
effective in the treatment of chronic hand eczema in atopic
patients.
PATIENTS AND METHODS
Eleven men and 36 women at least 1 8 years of age were
included in the study and completed at least 4 weeks of
treatment. All patients ha'd, or previously had, atopic
dermatitis based on the criteria of Hanifin and Rajka.4 At
the time of inclusion in the study, all patients had eczema
of the hands or ringers (or both) of at least 6 months' duration. All patients had been patch tested with the standard series of the International Contact Dermatitis
Research Group. None reacted to any of the substances,
and this was a requirement for participation in the study.
No explanation other than atopic dermatitis had been
found for the hand dermatitis in any of the patients.
The severity of the hand eczema was determined by a
scoring system that included erythema, vesicles, scaling,
pruritus, fissures, and the area involved. Each was scored
as follows: 0 = absent, 1 = mild, 2 = moderate, 3 = severe. The score for area of the hands involved was
1 =  1/3, 2 =  l/3 to  2/3, 3 = 2/3 of the hands. A minimum total score of 5 was required for admission to the
From the Dermatology Clinics, Aalborg,a Herning,b and Aarhusc; and the
Department of Dermatology, Marselisborg Hospital, Aarhus.d
Reprint requests: Niels K. Veien, MD, PhD, The Dermatology Clinic,
Vesterbro 99, DK-9000 Aalborg, Denmark.
J AM ACAD DERMATOL 1995;32:1056-7.
Copyright © 1995 by the American Academy of Dermatology. Inc.
0190-9622/95 $3.00 + 0 16/54/63757
study. The involved areas of the hands were recorded on a
drawing. At the initial visit, the duration of hand eczema
was determined together with the presence of any other
atopic symptoms.
The patients were randomly selected to receive oral
ranitidine, 300 mg twice daily, or placebo tablets of identical appearance. All patients were given betamethasone
valerate cream and ointment and a lubricating ointment
to be used only on the hands. No other topical or systemic
therapy for atopic dermatitis, apart from moisturizers,
was permitted during the trial.
The patients were seen at 4-week intervals for 16
weeks. At each visit, the severity of the hand eczema was
scored, and the overall result of treatment was assessed
and scored by the patient and physician as follows:
0 = unchanged/aggravated, 1 = slight improvement,
2 = marked improvement, and 3 = clear.
The code was broken when all the patients had
completed the study and all results were recorded. Statistical evaluations were based on the intention-to-treat
principle. Nonparametric method of statistical evaluation
were used throughout the study. After 16 weeks, differences in treatment results for the individual features indicating severity of dermatitis and the sum of scores for
the active drug and the placebo groups were calculated.
The overall result as determined by patient and physician
was classified either as successful (marked alleviation or
clear) or failed (slight alleviation or unchanged/aggravated). There was no difference between the evaluation of
the physician and the patient when the scores were grouped.
The study was approved by the regional medical ethics
committee.
RESULTS
Thirty-eight of the 47 patients completed 16 weeks of
treatment. Five men and 18 women had received ranitidine;
6 men and 18 women had received the placebo. The two
groups were comparable with regard to age, duration of
dermatitis, eczema at sites other than the hands, and the
presence of other atopic symptoms such as asthma and
hayfever. Two patients who had received ranitidine
Journal of the American Academy of Dermatology
Volume 32, Number 6
and seven who received the placebo left the study because
of aggravation of their dermatitis.
The total score was reduced from a mean of 10.17 to 4.91
in the group who received ranitidine and a topical steroid,
compared with a reduction from a mean of 10.58 to 7.46 in
the group who received a placebo and a topical steroid (p =
0.07, Kruskal-Wallis test). Score reduction was most
pronounced during the first 4 weeks of therapy. The score
continued to decrease for the group treated with ranitidine
during the next 12 weeks, whereas it remained nearly
constant for the group that received the placebo.
Assessment of the individual features showed that those
receiving ranitidine had a statistically significant reduction
in area of involvement after 16 weeks (p - 0.02), whereas
differences in favor of ranitidine for the reduction of
erythema (p = 0.15), scaling (p = 0.15), pruritus (p =
0.12), fissures (p = 0.08), and vesicles (p = 0.65) were
not statistically significant.
The eczema of 17 of 23 patients treated with ranitidine
cleared or had been markedly alleviated, compared with
that in 8 of 24 patients who received placebo. The
difference between the two groups is statistically
significant (p = 0.02, Fisher's exact test).
There were no side effects from either ranitidine or
placebo.
DISCUSSION
The results of this study indicate that as an adjuvant to
a topical steroid, ranitidine is more effective than a
placebo in reducing the signs and symptoms of atopic
hand eczema. Although the differences between the effect
of ranitidine and the placebo were not statistically
significant for all measurements, the group treated with
ranitidine did consistently better. The smallest difference
between the active drug and the placebo group was seen for
"number of vesicles." In retrospect, this feature should
probably be reserved for determination of the efficacy of
treatment of palmar and interdigital eczema because
vesicles occur in dorsal hand eczema only in very acute
dermatitis. In fact, calculation of the total score of all
features showed a statistically significant difference
between active treatment and placebo if "vesicles" was
omitted (p = 0.05, Kruskal-Wallis test).
The score reduction seen during the first 4 weeks
Brief communications
1057
for both groups of patients was probably primarily from
the effect of betamethasone. During the subsequent 12
weeks, the difference between the two groups increased.
The treatment period should perhaps have been longer
than 16 weeks because the group treated with ranitidine
continued to improve during the entire study period.
Ranitidine has an immunomodulatory effect. This
has led to studies of its effect in trauma, neo-plastic
diseases, and autoimmune diseases.3,5 Ranitidine also
appears to be effective as monotherapy in some patients
with treatment-resistant psoriasis.6,7 The mechanism by
which ranitidine acts in this disease remains speculative.
Possible mechanisms include the blocking of H2 receptors
presented by immunoactive cells as a part of the inflammatory process8 and an antioxidative action.9 These
mechanisms may be operative in atopic hand eczema.
REFERENCES
1. Meding B, Swanbeck G. Epidemiology of different types of
hand eczema in an industrial city. Acta Derm Venereol
(Stockh) 1989;69:227-33.
2. Moller H. The atopic hand eczema. In: Menne T, Maibach
HI, eds. Hand eczema. Boca Raton: CRC Press, 1993:43-8.
3. Nielsen HJ, Hammer JH. Possible role of histamine in
pathogenesis of autoimmune diseases: implications for immunotherapy with histamine-2 receptor antagonists. Med
Hypotheses 1992;39:349-55.
4. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Dermatol Venereol Suppl (Stockh) 1980;92:44-7.
5. Nielsen HJ. Role of histamine in the pathogenesis of
autoimmune disease: implications for drug therapy. Clin
Immunother 1994; 1:250-7.
6. Nielsen HJ, Nielsen H, Georgsen J. Ranitidine for improve
ment of treatment resistant psoriasis [Letter]. Arch Derma
tol 1991;127:270.
7. Witkamp L, Velthuis PJ, Verhaegh MEJM, et al. An open
prospective clinical trial with systemic ranitidine in the
treatment of psoriasis. J AM ACAD DERM ATOL 1993;28:77881.
8. Nielsen HJ. Histamine and histamine type 2 receptor
antagonists in psoriasis: mechanisms and speculations. Dan
Med Bull 1991;38:478-80.
9. Nielsen HJ, Nielsen H, Jensen S, et al. Ranitidine improves
postoperative monocyte and neutrophil function. Arch Surg
1994;129:309-15.