Effect of omega-3 fatty.acids oncanine atopic dermatitis

Twenty-nlne dogs were lncluded ln a double-bllnded,

placebo+ontrolled, randomlsed trlal and were orally

suppfemented for 10 weeks wlth elther flax oll (2OO mg/kg/dayl,elcosapentaenolc acld (5O mg/RC/day) and docosahexaenolc

acld (35 mg/Rg/day) ln a commerclal preparatlon, or mlneral

oll as a placebo. For each dog, cllnlcal scores were determlned

based on a scorlng system developed prlor to the trlal. Total

omegao and omega3 lntake and the ratlo of omega6:omega-3

(omega-6:3) were calculated before and after the trlal. The dogs'

cllnlcal scores lmproved ln those supplemented wlth flax oll

and the commerclal preparatlon, but not ln the placebo group.

No correlatlon was ldentlfled between total fatty acld lntake or

omega6:3 ratlo and cllnlcal scores. Based on the results of thls

study, the total lntake of fatty aclds or the omega€:3 ratlo do not

seem to be the maln factors ln determlnlng the cllnlcal response.

R. S. Mueu-en, K. V. FrEsEr-ER*,

M. J. FEnu¡N, S. Z¡sEl*,R. A. W RosvcHur, G. K, Ocrr-vrE

¡r.¡o T. L. GREe¡¡wnLr*

Journal of Small An¡mal Pract¡ce (2OO4)45,293-297

Department of Clin¡cal Sc¡ences,and x Department of veter¡naryTeach¡ng Hospital, College ofVeterinary Medicine and B¡omedicalSciences, Colorado State Un¡versltfFort Colllns, CO 80523, USA

R. Mueller's current address isMedizinische Tierkl¡nik,Veter¡naerstr. 13, 80539Munich, Germany

G. Og¡lvie's current address is CVS

Angel Care Cancer Center, 100 N

Rancho Santa Fe, San Marcos,cA 92024, USA

IIIRODUGnOil

Canine atopic dermatitis is a common skin

disease in small animal practice (Scott and

Paradis 1990). h is defined as an inherentpredisposition to the development ofimmunoglobulin (lg) E antibodies to envi-

ronmental allergens, resulting in clinicalsigns following exposure to these allergens(Halliwell and Gorman 1989). Sympto-maric trearment modalities for canine

atopic dermatiris inclucle glucocorticoids,anrihistamines and fatry acid supplemen-

tation (Griffin 1993, Mueller 1993, Scottand orhers 2001). The only specific treat-ment for atopic dermatitis is allergen-

specific immunotherapy wherein allergens

identified by intradermal testing or serum

resring for allergen-specific IgE are injected

subcutaneously. Allergen-specific immu-notherapy must usually be pursued For

months before an improvement in clinicalsigns is seen and it is not effective in all

patients (Scotr and others 1993, Muellerand Bettenay 1996). For these reasons,

symptomatic therapies are often explored.Because adverse reacrions to glucocorticoid

therapy are common, more attention has

been paid recenrly to treatments that have

been associated with fewer adverse effects,

such as antihistamines and fatty acid sup-

plementation (Campbell 1993, Paterson

1994).

Bsenrial fatry acids have been used totreat humans with atopic dermatitis (Price

1984, Biagi and others 1988, Fiocchi and

others 1994, Paterson 1995, Henz and

orhers 1999) and allergic asthma (Stenius-

Aarniala and others 1989, Okamoto and

others 2000), and have been shown tomodulate the infìammatory response inhumans, mice and rats (Higgs 1985, Horiiand others 1991, Schafer and Kragealle

1991, Vatanabe and others 1994, Teren-

cio and others 1998). Oral fatry acid sup-

plementation has been noted to decrease

rhe inflammation and pruritus associated

with canine atopy (Bond and Lloyd I 992b,

Scort and others 1992, Logas and Kunkle1994). These benefits have been related tosupplementation with certain omega-6

fatty acids (gamma-linoleic acid [GLA])(Scarffand Lloyd 1992), combinations ofGLA and omega-3 fatty acids such as

eicosapentaenoic acid (EPA) and docosa-

hexaenoic acid (DHA) (Bond and Lloyd1992a, Scott and others 1992), variable

doses of omega-3 fatry acids (Logas and

Kunkle 1994) or omega-3 supplemented

whole diets with fixed omega-6:omega-3(omega-6:3) ratios (Scott and others

1997).Emphasi.s has recently been placed

on the use of omega-3 latty acid sup-

plementation at doses higher than the

manufacturer's recommendation in the

management of canine atopic dermatitis.Combination supplements of EPA and

DHA given in the range of 66 mglkgldayhave been noted ¡o clinically benefit

pruritic dogs (Logas and Kunkle 1994).

The use of flax oil as a source of potentially

beneficial omega-3 fatty acids has also been

recommended.'Io che authors' knowledge,

there are no published data in the veteri-

nary literature to substatrtiate claims ofefficacy. The purpose of this randomised,

double-blinded, placebo-controlled study

l()t R¡..¡\1. ()I S\r^1.1.,\NlIri\l. PRi\(--lr(:[ . V()L 45. lUNlì 2004 293

was to evaluate the infìuence of supple-mentation with flax oil and a commercialproduct containing EPA and DHA on rhe

clinical signs ofatopic dogs.

¡IAÏERIA].S AND iIEÍHOD8

Approval for the study was obtained fromthe Animal Care and Use Committeeof Colorado State Universiry. Dogs withnon-seasonal aropic dermaticis were

included in the study. Atopic dermatitiswas diagnosed by history clinical examina-tion and exclusion ofdifferential diagnoses

such as food adverse reactions or scabies

with appropriate tesrs or trearments as

described elsewhere (Mueller 1993, Scortand others 1993,2001). Offending aller-

:...T: *.* identified with an intradermal

Dogs were fed the same recorded rypeand amount of diet for eight weeks prior toand during latty acid supplementation.The total amounrs of omega-3 and omega-6 latry acids received before and during thetrial were calculated for each dog using themanufacturer's informa¡ion outlining rhefatty acid contenr of rhe used commercialdiet and adding the fatry acid content ofthe administered supplement.

Each dog was assigned to one of threegroups of I 0 dogs using a table of randomnumbers and simple randomisarion. Thegroups were treated, ar a dose ofar least onecapsule per 5 kg of bodyweighr, with a com-mercial latry acid supplemenr (3V Caps;

DVM Pharmaceuticals), flax oil capsules

containing 570 mgof c-linolenic acid and170 mg of linoleic acid per capsule, or a

placebo containing mineral oil. Thus rhe

dose range for each animal varied from 50

to 85 mg ol tsPA/kg and 35 to 55 mg ofDHA,/kg every 24 hours for the dogs r€ceiv-

ing the commercial fatry acid supplement,arrd from 200 ro 335 mg/kg of flax oil every

24 hours for the second group. Neirherowner nor clinician was aware of the narureof the supplementation. Supplements were

given lor l0 weeks. Owners and clinicianscornpleted evalu:rtion forms immediately

before and after the fatry acid therapy.

Owner clinical scores were obtained byadding the scores for pruritus, skin lesions

and medication. Pruritus was scored o¡r a

continuous visual analogue scale o[ 0 to30, 0 being no pruritus, 30 being intense

pruritus noted at all times. Each observed

skin lesion (erythema, papule or crust) was

counted separately and graded as: mild,1.5 points; moderate, 3 points; and severe,

4'5 points. No concurrent medication was

scored as 0 poinrs, topical therapy as 5points and anrihisramines as l0 points.Frequent antibiotic therapy (more than 21

days during the I 0-week study) scored 20poinrs, while less frequent ântibioricadministration during this period scoredl0 points. The score Êor glucocorticoidswas determined by the dose. A calculateddaily average dose of I mg/kg or more

scored 40 points, benveen 0'5 mg/kg and Img/kg daily scored 30 points, becween 0.2mg/kg and 0.5 mg/kg daily scored 20

points and less than 0.2 mg/kg daily scored

l0 points. The overall maximum score foran animal was I17.5 points.

Clinician clinical scores were obtainedsimilarl¡ but prurirus scored 0 whenabsent, l0 poinrs when mild (scrarching

was not seen in the waiting or examinationroom, bur could be induced), 20 pointswhen moderate (scratching, licking or rub-bing could be observed in the examinationor waiting room, but ceased during the

examination) and 30 points when severe(scratching, rubbing or licking occurred

during the examination).'fhe nrean total number of positive

inrradermal reactions was derermined foreach group and compared wirh a Kruskal-Vallis resr. 'lotal dierary omega-3 andomega-6 farry acid inrakes before and afrersupplementation were calculated byadding dietary intake and supplementaryfatty acid content together.'fhe total latryacid intake of the three groups was com-pared with a Kruskal-Vallis test. Subjec-rive evaluations ofpruritus, performed by

continuous scale plotting, were quanri-rared and rhe scale distances were evaluared

xs corìtirìuous data lor normaliry of distri-

bution by the Kolmogorov-Smirnov test.

Normally disrributed data were compared

over time by one-way analysis of variance(ANOVA). Group means were compared

by a Kruskal-Vallis test, and clinician andowner scores within groups by a lVilcoxon

marched pair test. A Pearson's test was used

to evaluate correlations between intake ofomega-3 and omega-6 fatry acids oromega-6:3 ratio and clinician scores. Thecorrelation between clinician and ownerscores was also examined with a Pearsont

resr. A P value of less than 0'05 was consid-

ered significant.In addition to statistical evaluation, the

dietary inrake of fatry acids and the omega-

6:3 rario of the dogs responding fully totherapy were compared with a correspond-

ing number ofdogs in the same groups notresponding ât all to detect possible differ-ences that could not be identified with the

statistical evaluation, due to the large stan-

dard deviatio¡r of most values withingrouPs.

REIUtls

Thirry dogs were included in the study. Alldogs had positive intradermal testsi the

mean number of positive reactions was

nine in the placebo group (range three tol8) and l0 in borh the group treated witha commercial product and the flax oilgroup (ranges four to 19 and four to 22,

respectively). There was rro significantdifference in positive reactions between

groups using a Kruskal-Vallis test

(P=0.87).

Supplemerrtation was discontinued forone dog in rhe placebo group when irdeveloped diarrhoea. 1wenry-nine dogs

completed the study. Of these 29 dogs, l3dogs had been on antihistamines withincomplete Íesponse prior to the study. Inall dogs these antihistamines were contin-ued ar the same dose until the end ofthe study. Similarl¡ l3 dogs received

weekly shampoo therapy at the beginningofthe srudy and rhis continued unchanged

rhroughour the study. In one dog,

294 l()l. R\i\1. ()F S\1,\l l. ^\l\1,\l

I'RÀ(. I l(:t: . V()1. 45 ' JUNL 200.í

Table 2. Glinical scores reported by owners and cliniciansbefore and after treatment with placebo, flax oil or acommercial product (mean t standard dev¡at¡on)

fable 1. Total d¡etary intake of omega-3 and omoga-6 fattyac¡ds and standard deviation ¡n dogs supplemented withplacebo, flax oil or commercial EPA,/DHA capsules (meant standard deviation)

PlaceboFlax o¡lCommercial capsules

Om¡|Þel¡fty.oE¡(l'{,/l(t lod}ll.l¡rll

84r73327t437r LrA7

Om.Éahttyældr(rrylr¡ùffiil|

509r196468r199426iL74

Pretreatmentclin¡c¡an scoresPost treatmentclinlclan scores(P value)rPretreatmentownef scofesPost-tr€atmentownef scores(P valuelr

Plsbo

29.Or10.0

23.5i7'9(P=0.2e7)

36.8r11

30'2r14(P=0'313)

Flrroll Comilældc.e.llh.

25.2t12.2 31114.5

18.1113.0 15.4111.1(P=0.0o8) (P=0.01)

2e,7*L3.2 29'9115.6

20,5ÈL2'5 I7.3Ìll'2(P=0,004) (P=0.02)

'P wtues obl8¡ned by compsfirE cllnlcsl swæ ot clhlcimg/trnêB bofole 8nd âff.or

treatment wilñ a w¡lcoxon matched p8lß test

shampoo therapy was added during thestudy. None ofthese shampoos containedfatry acids.

Three dogs were on glucocorticoidmaintenance therapy prior to inclusion,with unsatisfactory results. In all threedogs, the dose was less then 0.2 mglkgldayand was continued throughout the study.In one of these dogs, the dose could be

decreased further, but due co the low ini¡ialdose the score assigned was unchanged.Two ofthe dogs improved by 25 per cenrin pruritus scores. One o[ these dogs was

on placebo, the other on commercial sup-plement. 'fhe last dog was on commercial

supplement without any improvement.Antibiotics were administered in seven

dogs prior to the study. Six dogs were onantibiotics at the end of the srudy. Fourdogs had developed a pyoderma during rhe

study. Two dogs received antibiotics as

pulse maintenance therapy prior to inclu-sion and throughout rhe srudy.

The daily dierary inrakes of omega-3and omega-6 fatry acids were calculated byadding the fatty acid content of the con-sumed diet and the supplement ('Iable l).'l-he dierary inrake of omega-3 arrd omega-6 farry acids was nor differenr berween thethree groups at the beginning of the trial(P=0'546 and P=0.489, respectively).'Ihedietary intake of omega-3 fatry acids morethan doubled with supplementation in the

group receiving the commercial capsules(to 141x67 mg/kg, P=0.0001) andquadrupled in the flax oil group (ro

326¡436 mg/kg, P=0.001 l).'l'he omega-6i¡rtake increascd by an average of l7 percent in the fìax oil group (to 5481218mg/kg, P=0.579).

There were no significant differences

between groups at the beginning of the

trial for clinical scores determined by clin-icians (P=0.623) or owners (P=0.612)

('lable 2). Clinical scores for dogs receiving

flax oil and commercial EPA/DHA sup-

plemenrs improved significantly duringthe l0 weeks of supplementation com-

pared with the control group (P=0.008,

P=0.01 and P=0.297, respectively) (Table

2). The mean scores o[dogs receiving the

commercial EPA/DHA supplement and

the flax oil capsules at the end of the studywere lower than those of dogs receiving

placebo. However, the difference was notsignificant lor owner or clinician scores.

Improvement of more than 50 per centwas seen in the owner scores of two dogs

and the clinician score of one dog in theplacebo group and in both scores of lourdogs in the group receiving flax oil cap-

sules. Five of the dogs receiving commer-cial EPA/DHAcapsules improved by more

than 50 per cent according to cliniciansand four of these improved based on

owner scores. Complete clinical remissionwith no other treatmerrt but the supple-menration was seen in two dogs receiving

commercial EPA/DHA capsules and one

dog given flax oil capsules. Irr rwo o[ these

dogs, supplementarion was discontinuedand clinical signs recurred. Dogs improved

again when supplementation was resumed.

In the third dog, supplementation was

administered continuously aFter the studyand no recurrence occurred during a l2-monrh follow-up period.

'l'here was ge nerally a good correlationbetween owner and clinician scores,

betwee¡r overall owner scores (the sum of

their pruritus, clinical and medicationscores) and owner pruritus scores, and

overall clinician scores and clinician pruri-tus scores (P=0.001, 12=0.754). Ownerand clinician scores differed by more than

20 per cent for judging improvement inseven ofrhe 29 dogs completing the study.

Owner scores revealed a better improve-menr in wvo dogs; clinician scores revealed

a better improvement in five dogs.

There was no correlation between clini-cian score and omega-3 fatry acid intake(P=0.19), omega-6 fatry acid intake(P=0.84) or omega-6:3 ratio (P=0'18).

Comparing the dogs in remission on ther-

apy with the corresponding dogs notimproving at all, there were no obvious dif-ferences in the dietary intake of omega-3

or omega-6 latty acids or the omega-6:3

ratio, or in the clinical scores at the s¡art olsupplementation.

DtsGUtStoil

Prurirus scores, overall clinician scores and

overall owner scores associated extremely

well for all groups before and after fattyacid supplementation. 'fhis suggests thatthe scoring system was valid and that the

degree of pruritus is generally a good indi-cator of the severiry of atopic dermatitis indogs.

Supplementation with essential lattyacids has been reported as a successful

alternative to glucocorticoid rherapy in the

rrearment of pruritic dermatoses in dogs

(Bond and Lloyd 1992b, Logas and Kun-kle 1994) and cats (Harvey 1991, 1993,Logas and Kunkle 1993). Proposed mech-

,()UR\i\l. ()F Sñl^1.1. ^Nll\1,\1.

PR^(;l l(:lì . VOl.45. JUNIÌ 2004 295

anisms of acrion include modulation ofeicosanoid production, inhibition of cellu-lar activation and an increase in the epider-

mal barrier funcrion, Eicosapentaenoic

acid (omega-3) and dihomogammalinoleicacid (IDHGLA], omega-6) both competewirh arachidonic acid ([AA], omega-6) as a

substrate For ryclo-oxygenæe and 5-lipoxy-genase, which converts these latry acids to

prostaglandins (PGs) and leukotrienes(LIs), respectively (Wright 1991). Pro-inflammatory PGs such as PGE2 and

PGF2,, and LIs such as LIB4 are derivedfrom AA. Eicosanoids derived fromDHGLA and EPA have less inflammatoryor anti-inflammatory action (Miller and

others 1991, Gallai and others 1995).

Increases in anti-infl ammatory eicosanoids

and concurrent decreases in their pro-inflammatory counterparts presumably

decrease cutaneous inflammation.Decreased concentrations of cutaneousLTB4 and decreased production of LTBa

by activated neutrophils have been

reported in dogs alter receiving diets withlower omega-6:3 rarios and diets higher inomega-3 farry acids, respectively (Vaughn

and others I 994, Byrne and others 2000).A number of clinical studies have been

published evaluating fatry acid supplemen-tation for the treatrnent ol canine atopicdermatitis. However, to the authors'

knowledge, none have quantifìed the totalfatry acid intake by calculating rhe sum ofdietary intake and supplementation.In this stud¡ intake of omega-3 and

omega-6 fatty acids, as well as their ratios,varied enormously beFore the ¡rial due tovariable dietary intake (240 rc 942 mglkgomega-6, 20 ro 260 mg/kg omega-3 fattyacids and 0'84:l to 20:l omega-6:3 ratio)and during the rrial due to the combina-tion of dietary intake and supplementation('lable l).

However, rhere was no correlarionberween omega-3 inrake, omega-6 in¡ake

or omega-6:3 ratio and pruritus scores,

clinician scores or owner scores before and

afrer the rrial. 'Ihis suggests rhac rhe effec-

tive dose depends on more than the totalintake or ratio ofessentiâl fatcy acids. fu of

yer unidentified individual idiosyncraticfactors may be relevant for individualresponses. Fatry acids can influence the

immune system by acting as second mes-

sengers, regulators of signal transducing

molecules or transcription factors (Hwang

2000). They have been reported to sup-

press interleukin-2 (lL-2) production and

mononuclear cell proliferation (Endres

and others 1993). To what degree directeffecrs of fatry acids on immune functionare responsible for the clinical effects ofomega-3 supplementation in the atopicdog is unknown.

In this stud¡ the response to flax oilsupplementation was less pronounced

than supplementation with a commercialproduct containing EPA and DHA. Flax

oil contains predominantly c-linolenicacid which is desaturated and elongated invarious steps to EPA, a subsrrate compet-ing with AA for cyclo-oxygenase and

lipoxygenase to be processed to less inflam-matory eicosanoids. Final concentrations

of EPA attained are therefore potentiellywidely variable, depending on the capabil-

ities oF the individual to process the u-linolenic acid as outlined above. To the

authors' knowledge, there are no data

quantirying this conversion in the dog todate. In contrast, commercial EPA/DHAcapsules contain predominantly EPA,

which should be immediately available forcompetitive metabolism with AA. Based

on rhe resuks in this stud¡ it is difficult toderermine rhe preferred fatry acid (a-linolenic acid versus EPA and DHA) lorsupplementation in dogs with atopic der-

matitis, due ro the small number of dogs irr

each group.In this stud¡ approximately half of the

l0 dogs in each treatmenr group improved

by more than 50 per cent. Completeremission was achieved in l0 to 20 per

cent ofdogs. However, although the onlysignificant improvement irr scores withrrearment was seerr in dogs treated with the

commercial producr containing EPA and

DHA, there was no significant difference

berween treatment groups and the placebo

group (in which one dog improved by

296 J()URN..^I. OF Srf,\t.t. ANIM^l. PR^(;rlcli . v()L 45. JUN[ 2004

more than 50 per cent) at the end of the

study. Neither total intake of omega-3 or

omega-6 fatry acids nor their ratio was cor-

related to clinical improvemen¡. Further

studies with larger numbers of animals are

needed to explore these findings furtherand to examine the benefit of supplements

conraining predominantly omega-6 fatry

acids for the treatment of canine atopic

dermatltis.

AcknowlodÉementsThis study was financially supported bya grant from the Shipley Foundation. Theplacebo capsules and the commercial fatry

acid supplements were kindly donated by

DVM Pharmaceuticals, Miami, FL, USA.

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