Veterinary Immunology and Immunopathology

81 (2001) 347±362

The ACVD task force on canine atopic dermatitis

(XXIII): are essential fatty acids effective?
Thierry Olivrya,*, Rosanna Marsellab, Andrew Hillierc
a
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University,
4700 Hillsborough Street, Raleigh, NC 27606, USA
b
Department of Small Animal Clinical Sciences, College of Veterinary Medicine,
University of Florida, Gainesville, FL, USA
c
Department of Veterinary Clinical Sciences, College of Veterinary Medicine,
The Ohio State University, Columbus, OH, USA

Abstract

Essential fatty acids (EFAs) exhibit the potential to affect allergic in¯ammation through the
modulation of prostaglandin and leukotriene production, the inhibition of cellular activation and
cytokine secretion as well as the alteration of the composition and function of the epidermal lipid
barrier. Because of these multi-facetted effects, EFA have been proposed for treatment of canine
atopic dermatitis (AD) since 1987. To date, more than 20 trials have been performed, reporting the
ef®cacy of either oral EFA supplements or EFA-rich diets. Unfortunately, most of these studies
were found to exhibit one or more of the following de®ciencies: heterogeneity of diagnoses used as
inclusion criteria, short duration of supplementation, lack of randomization of treatment allocation,
lack of blinding of investigators and/or owners, lack of placebo or active controls, lack of
documentation of plasma or skin EFA pro®les during supplementation, as well as lack of
standardization of the basal diets or supplements which could have provided additional EFA.
Consequently, there is presently insuf®cient evidence to recommend for or against the use of EFA to
control clinical signs of canine AD. Evidence of ef®cacy must await the performance of blinded,
randomized and controlled trials of at least 3 months duration in which diets are identical for all of
study subjects. In these trials, clinical ef®cacy should be evaluated in relation to plasma and
cutaneous EFA treatment-induced alterations. # 2001 Elsevier Science B.V. All rights reserved.

Keywords: Atopic dermatitis; Dog; Essential fatty acids; Epidermal lipids; Therapy

*
Corresponding author. Tel.: ‡1-919-513-6276; fax: ‡1-919-513-6336.
E-mail address: thierry_olivry@ncsu.edu (T. Olivry).

0165-2427/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 1 6 5 - 2 4 2 7 ( 0 1 ) 0 0 3 1 6 - 6
348 T. Olivry et al. / Veterinary Immunology and Immunopathology 81 (2001) 347±362

1. Introduction

Since the mid-1980s essential fatty acids (EFAs) have been evaluated in light of the
claim that these supplements could provide a safe ``natural'' alternative to anti-in¯am-
matory drugs for control of clinical signs of allergic pruritus and atopic dermatitis (AD) in
dogs. Unfortunately, at the beginning of the new millenium, our specialty awaits con-
®rmation that EFA truly are effective for treatment of canine AD. The objectives of this
review are to summarize the various known or suspected mechanisms by which EFA could
be of bene®t for cutaneous in¯ammation, and to critically evaluate previous reports
investigating EFA supplementation in human and canine patients with AD.

2. Mechanisms of action of EFAs

EFAs exhibit multiple anti-in¯ammatory and immunomodulating properties. Their

mechanisms of action, therefore, are likely to be explained by a combination of effects.
Whichever combination of mechanisms is responsible for putative reduction of clinical
sign severity in canine and human AD remains to be determined, however.

2.1. Modulation of eicosanoid production

The most commonly proposed mechanism of action of EFA in the treatment of

human AD is the modulation of the cutaneous production of prostaglandins (PG) and
leukotrienes (LT) (Bjorneboe et al., 1987; Lee et al., 1991; Broughton et al., 1997). The
skin lacks both delta-6 and delta-5 desaturase enzyme activities and thus processes
EFA differently from other organs. Indeed, it is not able to produce arachidonic acid
(AA) from its precursor, the omega-6 EFA linoleic acid (LA). Therefore, normal
human skin cannot desaturate LA to gamma-linolenic acid (GLA) whilst it can
elongate GLA to dihomogammalinolenic acid (DGLA) (Chapkin et al., 1986). The latter
is metabolized rapidly via the cyclo-oxygenase (CO) pathway, predominantly into
pro-in¯ammatory prostaglandins (e.g. PGD2, PGE2 and PGF2a). It can be processed
also by the 5-lipoxygenase (LO) pathway into in¯ammatory leukotrienes such as
LTA4, LTB4 and cysteinyl leukotrienes (e.g. LTC4, LTD4, LTE4) (reviewed in Wright,
1991).
The polyunsaturated fatty acid DGLA exhibits the unique potential to compete with AA
as substrate for LO and CO enzymes. In lieu of the production of AA-derived pro-
in¯ammatory eicosanoids, the degradation of DGLA thus leads to an increase in PGE1 and
15 hydroxyeicosatetraenoic acid (15-HETE) that possess anti-in¯ammatory properties
(Miller et al., 1988). Prostaglandin E1 inhibits further AA release from cell membranes,
while 15-HETE blocks the production of LTB4.
Omega-3 fatty acids also can alter the metabolism of AA-derived eicosanoids. For
example, eicosapentaenoic acid (EPA) will also compete with AA for substrate of CO
and 5-LO enzymes, thus favoring the production of PG3s and LTB5 (Ziboh et al., 2000).
Also, the epidermal 15-LO will transform EPA into 15-hydroxyeicosapentaenoic acid
(15-HEPE), and docosahexaenoic acid (DHA) into 17-hydroxydocosahexaenoic acid,
 T. Olivry et al. / Veterinary Immunology and Immunopathology 81 (2001) 347±362 349

respectively (Ziboh et al., 2000). These fatty acid metabolites exhibit anti-in¯ammatory
properties in vitro and can further suppress LTB4 synthesis (Miller et al., 1991; Gallai
et al., 1995).
Modulation of LT production with diets rich in omega-3 and omega-6 fatty acids also
has been reported in normal dogs (Vaughn et al., 1994). Compared to diets with higher
omega-6 to omega-3 fatty acid ratios, diets containing 5:1 and 10:1 ratios resulted in
decreased concentrations of pro-in¯ammatory LTB4 and increased concentration of
LTB5 in dog's skin and neutrophils. Whether these alterations in LT production were
due to the 5:1 and 10:1 speci®c ratios sensu stricto or to dietary supplementation with high
amounts of total omega-3 fatty acids remains to be determined, however. Indeed, an ex
vivo decrease in LTB4 production by stimulated peripheral neutrophils also has been
observed in dogs receiving an omega-3 EFA-rich diet with an omega-6:omega-3 ratio less
than 1 (Byrne et al., 2000).

2.2. Inhibition of cellular activation and cytokine secretion

Besides affecting LT and PG production, EFA exhibit numerous additional immuno-

modulating properties. More speci®cally, they have been reported to decrease the synthesis
of pro-in¯ammatory cytokines such as tumor necrosis factor (Carrick et al., 1994),
interleukin-1 (IL-1) and IL-6 (Endres et al., 1989), as well as IL-2 synthesis and T-
lymphocyte proliferation and activation (Rossetti et al., 1995). They can also affect the
expression of cell adhesion molecules (Lu et al., 1995; De Caterina and Libby, 1996), as
well as slow keratinocyte replication in culture (Garner et al., 1995).
Omega-3 polyunsaturated EFA in¯uence signaling within cells of the immune system
by changing the type of EFA in phospholipids involved in signal transduction (Calder,
1996). Supplementation with omega-3 polyunsaturated EFA also has been reported to
modulate the production of reactive oxygen species and nitric oxide by macrophages and
hence regulate cytotoxic activity of these cells (Erickson et al., 1995; Calder, 1996).
Finally, a diet rich in omega-3 FA has been shown to lead to a decreased production of
serum IgE and increased synthesis of IgG and IgA in rats (Gu et al., 1995).

2.3. Correction of epidermal lipid defects

Human patients with AD develop abnormal skin dryness (Linde, 1992). It is hypothe-
sized that physical and enzymatic defects result in changes in the chemical composition
of the epidermal lipid barrier and increased transepidermal water loss (Fartasch and
Diepgen, 1992; Fartasch, 1994). Preliminary investigations suggest that dogs with AD
also may exhibit abnormal epidermal lipids (see ACVD task force section VIII in this
issue). Of interest is that the epidermal lipid barrier is maintained primarily by sphingolipid
ceramides, including the LA-containing ceramide-1. Thus, the administration of high-
dose omega-6 LA has the potential to modulate the clinical signs associated with this
abnormal lipid barrier. Indeed, supplementation with LA-enriched diets can result in a
signi®cant decrease in transepidermal water loss, thus suggesting that orally administered
omega-6 fatty acids can be incorporated in epidermal intercellular lipids in the canine
species (Marsh et al., 2000).
350 T. Olivry et al. / Veterinary Immunology and Immunopathology 81 (2001) 347±362

3. EFAs for treatment of AD in humans

In humans with AD, a reduced conversion of LA to GLA due to delta-6 desaturase

de®ciency has been hypothesized as one of the underlying causes of atopy (Manku et al.,
1982). This hypothesis was based on the ®nding of low levels of GLA and AA and high
levels of LA in individuals with AD (Manku et al., 1982). This suspected delta-6 desaturase
de®ciency provided the premise for the concept that oral supplementation with GLA-rich
vegetable oils could be proposed for AD therapy. Unfortunately, the existence of such
desaturase de®ciency remains the subject of controversy. For example, signi®cant
decreases in the proportions of DGLA and AA in the plasma lipids of atopic patients
were not found in a recent study (Sakai et al., 1994).
The ef®cacy of oral supplementation with GLA-rich evening primrose oil was sum-
marized in a meta-analysis encompassing nine other studies, four with a parallel, and ®ve
with a cross-over study design (Morse et al., 1989). All trials with parallel design
demonstrated a marked improvement in AD symptoms, especially in the degree of
in¯ammation, dryness, scaling and overall disease severity (Morse et al., 1989). Aside
from a decrease in pruritus, similar conclusions could not be achieved in cross-over trials
(Morse et al., 1989). In general, a positive correlation was found between clinical
improvement and increases in plasma DGLA and AA (Morse et al., 1989).
Most recent studies have been performed to address the question whether GLA
supplementation would provide additional improvement over ``standard of care'' therapy
(e.g. topical glucocorticoids or emollients). Whereas the added bene®t of GLA adminis-
tration is dif®cult to assess when patients receive high potency glucocorticoid formulations,
the gain seems clearer when atopic patients are treated with hydrocortisone or emollients
(Horrobin, 2000). This author contends that the lack of ef®cacy of GLA supplementation
in some previously published controlled study might be due to the concurrent administra-
tion of potent glucocorticoid formulations masking GLA treatment effect over control.
In contrast to this interpretation, results of oral GLA supplementation for AD are not
always deemed favorable or even clear (Berth-Jones and Graham-Brown, 1993; Henz et al.,
1999). For example, a double-blind study evaluated the ef®cacy of high percentage (at least
23%) GLA-containing borage oil in adults with AD of moderate severity. In this report, the
difference in clinical sign reduction between GLA and placebo (miglyol lipid) groups was
not statistically signi®cant (Henz et al., 1999). However, when a subgroup analysis was
performed with the exclusion of patients who failed to show erythrocyte EFA changes after
supplementation, clinical signs reduction was higher in borage oil receiving patients (Henz
et al., 1999).
Topical GLA-containing evening primrose oil has also been used to treat patients with
AD with mixed success (Gehring et al., 1999). In a placebo-controlled study, topical
evening primrose oil in an amphophilic and stable water-in-oil emulsion was applied to
patients with AD (Gehring et al., 1999). Barrier function was assessed in terms of
transepidermal water loss and stratum corneum hydration after a 4-week treatment period
and 1 week without treatment. Evening primrose oil proved to have a stabilizing effect on
the stratum corneum barrier when used in a water-in-oil emulsion.
Supplementation with EPA rich-®sh oils also has been reported to reduce the severity
of signs of AD and atopic asthma (Bjorneboe et al., 1987; Lee et al., 1991; Broughton
 T. Olivry et al. / Veterinary Immunology and Immunopathology 81 (2001) 347±362 351

et al., 1997). Similarly, topical EPA has been reported to decrease symptoms of AD in
people (Watanabe and Kuroda, 1999). Finally, positive bene®ts were reported with
blackcurrant oil that is rich in both GLA and the EPA precursor stearidonic acid
(20:4n3) (Balli et al., 1992).
A caveat of numerous previously reported trials is that controlled studies compared the
ef®cacy of GLA or EPA supplementation to placebos consisting of various vegetal oils
such as sun¯ower oil (Hederos and Berg, 1996) or corn oil (Soyland et al., 1994). In one of
these studies, both GLA supplementation and placebo similarly resulted in signi®cant
decreases in erythema, dryness and pruritus (Hederos and Berg, 1996). In the second study,
dietary supplementation with both ®sh and corn oils resulted in equivalent reduction of
clinical signs (Soyland et al., 1994). Unfortunately, such reports failed to address the issue
that most vegetal oils also are rich with LA, an omega-6 EFA. Indeed, a good clinical
response of AD has been reported in human patients after the sole administration of high
doses of LA (Gimenez-Arnau et al., 1997).
Unfortunately, the results of the studies described herein do not allow us to
conclude whether omega-6 or omega-3 EFA supplementation consistently results in
improvement of clinical signs in both adults and children with AD. Indeed, a recent
paper evaluated all randomized and controlled trials for AD assessing the study
design, degree of blinding and analysis of all patients' data. This meta-analysis
concluded that there was insuf®cient evidence to make recommendations for evening
primrose oil supplementation as part of the treatment of AD in human patients (Hoare
et al., 2000).

4. EFAs for treatment of AD in dogs

Much of the ongoing debate and confusion of the potential use regarding EFA in the
treatment of canine AD stems from a lack of published large scale, long lasting,
randomized, blinded and controlled studies. In the following section, we will review
the parameters for appropriate study design, and then examine the results of previously
reported studies in light of these parameters.

4.1. Critical elements of fatty acid study design

4.1.1. General concepts of study design

As with most experimental trials investigating the clinical ef®cacy of a ``therapeutic
agent'', studies should be optimized with the following design: randomized assignment of
patients to a treatment group, control of the tested drug with either placebo or ``standard-of-
care medication'' and blinding of the owner and clinician to the treatments. The power of
the study should be clearly stated.

4.1.2. Documentation of total oral EFA intake

The total amount of EFA consumed by study subjects in their diet or in ``therapeutic''
supplements should be reported, with a clear indication that the basal diet was standardized
during the course of the study.
352 T. Olivry et al. / Veterinary Immunology and Immunopathology 81 (2001) 347±362

For EFA-enriched dietary trials, the information reported should include: (1) the source
of all EFA, (2) an analysis of total omega-3 and omega-6 FA reported as percent of dry
matter (DM) or energy intake (EN), (3) an analysis of speci®c EFA reported as %DM or
%EN, including but not limited to alpha-linolenic acid (ALA) (18:3n3), EPA (20:5n3),
DHA (22:6n3), LA (18:2n6), GLA (18:3n6) and DGLA (20:3n6), and (4) the method
for quanti®cation of dietary intake (weight or energy basis) and the actual dietary intake
of study subjects (Remillard, 1998).
In studies where an EFA nutritional supplement is being investigated, all animals (from
both treatment and control groups) should be maintained on the same diet, with the above
parameters made available for both diet and supplement (Remillard, 1998). Consequently,
the exact daily intake of total FA, total omega-6 and omega-3 FA, and individual EFA
administered in the diet and supplement will be calculated, tabulated and reported as a
mass/body weight/day (mg/kg/day) basis.
The dramatic importance of diet standardization for trials investigating the therapeutic
effects of EFA supplements is highlighted by two recent, yet unpublished, abstract
documenting EFA content in various premium dog foods.1,2 Indeed, these reports revealed
that total omega-6 and omega-3 EFA consumed by a dog fed these diets could vary from
235 to 940 mg/kg/day and 16 to 283 mg/kg/day, respectively. These amounts can exceed
dramatically those provided by oral EFA capsules!

4.1.3. Duration of the study

Alteration of EFA pro®les in the plasma and different organs and the attainment of a
stable state following a change of EFA dietary intake/supplementation is likely to be
variable between individuals, end organ, disease state, type of EFA supplement, and
baseline EFA levels. Although, signi®cant differences in EFA plasma levels can be
observed in dogs shortly after dietary EFA change (Hansen et al., 1998), permanent
EFA plasma alteration can take as long as 12 weeks after dietary conversion (Campbell and
Dorn, 1992; Campbell et al., 1995). These results suggest that trials investigating the
effects of dietary EFA alteration or supplementation should last a minimum of 3 months.
Moreover, such results also imply that a trimester of dietary standardization should be
considered for all study subjects prior to commencement of a study, and that similarly,
washout periods in cross-over studies should last at least 3 months. Indeed, some authors
(Hansen et al., 1998) recommended washout periods of at least 6 months, even though the
basis for this proposal was not clear.

4.1.4. Monitoring during the course of the study

Evaluation of plasma/serum and end organ (skin in the case of canine AD) EFA levels
should be performed: (1) to determine that dietary EFA change had an effect on

1
Roudebush, P., Bloom, P.B., Jewell, D.J. 1997. Consumption of essential fatty acids in selected commercial
dog foods compared to dietary supplementation. Proc. Ann. Meeting Amer. Acad. Vet. Dermatol. Amer. Coll.
Vet. Dermatol., Nashville, TN, pp. 10±11.
2
Roudebush, 2001. Consumption of essential fatty acids in selected commercial dog foods compared to
dietary supplementation: an update. Proc. Ann. Meeting Amer. Acad. Vet. Dermatol. Amer. Coll. Vet. Dermatol.,
Norfolk, VA, pp. 53±54.
 T. Olivry et al. / Veterinary Immunology and Immunopathology 81 (2001) 347±362 353

constitutional EFA levels, and (2) to determine whether any such effects were associated
with clinical improvement.
The assessment of clinical ef®cacy is best performed in an objective fashion, for
example, by evaluating treatment effect on a measurable response following allergen
challenge (e.g. bronchial allergen provocation in case of asthma studies). For canine AD,
such methods have yet to be standardized, however. In the past, various studies have
evaluated the macroscopic, microscopic or chemical response following provocation with
agents mimicking IgE-mediated cutaneous in¯ammation (e.g. intradermal testing with
allergen, anticanine IgE antibodies or lipopolysacharide). Even though these challenges
may be useful in demonstrating an effect on induced in¯ammatory responses, the results
may not necessarily be extrapolated to indicate ef®cacy for treatment of spontaneously
arising canine AD.
Currently, the use of lesional scoring schemes by clinicians (Olivry et al., 1997) and/or
owners can provide at least a semi-quantitative evaluation of changes in clinical signs.
Because EFA exhibit the potential to alter both cutaneous in¯ammation as well as the
epidermal lipid barrier, the assessment of both in¯ammatory symptoms (e.g. erythema,
pruritus) and coat quality changes (i.e. scaling, gloss, etc.) should be recommended. As
previously stated, the validity of these studies is highly dependent on a blinded and
controlled design.
Finally, it is also important that the concurrent administration of other anti-
in¯ammatory drugs be noted and considered, as their use may alter the dynamics of
EFA biosynthesis due to effects on enzymes involved in EFA metabolism pathways
(Marx, 1995; Boothe, 2001).

4.2. Are EFA effective for treatment of canine AD?

Numerous studies have reported the use of EFA for symptomatic therapy of canine AD
(Tables 1±4). Early studies (Pukay, 1987; Scott and Buerger, 1988; Lloyd and Thomsett,
1989; Miller et al., 1989; Scott and Miller, 1990; Paradis et al., 1991; Miller et al., 1992)
(Table 1) yielded variable results with reduction in pruritus greater than 50% or
improvements in overall clinical signs in 0 (Scott and Miller, 1990) to 40% of study
subjects (Pukay, 1987). Unfortunately, these studies were designed as open experi-
ments, such as a placebo effect was not considered. Moreover, the dosage of omega-6
EFA provided by the tested supplements varied tremendously from 14 (Paradis et al.,
1991) to 386 (Lloyd and Thomsett, 1989) mg/kg/day (Table 1). Supplementation
with omega-3 EFA generally was negligible. Nevertheless, the variation in EFA
supplementation probably was greater than that, even among subjects enrolled in the
same study, as in none of these trials were the diets standardized. Finally, the length of
many of these early trials was inferior or equal to 2 weeks (Scott and Buerger, 1988;
Scott and Miller, 1990; Paradis et al., 1991; Miller et al., 1992), or it was even not
speci®ed (Miller et al., 1989). This short duration of supplementation casts some
doubts whether the EFA had yielded their maximal bene®ts at the end of the study.
The lack of dietary control and short study length probably explain the dramatic
inconsistencies observed in trials investigating the same commercially available supple-
ment. For example, supplementation with DermCaps (DVM Pharmaceuticals, Miami, FL),
Table 1
a,b
Open experimental trials of EFA supplements for treament of dogs with AD
References

Pukay Scott and Lloyd and Miller et al. Scott and Paradis et al. Miller et al.
(1987) Buerger (1988) Thomsett (1989) (1989) Miller (1990) (1991) (1992)

Design O O O O O O O
Study subjects 20 AD 14 AD/31 AP 10 AD 58 AD 9 AD/11 AP 18 AD/12 AP 23 AD
Duration of EFA 2±4 1 9 ? 1 2 2
supplementation (weeks)
Was the diet controlled? No No No No No No No
Brand? DCR DCR EFO 5 ml/10 kg EFO ‡ EMO 4:1 DCR 2 X DCR DCR/DCES DCR
Dosage omega-6 EFA (mg/kg/day) 44 44 386 NA 44 88 44 (DCR)/14 (DCES) 44
Dosage omega-3 EFA (mg/kg/day) 5 5 0 NA 5 9 5 (DCR)/5 (DCES) 5
Omega-6:omega-3 ratio 9 9 NA NA 9 10 9 (DCR)/3 (DCES) 9
Assessment of outcome 8/20 (40%) >50% 5/45 (11%) >50% 30% reduction of 12% reduction of 18/58 (31%) >50% 0/20 (0%) >50% 8/30 (27%) >50% 4/23 (17%) >50%
reduction pruritus reduction pruritus overall assessment score overall assessment score reduction pruritus reduction pruritus reduction pruritus reduction pruritus
a
Note: the dosages of EFA supplements were estimated from authors' information, manufacturer's data or from the following abstracts: Roudebush, P., Bloom, P.B., Jewell, D.J., 1997. Consumption of EFAs in selected
commercial dog foods compared to dietary supplementation. Proceedings of the Annual Meeting American Academy of Veterinary Dermatology and American College of Veterinary Dermatology, Nashville, TN, pp. 10±11;
Roudebush, 2001. Consumption of EFAs in selected commercial dog foods compared to dietary supplementation: an update. Proceedings of the Annual Meeting American Academy of Veterinary Dermatology and American College
of Veterinary Dermatology, Norfolk, VA, pp. 53±54.
b
AD: atopic dermatitis; AP: allergic pruritus; DCR: DermCaps Regular; DVM Pharmaceuticals, Miami, FL; DCES: DermCaps Extra-Strength; DVM Pharmaceuticals, Miami, FL; EFO: Efamol Oil; Efamol, Guilford, UK;
EMO; Efamol Marine Oil, Efamol, Guilford, UK; NA: not assessable; O: open trial.
Table 2
Randomized blinded experimental trials of EFA supplements for treament of dogs with ADa,b
Reference

Scarff and Bond and Bond and Lloyd (1992b) Scott et al. (1992) Bond and Lloyd (1993) Logas and Kunkle (1994) Sture and Harvey (1999)
Lloyd Lloyd Lloyd (1995)
(1992) (1992a)

Design R, B, CP, X R, B, CP R, B, CA R, B R, B, CA R, B, X R, B, CP, X R, B, CP

Study subjects 35 AD 21 AD 37 AD controlled 14 AD/6AP 28 AD (well controlled on HGF 5 AD/11AP 30 AD 21 AD
on EVR before for 8 weeks entering study)
start of study
Duration of EFA 9 8 16 2 16 6 9 8
supplementation (weeks)
Was the diet controlled? No No No No No No No No
Brand? EFO EVR EVR HGF EPO CWMFO DCR EVR HGF HGG HGE EPA CO EVR VC
Dosage omega-6 EFA 128 138 138 GLA 280 mg 40 0 44 38 GLA 280 mg/caps. GLA 350 mg/caps. GLA 0 130 103 120 60
(mg/kg/day) 280 mg/caps.
Dosage omega-3 EFA 0 11 11 EPA 50 mg 0 16 5 3 EPA 50 mg/caps. EPA 50 mg/caps. EPA 250 mg/caps. 66 0 8 6 3
(mg/kg/day)
Omega-6:omega-3 ratio NA 12 12 NA NA NA 9 12 NA NA NA NA NA 12 20 20
Assessment of outcome 17% 9/11 (82%) 9/14 (64%) 6/14 (43%) 2/20 (10%) 2/20 (10%) 1/20 (5%) 1/20 (5%) 4/9 (44%) 4/9 (44%) 4/10 (40%) 9/16 (56%) 0/16 (0%) 40% 49% 57%
improvement improved unchanged, 0/14 unchanged, >50% >50% >50% >50% unchanged, unchanged, unchanged, >50% >50% improvement reduction reduction
in overall improved, 3/14 (21%) reduction reduction reduction reduction 1/9 (11%) 3/9 (33%) 0/10 (0%) overall overall in overall of total of total
severity 5/14 (36%) improved, 5/pruritus pruritus pruritus pruritus improved, improved, improved, improvement improvement scores scores scores
deteriorated 14 (36%) 4/9 (44%) 2/9 (22%) 6/10 (60%)
deteriorated deteriorated deteriorated detriorated
a
Note: the dosages of EFA supplements were estimated from authors' information, manufacturer's data or from the following abstracts: Roudebush, P., Bloom, P.B., Jewell, D.J., 1997. Consumption of EFAs in selected commercial dog foods compared to dietary
supplementation.Proceedings of the Annual Meeting American Academy of Veterinary Dermatology and American College of Veterinary Dermatology, Nashville, TN, pp. 10±11; Roudebush, 2001. Consumption of EFAs in selected commercial dog foods compared to dietary
supplementation: an update. Proceedings of the Annual Meeting American Academy of Veterinary Dermatology and American College of Veterinary Dermatology, Norfolk, VA, pp. 53±54.
b
AD: atopic dermatitis; AP: allergic pruritus; B: blinded; CA: controlled with active drug; CP: controlled with placebo; R: randomized; NA: not available; O: open trial; X: cross-over; CO: corn oil; CWMFO: Cold Water Marine Fish Oil; DCR: DermCaps Regular; DVM
Pharmaceuticals, Miami, FL; EPO: Evening Primrose Oil; Efamol Vet, London, UK; EMO; Efamol Marine Oil, Efamol, Guilford, UK; EPA: Meridian Veterinary Products, St Augustine, FL; EVR: Efavet Regular, Efamol Vet, London, UK; HGE: Efamol, Guilford, UK; HGF:
Efamol, Guilford, UK; HGG: Efamol, Guilford, UK.
356 T. Olivry et al. / Veterinary Immunology and Immunopathology 81 (2001) 347±362

Table 3
Open experimental trials of EFA-enriched diets for treament of dogs with ADa,b

Reference

Schick et al. (1996) Scott et al. (1997) Rosychuk and

Scott-Fieseler (2000)
Design O B(?) O
Study subjects 31 AP 18 AD 47 AD
Duration of EFA 8 8 68 (average)
supplementation (weeks)
Brand? Eukanuba FP (Iams) Eukanuba Natural Eukanuba FP (Iams)
Lamb & Rice (Iams)
Dosage omega-6 EFA (mg/kg/day) 235 269 235
Dosage omega-3 EFA (mg/kg/day) 44 50 44
Omega-6:omega-3 ratio 5 5 5
Assessment of outcome 14/31 (45%) ``good- 8/18 (44%) >50% 20/47 (43%) >50%
to-excellent'' response reduction pruritus reduction pruritus
a
Note: the dosages of EFA supplements were estimated from authors' information, manufacturer's data or
from the following abstracts: Roudebush, P., Bloom, P.B., Jewell, D.J., 1997. Consumption of EFAs in selected
commercial dog foods compared to dietary supplementation. Proceedings of the Annual Meeting American
Academy of Veterinary Dermatology and American College of Veterinary Dermatology Nashville, TN, pp. 10±
11; Roudebush, 2001. Consumption of EFAs in selected commercial dog foods compared to dietary
supplementation: an update. Proceedings of the Annual Meeting American Academy of Veterinary Dermatology
and American College of Veterinary Dermatology, Norfolk, VA, pp. 53±54.
b
AD: atopic dermatitis; B: blinded; AP: allergic pruritus; O: open trial; FP: Eukanuba Response Formula
Fish and Potato.

at the same dose of one capsule per 9.1 kg BW, was reported to lead to a greater than
50% reduction of pruritus in 5% (Scott et al., 1992), 11% (Scott and Buerger, 1988),
17% (Miller et al., 1992), 27% (Paradis et al., 1991), 31% (Miller et al., 1989) or 40%
(Pukay, 1987) of tested cases. In contrast, supplementation with the same formulation,
but at double dose, was deemed ineffective in the 20 tested subjects (Scott and Miller,
1990).
In conclusion, because these inconsistencies and lack of standardization cast serious
doubts on the validity of study design, the results of these early trials must be interpreted
with caution. One should keep in mind, additionally, that the diagnoses given to patients
enrolled in these trials were variable, encompassing not only dogs with AD but also dogs
with pruritus suspected to be of (unspeci®ed) allergic origin.
In contrast to these early trials, more recently reported studies of EFA supplementation
(Table 2) have been randomized, blinded and controlled with placebo and almost always
enrolled patients with the sole diagnosis of AD (Bond and Lloyd, 1992a,b; Scott
et al., 1992; Scarff and Lloyd, 1992; Bond and Lloyd, 1993; Logas and Kunkle, 1994;
Sture and Lloyd, 1995; Harvey, 1999). Three of these trials were designed as crossover
experiments (Scarff and Lloyd, 1992; Logas and Kunkle, 1994; Sture and Lloyd, 1995),
thus adding to the power of the study. Most of these trials investigated the effect
of omega-6 EFA dosages superior to 100 mg/kg/day (Bond and Lloyd, 1992a,b; Scarff
and Lloyd, 1992; Bond and Lloyd, 1993; Logas and Kunkle, 1994; Sture and Lloyd,
Table 4
Combination experimental trials of EFA supplements for treament of dogs with ADa,b

T. Olivry et al. / Veterinary Immunology and Immunopathology 81 (2001) 347±362

Reference

Scott and Miller (1990) Paradis et al. (1991) Bond and Lloyd (1994) Paterson (1995)
Design O O O B, CP
Study subjects 23 AP 18 AD/12AP 11 AD 32 AD
Duration of EFA supplementation (weeks) 1±2 2 12 24
Was the diet controlled? N N N N
Brand? DCR DCR/DCES HGF EFV 660 - 1 caps/10 kg
Co-administered drug and dosage Chlorpheniramine Clemastine Prednisolone Antihistamines
4±8 mg/dog q8h 0.5±1.5 mg/dog q12h
Dosage omega-6 EFA (mg/kg/day) 44 44 (DCR)/14 (DCES) GLA 280 mg 66
Dosage omega-3 EFA (mg/kg/day) 5 5 (DCR)/5 (DCES) EPA 50 mg 6
Omega-6:omega-3 ratio 9 9 (DCR)/3 (DCES) NA 11
Assessment of outcome 13/23 (57%) >50% 13/30 (43%) >50% Dose of prednisone EFA supplementation resulted in
reduction pruritus reduction pruritus reduced in 8/11 dogs improvement in scaling, erythema,
pruritus and coat condition scores
a
Note: the dosages of EFA supplements were estimated from authors' information, manufacturer's data or from the following abstracts: Roudebush, P., Bloom, P.B.,
Jewell, D.J., 1997. Consumption of EFAs in selected commercial dog foods compared to dietary supplementation. Proceedings of the Annual Meeting American
Academy of Veterinary Dermatology and American College of Veterinary Dermatology, Nashville, TN, pp. 10±11; Roudebush, 2001. Consumption of EFAs in selected
commercial dog foods compared to dietary supplementation: an update. Proceedings of the Annual Meeting American Academy of Veterinary Dermatology and
American College of Veterinary Dermatology, Norfolk, VA, pp. 53±54.
b
AD: atopic dermatitis; AP: allergic pruritus; CP: controlled with placebo; DCR: DermCaps Regular; DVM Pharmaceuticals, Miami, FL; DCES: DermCaps Extra-
Strength; DVM Pharmaceuticals, Miami, FL; EFV: Efavet 660, Efamol Vet, London, UK; HGF: Efamol, Guilford, UK; NA: not assessable; O: open trial.

357
358 T. Olivry et al. / Veterinary Immunology and Immunopathology 81 (2001) 347±362

1995; Harvey, 1999). In one study, the ef®cacy of 66 mg/kg/day of omega-3 EFA also was
investigated (Logas and Kunkle, 1994). The length of EFA supplementation varied from 6
(Logas and Kunkle, 1994) to 16 weeks (Bond and Lloyd, 1992b; Bond and Lloyd, 1993),
an improvement compared to earlier trials. In these trials, EFA supplements were reported
to reduce clinical severity scores by 17 (Scarff and Lloyd, 1992) to 57% (Harvey, 1999). In
contrast, there is again marked variability in the percentage of patients whose symptoms
were deemed to improve on these supplements, extending from 0 (corn oil group) (Logas
and Kunkle, 1994) to 82% (Bond and Lloyd, 1992a) of cases. Unfortunately, the observed
variation could be due to one of the same caveats described for the earlier studies, e.g. the
lack of normalization of EFA quantity provided by diets fed to study subjects. As a result, a
signi®cant variability in total oral EFA intake is likely to have occurred. This may explain
why, in studies that have monitored serum EFA levels following supplementation (Bond
and Lloyd, 1992a,b; Bond and Lloyd, 1993), the serum EFA levels did not always parallel
the quantity of EFA being supplemented. Furthermore, in none of these studies were
cutaneous EFA pro®les investigated during the course of the trial.
In fact, only trials with crossover designs would adequately remedy this lack of
dietary standardization. But, even when restricting our analysis to these three trials
(Scarff and Lloyd, 1992; Logas and Kunkle, 1994; Sture and Lloyd, 1995), the ef®cacy
of omega-6 or omega-3 EFA supplementation on clinical signs of canine AD is quite
variable (Table 2).
A study evaluated in vitro eicosanoid production in lipopolysaccharide-stimulated
normal canine skin and activated neutrophils isolated from normal dogs (Vaughn et al.,
1994). The results of this experiment suggested that omega-6 to omega-3 EFA ratios of 5-
10:1 were optimal in reducing neutrophil and cutaneous LTB4 formation. Based on these
results, EFA-rich diets with ``optimal ratios'' were designed and tested in three trials
comprising dogs with AD (Scott et al., 1997; Rosychuk and Scott-Fieseler, 2000) or
``allergic pruritus'' (Schick et al., 1996). These studies reported 43±45% good to excellent
response or at least 50% reduction of pruritus in tested subjects (Table 3).
However, all of these studies were performed with an uncontrolled and open design
(although Scott (Scott et al., 1997) reports a blinded study, it is unclear who was blinded).
Additionally, in one of this trial, there was no control over the intake of ``other foods''
(Rosychuk and Scott-Fieseler, 2000). In the latter study, the assessment of clinical response
was made either by phone conversation or by written responses to a questionnaire,
suggesting that the assessment of clinical responses were likely to encompass some
subjectivity. Of note is that these three studies provided total amounts of dietary EFA
(300 mg/kg/day) that usually exceeded those reported in previous studies, thus raising
the question whether the ``good response'' being reported in fact re¯ected the higher total
amount of EFA being given.
Finally, it must be kept in mind that the proposed ``optimal'' EFA ratios were derived
from studies investigating LTB4 production in neutrophils and skin collected from normal
dogs. Whether or not these results should be taken as ``proof'' that these ratios are optimal
for treatment of canine AD must await the performance of controlled, parallel and blinded
trials investigating diets with different ratios given to a high number of spontaneously
allergic dogs. In fact, it is possible that LTB4, even though present in canine AD skin
(Kietzmann, 1990), may not be an important in¯ammatory mediator in this disease.
 T. Olivry et al. / Veterinary Immunology and Immunopathology 81 (2001) 347±362 359

Indeed, pharmacological LT inhibitors were proven of minimal bene®t in two small clinical
trials (DeBoer et al., 1994).3
Four studies (Table 4) evaluated the ef®cacy of EFA supplements in combination with
other traditional anti-in¯ammatory therapies (Scott and Miller, 1990; Paradis et al., 1991;
Bond and Lloyd, 1994; Paterson, 1995). These studies suggested synergistic ef®cacy for
dogs with AD or allergic pruritus when EFA were added to antihistamines (Scott and
Miller, 1990; Paradis et al., 1991; Paterson, 1995) or prednisolone (Bond and Lloyd, 1994).
However, as with the studies described above, in none of these trials was the basal diet
controlled for EFA content, and only one study (Paterson, 1995) was designed as a blinded,
placebo-controlled experiment (Paterson, 1995).

5. Conclusion

Despite theoretical mechanistic reasons for the usefulness of EFA, and results from
studies reporting that EFA could be of bene®t for treatment of canine AD, it is still unclear
if, when and how EFA should be recommended as part of the overall management of dogs
with this in¯ammatory skin disease. Speci®cally, more controlled studies (as outlined
above) are needed to address the following questions:
1. Are omega-6 and/or omega-3 EFA useful in controlling clinical signs of canine AD?
2. What are the optimal dosages needed for omega-6 and/or omega-3 EFA?
3. Is the omega-6:omega-3 EFA ratio important and if so, what is the optimal one?
4. In which individuals are omega-6 and/or omega-3 EFA most beneficial?
5. Which subgroup of canine patients are most likely to respond to EFA?
6. Are there breed-specific differences for response to EFA supplementation?
7. What is the optimal duration of EFA supplementation for highest clinical efficacy?
8. Are omega-6 and/or omega-3 EFA synergistic with other anti-inflammatory drugs?

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