Borage Oil in the Treatment of Atopic Dermatitis

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Borage oil in the treatment of atopic dermatitis

ARTICLE in NUTRITION · JULY 2010 Impact Factor: 3.05 · DOI: 10.1016/j.nut.2009.10.014 · Source: PubMed

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Rachel Foster Gil Hardy University of Otago University of Auckland

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Raid G Alany Kingston University London

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Available from: Raid G Alany Retrieved on: 16 September 2015 ARTICLE IN PRESS NUT8304_proof 6 December 2009 1/11

Nutrition xxx (2010) 1–11

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53 Review 1 54 2 A review of borage oil in the treatment of atopic dermatitis 55 3 56 4 57 a a b,* 5 Rachel H. Foster B.Pharm. , Gil Hardy Ph.D. , Raid G. Alany Ph.D., M.P.S., Reg. Pharm. NZ, FNZCP 58 6 a School of Pharmacy, The University of Auckland, Auckland, New Zealand 59 7 b Drug Delivery Research Unit (DDRU), School of Pharmacy, The University of Auckland, Auckland, New Zealand 60 8 61 9 62 10 article info abstract 63 11 64 12 Article history: Nutritional supplementation with omega-6 essential fatty acids (u-6 EFAs) is of potential interest 65 13 Received 1 April 2009 in the treatment of atopic dermatitis. EFAs play a vital role in skin structure and physiology. EFA 66 Accepted 28 October 2009 14 deficiency replicates the symptoms of atopic dermatitis, and patients with atopic dermatitis have 67 15 been reported to have imbalances in EFA levels. Although direct proof is lacking, it has been 68 Keywords: hypothesized that patients with atopic dermatitis have impaired activity of the delta-6 desaturase 16 69 Borage oil enzyme, affecting metabolism of linoleic acid to gamma-linolenic acid (GLA). However, to date, 17 Atopic dermatitis 70 studies of EFA supplementation in atopicPROOF dermatitis, most commonly using evening primrose oil, Essential fatty acids 71 18 have produced conflicting results. Borage oil is of interest because it contains two to three times 72 19 more GLA than evening primrose oil. This review identified 12 clinical trials of oral or topical 20 borage oil for treatment of atopic dermatitis and one preventive trial. All studies were controlled 73 21 and most were randomized and double-blind, but many were small and had other methodological 74 22 limitations. The results of studies of borage oil for the treatment of atopic dermatitis were highly 75 23 variable, with the effect reported to be significant in five studies, insignificant in five studies, and 76 24 mixed in two studies. Borage oil given to at-risk neonates did not prevent development of atopic 77 25 dermatitis. However, the majority of studies showed at least a small degree of efficacy or were not 78 26 able to exclude the possibility that the oil produces a small benefit. Overall, the data suggest that 79 nutritional supplementation with borage oil is unlikely to have a major clinical effect but may be 27 80 useful in some individual patients with less severe atopic dermatitis who are seeking an alternative 28 81 treatment. Which patients are likely to respond cannot yet be identified. Borage oil is well tolerated 82 29 in the short term but no long-term tolerability data are available. 30 Ó 2010 Elsevier Inc. All rights reserved. 83 31 84 32 85 33 86 34 Introduction various cytokines and chemokines play an essential role. Most, 87 35 but not all, cases are IgE-mediated. Atopic dermatitis often co- 88 36 Atopic dermatitis (atopic eczema) is a chronic-relapsing occurs with other atopic conditions such as asthma and hayfever. 89 37 inflammatory skin condition that can be distressing, and when The condition has been linked to various regulatorygenes, and it is 90 38 Q1 severe, can be functionally and socially disabling [1]. It affects up strongly linked to a family history of atopy. The pathophysiology 91 39 to 15–20% of children in developed countries, and the incidence of atopic dermatitis includes skin barrier defects causing 92 40 is increasing [2,6]. The condition improves or resolves with age increased transepidermal water loss (TEWL) and increased 93 41 in most patients. However, many patients will require intermit- permeability to irritants and allergens. There is increased 94 42 tent treatment for exacerbations through to early adulthood or susceptibility to infection, and colonization of the skin with 95 43 beyond with agents such as topical corticosteroids that have Staphylococcus aureus contributes to inflammation of the skin. 96 44 significant adverse effects (Table 1) [2,6,15]. It has been proposed that atopic dermatitis is associated with 97 45 The pathogenesis of atopic dermatitis is multifactorial and an abnormality in essential fatty acid (EFA) metabolism, in 98 46 involves a complex interaction between environmental, immu- particular, affecting production of GLA, and possibly also 99 47 nological, and genetic factors [1,3].UNCORRECTED It is associated with hyperre- impaired incorporation of EFAs into membrane phospholipids 100 48 activity to environmental triggers. T-cell-mediated processes and [7–9]. In the body, EFAs and their products, particularly those of 101 49 the omega-6 (u-6) series, are important for skin structure and 102 50 physiology. EFAs play a crucial role in cell membrane fluidity and 103 * Corresponding author. Tel.: þ64 9 373 7599, ext: 86967; fax: þ64 9 367 104 51 7192. flexibility and affect activity of membrane-associated proteins 52 E-mail address: [email protected] (R. G. Alany). such as receptors and enzymes. Notably, EFAs are key 105

Please cite this article in press as: Foster RH, et al., A review of borage oil in the treatment of atopic dermatitis, Nutrition (2010), doi:10.1016/j.nut.2009.10.014 ARTICLE IN PRESS NUT8304_proof 6 December 2009 2/11

2 R. H. Foster et al. / Nutrition xxx (2010) 1–11

106 components in the membrane systems that maintain the struc- Key 170 Essential fatty acid 107 tural integrity of the skin and epidermal function as a perme- Metabolic enzyme 171 108 ability barrier. Furthermore, EFAs are metabolized to highly Impaired in atopic eczema 172 13-HODE Linoleic acid 109 active eicosanoid products, such as prostaglandins and leuko- 173 110 trienes, that modulate inﬂammatory, immunologic, and prolif- 174

111 erative responses including those of the skin cells [7,8,14,16]. Δ-6 desaturase 175 112 In states of EFA deficiency, skin changes similar to those of 176 113 atopic dermatitis are replicated [7,8]. The skin becomes inflamed 177 Gamma-linolenic 114 178 with dry, scaly, red, and weeping lesions. There is an increased acid 115 rate of proliferation of epidermal cells, metabolic activity, and 179 116 formation of sterol esters and abnormal keratinocytes. The skin’s 180 Elongase 117 normal function as a barrier to water loss becomes markedly 181 PG1s 118 impaired [7,8]. There is increased colonization with S. aureus [5]. 182 TxA1 119 This atopic dermatitis-like skin disorder is reversed by treatment Dihomo-gamma- 183 LT3s linolenic acid 120 with u-6 EFAs [14]. 15-HETrE 184 121 There remains controversy over the exact importance of EFA 185 122 disturbances as a pathophysiological factor in atopic dermatitis, Δ-5 desaturase 186 123 and current data fall short of direct proof. Nevertheless, the PG2s 187 124 finding that EFA abnormalities can be detected prior to the TxA2 Arachidonic acid 188 125 development of atopic dermatitis does support a causative role LT4s 189 15-HETE 126 [10]. EFA abnormalities could contribute to atopic dermatitis in 190 127 two ways: first, through a direct effect on the skin structure and Fig. 1. Pathways of omega-6 essential fatty acid metabolism of interest in the 191 128 function, and, second, by affecting maturation and sensitization treatment of atopic eczema. The black box indicates the metabolic step believed to 192 129 of the immune system affecting the skin [7]. The abnormalities in be impaired in atopic eczema. This potentially affects production of all metabolites 193 beyond this point. Supplementation with gamma-linolenic acid in borage oil is 130 EFA metabolism could potentially reduce levels of the prosta- 194 believed to shiftPROOF metabolism of dihomo-gamma-linolenic acid toward anti- 131 glandin PGE1, resulting in reduced levels of cyclic AMP, and inflammatory products such as PGE1 and 15-HETrE (shown by the black block 195 132 thereby affecting parts of the immune system causing selective arrow) rather than toward arachidonic acid and production of pro-inflammatory 196 133 Q2 hyperactivity. mediators such as LTB4 [7,8,14,16]. 13-HODE, 13-hydroxyoctadecadienoic acid; 15- 197 HETE, 15-hydroxyeicosatetraenoic acid; 15-HETrE, 15-hydroxyeicosatrienoic acid; 134 Such data have stimulated interest in whether EFA-containing 198 LT, leukotriene; PG, prostaglandin; Tx, thromboxane. 135 oils, particularly oils such as evening primrose oil that are rich in 199 136 the u-6 EFAs, are of value in the treatment of atopic dermatitis. present as unesterified fatty acids or as components of choles- 200 137 More recently, borage oil (also known as starflower oil) has terol esters, triacylglycerols, and phospholipids. For simplicity, 201 138 become of interest because of its high GLA content, which is two such distinctions will not be made in this article except where 202 139 to three times higher than that of evening primrose oil [11,12]. specifically necessary.) For both u-6 and u-3 EFAs, metabolism 203 140 While there have been a number of reviews on the use of involves alternating steps of desaturation and elongation. 204 141 evening primrose oil in atopic dermatitis, there have been very Binding to the desaturase enzymes is competitive and thus 205 142 few, if any, comprehensive reviews focused solely on borage oil. increasing the levels of u-6 EFAs can affect metabolism of the u- 206 143 One meta-analysis [13] considered all types of EFA supplemen- 3 EFAs and vice versa. 207 144 tation including borage oil but was published several years ago Borage oil normally contains approximately 35–40% linoleic 208 145 and does not include more recent important data. The aim of this acid and 22–24% GLA, although some individual products 209 146 article is to outline the rationale behind the interest in the contain more or less, as is shown in Table 2. Borage oil also 210 147 potential use of borage oil in atopic dermatitis and to review the contains saturated and monosaturated fatty acids and u-9 series 211 148 clinical data on its use in this indication. This review focuses only fatty acids. (u-9 fatty acids are not true EFAs because they can be 212 149 on data relating to borage oil specifically. Studies testing GLA synthesized within the body.) The GLA content of borage oil is 213 150 alone or other GLA-containing oils may not be applicable to higher than most other similar oils, with the possible exception 214 151 borage oil because activity of different GLA-containing oils is of fungal oils (GLA 15–25%) and some, but not all, preparations of 215 152 potentially affected not only by the GLA content but also by the blackcurrant oil (GLA 12–20%) [11,12,14,20]. The composition of 216 153 position of the GLA on the triglyceride and the balance between borage oil differs significantly from that of evening primrose oil, 217 154 u-6, u-3, u-9, and other fatty acids present in the oil [11,12,14]. which normally contains around 70–80% linoleic acid and 8–12% 218 155 219 GLA. Conventionally, evening primrose oil has been perceived as Q3 156 Rationale for borage oil supplementation in atopic one of the most reliable natural sources of GLA, and it is the most 220 157 dermatitis widely studied of the u-6 EFA oils in atopic dermatitis [42,43]. It 221 158 is not yet fully established whether the higher GLA content of 222 159 Borage oil contains high levels of the u-6 series EFAs that are borage oil directly translates in terms of relative in vivo potency 223 160 particularly important in skin structureUNCORRECTED and function, among and biological activity compared with evening primrose oil. 224 161 other functions [8]. Borage oil does not contain significant [11,12,14]. 225 162 amounts of the u-3 series EFAs; while the u-3 EFAs have some Although borage oil is edible, it is not widely used as a culi- 226 163 role in maintaining skin health, they are more important for nary oil. 227 164 neuronal development and are of particular importance in the 228 165 retina, brain, and cardiovascular systems [17]. 229 166 Within the body, the u-6 series of EFAs derives from linoleic Role of linoleic acid 230 167 acid, which is converted to GLA and subsequently other impor- 231 168 tant EFAs such as dihomo-gamma-linolenic acid (DGLA) and The linoleic acid in borage oil may contribute to its thera- 232 169 arachidonic acid, as shown in Figure 1. (Within the body, EFAs are peutic actions in atopic dermatitis. Linoleic acid has a direct role 233

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234 Table 1 298 * 235 Overview of treatments for atopic dermatitis (AD) 299 236 Treatment Role Limitations 300 237 Emollients Standard of care for both preventive Often underused. Need to be applied liberally at least 3–4 times daily 301 238 and maintenance therapy 302 239 Corticosteroid-sparing 303 240 Topical Standard of care for acute exacerbations Recommended only for short-term or intermittent use 304 corticosteroids Provide symptomatic relief Adverse cutaneous effects limit long-term use (e.g., striae, skin atrophy, telangiectasia) 241 Specialist monitoring required for infants <2 years and with 305 242 use of more potent steroids 306 243 Concerns regarding systemic effects (e.g., HPA suppression, reduction 307 b 244 of bone density, growth retardation in children) 308 Topical calcineurin Second-line use only in patients who have Can be used only in patients aged 2 years 245 309 inhibitors failed to respond adequately to, or cannot Recommended only for short-term or intermittent use 246 be treated with, topical corticosteroids Fewer adverse cutaneous effects but can cause a transient burning 310 247 Reduce severity of symptoms sensation at site of application 311 248 Tacrolimus: moderate-to-severe AD Concerns regarding malignancy with long-term continuous usey 312 249 Pimecrolimus: mild-to-moderate AD 313 Antihistamines Sedating antihistamines may be useful Nonsedating antihistamines have little effect on symptoms 250 when symptoms disrupt sleep 314 251 Oral antibiotics Treatment of secondary skin infections In the absence of infection, reduction of skin bacterial colonization with 315 252 use of antibiotics has little benefit in AD 316 253 Resistance concerns with excessive use 317 254 Oral Oral corticosteroids and cyclosporin Rebound flaring/relapse when treatment discontinued 318 immunomodulators Effective in refractory and severe AD Long-term use limited by serious adverse effects 255 319 256 GLA, gamma-linolenic acid; HPA, hypothalamic-pituitary-adrenal axis. 320 * Based on guidelines from the American Academy of Dermatology [15] and the Primary Care Dermatology Society and British Association of Dermatologists [6]. 257 y Data regarding the risk of these effects with topical application are inconclusive and such events are rare, but caution is warranted with extensive or long-term use. 321 258 322 259 in maintaining the integrity of the water permeability barrier of elderly people,PROOF borage oil capsules provide 360 or 720 mg/d. GLA 323 260 the skin [8,16,22,33]. significantly improved cutaneous barrier function with a mean 324 261 Topical application of borage oil normalized impaired barrier decrease of 11% in TEWL [34]. 325 262 function of the skin, as measured by TEWL, in infants and chil- The major metabolite of linoleic acid in the skin is 13- 326 263 dren with seborrheic or atopic dermatitis [32,56]. In healthy hydroxyoctadecadienoic acid (13-HODE), which has anti- 327 264 proliferative actions [16]. When compared with safflower oil in 328 265 Table 2 animal models, borage oil produced either similar or lower levels 329 266 Comparison of typical fatty acid compositions of borage oil and evening primrose of 13-HODE in the skin (Table 3) [35,40]. Safflower oil would be 330 * 267 oil [11,12,14,20,46], expected to produce significant levels of 13-HODE because it is 331 268 Common namey Lipid namey Borage Evening high in linoleic acid. 332 269 Primrose 333 270 Saturated fatty acids total 12–17 6–14 334 271 Palmitic 16:0 9–12 5–10 335 272 Stearic 18:0 3–5 1–4 Role of subsequent EFAs 336 273 Monounsaturated fatty acids total 5 – 337 Gadoleic 20:1 5 – 274 Omega-3 series polyunsaturated fatty acids 0–5 0–1 While linoleic acid has some role in skin function, it is the 338 275 total EFAs and eicosanoid products later in the u-6 metabolic 339 276 Omega-6 series polyunsaturated fatty acids 50–68 72–94 pathway, e.g., GLA, DGLA, and arachidonic acid and their prod- 340 277 total ucts, that are proposed to be more important in atopic dermatitis 341 Linoleic 18:2 (n-6) 34–42 65–80 278 342 Gamma-linolenic 18:3 (n-6) 16–26 7–14 and the possible therapeutic effects of borage oil [7,8,14,16]. 279 Eicosadienoic 20:2 (n-6) – – The vital first stage in the metabolic pathway of the u-6 EFAs 343 280 Dihomo-gamma-linolenic 20:3 (n-6) – – is desaturation by the enzyme delta-6-desaturase, which 344 281 Arachidonic 20:4 (n-6) – – converts linoleic acid to GLA. This is a rate-limiting step that is 345 282 Omega-9 series monounsaturated fatty acids 15–19 6–12 relatively inefficient in humans and is suggested to be impaired 346 total 283 Oleic 18:1 (n-9) 15–19 6–12 in patients with atopic dermatitis [8,14]. Such an impairment 347 284 Omega-9 series polyunsaturated fatty acids 5–6 – would affect production of not only GLA but also all subsequent 348 285 total EFAs and their products [7–9]. 349 286 Erucic 22:1 (n-9) 3–4 – Supporting the hypothesis of dysfunction of the delta- 350 Nervonic 24:1 (n-9) 2 – 287 6-desaturase enzyme, studies have shown atopic dermatitis to 351 288 d, negligible (generally <0.5%) or zero levels; however, in some cases these fatty be associated with increased levels of linoleic acid and decreased 352 acids may be present but were not reportedUNCORRECTED in the analysis the data were taken 289 levels of the subsequent u-6 EFAs such as GLA, DGLA, and/or 353 from. 290 354 * Ranges also include data from numerous individual commercially available arachidonic acid. Such EFA imbalances have been shown in the 291 products that provided an analysis of the fatty acid composition of their product. umbilical cord blood of neonates preceding development of 355 292 y Nomenclature is derived from: (i) GP Moss. IUPAC-IUB Commission on atopic dermatitis [10], in the breast milk of mothers of babies 356 293 Biochemical Nomenclature. Nomenclature of Lipids. Appendix A: Names of and who subsequently develop atopic dermatitis [23,24], and in 357 symbols for higher fatty acids [online]. Available from http://www.chem.qmul. 294 358 ac.uk/iupac/lipid (Accessed June 20 2007). (ii) Nutrition DatadFatty Acids adipose tissue and the phospholipids of serum, plasma, and red 295 [online]. Available from http://www.nutritiondata.com/topics/fatty-acids blood and mononuclear cells of children and adults with estab- 359 296 (Accessed June 20 2007). The full systematic name for each fatty acid can be lished atopic dermatitis [7,9,25–30]. However, not all data have 360 297 found at these sites. clearly shown such a relationship [7,31]. 361

4 R. H. Foster et al. / Nutrition xxx (2010) 1–11

362 426 * 363 427 364 428

365 and 83%. 429 366 ** 430 56 367 * 431 , c,e , all arms received 1% 368 ** 432 [40] * * 369 68% higher than control 433 f ,c

370 ,c 434 yy ** 371 * 435 increased by 74,

372 2 * * 436 373 437 . In Miller et al. 374 438 and PGD [35]

375 2 439 376 440 , PGE a 377 2 441

378 PGE1 increased to 2 ng/mg15-HETrE protein. increased 3-fold. PGF NS change in 12-HETE and 15-HETE 442 12-HETE increased 36% 15-HETE increased 12% Leukotriene inhibition potential 15-HETrE increased 4-fold. 379 Other effects of Bo vs control 443 , or safﬂower oil 380 444 [46]

381 c 445

382 0.59 LTB4 generation inhibited by 65% 6.3 7.94 13-HODE decreased by 55%. 2.45 NS change in 13-HODE. 446 lipoxygenase products derived from the essential fatty acids contained in brane; GLA, gamma-linolenic acid; LT, leukotriene; NR, not reported; NS,

383 oic acid; 15-HETrE, 15-hydroxyeicosatrienoic acid; –, trace or undetectable 447 y ,c * *

384 ** 448 ids; ph-s, phosphatidylserine; PMN, polymorphonuclear neutrophil; wk, weeks;

385 7.3 449 386 450 387 PROOF 451 c 388 452 1.450.280.44 9.77 0.97 0.74 9.332.6 0.67 LTB4 generation inhibited by 46% 0.5 10.62 0.260.900.71 3.77 0.64 14.26 1.92 11.30 7.30 1.91 6.16 389 453 ,c 390 * * * yy * * * * 454 yy 391 455 3.1 392 456

393 c 457 394 458 395 0.075 – 2.07 459

396 ,c 460 397 yy yy 461

398 Mean EFA levels at the end of treatmentGLA (% of total fatty acids) Bo Control Bo DGLA Control Bo AA Control 462 399 463 400 464 401 465 402 466 403 467 Epidermal ph-sEpidermal ph-i NR NR NR NR 2.50 2.70 PMN ph-LPMN ph-cPMN ph-eEM lipids – – – 0.76 – – – 0.71 1.96 0.64 1.67 0.90 1.81 3.53 3.91 Epidermal ph-e NR NR 2.85 404 Epidermal ph-c NR NR 1.27 468

405 d 469 406 470 1% a þ

407 b 471 408 b 472 409 473 410 474 411 475 412 476 413 477 414 478 415 479 safﬂower oil x 8 wks Bo 60 oral drops (GLA 16.5%) x 12 wks Bo (GLA 1500 mg/day) x 6 wks Bo 446 mg (GLA 103 mg/day) x 6 mo Plasma ph-L 0.11 Bo (GLA 480 mg/day) x 6 wks Bo (GLA 25%) as 4% w/w of diet x 8wk Epidermal ph-L 0.66 416 Bo-EE (GLA 39.5%) as 5% of diet 480 417 UNCORRECTED 481 418 482 419 483

420 4 years 484 [35] [40] 421 [46] 485 [38] [44] 422 486 levels undetectable in control group. 20) 121) 12) 1 0.05 versus control. 0.01 versus control. 0.005 versus control. 0.001 versus control. ¼ ¼ 423 ¼ 487 < < < < n n n with AD ( ( ( 424 Only borage oil and control arms from each study areLow-dose included; and some high-dose studies also Bo tested wereValues other tested estimated types in from of separate a oils. study Control graph. Dosage phases, was not olive separated reported. oil by [38,44] 6 sunflowerPGE months. oil The leukotriene inhibition potential was calculated by factoring in both the epidermal levelP and the potency in inhibiting LTB4P generation of all 15- P P 488 f y c Children aged Neonates at risk of AD Study group (reference) Regimen Tissue Human studies Healthy adult volunteers Animal studies Guinea pigs Guinea pigs * a e b d yy ** each oil. AA, arachidonic acid; AD, atopic dermatitis;not Bo-EE, significant; ethyl PG, ester prostaglandin; concentrate ph-c, ofw/w, phosphatidylcholine; borage weight ph-e, oil; by phosphatidylethanolamine; weight; DGLA, ph-i, 13-HODE, dihomo-gamma-linolenic 13-hydroxyoctadecadienoic phosphatidylinositol; acid; acid;levels. ph-L, EM, 15-HETE, phospholip erythrocyte 15-hydroxyeicosatetraenoic mem acid; 12-HETE, 12-hydroxyeicosatetraen Table 3 Mechanistic effects of oral supplementation with borage oil (Bo) 425 safflower oil, and the control group additionally received 5% hydrogenated coconut oil. 489

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490 If the proposed hypothesis of abnormal EFA metabolism in paralleled a decrease of 46–65% in the capacity of calcium 554 491 atopic dermatitis is correct, it is of potential therapeutic signifi- ionophore-activated PMN to generate LTB4 (Table 3) [44]. The 555 492 cance that borage oil supplies a high level of GLA directly. The ability of borage oil to suppress generation of LTB4 from PMNs is 556 493 GLA content is also important because linoleic acid is not con- believed to be primarily mediated by the hydroxy derivative of 557 494 verted into GLA to any significant extent in the skin itself because DGLA, 15-HETrE [40]. Epidermal levels of 15-HETrE were 558 495 the required desaturase enzyme is not present in adequate increased three- to four-fold after oral supplementation with 559 496 amounts. Only a small amount (5–10% or possibly even less) of borage oil (or ethyl ester concentrates of borage oil) in guinea 560 497 the linoleic acid in borage oil would be expected to be converted pigs [35,40]. Borage oil has also been reported to modify PMN 561 498 to GLA. Borage oil does not contain DGLA or arachidonic acid. activation responses in guinea pigs [45]. 562 499 However, GLA is readily converted to DGLA in the body by the Epidermal levels of the arachidonic acid-derived series 563 500 elongase enzyme [14,16,21]. The supply of GLA by oral borage oil 2 prostaglandins, including PGE2, PGF2a, and PGD2, were also 564 501 increases levels of DGLA in phospholipids, including the lipids of increased by oral borage oil supplementation in guinea pigs 565 502 the skin (Table 3) [35–38,40,44,46]. Levels of GLA itself can be (Table 3) [35]. While PGE2 is considered to be primarily pro- 566 503 relatively low because of its rapid metabolism. The reported inflammatory, this may be concentration-dependent. PGD2, and 567 504 effect of borage oil on arachidonic acid levels is more variable possibly PGF2a, has anti-inflammatory activity [62]. Oral borage 568 505 (Table 3). oil was also found to increase, or not significantly change, levels 569 506 These u-6 EFAs have effects on skin both as components of of the arachidonic acid derivative 15-hydroxyeicosatetraenoic 570 507 membrane structures and through biochemical effects such as acid, which is also anti-inflammatory [16,35,40]. 571 508 modulating cytokine release and activity [14]. The eicosanoids One clinical study that failed to find a greater improvement of 572 509 produced from the u-6 EFAs modulate normal skin physiological atopic dermatitis with borage oil than with olive oil placebo 573 510 processes, and they can have anti-inflammatory or pro-inflam- reported that erythrocyte membrane arachidonic acid levels 574 511 matory effects depending on concentrations and which agents were increased versus baseline with both borage oil and the olive 575 512 predominate [7,14,16]. Supplementation with u-6 EFAs is oil control (Table 3; statistical significance not reported) [38].Of 576 513 believed to alter eicosanoid metabolism to shift the balance note, with olive oil treatment there was an increase in levels of 577 514 toward production of anti-inflammatory prostaglandins (PG) the u-3 EFA eicosapentaenoic acid (EPA). In contrast, borage oil 578 515 and leukotrienes (LT) [7,8,16]. appeared toPROOF divert metabolism away from the u-3 pathway and 579 516 GLA supplementation increases levels of DGLA in the skin, slightly reduced EPA levels. EPA is a precursor to LTB5, which has 580 517 which leads to increased production of the anti-inflammatory lower inflammatory potential than LTB4. Furthermore, where 581 518 products PGE1 and 15-hydroxyeicosatrienoic acid (15-HETrE; there are greater levels of EPA, there is less production of LTB4 582 519 also known as 15-OH-DGLA) that are metabolites of DGLA and PGE2 from arachidonic acid. The authors of the latter study 583 520 [7,8,14,16]. Increased epidermal production of one or both of concluded that the therapeutic efficacy of borage oil was limited 584 521 these anti-inflammatory mediators has been demonstrated in by the inflammatory actions of arachidonic acid–derived eicos- 585 522 animals supplemented with borage oil or ethyl esters of borage anoids, which were not countered by greater EPA production as 586 523 oil (Table 3) [35,39,40]. Increased production of PGE1 is partic- was seen with olive oil [38]. In contrast, authors from another 587 524 ularly important because this prostaglandin has diverse desir- study concluded that although borage oil slightly increased 588 525 able actions. As well as being an anti-inflammatory agent, PGE1 arachidonic acid levels in infants, there appeared to be sufficient 589 526 modulates immune responses and inhibits phospholipase A2, production of the anti-inflammatory products of DGLA (i.e., PGE1 590 527 which is involved in the release of arachidonic acid during and 15-HETrE) to inhibit formation of pro-inflammatory arach- 591 528 inflammation [14]. idonic acid–derived metabolites [46]. 592 529 Arachidonic acid has important biological functions in the Interestingly, GLA also has an antibacterial effect. In partic- 593 530 skin and is an essential constituent of membranes. However, ular, it has bactericidal activity against S. aureus colonized on 594 531 some of the arachidonic acid–derived eicosanoids, especially skin, which is a common problem in atopic dermatitis [4]. 595 532 LTB4, have pro-inflammatory activity when present in high 596 533 concentrations and are at least partially responsible for the pain, 597 534 redness, and swelling of acute inflammation [14,16,19]. The Efficacy of borage oil in atopic dermatitis 598 535 balance between DGLA and its products and arachidonic and its 599 536 products may be one of the key factors in determining whether A literature search not limited by date or language identified 600 537 GLA supplementation produces pro-inflammatory or anti- 11 clinical trials of oral borage oil [20,36–38,47,49–51,53–55] and 601 538 inflammatory actions. Importantly, the activity of the enzyme one clinical trial of topical borage oil [52] for treatment of atopic 602 539 delta-5-desaturase required for conversion of DGLA into arach- dermatitis. Additionally, a study of preventive use of borage oil 603 540 idonic acid is rate-limited and effectively absent in the skin [16]. supplementation in neonates at risk of developing atopic 604 541 Thus, while oral borage oil supplementation does increase dermatitis was included [46]. All studies that assessed clinical 605 542 arachidonic acid levels in phospholipids, the increases are outcomes with use of borage oil for either treatment or 606 543 usually moderate compared to the proportional increases in prevention of atopic dermatitis were included. The total number 607 544 levels of DGLA (Table 3). As wellUNCORRECTED as being converted to anti- of patients in all studies was 812. 608 545 inflammatory products, DGLA seems to have a role in main- All the trials of borage oil were controlled, and most were 609 546 taining arachidonic acid in membranes, where it has desirable double-blind and randomized. However, most of the studies 610 547 actions. Furthermore, the presence of high levels of DGLA were likely underpowered given that power calculations indi- 611 548 prevents the conversion of arachidonic acid to potentially cated that a sample size of at least 120 patients was needed to 612 549 harmful metabolites [14]. provide an accurate result, a criterion that was met in only three 613 550 The most pro-inflammatory product of arachidonic acid is studies [36,46,55]. Many studies enrolled heterogeneous patient 614 551 LTB4. In healthy adult volunteers, dietary supplementation with populations without clearly defined inclusion and exclusion 615 552 borage oil 480 or 1500 mg/d elevated DGLA levels in poly- criteria. A wide variety of outcome measures were used in the 616 553 morphonuclear neutrophil (PMN) phospholipids, and this trials, but this reflects the current lack of consensus about how to 617

6 R. H. Foster et al. / Nutrition xxx (2010) 1–11

618 best measure disease severity in atopic dermatitis. All studies from other trials and may indicate that it was uncontrolled for 682 619 were conducted in Europe. placebo effect. 683 620 The data with regards to whether borage oil is corticosteroid- 684 621 Overview sparing are contradictory [20,36,38,55]. This issue is complicated 685 622 because corticosteroids may interfere with the effects of GLA 686 623 Of the 12 studies of oral or topical borage oil for treatment of supplementation [42]. Thus, a number of studies did not allow 687 624 atopic dermatitis, a significant effect was reported in five studies corticosteroids to be used during the study treatment period. 688 625 [20,37,47,51,54], while another five studies found borage oil to be There are only limited data regarding whether topical appli- 689 626 ineffective (Table 4) [38,49,52,53,55]. In the remaining two cation of borage oil is effective. In 100 adults and children with 690 627 studies, a response to borage oil was seen in only some patients atopic dermatitis affecting the extremities, 10% borage oil in 691 628 [36,50]. urea-containing emollient cream applied twice daily to the arm 692 629 Although it is difficult to draw firm conclusions about the or leg on one side of the body was no more effective than the 693 630 efficacy of borage oil on the basis of the available data, it is same urea-containing but GLA-free emollient cream applied to 694 631 reasonable to suggest that borage oil potentially has some the contralateral side [52]. However, both sides of the body 695 632 beneficial effect but is unlikely to have a profound clinical effect. would be expected to improve if topically applied borage oil has 696 633 Importantly, the majority of studies found at least some benefi- beneficial systemic effects and/or improves skin distant from the 697 634 cial effect or could not exclude the possibility that the treatment site of application, as has been previously reported [32,41]. In 698 635 had a small effect that was not detected. The reliability of the a small placebo-controlled Japanese study, erythema and itch in 699 636 data from studies that found borage oil to have a significant effect children with atopic dermatitis were improved by coating 700 637 is unclear because the studies were small and had other meth- undershirts with borage oil [56]. 701 638 odological limitations [20,37,47,51,54]. Results may also have 702 639 been confounded by the large placebo effect reported in Response according to patient characteristics 703 640 a number of studies [36,38,49,50,53]. 704 641 An important study that was not included in the previous Although data were not thoroughly analyzed in relation to 705 642 meta-analysis of GLA supplementation including borage oil [13] this, there is some evidence to suggest that some individuals will 706 643 was the large study by Takwale et al. that was reported in 2003 gain benefitPROOF from borage oil treatment, whereas other individ- 707 644 [55]. This study was well designed and adequately powered uals will not gain any benefit [36,50]. This might explain the 708 645 (n ¼ 151; 140 evaluable) and used a high dose of oral borage oil inconsistent and often relatively small magnitude of benefit 709 646 (4000 (GLA 920) mg/d for adults; 2000 (460) mg/d for children) reported for borage oil when averaged over the entire patient 710 647 for 12 weeks. Borage oil was not found to be effective. There was population. 711 648 a large placebo effect, and the mean six area, six sign atopic It would be helpful to be able to identify which individuals 712 649 dermatitis score fell from 30 to 27 in the borage oil group and will respond. Borrek at al. [50] reported that 10 of 24 patients 713 650 from 28 to 23 in the placebo group. However, the authors treated with borage oil for 10–14 wk in a crossover trial 714 651 concluded that their data could not exclude the possibility that responded to borage oil, but they were not able to identify any 715 652 borage oil has a small beneficial effect. characteristics to define a ‘‘responder type.’’ Two studies suggest 716 653 In the other large trial by Henz et al. [36], there was no that some benefit from borage oil may be achieved when the 717 654 significant difference between the borage oil and placebo groups individual is compliant and when there is good uptake and 718 655 over 24 weeks of treatment in the primary efficacy endpoint, appropriate metabolism of GLA [36,46]. Van Gool et al. [46] 719 656 which was the total amount of corticosteroid used up to the time found that in the first 3 mo of treatment with borage oil in 720 657 a response was achieved (defined as a 50% reduction in the Costa neonates, there was a strong negative correlation between the 721 658 Score). Borage oil did improve erythema, vesiculation, crusting, infant’s increase in GLA plasma phospholipid concentrations and 722 659 lichenification, and insomnia, but not pruritus, which is often the severity of symptoms. Similarly, Henz et al. [36] reported that 723 660 most distressing symptom from the patient’s perspective. borage oil had a significant effect when patients who met any of 724 661 Importantly, this study identified a subgroup of patients (with the following criteria were excluded: 725 662 adequate systemic absorption and metabolism of GLA and good 726 663 compliance) in whom borage oil had a significant effect (see negligible increase of DGLA levels in erythrocytes 727 664 Response according to patient characteristics). The results of this poorly compliant 728 665 study are somewhat difficult to interpret because they varied used excessive amounts of corticosteroid cream 729 666 greatly between the four treatment centers involved in the study, undertook treatment for <11 wk and did not have a response 730 667 which may have been related to different patterns of rescue in that time 731 668 corticosteroid use. Nevertheless, this study is important because had a decrease in Costa score to <18 within 2 wk; it is 732 669 of its size. Also it was one of the few to clearly define a relatively unlikely that such patients truly had stable moderate disease 733 670 homogeneous group of patients; only patients with moderate as required by the study’s inclusion criteria. 734 671 stable atopic dermatitis who were aged 14 y were included. 735 672 One hundred patients were treatedUNCORRECTED with oral borage oil 1500 mg Around one-third of patients treated with borage oil did not 736 673 twice daily (GLA z 690 mg/d) or placebo (bland miglyol oil) for have the expected increase in erythrocyte DGLA levels in this 737 674 24 wk. latter study [36]. While this could indicate noncompliance, it also 738 675 Only one study compared borage oil to another potential suggests that in some patients the GLA in borage oil is not 739 676 treatment for atopic dermatitis. Oral borage oil and evening appropriately absorbed or is not converted into DGLA. 740 677 primrose oil were compared at equivalent GLA dosages in a very Studies including young children [38,49,50,55] do not 741 678 small study (10 patients per group) [51]. However, the results are support the suggestion that treatment with borage oil at an 742 679 brought into question because there was no placebo arm. The earlier age before immunological hypersensitivity becomes fully 743 680 response rates of 90–100% that were reported for the two established would be more successful [7]. Borage oil was not 744 681 treatments appear to be unrealistic when compared to results more effective in children than in adults in the large Takwale 745

R. H. Foster et al. / Nutrition xxx (2010) 1–11 7

746 Q6 810 y ) 747 811 - , , , - -- , ------748 , 812 749 813 750 814 751 815 752 816 continued on next page (

753 Bo 817 754 k 818 755 819 756 820 757 821 758 822 759 823 with PL but not Bo.pts However, did 10 better with Bo(Costa than score/patient PL ratings) PL (ADASI) skin condition with PL thanBo with (SCORAD) than those with PL (SASSAD score, symptoms, CS use) groups in CS requirement or clinical response rate. improved all symptoms except pruritus. Significant benefit in subgroup of pts with adequate absorption and compliance (Costa) recipients and 10/10 EPo recipients (ADASI) improvement between Bo- and control-treated sides (Physician/ patient ratings) (43%) pts improved (ADASI) severity, response, area of involvement, and individual symptoms. PL: no significant improvement (Physician rating scales) oozing, itching, and vesicle formation but not scaling compared with PL (Physician/ patient ratings) 760 PL 824 Significant improvement overall Greater improvement in QOL and Improvements with Bo not better No significant difference between Results No significant difference in Main findings (scale) Rating Bo: significantly improved overall Bo: 5/7 pts significantly improved PL: 3/5 worsened (ADASI) Bo significantly reduced erythema, 761 Similar improvement with Bo and 825 762 826 763 827 764 828 765 829 7) AD

766 ¼ 830 4), moderate

767 ¼ 831 768 832 769 833

770 2 y with outpatient- 834 >

771 PROOF20), or severe (n 835 772 ¼ 836 AD outpatient-treated AD requiring CS or other symptomatic treatment treated AD (2-14 y) with subacute oroutpatient-treated chronic AD affecting the extremities symmetrically. Severe disease requiring CS excluded (15–38 y). Mild (n severity levels outpatient-treated AD (n with active lesions moderate AD Adults 18–61 y with mild-mod AD Signiﬁcantly more Bo (78%) than PL Patient population 773 presumed allergic origin 837 774 838 775 839 776 840 777 xx 841 151 Pts aged 20 Adults 18–53 y with AD Signiﬁcant improvement in 9/10 Bo 100 67 adults (17-70 y) and 33 children No. patients 778 842 779 843 780 844

781 {{ 845 782 846 783 847 784 848 785 849 786 850 OliveAdults: liq parafﬁn Children: olive oil 20 Young children (7–48 mo) with (GLA 120 mg/10 kg bw) Liq parafﬁn 31 18 children (2–14 y) and 13 adults 787 851 788 852 789 853 12 wk Miglyol 39 Children 1–12 y with AD Similar improvement with Bo and

790 12 wk EPo 854 12 wk NR 60 Younger adults (15–30 y) with 791 855 yy 60 792 4 wk Contralateral side 856 793 857 8 wk Liq parafﬁn 24 Pts aged 12–27 y with AD of 24 wk Miglyol 160 Aged 14–65 y with stable 3 mo Palm kernel 12 Adults 20–48 y with AD of different 12 wk Palm kernel10–14 wk 50 Maize (corn) seed 24 [co] Children 3–17 y with symptomatic

794 ) 858 x ) ) 14 wk 12 wk 795 z { 859 80 drops (548)

796 860 12 wk (GLA) mg/d Control oil * drops 797 (240)] 861 Bo 3000 (690 4000 (920) [ped 2000 (460)] Bo liq (GLA 16.5%) 2500 (400) [ped 1500 Regimen 4000 (1000 2000 (480) 3000 (720 1800 (360) 1000–2000 (240–480) 500 (125) mg/10 kg bw Bo cream 10% bid 798 Bo liq 862 799 863 800 864 yy 801 UNCORRECTEDyy 865 [51] zz yy 802 yy 866 yy [54] [53] [55] [50] 803 [37] 867 [52] [36] [49] 804 [38] 868

805 [20] 869 806 870 807 871 808 872 Study Henz et al. 1999 Don et al. 2003 Takwale et al. 2003 Oral borage oil versus eveningMelnik primrose & oil Bahmer (EPo) 1995 treatment Valsecchi et al. 1996 Placebo-controlled studies of oral borageLandi oil 1993 treatment (ordered by efﬁcacy rating) Topical borage oil treatment Borelli et al. 1994 Andreassi et al. 1997 Buslau et al. 1996 Borrek et al. 1997 Bahmer et al. 1992 [47,48] Kiehl et al. 1994

809 Table 4 Overview of efﬁcacy trials of borage oil (Bo) in atopic dermatitis (AD) 873

8 R. H. Foster et al. / Nutrition xxx (2010) 1–11

874 Q6 Q6 et al. trial [55]. Importantly, supplementation with borage oil 938 y 875 from 2 wk of age did not prevent development of atopic 939

876 - dermatitis in neonates at high risk (see Preventive use) [46]. 940 877 It is unclear whether the effect of borage oil differs 941 878 depending on whether or not there is an allergic IgE-mediated 942 879 basis to the patient’s atopic dermatitis. Borage oil had a signif- 943 880 icant effect in the one study that included only patients with 944 881 atopic dermatitis of presumed allergic basis, but this study was 945 882 small and had other methodological limitations [20]. The effect 946 883 of borage oil on IgE levels was inconsistent, with decreases [36], 947 884 increases [46], and no signiﬁcant changes [37,49,53] reported. 948 885 From the EFA cascade, it seems likely that EFA supplemen- 949 886 tation targets the inﬂammatory aspects of atopic dermatitis and 950 887 would therefore be expected to be most effective in patients 951

888 of AD. Trend (NS) toward reduction in severity of symptoms with Bo vs PL (SCORAD) with active inflammation [13]. However, borage oil did not 952 Main findings (scale) Rating Results 889 Bo did not prevent development provide a significant benefit in the studies involving only 953 890 patients with active lesions or symptomatic disease [50,53]. 954 il 446 mg (PL control) with vitamin C and E. Neonates were 891 ut Bo. The efficacy of borage oil according to severity of disease has 955 892 not been clearly reported and many patient populations were 956 893 heterogeneous. However, it seems unlikely that the oil is 957 894 effective in patients with severe disease. Borage oil was not 958

895 primrose oil; GLA, gamma-linolenic acid; liq, oral liquid; mo, months; mod, significantly effective in five of the six studies in outpatients or 959 896 patient; QOL, quality of life; SASSAD, six area, six sign, atopic dermatitis score; studies that specified that patients with severe disease were 960 897 included [38,50,52–55]. Patients with atopic dermatitis pre- 961 898 senting to an outpatient clinic may represent a more severe or 962 899 poorly responsivePROOF population than those treated in primary 963 900 care. 964 atopic mothers and at high risk for AD

901 Patient population 965 902 966 Response according to duration of treatment and dosage 903 967 904 968 The effects of GLA supplementation take up to 8 wk to 905 969 No. patients become fully evident [42]. Immediate responses would not be 906 970

). expected because adequate time is required for the normal fatty 907 971 acid balance in skin cells to be restored. The effects of borage oil 908 972 have been mainly studied over 12–24 wk of treatment. Little is 909 973 known about its efﬁcacy or tolerability beyond this timeframe. 910 974

, some efficacy parameters significantly improved but interpretation of results limited by mixed findings and/or poor study design; The only data on long-term efficacy come from five patients 911 975 who continued long-term open treatment (duration not stated)

912 -- 976 after completing double-blind treatment in one study [20]. 913 977 Beneﬁcial effects were reported to be maintained but no 914 978 speciﬁc data were provided. 915 3 y). 979 The dosage of oral borage oil capsules used in the studies of 916 980 treatment of atopic dermatitis varied from 2000 to 4000 mg/ 917 981 d (400–1000 mg GLA) in adults and young people and 1000 to 918 982 2000 mg/d (240–480 mg GLA) in children. No study provided 919 983 , no improvement. a rationale for the dose used. The GLA content of the borage oil 920 , 984 was normally 20–25%, although two studies [38,53] used 921 985

6 mo Sunflower 121 Neonates aged 7–14 d born to a borage oil with only around 16% GLA. Efficacy did not appear 922 4 y) or 240 mg/d (age 986 to be related to dose, and no significant effect of borage oil was 923 ** 987 found in the large study of high-dose borage oil (920 mg/d GLA) 924 988

(GLA) mg/d Control oil [55].

925 * 989

926 Regimen Bo 446 (103) 990 927 Preventive use 991 928 UNCORRECTED, most or all efﬁcacy parameters signiﬁcantly improved; 992 929 Atopic dermatitis develops early in infancy and EFA abnor- 993

930 --- malities in the umbilical cord blood of neonates preceding 994 [46] ) 931 4 wk and then 360 mg/d (age development of atopic dermatitis have been reported [10].To 995 932 investigate borage oil as a preventive measure, 121 neonates at 996 933 high risk of atopic dermatitis who were born to mothers with 997 continued

934 ( a history of atopy were formula fed and randomized to receive 998 935 a daily supplement powder containing either borage oil 446 mg 999

936 Oral capsules unless otherwise stated. Efficacy rating scale: GLA content not stated. BoEstimation stated based to on be description Glandol, ofGLA which GLA content is content not advertised being stated. to 17.6%/70. BasedPrimary contain on endpoint: 120 a mg cumulative minimum GLA amount 23% per ofThe of 500 CS intervention GLA mg was cream content Bo a used daily in capsule. until supplement Bo, response powder as (50% containing stated fish reduction gelatin in in 135 theGLA Costa mg, paper. 480 score maltodextrin mg/d 397 mg, silicicForeign acid language; 21 mg, papers and were either notOnly Bo fully 446 32 mg translated of or so the sunflower not 50 o For all patients each details were patient, are evaluable. one available. side was treated with urea-based emollient cream containing Bo and the(GLA other side was treated with the same emollient cream witho 103 mg) or sunflower oil 446 mg (placebo control) for the 1000 , improvement observed but not statistically significant; y z x Table 4 Oral borage oil for preventionVan of Gool AD et al. 2003 Study * k { yy zz xx ** {{ also formula-fed from age 2 wk with standard formula not containing GLA or other long-chain polyunsaturated fatty acids. - 937 ADASI, Atopic Dermatitis Area and Severitymoderate; no., Index; number; bid, NR, twice not daily; reported; Bo, NS,SCORAD, borage not Scoring statistically oil; Atopic significant; bw, ped, Dermatitis bodyweight; pediatric co, index; dosage crossover; given wk, CS, to weeks; the corticosteroid; y, children EPo, in years. evening the study; PL, placebo; pt, first 6 months of life (details provided in Table 4) [46]. 1001

R. H. Foster et al. / Nutrition xxx (2010) 1–11 9

1002 Supplementation with borage oil did not prevent the devel- they could not exclude the possibility that a small beneficial 1066 1003 opment of atopic dermatitis, which was diagnosed at 1 y of age in effect is achieved [13]. Similarly, the large, well-designed study 1067 1004 38% of borage oil recipients and 48% of placebo recipients [46]. by Takwale et al. [55] did not find borage oil to be significantly 1068 1005 However, there was a trend toward the severity of symptoms effective, but these authors also commented that they could not 1069 1006 being reduced in the borage oil group. This led the authors to exclude a small benefit, at most in the region of a two-point 1070 1007 conclude that GLA supplementation influenced the inflamma- improvement in six area, six sign atopic dermatitis score. 1071 1008 tory but not the IgE-mediated components of atopic dermatitis. It is not clear why results with borage oil have been so vari- 1072 1009 able. The available clinical studies have not identified any clear 1073 1010 Tolerability patterns in response according to age, presence of active lesions, 1074 1011 or IgE levels. Efficacy of borage oil does appear to require 1075 1012 The short-term tolerability of borage oil is good. Studies adequate intestinal uptake of GLA, appropriate metabolism, and 1076 1013 reported that either no adverse effects occurred or that adverse incorporation of the EFAs into phospholipids [36,46]. It seems 1077 1014 effects occurred with similar frequency with borage oil and probable that borage oil will be more effective in mild-to- 1078 1015 placebo oil (liquid paraffin, olive oil, miglyol, or sunflower oil) moderate atopic dermatitis rather than more severe cases. Other 1079 1016 [20,36,38,46,54,55]. Clinical laboratory parameters were not potential factors affecting response have not been investigated. 1080 1017 adversely affected by borage oil administration. 1081 1018 There are no data on the long-term tolerability of borage oil. Role of borage oil in the treatment of atopic dermatitis 1082 1019 Excessive intake of polyunsaturated fatty acids is not recom- 1083 1020 mended; intake from all sources should not exceed >10% of total Current guidelines for atopic dermatitis do not support the 1084 1021 dietary energy intake [59]. use of borage oil or other EFA supplementation because efficacy 1085 1022 has not been clearly demonstrated [15]. Importantly, borage oil 1086 1023 Discussion has not been compared to any of the established treatments for 1087 1024 atopic dermatitis. Any role of borage oil would be as a mainte- 1088 1025 The mainstay of treatment of atopic dermatitis is the use of nance treatment, along with continued emollient use, to control 1089 1026 emollients and avoiding aggravating factors, but acute exacer- the dermatitis and prevent flare-ups in mild-to-moderate 1090 1027 bations can require treatment with topical corticosteroids or disease. BoragePROOF oil is not expected to be of any significant value in 1091 1028 possibly other immunomodulators [2,6,15]. As outlined in Table the treatment of acute exacerbations or severe disease, where 1092 1029 1, existing treatment options have various limitations, including use of topical corticosteroids or other immunodulators is 1093 1030 significant adverse effects. recommended. 1094 1031 There is a proposed pathophysiological basis to support the Borage oil is not a proven or widely recognized treatment for 1095 1032 concept of u-6 EFA supplementation in the treatment of atopic atopic dermatitis. However, when a patient specifically expresses 1096 1033 dermatitis. EFAs play a vital role in skin structure and physiology; interest in a more natural treatment approach rather than use of 1097 1034 EFA deficiency replicates the symptoms of atopic dermatitis, and the established conventional treatments for atopic dermatitis, an 1098 1035 EFA imbalances have been reported in the blood of patients with 8- to 12-wk trial of nutritional supplementation with borage oil 1099 1036 atopic dermatitis [7–9]. However, to date, studies of EFA can be suggested along with continued use of emollients, 1100 1037 supplementation in atopic dermatitis have produced conflicting provided disease is not severe. The patient should be given 1101 1038 results, and the data for evening primrose oil have been sur- a realistic expectation of the relatively small benefit that can be 1102 1039 rounded by controversy [2,13,42,43,57]. The evening primrose oil expected with borage oil. Patients who perceive that borage oil is 1103 1040 Q4 product Epogam was initially licensed for use in atopic derma- beneficial may wish to continue the supplement but should be 1104 1041 titis in a number of countries. The product license for Epogam aware that it is not yet known whether efficacy is maintained or 1105 1042 was withdrawn in the UK in 2002 after a review by the UK whether there are any health risks over the long term. Dosages 1106 1043 Medicines Control Agency and Committee on Safety of Medicines used should not exceed those tested in clinical trials (1-2 g/d for 1107 1044 concluded that there was insufficient evidence that these prod- children and 2-4 g/d for adults). If any worsening of disease is 1108 1045 ucts reached the necessary standard of efficacy for them to be seen, treatment with borage oil should be discontinued. 1109 1046 licensed as medicines [43,57]. The greatest advantage of borage oil is its apparent good 1110 1047 It was proposed that borage oil could be more effective than tolerability, which may appeal to people who are concerned 1111 1048 evening primrose oil because of its much higher GLA content. about the adverse effects of corticosteroids. Topical corticoste- 1112 1049 However, as with evening primrose oil, this review shows that roids cause cutaneous and potentially, in rare circumstances, 1113 1050 borage oil does not meet rigorous standards for evidence-based serious systemic adverse effects [2,15]. As many as three-quar- 1114 1051 efficacy, even when given in high doses. Nevertheless, the ters of patients, or parents of young patients, with atopic 1115 1052 majority of studies of borage oil in atopic dermatitis have shown dermatitis express concerns about the adverse effects of topical 1116 1053 at least a small degree of efficacy, have found a benefit in corticosteroids [58]. One of the most important questions that 1117 1054 a subgroup of patients, or have not been able to exclude the remain to be answered is whether borage oil is corticosteroid- 1118 1055 possibility that the oil produces a small benefit. This is consistent sparing (see Directions for further research). 1119 1056 with findings from a well-performedUNCORRECTED meta-analysis of EFA 1120 1057 supplementation in atopic dermatitis [13]. Combining results for Directions for further research 1121 1058 evening primrose, borage oil, and blackcurrant oil, the overall 1122 1059 treatment effect for GLA supplementation (0.15 [range 0.25 to Although it has been proposed that disturbance in EFA 1123 1060 1.43]) was described as small and probably not clinically metabolism is an important factor in the pathogenesis of atopic 1124 1061 important, i.e., equivalent to a 1.5 reduction in Costa score values dermatitis [7,8], this concept is not universally accepted and 1125 1062 or about a 5% reduction in severity. For the four trials of borage remains controversial [57,60,61]. This review is not intended to 1126 1063 oil for which an effect size could be calculated in the meta- contribute to this debate, but rather to provide a balanced 1127 1064 analysis, the effect size ranged from 0.25 to 0.53. Although summary of the available data on borage oil in atopic dermatitis 1128 1065 a large clinical benefit could be excluded, the authors stated that to establish its clinical utility. Nevertheless, the question remains 1129

10 R. H. Foster et al. / Nutrition xxx (2010) 1–11

1130 as to why GLA supplementation with either borage oil or evening least a small degree of efficacy or were not able to exclude the 1194 1131 primrose oil is not highly effective if disturbance in EFA metab- possibility that the oil produces a small benefit. 1195 1132 olism does play a key role in atopic dermatitis. The most likely Thus, while borage oil is unlikely to have a highly significant 1196 1133 answer is that atopic dermatitis is multifactorial. Factors other clinical effect, it is possible that it will be therapeutically useful in 1197 1134 than deficiency of GLA may also affect the balance of prosta- some individual patients with less severe atopic dermatitis. 1198 1135 glandin production, and other pathophysiological factors may be Where patients, or parents of young patients, express a desire to 1199 1136 more important than such imbalances. Unfortunately, the val- try a more natural treatment approach, a 2- to 3-mo trial of 1200 1137 idity of some of the foundation research in this area has been borage oil can be suggested and the response monitored. If future 1201 1138 potentially compromised by commercial interests [60,61]. Any research can establish which patients are more likely to respond 1202 1139 further research into the use of GLA supplementation will be of to borage oil, its clinical utility may be increased. 1203 1140 limited value until direct proof of the role of GLA deficiency in We are still left with the fundamental question of what role EFA 1204 1141 atopic dermatitis can be established. metabolism plays in atopic dermatitis, and why attempts at GLA 1205 1142 Nevertheless, in the context of the existing clinical data on supplementation have not been as successful as would be expec- 1206 1143 borage oil, there are some important issues that have not yet ted if proposed EFA-mediated pathophysiological mechanisms are 1207 1144 been adequately explored. Perhaps the most important of these central to atopic dermatitis. 1208 1145 is whether borage oil is corticosteroid-sparing. Current data are 1209 1146 inconsistent [20,36,38,55] and further clarification is needed. Acknowledgments 1210 1147 Furthermore, how borage oil will interact with topical cortico- 1211 1148 steroids needs to be better understood [42]. Corticosteroids Rachel Foster was employed at the School of Pharmacy, 1212 1149 interfere with metabolism of DGLA to arachidonic acid and University of Auckland, when this work was initiated and now 1213 1150 prevent arachidonic acid being released from membranes and works on a freelance basis. Rachel Foster contributed to the 1214 1151 producing pro-inflammatory eicosanoids. However, corticoste- conception of the review, identification and collection of relevant 1215 1152 roids also block the release of DGLA, impeding production of its literature, drafting and revision of the manuscript, and approval 1216 1153 anti-inflammatory metabolites PGE1 and 15-HETrE. This may of the final version of the manuscript. Gil Hardy contributed to 1217 1154 counteract the effects of borage oil because the ability to increase the revisionPROOF of the manuscript, selection of target journal, and 1218 1155 PGE1 and 15-HETrE levels is thought to be key to the actions of approval of the final version of the manuscript. Raid Alany 1219 1156 borage oil in atopic dermatitis [35,40]. contributed to the conception of the review, collection of 1220 1157 Current data raise the possibility that some patients will relevant literature, revision of the manuscript, and approval of 1221 1158 respond to borage oil while others will not. Further research is the final version of the manuscript. 1222 1159 required to establish if this is the case, and what the possible 1223 1160 reasons are for this variability in response. One of the key References 1224 1161 questions to address is how patients who are most likely to 1225 1162 respond to borage oil can be identified. 1 The Merck Manuals Online Medical Library for Healthcare Professionals. 1226 Available online from http://www.merck.com/mmpe/index.html. Accessed 1 1163 It would also be of interest to determine whether combining December 2007. 1227 1164 borage oil with an u-3 oil would be more effective than borage 2 Hoare C, Wan Li, Po A, Williams H. Systematic review of treatments of atopic 1228 1165 oil alone in atopic dermatitis. Borage oil supplies only u-6 EFAs. eczema. Health Technol Assess(37):1–191, http://www.ncchta.org/fullmono/ 1229 1166 mon437.pdf, 2000;4. Available online from Accessed 1 February 2008. 1230 However, u-3 EFAs also have some role in skin health, and the 3 Leung DY, Jain N, Leo HL. New concepts in the pathogenesis of atopic 1167 u-3 EFA-derived eicosanoids are involved in inflammatory dermatitis. Curr Opin Immunol 2003;15(6):634–8. 1231 1168 responses [16–19]. The u-3 series EFAs such as EPA and doco- 4 Lacey RW, Lord VL. Sensitivity of staphylococci to fatty acids: novel inacti- 1232 1169 sahexaenoic acid are found primarily in fish and fish oils, but also vation of linolenic acid by serum. J Med Microbiol 1981;14(1):41–9. 1233 5 Bibel DJ, Miller SJ, Brown BE, Pandey BB, Elias PM, Shinefield HR, et al. 1170 some plant oils (mainly as alpha-linolenic acid). The u-3 and the Antimicrobial activity of stratum corneum lipids from normal and essential 1234 1171 u-6 EFAs compete for metabolism by the same rate-limiting fatty acid-deficient mice. J Invest Dermatol 1989;92(4):632–8. 1235 1172 desaturation enzymes, and combining them further shifts the 6 Primary Care Dermatology Society and British Association of Dermatologists. 1236 Guidelines for the management of atopic eczema (2005). Available online 1173 balance away from production of arachidonic acid–derived pro- from: http://www.bad.org.uk/healthcare/guidelines/PCDSBAD-Eczema.pdf. 1237 1174 inflammatory eicosanoids toward less inflammatory products Accessed 11 February 2008. 1238 1175 [16,19]. 7 Horrobin DF. Essential fatty acid metabolism and its modification in atopic 1239 eczema. Am J Clin Nutr 2000;71(suppl 1). 367S-72S. 1176 8 Wright S. Essential fatty acids and the skin. Br J Dermatol 1991;125(6):503– 1240 1177 Conclusions 15. 1241 1178 9 Manku MS, Horrobin DF, Morse N, Kyte V, Jenkins K, Wright S, et al. Reduced 1242 levels of prostaglandin precursors in the blood of atopic patients: defective 1179 The current review identified 11 clinical trials of oral borage delta-6-desaturase function as a biochemical basis for atopy. Prostaglandins 1243 1180 oil and one trial of topical borage oil for the treatment of atopic Leukot Med 1982;9:615–28. 1244 1181 dermatitis, and a further trial of borage oil for prevention of 10 Galli E, Picardo M, Chini L, Passi S, Moschese V, Terminali O, et al. Analysis of 1245 1182 polyunsaturated fatty acids in newborn sera: a screening tool for atopic 1246 atopic dermatitis in at-risk neonates. Although controlled and disease? Br J Dermatol 1994;130:752–6. 1183 usually double-blind and randomized, many of the studies had 11 Barre DE. Potential of evening primrose, borage, black currant, and fungal 1247 1184 significant methodological limitations particularly in regards to oils in human health. Ann Nutr Metab 2001;45(2):47–57. 1248 UNCORRECTED12 Gunstone FD. Gamma linolenic aciddoccurrence and physical and chemical 1185 small patient numbers and heterogeneous and poorly defined 1249 properties. Prog Lipid Res 1992;31(2):145–61. 1186 patient populations. Possibly in part as a consequence of this, 13 Van Gool CJ, Zeegers MP, Thijs C. Oral essential fatty acid supplementation in 1250 1187 results of the clinical trials of borage oil were highly variable. atopic dermatitisda meta-analysis of placebo-controlled trials. Br J Dermatol 1251 1188 Borage oil was reported to be effective for the treatment of 2004;150(4):728–40. 1252 14 Horrobin DF. Nutritional and medical importance of gamma-linolenic acid. 1189 atopic dermatitis in five studies, while another five studies found Prog Lipid Res 1992;31(2):163–94. 1253 1190 it to be ineffective. In the remaining two studies, a response to 15 Hanifin JM, Cooper KD, Ho VC, Kang S, Krafchik BR, Margolis DJ, et al. Guidelines 1254 1191 borage oil was seen in only some patients. Borage oil was not of care for atopic dermatitis. J Am Acad Dermatol 2004;50(3):391–404. 1255 16 Ziboh VA, Miller CC, Cho Y. Metabolism of polyunsaturated fatty acids by skin 1192 effective in preventing development of atopic dermatitis in epidermal enzymes: generation of antiinflammatory and antiproliferative 1256 1193 a neonatal study. However, the majority of studies showed at metabolites. Am J Clin Nutr 2000;71(suppl 1). 361S-6S. 1257

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1258 17 Connor WE. Importance of n3 fatty acids in health and disease. Am J Clin 41 Tollesson A, Frithz A. Borage oil, an effective new treatment for infantile 1313 1259 Nutr 2000;71(suppl). 171S-5. seborrhoeic dermatitis. Br J Dermatol 1993;129(1):95. 1314 18 Roland I, de Leval X, Evrard B, Pirotte B, Dogne´ JM, Delattre L, et al. Modu- 42 Morse NL, Clough PM. A meta-analysis of randomized, placebo-controlled 1260 lation of the arachidonic cascade with omega3 fatty acids or analogues: clinical trials of Efamol evening primrose oil in atopic eczema. Where do we 1315 1261 potential therapeutic benefits. Mini Rev Med Chem 2004;4(6):659–68. go from here in light of more recent discoveries? Curr Pharm Biotechnol 1316 1262 19 James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and 2006;7(6):503–24. 1317 inflammatory mediator production. Am J Clin Nutr 2000;71(suppl). 343S-8. 43 Morse PF, Horrobin DF, Manku MS, et al. Meta-analysis of placebo-controlled 1263 20 Landi G. Oral administration of borago oil in atopic dermatitis. J Appl studies of the efficacy of Epogam in the treatment of atopic eczema. Rela- 1318 1264 Cosmetology 1993;11(4):115–20. tionship between plasma essential fatty acid changes and clinical response. 1319 1265 21 Chapkin RS, Ziboh VA, Marcelo CL, et al. Metabolism of essential fatty acids Br J Dermatol 1989;121:75–90. 1320 by human epidermal enzyme preparations: evidence of chain elongation. 44 Ziboh VA, Fletcher MP. Dose-response effects of dietary gamma-linolenic 1266 1321 Q5 J Lipid Res 1986;27(9):945–54. acid-enriched oils on human polymorphonuclear-neutrophil biosynthesis of 1267 22 Elias PM, Brown BE, Ziboh VA. The permeability barrier in essential fatty acid leukotriene B4. Am J Clin Nutr 1992;55(1):39–45. 1322 1268 deficiency: evidence for a direct role for linoleic acid in barrier function. 45 Fletcher MP, Ziboh VA. Effects of dietary supplementation with eicosa- 1323 1269 J Invest Dermatol 1980;74(4):230–3. pentaenoic acid or gamma-linolenic acid on neutrophil phospholipid 1324 23 Wright S, Bolton C. Breast milk fatty acids in mothers of children with atopic fatty acid composition and activation responses. Inflammation 1270 eczema. Br J Nutr 1989;62(3):693–7. 1990;14(5):585–97. 1325 1271 24 Businco L, Ioppi M, Morse NL, Nisini R, Wright S. Breast milk from mothers of 46 van Gool CJ, Thijs C, Henquet CJ, et al. Gamma-linolenic acid supplementa- 1326 d 1272 children with newly developed atopic eczema has low levels of long chain tion for prophylaxis of atopic dermatitis a randomized controlled trial in 1327 polyunsaturated fatty acids. J Allergy Clin Immunol 1993;91(6):1134–9. infants at high familial risk. Am J Clin Nutr 2003;77(4):943–51. 1273 25 Wright S, Sanders TA. Adipose tissue essential fatty acid composition in 47 Bahmer FA, Schafer J. Die Behandlung der atopischen Dermatitis mit Bor- 1328 1274 patients with atopic eczema. Eur J Clin Nutr 1991;45(10):501–5. retschsamen-Ol (Glandol)deine zeitreihenanalytische Studie [Treatment of 1329 d 1275 26 Lindskov R, Holmer G. Polyunsaturated fatty acids in plasma, red blood cells atopic dermatitis with borage seed oil (Glandol) a time series analytic 1330 and mononuclear cell phospholipids of patients with atopic dermatitis. study] (German). Kinderarztl Prax 1992;60(7):199–202. 1276 Allergy 1992;47:517–21. 48 Bahmer FA, Schafer J. Die behandlung der atopischen dermatitis mit bor- 1331 1277 27 Oliwiecki S, Burton JL, Elles K, et al. Levels of essential and other fatty acids in retschsamenol (glandol) deine zeitreihenanalytische studie [Treatment of 1332 1278 plasma and cell phospholipids from normal controls and patients with atopic dermatitis with borage oil (Glandol) dA time series analysis study] 1333 atopic eczema. Acta Derm Venereol 1991;71:224–8. (German). Aktuelle Derm 1992;18(3):85–8. 1279 28 Shimasaki H. PUFA content and effect of dietary intake of gamma-linolenic 49 Kiehl R, Ionescu G, Manuel P, et al. Klinische, immun- und lip- 1334 1280 acid-rich oil on profiles of n-6, n-3 metabolites in plasma of children with idmodulatorische effekte einer behandlung mit ungesattigten fettsauren bei 1335 1281 atopic eczema. J Clin Biochem Nutr 1995;19(3):183–92. atopischer dermatitis [Clinical, immuno- and lipid modulating effects of 1336 29 Strannegård IL, Svennerholm L, Strannegård O. Essential fatty acids in serum unsaturated fatty acids in patients with atopic eczema] (German). Z Hautkr 1282 lecithin of children with atopic dermatitis and in umbilical cord serum of 1994;69(1):42–8. 1337 1283 infants with high or low IgE levels. Int Arch Allergy Appl Immunol 50 Forster J. Gammalinolensaure-reichePROOF Borretschsamenol-Kapseln bei Kindern 1338 1284 1987;82(3–4):422–3. mit Atopischer Dermatitis. Eine placebo-kontrollierte Doppelblind-Studie 1339 1285 30 Manku MS, Horrobin DF, Morse NL, Wright S, Burton JL. Essential fatty acids [Gamma-linolenic-acid-rich borage seeBorrek S, Hildebrandt A, d oil 1340 in the plasma phospholipids of patients with atopic eczema. Br J Dermatol capsules in children with atopic dermatitis. A placebo-controlled double- 1286 1984;110(6):643–8. blind study] (German). Klin Padiatr 1997;209(3):100–4. 1341 1287 31 Sakai K, Ueno K, Ogawa Y, Okuyama H. Fatty acid composition of plasma 51 Melnik BC, Bahmer FA. Die behandlung des atopischen ekzems mit glan- 1342 d 1288 lipids in young atopic patients. Chem Pharm Bull 1986;34:2944–9. dol(tm) und epoleum(tm) eine vergleichende studie. [Treatment of atopic 1343 32 Tollesson A, Frithz A. Transepidermal water loss and water content in the dermatitis with GlandolÔ and EpoleumÔda comparative study] (German). 1289 stratum corneum in infantile seborrhoeic dermatitis. Acta Derm Venereol Aktuelle Derm 1995;21(7):215–9. 1344 1290 1993;73(1):18–20. 52 Borelli S, Bresser H, Belsan I. Externe therapie mit gamma-linolensaur- 1345 d 1291 33 Hansen HS, Jensen B. Essential function of linoleic acid esterified in acylgluco- e ergebnis einer doppelblindstudie [External therapy with gamma-linolenic 1346 sylceramide and acylceramide in maintaining the epidermal water permeability aciddresults of a double-blind study] (German). Z Hautkr 1994;69(8):523–4. 1292 barrier. Evidence from feeding studies with oleate, linoleate, arachidonate, 53 Valsecchi R, Di Lnadro A, Pansera B, et al. Gammalinolenic acid in the 1347 1293 columbinate and a-linolate. Biochim Biophys Acta 1985;834:357–63. treatment of atopic dermatitis [letter]. J Eur Acad Dermatol Venereol 1348 1294 34 Brosche T, Platt D. Effect of borage oil consumption on fatty acid metabolism, 1996;7(1):77–9. 1349 transepidermal water loss and skin parameters in elderly people. Arch 54 Andreassi M, Forleo P, Di Lorio A, et al. Efficacy of gamma-linolenic acid in 1295 Gerontol Geriatr 2000;30(2):139–50. the treatment of patients with atopic dermatitis. J Int Med Res 1350 1296 35 Miller CC, Ziboh VA. Gammalinolenic acid-enriched diet alters cutaneous 1997;25(5):266–74. 1351 1297 eicosanoids. Biochem Biophys Res Commun 1988;154(3):967–74. 55 Takwale A, Tan E, Agarwal S, Barclay G, et al. Efficacy and tolerability of 1352 36 Henz BM, Jablonska S, van de Kerkhof PC, Stingl G, Blaszczyk M, borage oil in adults and children with atopic eczema: randomised, double 1298 Vandervalk PGM, et al. Double-blind, multicentre analysis of the efficacy of blind, placebo controlled, parallel group trial. BMJ 2003;327(7428):1385–8. 1353 1299 borage oil in patients with atopic eczema [see comment]. Br J Dermatol 56 Kanehara S, Ohtani T, Uede K, Furukawa F. Clinical effects of undershirts 1354 1300 1999;140(4):685–8. coated with borage oil on children with atopic dermatitis: a double-blind, 1355 1301 37 Buslau M, Thaci D. Atopische dermatitis: Borretschol zur systemischen placebo-controlled clinical trial. J Dermatol 2007;34(12):811–5. 1356 therapie [Atopic dermatitis: Borage oil for systemic therapy]. (German) 57 Williams HC. Evening primrose oil for atopic dermatitis: time to say good- 1302 Zeitschrift Dermatol 1996;182(3):131–6. night. BMJ 2003;327:1358–9. 1357 1303 38 Don M, Melli P, Braida F, Comici A, Barbi F, Spano C, et al. Efficacy of essential 58 Charman CR, Morris AD, Williams HC. Topical corticosteroid phobia in 1358 1304 fatty acids in the treatment of atopic dermatitis and correlations of their patients with atopic eczema. Br J Dermatol 2000;142(5):931–6. 1359 changes with clinical response. Ital J Pediatr 2003;29(6):427–32. 59 Eritsland J. Safety considerations of polyunsaturated fatty acids. Am J Clin 1305 39 Miller CC, Ziboh VA, Wong T, Fletcher MP. Dietary supplementation with oils Nutr 2000;71(suppl):197S–201. 1360 1306 rich in (n-3) and (n-6) fatty acids influences in vivo levels of epidermal 60 Richmond C. Obituaries: David Horrobin. BMJ 2003;326:885. 1361 1307 lipoxygenase products in guinea pigs. J Nutr 1990;120(1):36–44. 61 Barrett S. Primrose oil and eczema: how research was promoted and suppressed. 1362 40 Miller CC, Tang W, Ziboh VA, Fletcher MP. Dietary supplementation with Available online from: http://www.quackwatch.org/01QuackeryRelatedTopics/ 1308 ethyl ester concentrates of fish oil (n-3) and borage oil (n-6) polyunsaturated DSH/epo.html (Accessed March 1, 2008). 1363 1309 fatty acids induces epidermal generation of local putative anti-inflammatory 62 Scher JU, Pillinger MH. The anti-inflammatory effects of prostaglandins. 1364 1310 metabolites. J Invest Dermatol 1991;96(1):98–103. J Invest Med 2009;57(6):703–8. 1365 1311 1366 1312 UNCORRECTED 1367

Please cite this article in press as: Foster RH, et al., A review of borage oil in the treatment of atopic dermatitis, Nutrition (2010), doi:10.1016/j.nut.2009.10.014