EPA for Remission of Autoimmune Small-Vessel Vasculitis
This article at a glance 
Vasculitis refers to inflammation of the vasculature, and is composed of an array of manifestations that can be caused by infections and by autoimmune reactions. A classification of the various types of vasculitis that is suitable for clinical diagnosis has proven difficult to achieve given the different types and overlapping manifestations, and is still in development. In several forms of autoimmune vasculitis, antibodies are present that are known to react with specific proteins located intracellularly within neutrophils. The antineutrophil-cytoplasmic-autoantibodies (ANCA)-auto-antibodies stimulate various arms of the immune system to amplify an inflammatory response that leads to extravascular granulomatous inflammation. ANCA-associated vasculitides (AAV) are relatively rare autoimmune disorders with an estimated incidence of 10 to 20 cases per million per year, affecting mostly elderly people. Treatment of AAV is based on the use of glucocorticoids, methotrexate, azathioprine, cyclophosphamide, and plasma exchanges, which allow the disease to present itself as a relapsing-remitting condition instead of a progressive and fatal inflammatory disorder. A major need for further improvements in the treatment of AAV, and auto-immune disease in general, exists given the marked side effects of currently available pharmacological approaches to control AAV. A recent anecdotal description of two cases has proposed the hypothesis that adding eicosapentaenoic acid (EPA) as an adjunct to drug treatment might contribute to control autoimmune disease. The case report by Hirahashi and colleagues from the Department of Nephrology and Endocrinology, University of Tokyo, and several other academic and private laboratories in Japan, reported on two patients. In the first clinical case, a 73-year old man diagnosed with microscopic polyangiitis, a type of autoimmune vasculitis affecting the capillaries, was treated daily with 1.8 g highly purified EPA and a low-dose aspirin in addition to methylprednisolone. The patient remained in remission for five years, during which his methylprednisolone dose was gradually lowered, and no other immunosuppressants were needed. During this period autoantibody titers remained low and he developed no deterioration typically associated with AAV, such as accelerated atherosclerosis or mineral bone disease resulting from chronic kidney disease. In the second clinical case, a 79-year old woman with necrotizing vasculitis of the small vessels of the kidney, high titers of autoantibodies, and elevated C-reactive protein, was placed on methylprednisolone therapy to induce remission and treated with 1.8 g/day highly purified EPA and low-dose aspirin. Methylprednisolone was gradually decreased and the patient maintained remission of AAV for more than five years without recurrence of adverse events. In both cases, after several weeks of induction of remission, the autoantibody titers and CRP levels in blood had decreased to a low level, and were shown to remain low for at least one year. 
The study next explored potential mechanisms by which EPA might affect remission using a mouse model for AAV. The SCG/Kj mice employed for this research spontaneously develop small-vessel vasculitis, produce autoantibodies against myeloperoxidase (a neutrophil protein) and develop glomerulonephritis that ultimately leads to renal failure after 2-3 months. Feeding the mice a diet containing 5% EPA led to a significantly increased life-span compared to mice eating a normal rodent diet or one supplemented with 5% corn oil. Measurement of tissue levels of PUFA showed that EPA levels were significantly increased in kidney, lung, spleen, and in plasma, whereas arachidonic acid (AA) levels had decreased. There was no change in DHA content. An exhaustive analysis of polyunsaturated fatty acid-derived lipid mediators in these tissues revealed the formation of the anti-inflammatory substances 18-HEPE, resolvin E2 and 17,18-EpETE, all formed from EPA, as well as marked decreases in several AA-derived eicosanoids that have been associated with inflammation. Appearance of blood in urine was nearly abolished in EPA-treated mice, and blood urea nitrogen levels and auto-antibody titers significantly decreased. No measurable effect on proteinuria or serum creatinine levels was found. The beneficial effects of EPA on the kidneys were confirmed by histological analysis showing reduced glomerulonephritis, and less endothelial cell damage in the glomeruli and peritubular capillaries. Analysis of lymph nodes of EPA-treated mice revealed lower numbers of mature T-cells and double negative (CD4-/CD8-) CD220+ T cells in draining lymph nodes, as well as an increased number of regulatory T cells that may play a role in counteracting the autoimmune response. 
The researchers initially appeared to have used EPA to treat dyslipidemia in the patients, and proposed that it might help normalize the inflammatory status of the patients and maintain remission. Redirecting the immune response with inhibition of auto-antibody formation, stimulation of regulatory T cells, and protection from neutrophil-mediated vascular damage by employing oral intake of highly purified EPA is an interesting approach to complement current treatment possibilities that should be evaluated. It needs to be pointed out that in addition to steroid treatment to control inflammation, the two patients also took low-dose aspirin. Aspirin has been reported to favor the formation of specific aspirin-triggered resolvins from EPA. In the animal study, merely supplementing with EPA was sufficient to induce beneficial effects on auto-immunity. However, the animal model mimics additional pathologies such as immune-complex mediated vascular pathology. The animal study has provided new insight into possible mechanisms whereby adding EPA to the treatment scheme might improve control over autoimmune disease. Much further research and in particular properly designed controlled trials will be necessary to explore potential effects. Although autoimmune small-vessel vasculitis is a relatively rare disorder, this research is important since there are common mechanisms that drive auto-immune disease. Omega-3 LCPUFA have been recently reported to play a role in the regulation of the adaptive immune response via control over antibody formation. Possibly autoimmune reactivity, when viewed as a disorder of self-tolerance leading to deregulated inflammatory responses, is another manifestation of select deficiencies in specific essential fatty acids and the mediators formed from these. Löfvenborg and colleagues at the Institute of Environmental Medicine at the Karolinska Institutet in Stockholm, Sweden, together with researchers from Uppsala University and Lund University in Sweden, and Helsinki University Hospital, Finland, reported an inverse relationship between omega-3 LCPUFA intake and the incidence of latent autoimmune diabetes in adults. Hirahashi J, Kawahata K, Arita M, Iwamoto R, Hishikawa K, Honda M, Hamasaki Y, Tanaka M, Okubo K, Kurosawa M, Takase O, Nakakuki M, Saiga K, Suzuki K, Kawachi S, Tojo A, Seki G, Marumo T, Hayashi M, Fujita T. Immunomodulation with eicosapentaenoic acid supports the treatment of autoimmune small-vessel vasculitis. Sci. Rep. 2014;4:6406. [PubMed] Löfvenborg JE, Andersson T, Carlsson PO, Dorkhan M, Groop L, Martinell M, Tuomi T, Wolk A, Carlsson S. Fatty fish consumption and risk of latent autoimmune diabetes in adults. Nutr. Diabetes 2014;4:e139. [PubMed] Worth Noting American Autoimmune Related Diseases Association: http://http://www.aarda.org/autoimmune-information/list-of-diseases/ Autoimmune Society. http://autoimmunesociety.org/ Fairweather D, Rose NR. Women and autoimmune diseases. Emerg. Infect. Dis. 2004;10(11):2005-2011. [PubMed] Heeringa P, Little MA. In vivo approaches to investigate ANCA-associated vasculitis: lessons and limitations. Arthritis Res. Ther. 2011;13(1):204. [PubMed] Jennette JC, Falk RJ, Hu P, Xiao H. Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Annu Rev. Pathol. 2013;8:139-160. [PubMed] Kallenberg CG. The last classification of vasculitis. Clin. Rev. Allergy Immunol. 2008;35(1-2):5-10. [PubMed] Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front. Neuroendocrinol. 2014;35(3):347-369. [PubMed] Ntatsaki E, Watts RA, Scott DG. Epidemiology of ANCA-associated vasculitis. Rheum. Dis. Clin. North Am. 2010;36(3):447-461. [PubMed] Patarroyo PA, Restrepo JF, Rojas SA, Rondon F, Matteson EL, Iglesias-Gamarra A. Are classification criteria for vasculitis useful in clinical practice? Observations and lessons from Colombia. J. Autoimmune Dis. 2009;6:1. [PubMed] Ramon S, Baker SF, Sahler JM, Kim N, Feldsott EA, Serhan CN, Martinez-Sobrido L, Topham DJ, Phipps RP. The specialized proresolving mediator 17-HDHA enhances the antibody-mediated immune response against influenza virus: a new class of adjuvant? J. Immunol. 2014;193(12):6031-6040. [PubMed] Serhan CN, Chiang N. Resolution phase lipid mediators of inflammation: agonists of resolution. Curr. Opin. Pharmacol. 2013;13(4):632-640. [PubMed] Smilek DE, St Clair EW. Solving the puzzle of autoimmunity: critical questions. F1000Prime Reports 2015;7:17. [PubMed] Watts R. Vasculitis syndromes: vasculitis therapy - between Scylla and Charybdis. Nat. Rev. Rheumatol. 2009;5(4):183-184. [PubMed]
- In two clinical cases, EPA was recognized to possibly offer support to the long-term remission of autoimmune small vessel vasculitis, when used in combination with methylprednisolone and aspirin.
- The study next addressed the mechanisms whereby this may occur. A potential role for EPA as an adjunct to drug treatment for attenuating the activity of autoimmune ANCA-associated vasculitides deserves to be tested in properly designed trials.
Vasculitis refers to inflammation of the vasculature, and is composed of an array of manifestations that can be caused by infections and by autoimmune reactions. A classification of the various types of vasculitis that is suitable for clinical diagnosis has proven difficult to achieve given the different types and overlapping manifestations, and is still in development. In several forms of autoimmune vasculitis, antibodies are present that are known to react with specific proteins located intracellularly within neutrophils. The antineutrophil-cytoplasmic-autoantibodies (ANCA)-auto-antibodies stimulate various arms of the immune system to amplify an inflammatory response that leads to extravascular granulomatous inflammation. ANCA-associated vasculitides (AAV) are relatively rare autoimmune disorders with an estimated incidence of 10 to 20 cases per million per year, affecting mostly elderly people. Treatment of AAV is based on the use of glucocorticoids, methotrexate, azathioprine, cyclophosphamide, and plasma exchanges, which allow the disease to present itself as a relapsing-remitting condition instead of a progressive and fatal inflammatory disorder. A major need for further improvements in the treatment of AAV, and auto-immune disease in general, exists given the marked side effects of currently available pharmacological approaches to control AAV. A recent anecdotal description of two cases has proposed the hypothesis that adding eicosapentaenoic acid (EPA) as an adjunct to drug treatment might contribute to control autoimmune disease. The case report by Hirahashi and colleagues from the Department of Nephrology and Endocrinology, University of Tokyo, and several other academic and private laboratories in Japan, reported on two patients. In the first clinical case, a 73-year old man diagnosed with microscopic polyangiitis, a type of autoimmune vasculitis affecting the capillaries, was treated daily with 1.8 g highly purified EPA and a low-dose aspirin in addition to methylprednisolone. The patient remained in remission for five years, during which his methylprednisolone dose was gradually lowered, and no other immunosuppressants were needed. During this period autoantibody titers remained low and he developed no deterioration typically associated with AAV, such as accelerated atherosclerosis or mineral bone disease resulting from chronic kidney disease. In the second clinical case, a 79-year old woman with necrotizing vasculitis of the small vessels of the kidney, high titers of autoantibodies, and elevated C-reactive protein, was placed on methylprednisolone therapy to induce remission and treated with 1.8 g/day highly purified EPA and low-dose aspirin. Methylprednisolone was gradually decreased and the patient maintained remission of AAV for more than five years without recurrence of adverse events. In both cases, after several weeks of induction of remission, the autoantibody titers and CRP levels in blood had decreased to a low level, and were shown to remain low for at least one year. 
The study next explored potential mechanisms by which EPA might affect remission using a mouse model for AAV. The SCG/Kj mice employed for this research spontaneously develop small-vessel vasculitis, produce autoantibodies against myeloperoxidase (a neutrophil protein) and develop glomerulonephritis that ultimately leads to renal failure after 2-3 months. Feeding the mice a diet containing 5% EPA led to a significantly increased life-span compared to mice eating a normal rodent diet or one supplemented with 5% corn oil. Measurement of tissue levels of PUFA showed that EPA levels were significantly increased in kidney, lung, spleen, and in plasma, whereas arachidonic acid (AA) levels had decreased. There was no change in DHA content. An exhaustive analysis of polyunsaturated fatty acid-derived lipid mediators in these tissues revealed the formation of the anti-inflammatory substances 18-HEPE, resolvin E2 and 17,18-EpETE, all formed from EPA, as well as marked decreases in several AA-derived eicosanoids that have been associated with inflammation. Appearance of blood in urine was nearly abolished in EPA-treated mice, and blood urea nitrogen levels and auto-antibody titers significantly decreased. No measurable effect on proteinuria or serum creatinine levels was found. The beneficial effects of EPA on the kidneys were confirmed by histological analysis showing reduced glomerulonephritis, and less endothelial cell damage in the glomeruli and peritubular capillaries. Analysis of lymph nodes of EPA-treated mice revealed lower numbers of mature T-cells and double negative (CD4-/CD8-) CD220+ T cells in draining lymph nodes, as well as an increased number of regulatory T cells that may play a role in counteracting the autoimmune response. 
The researchers initially appeared to have used EPA to treat dyslipidemia in the patients, and proposed that it might help normalize the inflammatory status of the patients and maintain remission. Redirecting the immune response with inhibition of auto-antibody formation, stimulation of regulatory T cells, and protection from neutrophil-mediated vascular damage by employing oral intake of highly purified EPA is an interesting approach to complement current treatment possibilities that should be evaluated. It needs to be pointed out that in addition to steroid treatment to control inflammation, the two patients also took low-dose aspirin. Aspirin has been reported to favor the formation of specific aspirin-triggered resolvins from EPA. In the animal study, merely supplementing with EPA was sufficient to induce beneficial effects on auto-immunity. However, the animal model mimics additional pathologies such as immune-complex mediated vascular pathology. The animal study has provided new insight into possible mechanisms whereby adding EPA to the treatment scheme might improve control over autoimmune disease. Much further research and in particular properly designed controlled trials will be necessary to explore potential effects. Although autoimmune small-vessel vasculitis is a relatively rare disorder, this research is important since there are common mechanisms that drive auto-immune disease. Omega-3 LCPUFA have been recently reported to play a role in the regulation of the adaptive immune response via control over antibody formation. Possibly autoimmune reactivity, when viewed as a disorder of self-tolerance leading to deregulated inflammatory responses, is another manifestation of select deficiencies in specific essential fatty acids and the mediators formed from these. Löfvenborg and colleagues at the Institute of Environmental Medicine at the Karolinska Institutet in Stockholm, Sweden, together with researchers from Uppsala University and Lund University in Sweden, and Helsinki University Hospital, Finland, reported an inverse relationship between omega-3 LCPUFA intake and the incidence of latent autoimmune diabetes in adults. Hirahashi J, Kawahata K, Arita M, Iwamoto R, Hishikawa K, Honda M, Hamasaki Y, Tanaka M, Okubo K, Kurosawa M, Takase O, Nakakuki M, Saiga K, Suzuki K, Kawachi S, Tojo A, Seki G, Marumo T, Hayashi M, Fujita T. Immunomodulation with eicosapentaenoic acid supports the treatment of autoimmune small-vessel vasculitis. Sci. Rep. 2014;4:6406. [PubMed] Löfvenborg JE, Andersson T, Carlsson PO, Dorkhan M, Groop L, Martinell M, Tuomi T, Wolk A, Carlsson S. Fatty fish consumption and risk of latent autoimmune diabetes in adults. Nutr. Diabetes 2014;4:e139. [PubMed] Worth Noting American Autoimmune Related Diseases Association: http://http://www.aarda.org/autoimmune-information/list-of-diseases/ Autoimmune Society. http://autoimmunesociety.org/ Fairweather D, Rose NR. Women and autoimmune diseases. Emerg. Infect. Dis. 2004;10(11):2005-2011. [PubMed] Heeringa P, Little MA. In vivo approaches to investigate ANCA-associated vasculitis: lessons and limitations. Arthritis Res. Ther. 2011;13(1):204. [PubMed] Jennette JC, Falk RJ, Hu P, Xiao H. Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Annu Rev. Pathol. 2013;8:139-160. [PubMed] Kallenberg CG. The last classification of vasculitis. Clin. Rev. Allergy Immunol. 2008;35(1-2):5-10. [PubMed] Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front. Neuroendocrinol. 2014;35(3):347-369. [PubMed] Ntatsaki E, Watts RA, Scott DG. Epidemiology of ANCA-associated vasculitis. Rheum. Dis. Clin. North Am. 2010;36(3):447-461. [PubMed] Patarroyo PA, Restrepo JF, Rojas SA, Rondon F, Matteson EL, Iglesias-Gamarra A. Are classification criteria for vasculitis useful in clinical practice? Observations and lessons from Colombia. J. Autoimmune Dis. 2009;6:1. [PubMed] Ramon S, Baker SF, Sahler JM, Kim N, Feldsott EA, Serhan CN, Martinez-Sobrido L, Topham DJ, Phipps RP. The specialized proresolving mediator 17-HDHA enhances the antibody-mediated immune response against influenza virus: a new class of adjuvant? J. Immunol. 2014;193(12):6031-6040. [PubMed] Serhan CN, Chiang N. Resolution phase lipid mediators of inflammation: agonists of resolution. Curr. Opin. Pharmacol. 2013;13(4):632-640. [PubMed] Smilek DE, St Clair EW. Solving the puzzle of autoimmunity: critical questions. F1000Prime Reports 2015;7:17. [PubMed] Watts R. Vasculitis syndromes: vasculitis therapy - between Scylla and Charybdis. Nat. Rev. Rheumatol. 2009;5(4):183-184. [PubMed]