Methotrexate: An old dog with new tricks? A historical perspective Jan Dutz, MD, FRCPC

Transcription

1 Methotrexate: An old dog with new tricks? A historical perspective Jan Dutz, MD, FRCPC Professor Department of Dermatology and Skin Science University of British Columbia Vancouver, Canada

2 Conflict of Interest Declaration Clinical Trials:» Abbvie, Novartis Speaker s Bureau:» Janssen-Ortho, Abbvie, Amgen, Leo Pharma, Celgene, Novartis Consultant / Ad board:» Janssen-Ortho, Abbvie, Amgen, Leo Pharma, Celgene, Lilly, Novartis, Cipher

3 Declarations

4 Methotrexate A history Folic Acid and anemia 1928 Lucy Wills Folic Acid and leukemia 1946 Farber Folic Acid Antagonists Aminopterin and Amethopterin 1946 Yellpragada Subbarao Aminopterin and psoriasis 1951 Gubner Methotrexate and psoriasis 1960s

5 Lucy Wills Graduate of the London (Royal Free Hospital) School of Medicine for Women Travel to Bombay - study pernicious anemia of pregnancy (related to diet) Anemia in India did not respond to Vitamin B12 did respond to Marmite = Wills Factor = Folic acid

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9 Sydney Farber September 30, 1903 March 30, 1973 American pediatric pathologist the father of modern chemotherapy after whom the Dana-Farber Cancer Institute is named

10 Sidney Farber Would adding folic acid to children with leukemia restore their blood? Folic acid accelerated leukemia Search for an anti-folate: aminopterin

11 Yellapragada Subbarao Born in India Madras Medical College Moved to Harvard 1922 Discoverer of function of ATP in muscle with C Fiske PhD thesis Moved from Harvard to Lederle (American Cyanamid Wyeth Pfizer) Synthesized Folic acid Aminopterin Amethopterin

12 First clinical use of aminopterin Dec 28, 1946 Farber uses aminopterin on 2 year old Robert Sandler First remission ever in pediatric leukemia

13 First clinical use of aminopterin

14 Aminopterin use for skin disease and joint disease Gubner R Am J Med Sci 1951;221:176

15 Aminopterin use for skin disease

16 Aminopterin use for skin disease

17 Aminopterin use for skin disease

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19 Methotrexate

20 Methotrexate for psoriasis

21 Methotrexate for psoriasis Edmunson and Guy AMA Arch Dermatol 78:200 (1958) Compare aminopterin to methotrexate toxicity and efficacy Hunter GA Australian J of Dermatol 7:91 (1963) First controlled trial

22 Methotrexate for psoriasis Weinstein JID 59:121 (1972)

23 Methotrexate for psoriasis Weinstein Ann Int Med 86:199 (1977)

24 Methotrexate for psoriasis Jeffes EW J Invest Dermatol Feb;104(2): Lymphocytes 1000x more sensitive to effects of MTX than keratinocytes Role of increased adenosine production?

25 Methotrexate in the 21 st century New methods of action New uses

26 Drug survival of first TNFi is affected by MTX Fagerli KM Ann Rheum Dis Jan;73(1):132-7

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29 Methotrexate not only an antimetabolite Methotrexate is effective in the treatment of CLE Wenzel J Br J Dermatol 153:157 (2005) Methotrexate prevents CLA expression Sigmundsdottir H Exp Dermatol Jul;13(7):426 Johnston A Clin Immunol Feb;114(2):154

30 Methotrexate not only an antimetabolite Sigmundsdottir H Exp Dermatol Jul;13(7):426

31 Methotrexate not only an antimetabolite Sigmundsdottir H Exp Dermatol Jul;13(7):426

32 Methotrexate not only an antimetabolite Sigmundsdottir H Exp Dermatol Jul;13(7):426

33 Methotrexate not only an antimetabolite Sigmundsdottir H Exp Dermatol Jul;13(7):426

34 IL-17 inhibition? Which pathways are affected in CLE? IFN gamma NOT IL-17 Jabbari A J Invest Dermatol Jan;134(1):87-95.

35 IFN gamma inhibition? Tofacitinib, Ruxolitinib

36 JAK inhibitor ruxolitinib treats skin lesions in MRL/lpr mouse Chan ES J Invest Dermatol Sep;135(9):2338-9

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38 JAK inhibitor ruxolitinib treats skin lesions in MRL/lpr mouse Chan ES J Invest Dermatol Sep;135(9): Ruloxitinib prevents CXCL9 and 10 up-regulation by IFN alpha or gamma

39 SAVI A new vasculopathy STING (Stimulator of interferon genes) -associated vasculopathy with onset in infancy Liu Y NEJM 371: 507 (2014)

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41 SAVI A new vasculopathy STING (Stimulator of interferon genes) -associated vasculopathy with onset in infancy Liu Y NEJM 371: 507 (2014)

42 Dermatomyositis and SAVI Clinical features SIMILAR to SAVI Cutaneous involvement Lung involvement Primo facie a vasculopathy

43 Methotrexate the old ruxolitinib? Thomas S (2015)PLoS ONE 10(7): e doi: /journal. pone

44 Methotrexate the old ruxolitinib? Thomas S (2015)PLoS ONE 10(7): e doi: /journal. pone

45 Methotrexate the old ruxolitinib? Thomas S (2015)PLoS ONE 10(7): e doi: /journal. pone

46 A unifying hypothesis? DM differs from CLE by representing an interferonopathy due to activation of STING and other cytosolic danger receptors DM responds to methotrexate DM should respond to ruxolitinib/tofacitinib

47 Ruxolitinib for cutaneous CTD? Hornung NEJM 371:2537 (2014) 47

48 Treatment Methotrexate may be first line agent Hornung Clin Exp Dermatol 37:139 (2012)

49 Skin DM Treatment An algorithm Antimalarials (HQ+Q, CQ) Methotrexate MMF, IVIG Dapsone, thalidomide, leflunomide, CSA, CYP, azath rituximab, tofacitinib, ruxolitinib Femia AM Am J Clin Dermatol (2013) 14:291

50 A drug with two identities High dose MTX Dosed in grams Inhibits DHFR = cell death Low dose MTX Dosed in milligrams Does not inhibit DHFR Inhibits ICAR-T = increased adenosine Inhibits T cell homing adhesion molecules Inhibits JAK signaling?

51 Is methotrexate safe? No increase in infection Baradat C RMD Open Feb 22;3(1):e

52 Is methotrexate safe? No clinically signif increase in malignancy Incidence of malign melanoma in Sweden Poelsie S Br J Dermatol Nov 10. doi: /bjd.15170

53 Is methotrexate safe? Social drinking is safe No LFT change if under 14 Units/week Humphreys JH, et al. Ann Rheum Dis 2017;0:1 6. doi: /annrheu mdis

54 Is methotrexate effective? Median drug survival = 1.8 years Lancet Feb 4;389(10068): Br J Dermatol Jan 12. doi: /bjd.15305

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