SPIN2019

Conference summaries


SYSTEMIC THERAPIES

Classical systemic therapies – Methotrexate

Presented by: Rolland Gyulai, MD, PhD, DSc
Department of Dermatology, Venerology and Oncodermatology, University of Pécs, Hungary
  • Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune system suppressant.
  • MTX was made in 1947 and initially came into medical use to treat cancer, as it was less toxic than the then-current treatments.
  • MTX is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.
  • MTX has been used for 50 years and is a competitive folate inhibitor and restores the function of peripheral regulatory T cells, which is especially important in psoriasis (PsO) [1].
  • MTX must be transported into the cells and then undergoes a polyglutamation (MTXPG) to become active.
  • The efficacy of MTX (responders or non-responders) depends on the level of MTXPG [2].
  • MTX has shown a consistent efficacy in clinical trials [3], and around 40% of patients reach PASI 75 by week 12- week 16 [4).
  • The METOP trial proved however that an intensified dosing schedule (17.5 mg/week + dose escalation up to 22.5 mg/week) of subcutaneous (SC) MTX provides better therapeutic results [5). However, there was no direct oral vs. SC comparison in PsO.
  • Efficacy measurements should begin at week 8 and for non-responders (PASI <50) dosage should be increased. If there is no response at week 12 the patient is a likely non-responder. The maximum MTX efficacy is at week 16 [6].
  • The prediction of MTX treatment success has been associated with serum Ca2 level [7], but there is no evidence yet to suggest whether increasing the serum Ca2 levels prior to treatment increases MTX efficacy, HLA-Cw6 positivity and FOXP3 [8].
  • In both childhood and adolescent PsO, the efficacy (PASi 75 at week 16 in ~35%) and safety are comparable to those reported in the adult population [9].
  • For PsO, oral administration over 15 mg is not recommended, as subcutaneous administration reaches a higher efficacy with higher doses [10].
  • Acute MTX toxicity is the most serious adverse event, clinically recognisable by ulceration of the PsO plaque and mucous membrane ulceration and keratinocyte dystrophy at histology.
  • The most common other side effects include nausea and vomiting (3.6%) abnormal liver function tests (2.8%) and leucopenia (2%) [8].
  • PsO patients are more likely to develop liver disease, and this has been correlated with skin disease severity. In patients requiring systemic therapy, a higher hazard ratio for fibrosis and any liver disease has been observed [11].
  • A metanalysis found an increased risk for liver damage in patients on MTX, but not on its own. The cumulative dose and duration of MTX therapy were not found to be associated with fibrosis/cirrhosis and this led to the conclusion that MTX increases the risk of fibrosis but not in everyone and/or on its own [12]. So, in PsO patients with a predisposition for liver disease, MTX could augment this risk.
  • Diabetes and obesity are risk factors for both MTX and induced liver injury.
  • The non-alcoholic fatty liver disease (NAFLD) fibrosis score can be used to screen patients prior to MTX initiation [13-14].
  • Long-term toxicity can be monitored with transient elastography.
  • There is a correlation between fibrosis and body mass index but not with cumulative MTX dose (unpublished data) and with changes of TE score during follow-up, MTX should be stopped.
  • In terms of family planning, the MTX half-life is 3-10 hours and in 24 hours it is undetectable but should be stopped 12 weeks prior to conception in females. In males there is no mutagenic or teratogenic effect and there is no evidence that MTX needs to be discontinued.
  • Before MTX initiation:
    • Consider risk factors: obesity, diabetes, liver and renal disease, alcohol intake, family planning, etc.
    • Screen patients: complete blood count, liver and renal function tests, hepatitis C and hepatitis B virus, IGRA (Interferon Gamma Release Assay, used to screen for tuberculosis), chest X-ray, transient elastography (pregnancy).
  • Start MTX:
    • Starting dose: 15 mg/week SC + folic acid 3 or 4 mg 1x/week.
  • Maintenance:
    • Monitor side effects: complete blood count (1 week), liver and renal function tests, chest X-ray (every 2 weeks, then 2-3 months), transient elastography (every 1-2 years).
    • Adjust dose (up to 25 mg).
  • MTX has shown a consistent efficacy in clinical trials [3], and around 40% of patients reach PASI 75 by week 12- week 16 [4).
  • The METOP trial proved however that an intensified dosing schedule (17.5 mg/week + dose escalation up to 22.5 mg/week) of subcutaneous (SC) MTX provides better therapeutic results [5). However, there was no direct oral vs. SC comparison in PsO.
  • Efficacy measurements should begin at week 8 and for non-responders (PASI <50) dosage should be increased. If there is no response at week 12 the patient is a likely non-responder. The maximum MTX efficacy is at week 16 [6].
  • The prediction of MTX treatment success has been associated with serum Ca2 level [7], but there is no evidence yet to suggest whether increasing the serum Ca2 levels prior to treatment increases MTX efficacy, HLA-Cw6 positivity and FOXP3 [8].
  • In both childhood and adolescent PsO, the efficacy (PASi 75 at week 16 in ~35%) and safety are comparable to those reported in the adult population [9].
  • For PsO, oral administration over 15 mg is not recommended, as subcutaneous administration reaches a higher efficacy with higher doses [10].
  • Acute MTX toxicity is the most serious adverse event, clinically recognisable by ulceration of the PsO plaque and mucous membrane ulceration and keratinocyte dystrophy at histology.
  • The most common other side effects include nausea and vomiting (3.6%) abnormal liver function tests (2.8%) and leucopenia (2%) [8].
  • PsO patients are more likely to develop liver disease, and this has been correlated with skin disease severity. In patients requiring systemic therapy, a higher hazard ratio for fibrosis and any liver disease has been observed [11].
  • A metanalysis found an increased risk for liver damage in patients on MTX, but not on its own. The cumulative dose and duration of MTX therapy were not found to be associated with fibrosis/cirrhosis and this led to the conclusion that MTX increases the risk of fibrosis but not in everyone and/or on its own [12]. So, in PsO patients with a predisposition for liver disease, MTX could augment this risk.
  • Diabetes and obesity are risk factors for both MTX and induced liver injury.
  • The non-alcoholic fatty liver disease (NAFLD) fibrosis score can be used to screen patients prior to MTX initiation [13-14].
  • Long-term toxicity can be monitored with transient elastography.
  • There is a correlation between fibrosis and body mass index but not with cumulative MTX dose (unpublished data) and with changes of TE score during follow-up, MTX should be stopped.
  • In terms of family planning, the MTX half-life is 3-10 hours and in 24 hours it is undetectable but should be stopped 12 weeks prior to conception in females. In males there is no mutagenic or teratogenic effect and there is no evidence that MTX needs to be discontinued.

My preference of MTX treatment

  • Before MTX initiation:
    • Consider risk factors: obesity, diabetes, liver and renal disease, alcohol intake, family planning, etc.
    • Screen patients: complete blood count, liver and renal function tests, hepatitis C and hepatitis B virus, IGRA (Interferon Gamma Release Assay, used to screen for tuberculosis), chest X-ray, transient elastography (pregnancy).
  • Start MTX:
    • Starting dose: 15 mg/week SC + folic acid 3 or 4 mg 1x/week.
  • Maintenance:
    • Monitor side effects: complete blood count (1 week), liver and renal function tests, chest X-ray (every 2 weeks, then 2-3 months), transient elastography (every 1-2 years).
    • Adjust dose (up to 25 mg).


References

References


  1. Friedman B, Cronstein B. Methotrexate mechanism in treatment of rheumatoid arthritis. Joint Bone Spine. 2018;pii: S1297-319X(18)30181-7.
  2. Rahman SI, Siegfried E, Flanagan KH, et al. The methotrexate polyglutamate assay supports the efficacy of methotrexate for severe inflammatory skin disease in children. J Am Acad Dermatol. 2014;70:252-6.
  3. Schmitt J, Rosumeck S, Thomaschewski G, et al. Efficacy and safety of systemic treatments for moderate-to-severe psoriasis: meta-analysis of randomized controlled trials. Br J Dermatol. 2014;170:274-303.
  4. West J, Ogston S, Foerster J. Safety and Efficacy of Methotrexate in Psoriasis: A Meta-Analysis of Published Trials. PLoS One. 2016;11:e0153740C.
  5. Warren RB, Mrowietz U, von Kiedrowski R, et al. An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:528-37.
  6. Reich K, Langley RG, Papp KA, et al. A 52-Week Trial Comparing Briakinumab with Methotrexate in Patients with Psoriasis. N Engl J Med. 2011; 365:1586-96.
  7. Zhai Z, Chen L, Yang H, et al. Can pretreatment serum calcium level predict the efficacy of methotrexate in the treatment of severe plaque psoriasis? J Am Acad Dermatol. 2015;73:991-7.e3.
  8. West J, Ogston S, Berg J, et al. HLA-Cw6-positive patients with psoriasis show improved response to methotrexate treatment. Clin Exp Dermatol. 2017;42:651-655.
  9. Papp K, Thaçi D, Marcoux D, et al. Efficacy and safety of adalimumab every other week versus methotrexate once weekly in children and adolescents with severe chronic plaque psoriasis: a randomised, double-blind, phase 3 trial. Lancet. 2017;390:40-49.
  10. Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses ≥15 mg may be overcome with subcutaneous administration. Ann Rheum Dis. 2014;73:1549-51.
  11. Ogdie A, Grewal SK, Noe MH, et al. Risk of Incident Liver Disease in Patients with Psoriasis, Psoriatic Arthritis, and Rheumatoid Arthritis: A Population-Based Study. J Invest Dermatol. 2018;138:760-7.
  12. Maybury CM, Jabbar-Lopez ZK, Wong T, et al. Methotrexate and liver fibrosis in people with psoriasis: a systematic review of observational studies. Br J Dermatol. 2014;171:17-29.
  13. Shetty A, Cho W, Alazawi W, et al. Methotrexate Hepatotoxicity and the Impact of Nonalcoholic Fatty Liver Disease. Am J Med Sci. 2017;354:172-81.
  14. NAFLD fibrosis score.

Presenter disclosure(s): The work was not paid by and commercial organization either directly or indirectly through an intermediary. No ownership of shares n any commercial companies. Consultancy / speaker’s honoraria from Abbvie/Abbot, Janssen, MSD. Pfizer, Novartis, LEO Pharma, Brystol-Myers-Squibb, Glaxo-Smithkline, Celgene. Trials have been conducted for Abbvie, Amgen, Janssen, Eli-Lilly, MSD; Novartis, Pfizer, Gladerma, rystol-Myers_Squibb, Glaxo-Smithkline.

Written by: Johanna Chester, BA

Reviewed by: Martina Lambertini, MD


All report

Welcome to the SPIN 2019 Highlights

Jo Lambert, MD, PhD

With this collection of summaries from selected presentations at SPIN 2019, and interviews with international experts, we hope to share with you some of the highlights of this year’s congress. The international network met … [ Read all ]

SUMMARIES

ATOPIC DERMATITIS & PSORIASIS

Atopic dermatitis and psoriasis: On a spectrum?

Presented by: Emma Guttman-Yassky, MD, PhD

INFLAMMATORY SKIN DISEASES

PSORIASIS

Which drug for which patient?

Presented by: Emilie Sbidian, MD, PhD

PSORIASIS

Effects of biotherapy on vascular disease in psoriasis

Presented by: Nehal N. Mehta, MD, MSCE, FAHA

SYSTEMIC THERAPIES

Classical systemic therapies – Methotrexate

Presented by: Rolland Gyulai, MD, PhD, DSc

SMALL MOLECULES

Small molecules, apremilast, and beyond

Presented by: Richard G.B. Langley, MD

PSORIASIS

Treatment goals in psoriasis

Presented by: Ulrich Mrowietz, MD

PSORIASIS

Combined therapy in psoriasis

Presented by: Pablo Coto-Segura, MD, PhD

MEASURING OUTCOMES

PSORIASIS & ADHERENCE

How can we support optimal medication adherence?

Presented by: Rachael Thorneloe, MD