Optimizing the use of topical and standard systemic treatments for psoriasis Prof. Errol Prens Department of Dermatology, Erasmus University Medical Center Rotterdam, The Netherlands IPC Psoriasis Masterclass, 15 &16 November 2019, Vienna, Austria
Optimizing the use of topical and standard systemic treatments for
psoriasis
Prof. Errol Prens Department of Dermatology, Erasmus University Medical
Center Rotterdam, The Netherlands
IPC Psoriasis Masterclass, 15 &16 November 2019, Vienna, Austria
I have served as an advisory board member, consultant, speaker and/or received investigator initiated grants (paid to the Erasmus MC) from: AbbVie, Amgen, Astra Zeneca, Baxter, Biogen, Celgene, Eli Lilly, Fresenius, Galderma, InflaRx, Leo Pharma, Janssen-Cilag, Novartis, Pfizer, Regeneron, Sandoz, UCB.
Disclosures / Conflicts of Interest
The therapeutic ladder of psoriasis
fumarates
tazarotene
+ betametasone
Excimer / UVB laser
Topicals for psoriasis: emollients
• Emollients and keratolytics are needed
• Emollients hold the potential to act as steroid-sparing agents
Based on current evidence, the “best” emollient is the one that the individual prefers after a period of testing
Ridd MJ et al. BMJ 2019;367:l5882 Published 24 October! psoriasis
Corticosteroids: class III and IV are used
Apply cortico’s under occlusion
Topicals for psoriasis
In resistant plaques, even under biologic treatment, intralesional corticosteroids may clear problematic plaques
An overnight application of a class IV corticosteroid under occlusion may prevent or aleviate injection site reactions to biologics
Class III corticosteroids may reduce skin irritation caused by anthralin or tazarotene
Calcipotriol/Betamethasone
Kim ES & Frampton JE. Calcipotriol/Betamethasone Dipropionate Foam: A Review in Plaque Psoriasis. Drugs 2016, 76:1485–1492.
• Not suitable for hairy scalp application
• Use keratolytics with a corticosteroid in an oil-in-water emulsion or water/shampoo soluble grease (coconut-oil)
Conclusions: HP/TAZ lotion was associated with significant reductions in the severity of the clinical signs of psoriasis, with no safety concerns.
J Am Acad Dermatol 2018;79:287-93.
Pipeline of topicals for PsO Eucrisa crisaborole /AN2728
LAS41004 bexarotene/betamethasone
PF-06700841 JAK1 and TYK2 inhibitor
Pegcantratinib tropomyosin receptor kinase blocker
Tapinarof DVMT-505 / AhR agonist
Other JAK-inibs (tofacitinib, ruxolitinib)
Crow JM. Nature. 2012 Dec 20;492(7429):S50-1.
Psoriasis is heterogeneous
RESPONSE TO PSORIASIS THERAPY IS ALSO HETEROGENEOUS
Success is tightly linked to the efficacy / side effect ratio
• Efficacy in psoriasis sub-types such as psoriatic arthritis, palmo-plantar, nail, pustular, guttate
• Crohn’s, Celiac disease
• Serious infections
• No worsening of metaboic / cardiovascular co-morbidities
• Malignancies
One example
A patient with psoriasis, psoriatic arthritis and Crohn’s disease:
All conditions not well controlled under biologic treatment (ada), already failed etanercept and ustekinumab.
In this case we managed to maintain the patient on adalimumab by combining with Sulfasalazine.
Acitretin Mechanism of action Normalises epidermal proliferation, differentiation and cornification; inhibition of Th-17 cells
Contra-indications Liver- or kidney insufficiency; Hepatitis / Alcohol abusus
Pregnancy / breastfeeding (effective contraception until 2 years after stop of acitretin)
Blood donations; Relative: DM, History of pancreatitis, Hyperlipidemia
Cell. 2007, 129: 649–651
Retinoid metabolism & biological effects
Alcohol Increases hepatotoxicity Re-esterification of acitretin to etretinate (teratogenicity)
Tetracyclines Photosensitivity, intracran.hypertension
Vitamin A (>4,000-5,000 IU/d)
Corticosteroids Altered lipids, intracranial hypertension
Methotrexate Potential hepatotoxicity Raises methotrexate levels
Ciclosporin Alteration of lipid profile Increases cardiovascular risk
Phenytoin Increases blood levels of phenytoin
Oral antidiabetics (glibenclamide) Fluctuations in blood sugar levels, reduces hypoglycemic effect of glibenclamide
Progestogen contraceptives (in mini doses), reduces contraceptive effect
Carretero G, et al. Actas Dermosifiliogr.2013;104:598-616
Drug Interactions Acitretin
Phototherapy + acitretin • May reduce phototherapy dose up to 50% • Add and increase acitretin up to 25mg/day • Gradually increase phototherapy dose (response/phototoxicity) • Maintain acitretin and phototherapy until clearing
Biologics + acitretin • Maintain dose of biologic • Add acitretin at a low dose (10-25 mg/day) • Gradually escalate acitretin according to response * acitretin, is particularly effective in palm and sole psoriasis
Acitretin Combination Strategies.
Adapted from Lebwohl et al.
EU S3 Psoriasis Guidelines – Update 2015 acitretin combination therapies
Ciclosporin Mechanism of action Inhibition of (mainly)Th1 and other proinflammatoiry cytokines
CsA has a rapid TOA
Effective at inhibiting flares of psoriasis
Contra-indications Hypertension, Renal dysfunction, History of malignancy
Infection
Ciclosporin metabolism & biological effects
Ciclosporin drug interactions
Test ciclosporin trough levels!!!!
Also usable to check compliance!
Antibiotics
Antimycotics
Calcium-antagonists
EU S3 Psoriasis Guidelines – Update 2015 cyclosporin
EU S3 Psoriasis Guidelines – Update 2015 cyclosporin combination therapeis
Methotrexate Mechanism of action Folic acid-antagonist; inhibition of cell proliferation
Contra-indications Serious infections, Liver disease, Renal insufficiency
Child wish / pregnancy / breasfeeding
Alcohol abuse, Bone marrow abnormalities, Gastric ulcer
Reduced lung capacity
Methotrexate Dosing Start with 5 mg/week (orally)
Escalate dose up to 25 mg/week
5 mg folic acid 24 hr after intake of methotrexate
Liver fibrosis? Liverbiopsy: remains an invasive procedure
Procollagen type III N-terminal propeptide / Fibroscan/Fibrotest
Risk factors: obesitas, type 2 DM
Drug Interactions Methotrexate
EU S3 Psoriasis Guidelines–Update 2015 MTX
Fumarates Mechanism of action:
Inhibition of NF-kβ mediated transcription
Shift from Th-1 response to T-helper 2
Apoptosis of T-cells and keratinocytes
Contra-indications: Chronic gastro-intestinal disease
Chronic liver and kidney disease
Hematologic disorders
Pregnancy and lactation
DMF-regulated genes in psoriatic skin
Balak, Prens et al. Br J Dermatol, 2014, 171:732-741.
Fumarate preparations available • Fumaderm® Initial / Fumaderma® (Dimethyl fumarate (DMF) &
monoethyl fumarate (MEF) combination salts (Swiss, Fumapharm, Fumedica).
• Dimethylfumarate 120 mg
• Psorinovo
• Skilarence
• BG-12 (Tecfidera) for MS, by far more expensive than other fumarates
Dimethyl fumarate (DMF) vs. monoethyl fumarate (MEF) salts for the treatment of plaque psoriasis: a review of clinical data. Mrowietz et al. Arch Dermatol Res 2018,310:475–483.
Management of adverse effects fumarates Patient education! Patient education! Patient education!
Spread intake of tablets over the day
Not on an empty stomach
Intake with milk or yoghurt
Don’t increase dose too fast
Pharmacologically
Take anti-emetic / diarrhoea Take a NSAID or aspirin Antihistamines don’t work
Fumarate-associated PML
Since 2013 nine (9) cases have been reported
All had grade 1 to grade 3 lymphopenia (lower limit of normal to 0.2 x 109)
The mean duration of treatment was 2.4 years (range 1-5 years)
No cases of PML have been reported in persons with normal lymphocyte counts
Monitoring of lymphocyte levels Stop immediately when: Leukocytes < 3.0 x 109/L Lymphocytes < 0.5 Reduce the dose by 50% and recheck after one month: When lympho’s reach 0.7x 109/L
What about oral JAKs and PDE inhibitors?
• Therapeutic efficacy in psoriasis not spectacular
• Safety / benefit issues with Tofacitinib (at least in RA)
• PDE (apremilast) shows a better safety profile
PDE4 controls cAMP levels in many cells
PDE4 promotes pro-inflammatory mediator production by converting cAMP to AMP
Pro-inflammatory mediators (i.e. TNF-α, IL-17, IFN-γ)
Anti-inflammatory
mediators (i.e. IL-10)
Immune cell
PKA
cAMP
AMP AMP
AMP
PDE4 (+)
(─) R
NF-κB
CREB
AMP, adenosine monophosphate; cAMP, cyclic AMP; CREB, cAMP response element-binding protein; IL, interleukin; IFN, interferon; NF, nuclear factor; PDE4, phosphodiesterase-4; PKA, protein kinase A; TNF, tumour necrosis factor.Schafer P, et al. Br J Pharmacol 2010;159:842–855; Ma R, et al. Int Immunopharmacol 2008;10:1408–1417; Youngbaré I, et al. Can J Physiol Pharmacol 2013;91:353–361; Schafer P. Biochem Pharmacol 2012;83:1583–1590.
cAMP mediates through PKA, NF-κB, and CREB
AMP, adenosine monophosphate; cAMP, cyclic AMP; CREB, cAMP response element-binding protein; IL, interleukin; IFN, interferon; NF, nuclear factor; PDE4, phosphodiesterase-4; PKA, protein kinase A; TNF, tumour necrosis factor.Schafer P, et al. Br J Pharmacol 2010;159:842–855; Ma R, et al. Int Immunopharmacol 2008;10:1408–1417; Youngbaré I, et al. Can J Physiol Pharmacol 2013;91:353–361; Schafer P. Biochem Pharmacol 2012;83:1583–1590.
Elevated cAMP level activates PKA, which modulates the activity of NF-κB and CREB
PKA
cAMP (+)
cAMP cAMP
AMP
PDE
Apremilast
R
Immune cell Anti-
inflammatory mediators (i.e. IL-10)
Pro-inflammatory mediators (i.e. TNF-α, IL-17, IFN-γ)
(─)
(+)
NF-κB
CREB
Apremilast dosing
Apremilast clinical trial outcomes
Drug Interactions Apremilast
Avoid concomitant use of Cyp3A4 inducers!!!
Rifampin
Phenobarbital
Carbamazepine
Phenytoin
St. John’s wort
Long-term safety remains key!!! Don’t take risks with systemic medications!
Thank you!