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.

Presenter

Presentation Notes

Fig 3. Improvement in signs of psoriasis erythema, plaque elevation, and scaling at each study visit in subjects who were treatment successes (defined as at least a 2-grade improvement from the baseline score) (individual study data for the intent-to-treat population). HP/TAZ, Halobetasol propionate plus tazarotene.

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!