Childhood psoriasis. Where are we now? - CROATIA Slobodna Murat-Sušić Department of dermatology and venereology University Hospital Zagreb - espd.info
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Childhood psoriasis. Where are
we now?
Slobodna Murat-Sušić
Department of dermatology and venereology
University Hospital Zagreb
CROATIA
Scope of the lecture Specificities of psoriasis in children Comorbidities Overview of therapies News in treatment modalities
Epidemiology
One of the most common chronic skin diseases – 1-3%
in around 30% of cases it begins in childhood
In children and adolescents – 0,7% 1, 2
the occurrence of psoriasis varies according to
geographic region, being more frequent in countries
more distant from the equator 3
The prevalence of psoriasis in children seemed to have
doubled from 1970 to 2000’s 4
1. J Eur Acad Dermatol Venereol 2015;29:2277-94.
2. Br J Dermatol 2010;162(3):633-636.
3. Invest Dermatol 2013;133(2):377–385.)
4. J Am Acad Dermatol 2010;62(6):979–987.
Diagnosis and clinical picture • Plaque psoriasis most prevalent • Guttata psoriasis • Psoriasis inversa • Psoriasis follicularis • Psoriasis palmoplantaris • Pustular psoriasis • Erythorodermic • Linear, nevoid psoriasis • Arthropathic psoriasis • Napkin psoriasis
Comorbidities in childhood psoriasis
Overweight/obesity, hyperlipidaemia,
hypertension, type 2 diabetes mellitus,
metabolic syndrome 1,2
Overweight/obese children have an
increased risk to develop psoriasis 3
1. Br J Dermatol 2010;162(3):633-6.
2. JAMA Dermatol. 2013;149(2):166.
3. J Pediatr. 2011;159(4):577-583.Comorbidities in childhood psoriasis
Anxiety, depression
Arthritis
Uveitis
Inflammatory bowel diseases: Mb. Crohn, ulcerative
colitis
Paediatric psoriasis comorbidity screening guidelines
developed in 2017.
JAMA Dermatol 2017;153:698-704.Comorbidity screening guidelines
1. BMI percentile, yearly starting at 2 years of age
2. Fast serum glucose levels (if obese or overweight + risk factors) every 3 years
starting at age 10 years or the onset of puberty
3. Universal lipid screening during the following 2 age ranges: 9 to 11 years old and
17 to 21 years old. Outside of the specified age ranges, screening is also
recommended in the presence of any additional cardiovascular risk factors
4. Blood pressure yearly starting at 3 years of age, using age, sex, and height
reference charts
5. NAFLD – ALT starting 9 to 11 years, every 2-3 years in children with risk factors
6. Development of arthritis by a directed review of systems and physical
examination
7. Early for depression and anxiety regardless of age. Screen yearly for substance
abuse beginning at 11 years of age
JAMA Dermatol 2017;153:698-704TREATMENT many of the therapies commonly administered are same for adults lack of high-quality trials assessing efficacy in children as well as guidelines for treatment of psoriasis in the paediatric population The majority of patients can be treated with topical medications significant percentage needs phototherapy and/or systemic treatment
TREATMENT appropriate choice of therapy depends: ✓ type ✓ stage ✓ distribution ✓ extension ✓ age Treatment success depends largely on parental involvement and education
BEFORE TREATMENT education of psoriatic children and their parents inform about: - the chronic nature of the disease and its tendency for exacerbations - possible provoking factors for disease exacerbations - treatment options and risks - performing therapy (topical) Insist on diaries!
Topical treatment • corticosteroid preparations • keratolytics • Vitamin D analogs • Topical calcineurin inhibitors • tars • retinoids
Topical corticosteroids First line therapy antiproliferative, anti-inflammatory, immunosuppressive and vasoconstrictive properties Lower-potency are especially recommended for ther use on “sensitive” skin areas mid or higher potency corticosteroids can be used on thick psoriatic plaques Mandatory supervision
Topical vitamin D analogs As an adjunctive therapy and CS sparing agent Calcipotriol (calcipotriene), calcitriol and tacalcitol simultaneous application with CS or alternating application with CS skin irritation Reversible hypercalcemia if used on large areas of the skin
Topical calcineurin inhibitors Tacrolimus, pimecrolimus Used as first-line treatment for psoriasis in children on sites with the greatest risk for corticosteroid-induced skin atrophy Generally well tolerated, but transient burning, erythema and pruritus can develop
Other topical therapies Keratolytics Tars Anthralin Retinoids – tazarotene
Phototherapy UVB narrow band UVB (311 ± 1 nm) PUVA bath PUVA cream oral PUVA (rarely used in children)
Systemic therapy
• Indicated in 10-20% of children with psoriasis
• Moderate and severe forms of plaque psoriasis if topical
treatment is inefficient, in erythrodermic, pustular and
arthritic psoriasis
• Methotrexate
• Oral retinoids
• Cycosporine
• Fumaric acid esters
• Biologics
JEADV 2015; 29: 2277–2294.
JEADV 2017;31:1951-63.Methotrexate
• an antimetabolite drug that modulates the immune system
and inflammatory processes
• for moderate to severe plaque psoriasis, arthritis, also for
erythrodermic and GPP
• Dosage 0,2-0,7 mg/kg/weekly (orally or s.c.)
• Effect on PASI is slow
• Adverse effects: GI, fatigue, abnormal liver functions tests,
haematological abnormalities
• Folic acid – dosage and timing still questionable
• Liver fibrosis in children is rare
JAMA Dermatology 2017;153(11):1147-57.
J Dermatolog Treat. 2015 Oct;26(5):406-12Acitretin Second-generation aromatic retinoid Indicated for GPP, erythrodermic and severe plaque psoriasis Dosage 0,5 - 1 mg/kg
Acitretin • Common adverse effects: xerosis, cheilitis, epistaxis, increase of hepatic enzymes, serum lipids • Teratogenicity (avoid pregnancy 2 (3) years after drug withdrawal) ! • Only long-term use, and high doses seem to be associated with effect on bones • Regular growth assessment, enquire about possible spine and joint complaints (bone and spine RTG if given for prolonged time in symptomatic patients )
Acitretin and skeletal abnormalities
• in children on long-term therapy with etretinate reports of
bone changes: premature epiphyseal closure, skeletal
hyperostosis and extraoseous calcification,
osteopenia/osteoporosis
• Prospective follow-up of patients on acitretin did not reveal
bone abnormalities or effect on growth
• Regular RTG evaluation exposes the child to unnecessary
radiation, routine RTG assessment are not required
• Targeted X-rays for atypical musculoskeletal pain may be
indicated
Br J Dermatol 1992;127:387-91.
Br J Dermatol 2010;162:952-63.Cyclosporine Immunosuppressant drug approved for treatment of psoriasis in adults Recommended initial dose 3- 5 mg/kg, once remission is achieved dose is tapered down every 2 weeks Indicated for erythrodermic, pustular psoriasis and refractive plaque and palmoplantar psoriasis Onset of action is rapid (2 weeks..) Adverse effects (dose dependent): nephrotoxic, hypertension
Fumaric acid esters
Small molecules with immunomodulatory effects
In 2017 EMA approved FAE for treatment of moderate to
severe plaque psoriasis in adults (Skilarence), European
expert consensus for clinical use published 2018. 1
Adverse effects: GI complaints, flushes, leukopenia,
lymphopenia, eosinophilia
Experience with treatment of children is small 2, 3
Dosage for children is not precisely defined
1. JEADV 2018, 32 (Suppl. 3), 3–14.
2. J Dtsch Dermatol Ges. 2016;14(1):50-8.
3. J Dermatol Treat 2016;27(3)214-20.Apremilast
selective inhibitor of the enzyme phosphodiesterase 4
Not approved for children
Only case report studies using Apremilast in children 1,2
An on-going phase 2, multicentre, open-label study in
subjects with moderate to severe plaque psoriasis
aged 6 to 17 years
1. JAAD Case Reports 2016;2:89-91.
2. Case Rep Dermatol 2016;8:179–184.BIOLOGICS FOR PSORIASIS
The biologics represent a novel class of pharmacological
agents engineered to target specific mediators of
inflammation.
• TNF inhibitors (etanercept, adalimumab, infliximab,
certolizumab )
• IL12/23 inhibitors (ustekinumab)
• IL-17 inhibitors (Secukinumab, Ixekizumab, Brodalumab)
• IL-23 inhibitor ( Guselkumab, Tildrakizumab,
Risankizumab)
J Am Acad Dermatol 2019;80:1029-72.Etanercept • Soluble TNF factor receptor fusion protein that reversibly binds to TNFα and TNFβ • Approved for adults: rheumatoid arthritis, active psoriatic arthritis, active enclosing spondylitis, and moderate to severe plaque psoriasis • FDA approved it for adult plaque psoriasis in 2004 • In United States it is approved in children with moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) down to 2 years of age
Etanercept
EMA approved Etanercept in 2009 for severe plaque psoriasis
refractory to, or intolerant of, other systemic therapies or
phototherapy for children 6 years of age and older
FDA approved it 2016 for moderate to severe psoriasis in children
aged 4 – 17 years
Dosage 0,8 mg/kg/weekly s.c. (>63 kg 50 mg s.c. weekly)
Conflicting data for the treatment with etanercept of
erythrodermic and pustular and psoriasis in children 1-4
1. BMC Res Notes. 2014;7:929.
2. An Bras Dermatol. 2011;86:S144–7.
3. Br J Dermatol 2006;155(1):156-9.
4. Dermatol Ther 2014;27(2):105-8.Etanercept
Randomised, double-blind phase III clinical trial in which 211
paediatric patients with plaque psoriasis 4-17 years old were
treated with etanercept 0,8 mg/kg/week s.c. during 48
weeks demonstrated statistically significant reduction of
disease severity (57% of patients achieved PASI 75 at 12
weeks of treatment) 1
Subsequent 264 week open label for patients who
completed previous study with substantial benefits - good
efficacy and no significant adverse effects 2,3
1. N Eng J Med 2008;385:241-51.
2. J Am Acad Dermatol 2010;63:762-8.
3. J Am Acad Dermatol 2016;74:280-7.Adalimumab • Human monoclonal antibody agains TNFα • FDA approved in 2008 for treatment JA of children >4 years, 2014 for ulcerative colitis and Crohn’s >6 years • EMA approved adalimumab (2015) for the treatment of severe chronic plaque psoriasis in childern from 4 years of age who have had an inadequate response to or are inappropriate candidates for topical therapy and phototherapies • 0,8 mg/kg s.c. (up to maximum 40 mg) at week 0 and 1 and than every 2 weeks
Adalimumab
Randomised, double blinded phase 3 trial that included 114
patients aged 4 to 18 years with severe plaque psoriasis who had
not responded to topical therapy
They received either adalimumab 0.4mg/kg or 0,8mg/kg s.c. at
week 0, 1 then every other week, or oral MTX 0,1-0,4mg/kg
Treatment for 16 weeks, withdrawn from treatment for up to 36
weeks and re-treated with adalimumab for 16 weeks
At week 16 the response PASI 75 was achieved in 58% of patients
treated with adalimumab 0,8 mg/kg (MTX 32%), adalimumab
0,4mg/kg 44%)
No differences in safety profile
Lancet 2017;1;390:40-9.Ustekinumab • Human monoclonal antibody that binds to p40, a protein subunit shared by IL-12 and IL-23 • Approved by EMA (2015), and FDA (2017) for children >12 years of age with severe chronic plaque psoriasis after inadequate response to/or intolerance to systemic therapy and phototherapy • 0,75 mg/kg s.c. for patients
Ustekinumab
• CADMUS study, phase III multicentre randomized double-
blind placebo controlled trial in 110 patients 12-17 years of
age with moderate to severe plaque psoriasis (52 WEEKS)
• Efficacy and safety was studied with standard dose (SD) and
half SD (HSD)
• At week 12 80,6% patients on the SD achieved PASI 75 (61,1%
PASI 90) , HSD PASI 75 78,4%. Beyond week 12 clinical
response in the SD group was generally higher and better
sustained (52 weeks)
• No difference in the frequency of adverse effects compared
to the placebo group
J Am Acad Dermatol 2015;73(4):594-603.Infliximab
• Chimeric protein that binds with high affinity to both soluble
and transmembrane TNF-α
• 3-5 mg/kg i.v. at week 0, 2, and 6, then every 8 weeks
• FDA and EMA approved for treatment of Crohn disease and
ulcerative colitis in children >6 years of age
• The exact role in the treatment of psoriais other than
pustular psoriasis is yet to be determined1,2
• In children with Crohn it can worsen existing psoriasis or be
the cause of new onset of psoriasis 3,4
1. J Eur Acad Dermatol Venerol 2016;30:e117-e119.
2. Pediatr Dermatol 2015;32(1):e13-14.
3. J Am Acad Dermatol 2017;76:334-41.
4. J Pediatr Gastroenterol Nutr 2013;56:512-8.Ongoing studies in children Secukinumab (6 to 18 years) Ixekizumab (6 to 18 years)
Safety of biologics Risk of infection TBC (TNF inhibitors) Increased risk for NMSC (possible slightly increased risk for overall malignancy with TNF inhibitors) Possible risk of major adverse cardiovascular events in early trials but not confirmed in later, larger trials (ustekinumab) Aggravation of preexisting or induction of new autoimmune diseases (LE), paradoxical psoriasis - specific for TNF inhibitors Demyelinating disease, aggravation of MS (causal association remains to be proven between MS and TNF inhibition)
Follow-up for biologics
• Today there are no guidelines for evaluation for paediatric
patients on biologic therapy
• European S3 guidelines for monitoring adult patients on
systemic treatment for psoriasis including biologics 1.2
• USA guidelines for monitoring adult patients on biologic
treatment for psoriasis 3
1. JEADV 2015; 29: 2277–2294.
2. JEADV 2017;31:1951-63.
3. J Am Acad Dermatol 2019;80:1029-72.Pre-treatment evaluation
Objective assessment of severity of the disease, and quality of life
(PASI/BSA/PGA; arthritis; HRQoL (DLQI/Skindex-29, 17)
Patient history – prior treatment, malignancy, infection, CHF,
neurological symptoms
Check for: malignancy, skin Ca, pre-malignant lesions,
lymphadenopathy, laboratory parameters (blood count, liver
enzymes, serum creatinine, urine, pregnancy test, CRP), HBV/HCV,
HIV, exclusion of tuberculosis, evidence of infection
contraception
1. JEADV 2015; 29: 2277–2294.
2. J Am Acad Dermatol 2019;80:1029-72.Follow-up for biologics
Objective assessment of the severity of the disease,
and quality of life
Infections, TBC, malignancy, CHF, neurological
symptoms, lymphadenopathy
LABORATORY PARAMETERS periodically (blood
count, liver enzymes, serum creatinine, urine)
AAD guidelines: need for laboratory workup not
supported by evidence (except for infliximab – liver
function tests), TNF inhibitors considered safe in
pregnancy and lactation 1. JEADV 2015; 29: 2277–2294.
2. J Am Acad Dermatol 2019;80:1029-72.Instead of conclusions Psoriasis is a chronic inflammatory skin disease that has a high prevalence in children Clinical suspicions for the diagnosis is therefore necessary Many treatment modalities: topical, systemic and biologics available Approval of many drugs used in treatment is lacking Absence of guidelines for the treatment of children, many drugs prescribed are not approved Evidence on systemic treatment efficacy and safety is still limited More prospective multicentre studies are necessary in order to develop international guidelines for the treatment in children
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