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? - CROATIA Slobodna Murat-Sušić Department of dermatology and venereology University Hospital Zagreb - espd.info
Childhood psoriasis. Where are
          we now?
              Slobodna Murat-Sušić
    Department of dermatology and venereology
            University Hospital Zagreb
                     CROATIA
Childhood psoriasis. Where are we now? - CROATIA Slobodna Murat-Sušić Department of dermatology and venereology University Hospital Zagreb - espd.info
Scope of the lecture

   Specificities of psoriasis in children
   Comorbidities
   Overview of therapies
   News in treatment modalities
Childhood psoriasis. Where are we now? - CROATIA Slobodna Murat-Sušić Department of dermatology and venereology University Hospital Zagreb - espd.info
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.
Childhood psoriasis. Where are we now? - CROATIA Slobodna Murat-Sušić Department of dermatology and venereology University Hospital Zagreb - espd.info
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
Childhood psoriasis. Where are we now? - CROATIA Slobodna Murat-Sušić Department of dermatology and venereology University Hospital Zagreb - espd.info
Childhood psoriasis. Where are we now? - CROATIA Slobodna Murat-Sušić Department of dermatology and venereology University Hospital Zagreb - espd.info
Childhood psoriasis. Where are we now? - CROATIA Slobodna Murat-Sušić Department of dermatology and venereology University Hospital Zagreb - espd.info
Childhood psoriasis. Where are we now? - CROATIA Slobodna Murat-Sušić Department of dermatology and venereology University Hospital Zagreb - espd.info
Childhood psoriasis. Where are we now? - CROATIA Slobodna Murat-Sušić Department of dermatology and venereology University Hospital Zagreb - espd.info
Childhood psoriasis. Where are we now? - CROATIA Slobodna Murat-Sušić Department of dermatology and venereology University Hospital Zagreb - espd.info
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;153:698-704
TREATMENT
 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):406-12
Acitretin
 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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