Childhood psoriasis L40.-

Psoriasis is a common, acute or chronic polygenic skin disease with T-cell mediated autoimmune disease, provoked by exogenous and endogenous stimuli, occurring at all stages of life and affecting about 2% of the Central European population. There are characteristic, stretched, localized or generalized, mostly symmetrical, varying degrees of increased consistency (palpation findings leathery firm), sharply defined, red or with white scales covered papules or plaques. Joint involvement of varying degrees is found in 30% of psoriatics. Psoriasis is also an indicator disease for metabolic comorbidities when it occurs during childhood.

A prevalence of 0.7% is reported for childhood psoriasis. In a recent large survey (n= 293,181 children+young people up to 18 years) a prevalence of 0.45% was stated. The prevalence figures rise from 0.13 % (age< 2 years) to 0.67 % (age group 14-18 years).

14.8% of psoriasis cases occur before the age of 15. In the USA, the prevalence of childhood psoriasis was reported to be 128/100,000 in a collective of 4.3 million people in 2018, and 16/100,000 for moderate to severe psoriasis (Paller AS et al. 2018). As with adults, there is no established gender preference.

Genetic factors: it is undisputed that genetic disposition plays a decisive role. Genes associated with psoriasis are based on different genetic factors. chromosomes (polygenetic inheritance). A genetic risk factor is PSORS1 (acronym for PSORiasis- S = susceptibility locus) a susceptibility locus within the major histocompatibility complex on the chromosome locus 6p21.3. PSORS1 is the main predisposing factor for psoriasis in the early years of life (type I psoriasis). The susceptibility locus PSORS2 (gene locus: 17q24-q25) with the associated genes for RUNX-1 and RAPTOR, PSORS3 (gene locus: 4q) PSORS4 (gene locus: 1cen-q21), PSORS5 (gene locus: 3q21), PSORS6 (gene locus: 19p), PSORS7 (gene locus: 1p), PSORS8 (gene locus: 4q31) have various other functions in psoriatic inflammation. Apparently a genetic network with a "variable, disease-typical gene signature that can be activated by various factors" exists. In psoriasis (see also atopic eczema), this gene network is influenced by inflammatory (Th1 and Th17 cells) cytokines (e.g. interferon gamma/TNF alpha). It has been shown that a single nucleotide polymorphism (SNP+489 variant of allele A) of the TNF-alpha gene is a significant predisposition for psoriatic arthritis. This TNF-alpha gene polymorphism is also related to the severity of psoriasis or its response to Etanercept.

HLA: described are associations with HLA-B13, HLA-Bw57, HLA-Cw6, HLA-B27, HLACw2, HLA-DR4 and HLA-DR7. However, HLA-Cw*06:02 seems to play a special role (carriers of this allele are 10 times more likely to be affected by psoriasis).

Antimicrobial peptides (AMPs): an overexpression of antimicrobial peptides, in particular cathelicidin, beta-defensin, and psoriasin, seems to play an important role in the pathogenesis of psoriasis (see also the low tendency to infections in psoriasis vulgaris!) It has been shown that cathelicidin LL37 binds and complexes the body's own cytosolic DNA (which is detected in psoriatic keratinocytes!). The complexes can induce an interferon response with an inflammatory reaction (see below Inflammasome).

Trigger factors in children are:

Infections (mostly infections with beta-hemolytic streptococci, e.g. in streptococcal angina);

mechanical traumas

solar dermatitis

emotional burdens

Keratinocytes/keratins: Mediators stimulating keratinocytes (TNF alfa, IL-8, Granulocyte macrophage colony-stimulating factor = GM-CSF) result in a proliferation stimulus. The cell cycle of the keratinocytes is accelerated more than 8 times. Cells of the basal cell layer need only 4 days to reach the str. corneum. 25% of the keratinocytes (3-fold increase) are in the proliferative S-cell cycle phase. Such proliferation-promoting mediators are also produced by keratinocytes themselves (interleukins - IL-1, IL-6, IL-8, IL-17A, interferon gamma, TNF, transforming growth factor alpha (TGF-alpha) and GM-CSF (see below growth factors). Furthermore, interleukins 17 and 22 are responsible for keratinocyte hyperplasia. These are produced by the Th17 cells. The structural proteins of the keratinocytes are also altered (reduction of suprabasal keratins 1 and 10; neo-expression of keratins 6 and 16). The role of the cytokine "thymic stromal lymphopoietin", which is produced in psoriatic keratinocytes, has not yet been finally clarified.

Autoantigens: Various potential autoantigens are important for psoriatic inflammation, such as the ADAMTS-like protein 5 expressed by melanocytes and the antimicrobial peptide LL37. Both proteins are recognised by TH17 cells after binding to the protein HLA-C*06:02 (s.HLA system) and thus initiate psoriatic inflammation. Remarkable is a structural homology of keratin 17 with M-proteins of streptococci. In this respect keratin 17 also presents itself as a potential autoantigen.

Lymphocyte/homing signals: probably at the beginning of the psoriatic inflammation cascade activated dendritic cells (DCs) and macrophages are present, which are stimulated to secrete pro-inflammatory cytokines such as IL-1, IL-6, IL-12, IL-23 and TNF-alpha. This activates interferon gamma producing CD4+ T lymphocytes. This process leads to the maturation of naive T cells into Th17 cells and other inflammatory Th cell populations like Th-1 lymphocytes (Th1 lymphocytes; no IL-4 production). Th-1 lymphocytes (as well as Th17 cells) play a central role in the pathogenesis of psoriasis (blocking of CD4-T lymphocytes by anti-CD4-AK leads to a clinical improvement of psoriasis, other lymphocyte-suppressive drugs such as Ciclosporin, fumaric acid ester, also PUVA therapy, cause this effect, among others). The activated T-lymphocytes receive an "address" through the expression of certain surface markers, thus defining the place where they are needed. These so-called "homing" signals, which are mediated by cutaneous lymphocyte-associated antigens (CLA), enable the lymphocytes to infiltrate both compartments, epidermis and dermis. In psoriatic patients, it has been shown that inflammatory T cells produce the receptor alpha-1-beta-1-integrin (VLA-1) directed against collagen IV (collagen of the basement membrane). This integrin is expressed on epidermal lymphocytes in lesional (not unaffected) skin. This suggests that epidermal T cells are central effectors in psoriasis. Blocking VLA-1 significantly inhibits the migration of human VLA-1 expressing T cells.

Dendritic cells: Dendritic cells (DCs) are outposts of the immune system and are the link between the specific (acquired) and non-specific (innate) immune system (see below, Immunity, innate / acquired). As so-called professional APs they express both antigen-presenting HLA class II molecules and co-stimulating molecules. Myeloid DCs are increasingly found in the psoriatic lesion. Under PUVA the lesional myeloid DCs decrease.

Chemokines: The infiltrating Th1 lymphocytes interact with different dermal and epidermal cell systems. A number of chemokines, chemokine receptors, integrins and adhesion molecules are involved (CCR5, CXCR3 receptors, E-selectin, LFA-1, ICAM-1, VLA-4, VCAM-1, etc.). These promote the adhesion of T-lymphocytes and neutrophilic granulocytes. Furthermore IL-8 and RANTES (see below chemokines), which induce the migration of certain T-lymphocytes.

Inflammatory mediators (see below cytokines): In psoriatic inflammation, numerous inflammatory mediators are detected: TNF-alpha, IL-8, IL-19. Peripheral mononuclear cells show increased titers of TNF-alpha, IL-1beta, IL-6, monocytes produce increased amounts of IL-1alpha, IL-1beta, IL-8. The detection of these proinflammatory mediators proves that psoriasis is not only a local inflammation but also a systemic disease.

Endothelial cells: Angiogenesis factors (ESAF = Endothelial cell stimulating angiogenesis factor; Vascular endothelial growth factor = VEGF) are strongly increased in the psoriatic lesion and in serum. They cause vascular proliferation. ESAF is mainly formed by keratinocytes and fibroblasts, VEGF by keratinocytes. The activated dermal capillaries express adhesion molecules (ICAM-1, ELAM-1, VCAM-1) that enable CD4+ T lymphocytes to dock to the endothelium and penetrate through the vessel wall. The role of nitrogen oxides (NO) (INF-gamma is an inducer of NO), which have a vasodilating effect, is still unclear.

The most frequently affected areas in children are the scalp, especially the capillitium, elbows, knees, auricles and navel. In 44% of children the genito-anal area is affected.

15% of all children with psoriasis show psoriatic nail dystrophies (dimples, nail thickening, oil stains, complete onychodystrophies).

Plaque type: With 60-70% of cases, classical plaque psoriasis is the predominant type of psoriasis in childhood. Mostly the scalp is affected with large, coarse lamellar red plaques.

Flat psoriasis can also develop in the diaper area ("diaper psoriasis").

Guttate psoriasis: The second most common form of psoriasis in children is guttate psoriasis (probably triggered by bacterial infections such as acute tonsillitis) as the first manifestation of childhood psoriasis (guttate psoriasis occurs in 40% of cases for the first time in childhood).

Diagnostically important is the triggering of various "psoriasis phenomena" within the foci:

• Candle spot phenomenon
• Phenomenon of the last cuticle
• Pointed out sign.

Clinical variants of psoriasis are:

• chronic inpatient plaquepsoriasis
• psoriasis anularis
• psoriasis capillitii
• Erythema anulare-like psoriasis
• Erythrodermia psoriatica (erythrodermal maximum form of psoriasis)
• psoriasis follicularis
• guttate psoriasis
• intertriginous psoriasis
• Inverted psoriasis
• Pustulosis palmaris et plantaris
• Pustular psoriasis palmaris et plantaris
• psoriasis seborrhoides
• Psoriasis of the nails.

Comorbidities: allergic rhinitis (15.2%), bronchial asthma (12.2%), obesity (7.1%). Compared to healthy children, the following increased prevalence figures for the individual comorbidities were found (P= psoriasis, G:healthy children)

• Obesity (P:7.1 %/G: 3.6 %)
• Hyperlipidemia (P: 1,1 %/G: 0,64 %)
• arterial hypertension (P: 0,9 %/G: 0,4 %)
• Diabetes (P: 0.6 %/G:0.3 %)
• Iridocyclitis (P: 0,4 %/G: 0,04 %)

Arthritis (P: 0.5 %/G: 0.3 %); usually only oligoarthricular infestation pattern is found. Psoriatic arthritis mainly affects the metacarapophalangeal joints (MCP) and the interphalangeal joints (PIP), more rarely the sacroiliac and intervertebral joints.

The S3 guideline for the treatment of psoriasis in adults cannot be applied to children because most preparations are not approved for children. There are few controlled clinical trials for children. This makes it almost impossible to produce an evidence-based guideline. The approval of some biologicals for children, however, expands the treatment options.further information, see below Psoriasis

Climatotherapy: Stays of several weeks in a marine or high mountain climate are often very effective for a few weeks or months, but their effectiveness is limited after the end of the stay. Cures have proven themselves, e.g. at the North or Baltic Sea as well as at the Dead Sea (German Medical Center (DMZ) at the Dead Sea in Ein Bokek, Israel or Dead Sea Spa Medical Center in Jordan).

Psoriasis and tonsillectomy: Opinions on the success of tonsillectomy are divided. Carriers of the HLA-Cw6 allele are 10 times more likely to suffer from psoriasis. The homocytology of HLA-Cw6 is associated with a higher risk of disease. At the same time, these patients are more frequently affected by streptococcal-based pharyngitis. Apparently, this special (mostly childhood/youthful) psoriasis clientele profits from tonsillectomy.

Note: In children, topical therapy should be preferred. A systemic therapy is only indicated in refractory cases. The decision has to be made individually.

The classical external treatment methods are: dithranol, retinoids, salicylic acid, urea, glucocorticoids, vitamin D3-analogues, phototherapy (UV-therapy), balneo-phototherapy, tacrolimus (strictest indication because of unclear long-term side effects! Off-Label-Use!), Pimecrolimus (strictest indication because of unclear long-term side effects! Off-Label-Use!).

Vitamin D3-analogues(Calcipotriol): In 0,005% ointment basis (e.g. Daivonex is approved for children from 6 years on) well suited for ambulant therapy. Cave! Resorptive NW (hypercalcemia, nephrocalcinosis)! The ointment should therefore be applied twice daily to the diseased skin areas. The amount of ointment used weekly should not exceed 50 g for children between 6 and 12 years of age (with a body weight of at least 35 kg) and 75 g for children over 12 years of age (with a body weight of at least 50 kg). Children in these age groups with a lower body weight should use 1.4 g of ointment per kg body weight. The duration of application for children and adolescents is up to 8 weeks. Irritations in the facial area may occur.

Combination with glucocorticoids is possible (Kravvas G et al. 2018), e.g. Daivobet®; this combination is also available as spray foam - (Enstilar®).

Tacalcitol (Curatoderm): application 1 time a day. Treatment of the facial area and, if necessary, of the intertrigines is possible. In 0.0004% ointment base and emulsion for application 1mal/day, also suitable for sensitive areas. Approved for children over 12 years, maximum daily amount 10 g.

Vitamin D3 analogues in rotation with dithranol (psoradexane) have proven to be effective (under stationary conditions). If necessary in combination with UVB irradiation.

Dithranol: In-patient treatment: Classic dithranol long-term therapy (see Table 1) with increasing concentrations (psoradexan, psoradexan mite/forte). The dithranol-1 ointment (vaseline based) is provided with a 2% salicylic acid addition for preservation reasons. Treatment is always carried out 2 times/day. Start with 0.05% dithranol, increase depending on the skin condition to 0.1%, 0.25%, 0.5%, 1%, 2% to max. 3%. A rotation principle with dithranol in alternation with medium-strength glucocorticoids such as 0.1% betamethasone cream (e.g. Betagalen) or 0.1% triamcinolone cream (e.g. Triamgalen) or a 0.05% calcipotriol ointment (e.g. Daivonex ointment) has proven successful. Supplementation by balneo-phototherapy: Before morning ointment therapy, a brine bath in 1% NaCl-solution with a bath duration of 25-20 minutes. Initial dose 1/3 of the individual MED. Increase every 3 days by the initial dose.

Calcineurin inhibitors: Topical treatment with calcineurin inhibitors is useful and successful in children for circumscribed foci (Kravvas G et al. 2018)

Glucocorticoids: In the case of extensive psoriasis, glucocorticoids are contraindicated as the sole therapeutic principle (risk of systemic side effects due to absorption of the highly potent external glucocorticoids). In a few chronically inpatient foci, initial therapy with glucocorticoid ointments/creams is acceptable. Combinations of glucocorticoid externa with salicylic acid (have proved successful). Note: Concentration of salicylic acid in Externa: in infants: 1-1.5%; infants: 1.5-2.0%; older children: 2.0-3.0%. Important: do not apply to large areas: infants <5% of body surface (KO), infants <10% KO; older children <20% KO. No applications in the intertriginous area due to increased absorption and irritation.

Salicylic acid: this keratolytic and anti-inflammatory agent is rightly used based on the good and decades of clinical experience. The study documents for this form of therapy are inadequate and are not expected to improve in the next decades. Nevertheless, the keratolytic application can be useful in case of strongly scaling psoriasis in childhood: e.g. in case of psoriasis capitis: 1-3% application form (e.g. Lygal head ointment). Body foci: infants: 1-1.5%; small children: 1.5-2.0%; older children: 2.0-3.0%. Important: no large-area applications: infants <5% KOF; infants<10% KOF, older children < 20% KOF. Note: no applications in intertriginous areas, increased risk of absorption, increased irritation.

Note: Individual psoriatic plaques (knee, elbow, sacrum) are very resistant to topical antipsoriatics. At these sites, an application of dithranol under occlusive foils such as hydrocolloid foils (e.g. Varihesive Foil) or simple household foils, possibly alternating with glucocorticoid ointments, is recommended over a period of 2 hours twice a day.

SUP: Favourable effects can be achieved by selective ultraviolet phototherapy (SUP), which uses UVB rays with an emission maximum at 305 and 325 nm. In particular in combination with dithranol ointments and brine baths, this form of therapy has proven to be effective in the treatment of chronic inpatient psoriasis. Disadvantage: High expenditure of time, as usually about 30 applications are necessary to achieve a satisfactory result. UVB 311 nm narrow spectrum irradiation is preferable to conventional UVB broadband therapy due to better or at least the same therapeutic effectiveness and at the same time less erythema. It is recommended to use 70% of the previously determined MED as the first therapeutic dose.

If the psoriasis is moderate, UVB irradiation which can be localized precisely is preferable due to the significantly lower UV exposure, e.g. with B-Clear (high equipment acquisition costs!).

Balneophototherapy: Several larger studies (evidence level Ib) prove a superiority of a brine UVB therapy compared to pure UVB therapy.

Notice! In the execution of this treatment method the required brine concentrations between 4.5-12% prove to be only conditionally practicable!

In principle, phototherapy can be combined with systemic therapies. Experience is available for MTX. There are no discernible contraindications for fumarates. For Ciclosporin A the combination has to be rejected because of the increased carcinogenicity.

The indication for systemic therapy of psoriasis must be subjected to particularly strict conditions in children.

The classical external treatment methods should be sufficiently exhausted. Only if no acceptable skin condition can be achieved by the external therapy approaches, a systemic therapy should be applied. Thus, systemic therapies are reserved for the most severe and severe forms. These include the chronically active, therapy-resistant, large-area psoriasis vulgaris, pustular psoriasis, psoriatic erythroderma, all forms of psoriasis arthropathica which cannot be sufficiently treated monotherapeutically with non-steroidal anti-inflammatory drugs, severe therapy-resistant psoriasis capitis as well as psoriasis palmaris et plantaris.

Acitretin: Acitretin is evaluated as a "second-line therapy" after exhaustion of the external therapy options for childhood psoriasis (Subedi S et al. 2018). In a larger North American study (Bronckers IMGJ et al. 2017; n=390 children average age 8.4 years) 14.6% were treated with acitretin. Depending on the clinical findings, the initial doses were 0.3-1.0 mg/kg bw/day. Depending on the response, the dose is reduced to 0.2 mg/kg bw/day; the best effects are found in pustular psoriasis or in erythrodermal forms. Acitretin causes a rapid loss of psoriatic scaling. Clinical freedom is achieved in almost 25% of patients with psoriasis vulgaris. Acitretin can be used in combination with radiation therapy (ReSUP).

Methotrexate (MTX): Despite lack of approval (off-label use), the preparation is successfully used in this age group. Dosage: 10-15 mg/m2 KO/week. Alternatively 0.2-0.4 mg/kg bw/week. In a larger North American study (n=390 children, average age 8.4 years) 62.9% were treated with MTX. In 48.1% of these cases, a drug-related adverse event occurred, mainly of a gastrointestinal nature. The increase in hepatic side effects (13.0%) was associated with overweight.

Ciclosporin A (not approved for children): High response rate. Nephrotoxicity and possible carcinogenicity in long-term therapy are known NW. There is limited experience in children. In a larger North American study (Bronckers IMGJ et al. 2017; n=390 children, mean age 8.4 years) 7.7% were treated with Ciclosporin A. Ciclosporin A (Cy A) represents a fast acting, systemic treatment strategy. Good success is observed in generalised plaque psoriasis, pustular forms and psoriatic erythroderma, usually starting with a dosage of 2.5-5.0 mg/kg bw/day; as a long-term therapy, reduced individualised dosage depending on the success of the therapy. Regular laboratory checks, especially of the blood, liver and kidney status, are required.

Fumaric acid esters: Clinical studies for children are not available. However, the therapy results are encouraging. In a larger North American study (Bronckers IMGJ et al. 2017; n=390 children average age 8.4 years) 4.9% of the children were treated with fumaric acid ester. As a dosage guideline, the weight-adapted amount that would be applied to a normal-weight adult can be used (Fumaderm e.g. up to 3 tbl/day for a 35 kg child).

Etanercept (Enbrel®): Fusion protein (dimeric protein) of human tumor necrosis factor receptor and human IgG1, which specifically binds to TNF-α, biologically inactivates it and thus allows the treatment of plaque-type psoriasis vulgaris in children and adolescents as well as in adults. The approval refers to children > 5 years with severe juvenile plaque psoriasis. There is a double-blind, placebo-controlled study in 211 children and adolescents with severe plaque psoriasis (8 years and older). The effect of the preparation usually occurs after the first injection. In a larger North American study (Bronckers IMGJ et al. 2017; n=390 children, average age 8.4 years) 27.2% of the children were treated with biologicals, especially Eternacept.

Ustekinumab (Stelara®): Human monoclonal antibody directed against the p40 subunits of the cytokines interleukin-12 (IL-12) and -23 (IL-23). The differentiation of Th1 lymphocytes is moderated, as is the IL-23/IL-17A axis of the TH17 immune response. Ustekinumab is approved for the treatment of moderately severe to severe plaque psoriasis in adults and children >12 years of age in whom other basic therapies (e.g. MTX, Ciclosporin A, Fumarate, PUVA therapy) have failed to respond or have failed adequately, or in whom contraindications or intolerances have arisen. The therapy is successful (Leiner P 2015). Dosage: At the beginning of therapy and after 4 weeks 45 mg s.c. each. Maintenance dose: 45 mg s.c. every 12 weeks. Compared to Etanercept, Ustekinumab shows the highest 5-year efficacy in adults (Zweegers J et al. 2017). The side effects in children and adolescents aged 12 years and older with plaque psoriasis were investigated in a phase 3 study with 110 patients aged 12 to 17 years for up to 60 weeks. The adverse events reported in this study were similar to those observed in previous studies in adults with plaque psoriasis (Dogra S et al. 2018).

Glucocorticoids: Used only for a very short period of time during high relapsing psoriatic activity. Glucocorticoids are to be rejected as systemic long-term antipsoriatic drugs. Their use generally leads to prompt clinical effects. In this respect, they can be used in a medium dosage for a short period (2-3 days) in highly exudative forms of psoriasis (e.g. in an acute flare of pustular psoriasis).

Spontaneous remissions are observed more frequently in children than in adults. Typical, however, is a chronic, stationary or recurrent course that lasts for decades.

There is a legal liability risk in the case ofadverse drug reactions(ADRs) under off-label therapy. It is therefore essential to discuss this with the parents (and, depending on age, also with the child). These discussions should be documented. Cave: Determination of the custody!

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