Hiroo Onoda had taken an oath. In 1944, as he and his fellow Japanese soldiers were posted to Lubang Island in the Philippines, he swore to his commanding officer that he would never relinquish control of the island to Allied Forces. Merely two months after landing, the island was overrun with Allied soldiers, and with many Japanese surrendering, Onodas dedication to his mission was tested. Armed with specialised training in intelligence gathering and guerrilla warfare, he and three other comrades dug in for the long fight. No one could have imagined just how long their fight would last. Whilst the rest of the world rejoiced at the end of WWII in September 1945, Onoda and Co. were unconvinced the war could end so quickly in defeat for Japan. They continued their fight. Repeated leaflet drops and visits from Japanese diplomats (calling through loudspeakers into the jungle) informing of a Japanese surrender, were deemed Allied propaganda by the soldiers, and ultimately ignored. The troop survived for many years in isolation, fulfilling their sworn duties of intelligence gathering and attacking the enemy (local islanders). Onoda survived the longest, an astounding 29 years in jungle warfare. Finally, in 1974, Onoda was tracked down and his retired commanding officer (the only man Onoda would accept orders from) was brought back to Lubang to issue the surrender order.
Psoriasis is a common, chronic, autoimmune condition affecting the skin, with parallels to the above remarkable story. The condition is perpetrated by the bodys own immune cells, most notably T-lymphocytes (though involvement of other cell types such as neutrophils, macrophages and dendritic cells occurs). These highly specialised cells are trained to defend the body from harm. However, in psoriasis, they run amok (as if in search of the enemy that no longer exists), infiltrating dermal and epidermal layers and causing the inflammatory damage which contributes to other hallmark features including hyper-proliferation and aberrant differentiation of keratinocytes, hyperkeratosis, and dilated, hyperplastic blood vessels. Indeed, the characteristic markings (i.e. sharply demarcated erythematous plaques covered by silvery white scales) associated with the most common form of psoriasis, plaque psoriasis, could well be imagined as indicating topographical locations where rogue cells congregate and disrupt the peace. Although it is uncertain as to what triggers psoriasis, genetic predisposition involving both skin-specific and immune-specific genes has been identified, and physical trauma and infection (especially streptococcal infection) are considered amongst the possible initiating events. Our understanding of the molecular dynamics that drive chronic psoriasis is still evolving, with a whole raft of cytokine and chemokine messengers implicated in immune dysfunction. Worthy of special mention are the cytokines; tumour necrosis factor alpha (TNFα), interferon gamma (IFNγ), interleukin-23 (IL-23) and interleukin-17 (IL-17), not only for their potent role on promoting T-lymphocyte infiltration and keratinocyte growth and aberrant differentiation, but also because several of these cytokines have become targets for therapeutic approaches to psoriasis (See Biologic Systemic Treatments, below).
Psoriasis in Children
Paediatric psoriasis is a common occurrence, and is associated with obesity and metabolic syndrome, adding credence to the hypothesis that excess adipose tissue propagates a systemic pro-inflammatory state. Treatment of paediatric psoriasis is complicated by pharmacokinetic differences between children and adults, and further compounded by poor official guidance on approved therapies, as well as limited availability of clinical trial data, making treatment of children reliant on rough extrapolation from the treatment options used in adults. The complex interplay of immune cells and keratinocytes in concocting the inflammatory environment that drives psoriasis, makes finding an effective one-size-fits-all treatment a little tricky. In general, the central approaches to treating psoriasis involve dampening the inflammatory environment which perpetuates the condition, as well as normalising keratinocyte function. Mild forms of psoriasis are generally rescued using topical corticosteroids and Vitamin D analogues, and children generally respond very well to phototherapy. However, for moderate-to-severe disease, where topical therapy and phototherapies prove inadequate or inappropriate, systemic therapies are required.
Systemic Therapies in the Paediatric Population
Non-biologic Systemic DrugsThough not specifically FDA-approved for the paediatric population (due to lack of appropriate clinical trial data for this age group), non-biologic drugs are considered first-line systemic therapies in treating paediatric psoriasis. The immunosuppressant methotrexate (MTX) has been the drug of choice for treating moderate-to-severe plaque psoriasis, though it does suffer from interindividual variability in dosage, requiring dose individualisation. A significant list of side-effects also accompany MTX use (including nausea, vomiting, hepatotoxicity, pulmonary toxicity), especially with long term use, and so the use of MTX in children requires significant monitoring. Acitretin, a non-immunosuppressing retinoid, is used as a replacement for its related predecessor, Etretinate, due to a more favourable pharmacokinetic profile. Acitretin is thought to work by normalising the growth rate of skin cells. Overall, its use is well tolerated and effective, however it use does carry some serious adverse effects (including teratogenicity), and so it should be avoided in young females of childbearing potential. Cyclosporine is an immunosuppressant which dampens the function of T-lymphocytes and is reported as useful in treating other psoriasis subtypes such as erythrodermic and palmoplantar psoriasis. Its rapid onset of action makes it useful for controlling unstable disease states. Fumaric acid esters (FAEs) are immunomodulators with ill-defined mechanisms of action, and have been used to treat plaque psoriasis for decades. FAE therapy appears to be relatively safe (though gastrointestinal complaints are very common), and unlike the other non-biologics, the dosage recommended for adults is effective and well tolerated in children.
Biologic Systemic Treatments
Newer targeted treatments aim to tackle the specific cytokines suspected of playing a central role in disease pathogenesis. TNFα is by far the most well-known of these targets, appearing as a recurring culprit in several other inflammatory diseases, such as rheumatoid arthritis and ulcerative colitis. TNFα antagonists have been designed to block the activities of TNF signalling, and thus help to redress the inflammatory imbalance seen in psoriasis. Etanercept (the first fusion protein to be approved for human use) is a fusion protein that joins the TNF receptor to the Fc chain of an immunoglobulin G (IgG) antibody, which acts as a decoy receptor for TNFα and TNFβ. Although its use in children is only FDA-approved for juvenile idiopathic arthritis, the European Commission approved it for the treatment of paediatric plaque psoriasis in children six years and above. It is administered subcutaneously and has an elimination half-life of about five days. Limited clinical trial data has shown it to significantly reduced disease severity in a paediatric population and its use was not associated with severe adverse events. Infliximab is a chimeric monoclonal antibody which incorporates a human IgG Fc chain with a murine variable region. It differs from Etanercept in that it binds to TNFα (and not to TNFβ) and blocks TNFα from interacting with its receptor. It is administered intravenously and has an elimination half-life of around nine days. Scant reporting of its use in children means it is difficult to assess its efficacy, although some success in treating pustular psoriasis has been documented. From wider studies in adults, infliximab seems to carry a higher infection and hepatotoxicity risk than other TNF antagonists. Adalimumab is a fully human monoclonal antibody directed against TNFα. Its mode of action is similar to that of infliximab, though Adalimumab has a larger antigen-antibody binding interface, and it does not bind TNFβ. Adalimumab is formulated for subcutaneously administration and has a long elimination half-life of between 10 – 20 days. In the EU it can be used for severe chronic plaque psoriasis in children aged 4 years and older. Due to the fact that TNFα plays a central role in general host defences, each of the TNFα antagonists do carry an increased risk of infection, to a lesser or greater degree, with infliximab thought to carry a higher infection risk than the other two contenders. Subtle differences in their modes of action, binding targets and pharmacokinetics reflect the different clinical outcomes observed. The clinical successes achieved with the use of TNFα inhibitors have led investigators to examine the blockade or modulation of several other cytokines pathways implicated in psoriasis. Ustekinumab, an anti-IL-23/anti-IL-12 antibody, and secukinumab, an anti-IL-17 antibody, are relatively new biologics aimed at tackling the IL-23/IL-17 axis implicated in psoriasis. IL-23 has been shown to promote the survival and proliferation of the T helper 17 subset of T-lymphocytes, which in turn are major drivers of keratinocyte growth and differentiation (through IL-17 secretion). A final mention goes to apremilast, a phosphodiesterase 4 inhibitor which modulates inflammatory signals across several cell types. Though it is early days for the use of these therapeutics in paediatric psoriasis, it is likely that they will become prevalent in the coming years.
Ultimately, unpicking the intricacies of inflammatory signalling will lead to a better understanding of psoriasis pathogenesis and may help us to more effectively recall the misguided immune cells to surrender their ill-fated attack.
References Napolitano M, Megna M, Balato A, Ayala F, Lembo S, Villani A and Balato N. Systemic Treatment of Pediatric Psoriasis: A Review. Dermatology and Therapy, 16 April 2016. Schön MP and Boehncke WH. Psoriasis. The New England Journal of Medicine, 5 May 2005. Deng Y, Chang C and Lu Q. The Inflammatory Response in Psoriasis: a Comprehensive Review. Clinical Reviews in Allergy & Immunology, 30 March 2016. Feldman SR. Treatment of Psoriasis. UpToDate® Wolters Kluwer, 11 July 2016