PracticalDermatology

Pediatric inflammatory skin disorders such as atopic dermatitis (AD) and psoriasis are characterized by intense pruritus and significant impairment of quality of life. The cumulative lifetime prevalence of inflammatory skin disorders has been reported to be up to 30%, with period prevalence estimated to be 7-14% in children. Management of these disorders has always been complex due to the absence of a cure and lack of clarity in their pathogenesis.

Until recently, the mainstay treatments of emollients, steroids, calcineurin inhibitors, and off-label immunosuppressants have had qualified efficacy but potentially serious side effects with spotty and often non-rigorous long-term data. Although efficacious, topical corticosteroids have important limitations regarding duration, location, and extent of use, leading to recurrence of symptoms associated with reduced frequency or cessation of treatment. Their effectiveness may also be limited by the potential for tachyphylaxis and topical steroid withdrawal (TSW), although clinical evidence for these side effects remains inconclusive. Other topical agents, such as calcipotriene and tazarotene, have well-documented adverse events, such as skin irritation, and newer topical therapies such as topical immunomodulators can be expensive and difficult to access and have significant safety considerations that can be concerning to patients.

More recently, the FDA-approved biologic agents for both AD and psoriasis have raised the bar with impressive effectiveness and favorable safety profiles, but the fact that they are injections, and their generally high cost can relegate them to more extensive and severe disease. Although great progress has been made in pharmacologic and biologic therapies for skin disorders, only a few are FDA-approved in children and there is still a large unmet need for development of safe, well-tolerated, and effective therapies to increase probability of achieving disease control.

The Promise of New Therapies

There are exciting medications in the pipeline, however, some of which may change this narrative. A novel small-molecular topical therapeutic aryl hydrocarbon receptor (AhR) modulating agent called Tapinarof is on the horizon for the treatment of psoriasis and atopic dermatitis. AhR is a ligand-dependent transcription factor that regulates gene expression in cells and plays an integral part in maintaining skin homeostasis by regulating skin immune network, keratinocyte differentiation, skin barrier function and pigmentation, and oxidative stress. Endogenous and environmental AhR ligands include arachidonic acid metabolites, polycyclic aromatic hydrocarbons, and polychlorinated biphenyls.

Nonspecific modulation of AhR signaling has a similar mechanism of action of coal tar, which contains a mixture of organic compounds including polycyclic aryl hydrocarbons that may activate AhR to exert a therapeutic effect. One of the proposed mechanisms for the clinical effect of AhR modulating agents in patients with psoriasis is the suppression of key inflammatory cytokines Th17/Th22 in skin tissue. The similar mechanisms of newer promising medications like Tapinarof with coal tar preparations, as well as the long-known effectiveness and safety of Goeckerman therapy, have renewed interest in this area, especially for consideration in pediatric patients.

The Comfort of Old Friends

The accessibility, efficacy, and safety of coal tar warrants re-evaluation for use in the treatment of inflammatory skin disorders. Coal tar solution has been in use for decades. Since 1925, the Goeckerman regimen has been a standard therapy for psoriasis vulgaris and has also been used previously in the treatment of numerous other skin conditions including AD, scabies, neurodermatitis, sarcoidosis, and pityriasis lichenoides chronica.

Coal tar is obtained by heating coal in the absence of air, and its composition depends mainly on the temperature of distillation. High-temperature coal tars (1000–1300ºC) have a higher polycyclic aromatic hydrocarbon (PAH) content than low-temperature coal tars (400–700ºC). Various coal tar distillates, such as medical pix lithantracis and liquor carbonis detergens (LCD), can be extracted depending on the coal used, the temperature at which it is produced, and the kind of vessel used. Figure 1.

FIGURE 1: Process of Forming Coal Tar Distillates from Coal

Although the exact pharmacologic mechanism of coal tar remains unknown, a compound called carbazole with antiangiogenic and anti-inflammatory properties has been found from fractionated coal tar that decreases the production of pro-inflammatory mediators IL-15 and nitric oxide synthase. Furthermore, carbazole inhibits signal transduction and activation of Signal Transducer and Activator of Transcription 3 (STAT3)-mediated transcription that is part of the pathophysiology of psoriasis. Thus, coal tar has anti-inflammatory, antibacterial, and antipruritic effects.

At the start of coal tar treatment, hyperplasia of the skin is seen; continued application, however, has a cytostatic effect that causes epidermal thinning, and a transformation in the parakeratotic regions in the epidermis of psoriatic skin to orthokeratotic regions. This can be explained by the coal tar’s ability to increase the mitotic labeling index of epidermal keratinocytes and suppress DNA synthesis which decreases the net mitotic rate of the epidermis.

Clinical Evidence

Multiple retrospective studies have converged on evidence that the long-term effects of coal tar therapy show minimal side effects. In two parallel retrospective studies, data collected from patients who had been hospitalized in the period 1950-1954 and had received treatment with coal tar and UVB (Goeckerman regimen) for psoriasis or eczema showed no increased risk of skin cancer after 25 years. Not only does this class demonstrate an excellent safety profile, but it also has long remission rates, something especially notable given the rebound effect that has been well-characterized with corticosteroids.

A retrospective study on the Goeckerman treatment in children with moderate to severe psoriasis showed minimal adverse effects and sustained remission. Results of the study showed that 85% of the patients had >80% clearance of their psoriatic plaques, which is comparable with the success rates observed in adults who received the same treatment. Moreover, in follow-up of these patients, remission was sustained for a mean of 2.6 years. This long duration of remission is consistent with other reports that indicated that duration of remission was longer for Goeckerman treatment than for systemic agents available at that time for psoriasis (etretinate, cyclosporine, and methotrexate). Table 1 summarizes the Goeckerman coal tar treatment outcomes of various clinical studies during the past several decades.

Coal tar’s excellent safety profile and sustained remission is especially important in children due to their higher rates of percutaneous drug absorption and thus greater risks for toxicity. Compared with adults, infants and children have an increased ratio of skin surface area to volume, as well as a relatively immature barrier function of skin, which enhances the danger of accumulating significant serum drug levels. In addition, children with generalized skin disorders may have an even greater rate of drug absorption secondary to impairment of the normal skin barrier. This makes coal tar especially desirable in pediatric skin disorders and in sensitive skin areas. For example, LCD has been used in combination with barrier creams and moisturizers to treat steroid-resistant cases of lichen sclerosus.

Coal tar treatment today is mostly used as an adjunct to treat psoriasis, particularly in its chronic stable plaque form, although it is still the first-line therapy in some parts of the world. The primary reason for its decreased use seems to be decreased reimbursement for hospitalization of patients and lack of facilities for this treatment. The Goeckerman treatment can only be given in specialized centers with access to the necessary equipment, space, pharmaceutical products and trained support staff, and a lot of patients cannot afford the time commitment. Furthermore, although not a true adverse effect, the staining and odor can lead to patient nonadherence.

In addition, cost is another advantage for coal tar products versus other topical therapies for psoriasis and AD. A 120-gram unit of calcipotriene ointment has an average wholesale price (AWP) of $240.65 and a 100-gram unit of 0.03% tacrolimus has an AWP of $195.13, whereas 100 grams of petrolatum compounded with 5% LCD might cost $124.77. Considering how coal tar treatments also have long remission rates, the cost advantage for maintenance therapy in between flares is significant for coal tar-based emollients versus other regiments. All these benefits of coal tar make them valuable considerations for pediatric patients who continue to have unmet needs and remain an attractive potential adjuvant or replacement therapy.

Conclusion

Pediatric inflammatory skin disorders such as AD and psoriasis remain complex and challenging diseases with many unmet needs. While current conventional treatments do offer relief for many, the potential risks, financial burdens, and routes of administration may lead to the re-exploration of coal tar treatments. These therapies remain attractive potential adjuvant or alternative treatments with room for further research into different methods of preparations and compositions that can make it more easily accessible and usable at home.

Conflicts of Interest:

PAL reports research grants/funding from the National Eczema Association, AOBiome, Regeneron/Sanofi Genzyme, and AbbVie; is on the speaker’s bureau for Regeneron/Sanofi Genzyme, Pfizer, Incyte, Eli Lilly, LEO, Galderma, and L’Oreal; reports consulting/advisory boards for Almirall, ASLAN Pharmaceuticals, Dermavant, Regeneron/Sanofi Genzyme, Pfizer, LEO Pharmaceuticals, AbbVie, Eli Lilly, Micreos, L’Oreal, Pierre-Fabre, Johnson & Johnson, Level Ex, KPAway, Unilever, Menlo Therapeutics, Theraplex, IntraDerm, Exeltis, AOBiome, Realm Therapeutics, Altus Labs, Galderma, Verrica, Amyris, Bodewell, Burt’s Bees, My-Or Diagnostics, and Kimberly-Clark. In addition, Dr. Lio has a patent pending for a Theraplex product with royalties paid and is a Board member and Scientific Advisory Committee Member of the National Eczema Association.

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