Does Treatment Recapitulate Pathogenesis?
Recent studies of successful and unsuccessful treatments for GA, although limited by size and their observational nature, nevertheless allow us to an opportunity to contemplate GA pathogenesis vis-à-vis treatment. The moderate efficacy of corticosteroids[58,59,81] and other anti-inflammatory agents, such as dapsone, methotrexate, pentoxifylline, and sulphasalazine, is consistent with the long-established inflammatory nature of GA. However, not all cases of GA are responsive to global anti-inflammatory therapy, suggesting that the inflammation seen in GA exists along a spectrum: milder and moderate GA can be controlled by topical and intralesional corticosteroids, yet severe cases remain recalcitrant to non-targeted immunosuppression.
The relative inefficacy of antimicrobials supports the putative non-infectious etiology of GA.[43,58] The response to antimicrobials that is seen in some GA patients is most likely due to the anti-inflammatory rather than bactericidal activity of antimicrobials. The moderate response seen to dapsone and doxycycline[43,58] supports this hypothesis, as both dapsone and doxycycline also have strong anti-inflammatory action.
The excellent response of GA to anti-TNFα therapy seen in several patients[51,73–75] supports recent studies that implicate overactivation of the Th1 pathway in GA.[35,36] Recent cases demonstrating response of GA to apremilast[69–72] further indite Th1 axis dysregulation in GA, as apremilast also downregulates TNFα expression. The response of GA to dupilumab, as reported by Song et al. suggests that the Th2 pathway may also be hyperactive in GA, supporting the study by Min et al., which found a marked increase in IL-4 mRNA expression in GA lesional skin compared with non-lesional skin. However, as the study by Wang et al. did not show elevated IL-4 mRNA expression, such an association is tenuous.
The regression of GA in response to oral[36,90] and topical[91,92] tofacitinib is consistent with the studies by Min et al. and Wang et al., both of which identify JAK-STAT pathway dysregulation in GA. Furthermore, as previously discussed, JAK-STAT pathway upregulation may be the initial event driving GA pathogenesis; thus, JAK inhibitors may represent targeted upstream therapies for GA.
A recent case of GA unresponsive to tildrakizumab, an IL-23 inhibitor, is somewhat inconsistent with the study by Min et al., which demonstrated Th17 axis upregulation in GA. Nonetheless, the inefficacy of Th17 blockade may not be entirely incongruent with the study by Min et al. Indeed, while Min et al. observed Th17 pathway upregulation, they also reported Th1 and Th2 pathway hyperactivation. We speculate that perhaps the Th1 and Th2 pathways are the major axes that incite GA, whereas the Th17 pathway, although upregulated, is not the major culprit in GA pathogenesis. Thus, perhaps a Th17 blockade alone is insufficient to induce GA regression. Perhaps, a randomized study involving biologics targeting the Th1, Th2, and Th17 axes may not only help establish an evidence-based biologic therapy for GA but may also help in the ascertainment of GA pathogenesis
GA induced by IL-17 and TNFα inhibitors is more difficult to explain and defies our current understanding of GA pathogenesis; however, we can attempt an explanation by considering the relationship between the Th1 and Th17 arms of the immune system. Studies of autoimmunity in mice have shown that ablating either axis causes an upregulation of the other, leading us to speculate that in some patients, Th1 blockade causes pronounced upregulation of the Th17 axis, and vice versa.
Perhaps upregulation of the other axis is overcompensating, inducing GA. Nevertheless, this explanation is inadequate to explain the report of apremilast-induced GA, as apremilast suppresses both IL-17 and TNFα production. Clearly, GA pathogenesis is not amenable to simple explanation and further studies are needed to better understand the immunology underpinning GA.
Am J Clin Dermatol. 2022;23(1):37-50. © 2022 Adis Springer International Publishing AG