Psoriasis, psoriatic arthritis, and other spondyloarthropathies such as those associated with inflammatory bowel disease (IBD) and IBD itself (Crohn disease being the paradigm), share many pathogenic features. The first characteristic to be identified, and one that was key for defining the concept of immune-mediated inflammatory disease (IMID), was the response of all these conditions to biologic agents that block tumor necrosis factor (TNF). However, there are subtle differences in the pattern of response that are worthy of comment. Examples include the lack of efficacy of etanercept in Crohn disease1 (which has never been satisfactorily explained),2 the fact that ustekinumab is only effective in Crohn disease after prior failure of at least one other anti-TNF agent,3 and clinical worsening in patients treated with interleukin (IL) 17A inhibitors,4 whose spectacular efficacy in psoriasis confirms the fundamental pathogenic role of IL-17A in this disease.5

Another feature common to IMIDs is the appearance of paradoxical manifestations during treatment with anti-TNF agents. Explanations have been proposed for this contradictory behaviour, such as the activation of alternative cytokine pathways. For example, TNF blockade through treatment might induce an increased production of interferon alpha by plasmacytoid dendritic cells, which in turn may then activate production of IL-17A (sustained by IL-23) and IL-22 by the corresponding T-cell subpopulations, as well as expression of IL-22 receptors in keratinocytes.6 This would explain the onset of paradoxical psoriasis in some patients (for example patients with Crohn disease) who receive anti-TNF agents. These patients may have a certain genetic predisposition due to uncommon alleles of the IL23R gene and respond to treatment with ustekinumab,7,8 whereas activation of another feedback circuit in which the cytokines IL-17C and IL-36γ participate may go some way towards explaining the activation of keratinocytes in paradoxical psoriasis. These observations may provide a basis for a new therapeutic approach to this disease9 and perhaps to other pustular dermatoses.

With regards to the counterproductive effect of IL-17A blockade in Crohn disease, it has been observed that patients with active disease have lower circulating CD45RO+CD4+T helper (Th) 17 cell levels than those present when the disease is controlled with adalimumab; the lymphocyte count inversely correlates with mucosal inflammation estimated from the levels of fecal calprotectin.10

This apparent paradox requires an explanation, given that IL-23 (which in principle can expand Th17 cell populations and is able to activate tissue-resident IL-17A–producing Tγδ cells) has a fundamental role in autoimmune intestinal inflammation in murine models of IBD.11 There are probably different types of Th17 cells, able to produce different combinations of cytokines that determine a relatively specific antimicrobial action, and the imbalanced intestinal microflora in Crohn disease, and certain Gram+ bacteria in particular—segmented filamentous bacteria—may play a key role in differentiation of Th17 cells and induction of colitis in murine models of IBD.11

The levels of IL-22 produced by type 3 innate lymphoid cells in the intestine are critical for maintaining intestinal barrier function, and in absence of IL-22, overgrowth of segmented filamentous bacteria may occur, along with an increase in the number of Th17 cells both in the mucosa and the corresponding lymph nodes.12,13 Inhibition of IL-17A, one of the cytokines produced by Th17 cells, exacerbates intestinal disease in some patients with Crohn disease, thus suggesting a protective role of IL-17A, consistent with the observations in some murine models of colitis.14 Although a pathogenic role has been proposed for IL-17F and IL-25 in IBD,15 treatment with brodalumab has not proved effective.2 On the other hand, it has been postulated that exacerbations observed in patients treated with IL-17A inhibitors may be related to altered intestinal mycological flora.16

Currently, it is accepted that a disturbed immune response to an altered intestinal microbiome at the mucosal interface has a fundamental role in the pathogenesis of Crohn disease and ulcerative colitis in individuals with a certain genetic predisposition.17 The microbiome is the set of commensal bacteria associated with each individual, located in the skin, vagina, oral cavity, and principally (70%), the gastrointestinal tract. The dominant phyla are Bacteroidetes and Firmicutes. The intestinal microbiome contributes to digestion of fiber and polyphenols, the production of certain vitamins, and maintenance of epithelial barrier integrity, regulating homeostasis of the host immune system.18 Taxonomic alterations or imbalances in the intestinal microbiome (dysbiosis) have been associated with a range of conditions, including obesity, colorectal cancer, liver diseases, irritable colon, IBD, and other IMIDs.19 Both in IBD and spondyloarthritis, disturbances in the intestinal microbiome have been reported, with a decrease in the number of Firmicutes, which may indicate another common pathogenic mechanism,20 and the existence of analogous disturbances (relative decrease of Coprococcus and other beneficial taxa) in psoriatic arthritis.21

Numerous studies have shown that the intestinal microbiome may have an impact on Th17/Treg balance in the lamina propria, and that intestinal Th17 cells may be responsible for the onset of arthritis in experimental models. The activation of Toll-like receptors plays a key role in the differentiation of Th17 cells in the lamina propria and in the induction of autoimmune arthritis; possible mechanisms include cross-recognition of bacterial and endogenous antigens, migration of Th17 cells of intestinal origin to the joints, and an alteration in the microenvironment of cytokines that may stimulate differentiation of autoreactive Th17 cells.22

Although this mechanism may provide a plausible explanation for the role of a possible dysbiosis in the pathogenesis of psoriasis and psoriatic arthritis, in the case of psoriasis, more attention has been paid to possible alterations in the skin microbiome, by analogy with atopic dermatitis.23

The pathogenic role of intestinal dysbiosis, that is, disturbed immunologic tolerance of intestinal microflora, would seem an important and common feature of different IMIDs. Some physicians, however, may be reluctant to explore the possible therapeutic implications (fecal transplantation) of this mechanism. They may prefer an alternative explanation involving alteration in the skin microbiome, which may have a similar role (alternative or complementary) to intestinal dysbiosis in psoriasis24 and psoriatic arthritis.25

In conclusion, psoriasis, psoriatic arthritis, and Crohn disease share common pathogenic features, but they also show differences that may help elucidate the complete inflammatory cycles implicated and so develop new therapeutic approaches.