Two types of comorbid diseases have been reported in patients with PS: Those diseases sharing the main pathogenic mechanisms and those not sharing pathogenesis but with clinically severe chronic inflammatory conditions (24). SLE belongs to the latter category (25). According to an epidemiological study of PS comorbidity, patients with PS were at greater risk of developing an immune-mediated inflammatory disease (IMID) compared with general population controls (26). The majority of concurrent IMIDs appeared before the diagnosis of PS, indicating that there could be a pathophysiologic mechanism underlying PS and concurrent IMIDs (27-33). A population-based case-controlled study of the coexistence of PsA and SLE in Israel revealed a 2.3-fold increase in the prevalence of SLE among patients with PsA compared with age and sex-matched controls from the general population (34). According to research reports, when analyzed by level of severity, severe PS demonstrated a 3- to 7-fold increased risk for SLE compared with mild PS, especially in Asian patients (28,35,36). The explanation was that patients with moderate to severe PS may be more likely to be receiving additional phototherapy. Both of these treatments increase the risk for the development of SLE (37,38). A 10-year retrospective study identified 42 cases of SLE in 9,420 patients with PS (39). In the same study, the prevalence rate of PS that coexists with SLE was ~1.1%, and was slightly higher in female patients due to the fact that prevalence of SLE is higher in women compared with men. Therefore, when treating female patients with PS, caution should be exercised in medication and vigilance should be exercised against the occurrence of SLE.

A previous study, investigating the prevalence of PS in patients with principally diagnosed SLE, analyzed a large national population database for admission probabilities of patients with SLE, and demonstrated that 150 of a total of 20,630 hospitalized patients with SLE (0.7%) had a co-existing PS condition (40). In another study, it was reported that 0.6% of 520 patients with SLE had PS (41). Patients have a sequential occurrence of PS and SLE, but the probability of both occurring together is <1.2%, and the lower incidences in both cases suggest that comorbidity between two diseases could be an accidental event. According to reports, patients with SLE experienced a psoriatic flare that was likely due to the use of antimalarial drugs such as hydroxychloroquine (10,42). Therefore, when treating patients with SLE and a family history of PS, an alternative drug to hydroxychloroquine would be more appropriate, such as mycophenolate mofetil.

Prior to the discovery of comorbid PS and SLE, it was hypothesized that the pathological mechanisms of PS and SLE were different; PS is a systemic inflammatory reaction caused by Th1 cell activation while abnormalities of SLE are due to highly reactive Th2 responses (43,44). To initiate an inflammation, exposure to external infectious or non-infectious substances, such as bacteria, viruses and ultraviolet radiation, damage the host cells to form an antigen complex with released nucleotides and antimicrobial peptides in the epidermis. Antigen-presenting cells, such as plasmacytoid dendritic cells (DCs), identify this complex and stimulate antigen-specific T cell growth in the skin and lymph nodes (45). The plasmacyte DCs secrete type I interferon that increases the production of IL-23 and TNF-α in myeloid DCs (46). These cytokines promote Th17 cell differentiation, which together with IL-1 stimulation, produce IL-17 and IL-22 that further increase the expression of TNF-α, C-C motif chemokine ligand 20 (CCL20) and antimicrobial peptides such as LL37(47), leading to an inflammatory response in the skin and to keratinocyte proliferation (48). Cytokines associated with SLE include IFN-α, IL-6 and IL-17(49). These inflammatory cytokines, in particular B-cell activating factor of the TNF family (BAFF), also serve roles in autoimmunity and autoantibody production in SLE.

A number of B cell subsets may be strongly associated with SLE. Currently, there are three known B cell effectors involved in the pathogenesis of SLE: i) Pathogenic plasmablasts may be produced without the assistance of T cells, as demonstrated in the BAFF transgenic model (50); ii) autoreactive B cells and CD4⁺ T cells interact at the T cell: B cell boundary after initial autoantigen recognition; and iii) co-stimulatory signals and cytokine crosstalk activate B cells and autoantibody production through a T cell-dependent extrafollicular route or inside spontaneous, autoimmune germinal centers (51,52). Therefore, the aberrant activation of human B cells is a phenotypic hallmark of SLE and is associated with the progress of the disease.

Th17 cells are associated with the pathogenesis of various autoimmune and inflammatory diseases, such as rheumatoid arthritis, SLE, multiple sclerosis, PS, inflammatory bowel disease and allergy and asthma (53), by producing several effector molecules. They are characterized by the expression of the orphan nuclear factor receptor retinoic acid receptor-related orphan receptor-γ-t (RORγt), the cytokines IL-17 and IL-22, the chemokine CCL20, and the inflammatory chemokine receptor C-C motif chemokine receptor 6 (CCR6) (54-56). IL-17 is a potent proinflammatory cytokine produced by highly activated Th17 cells and is known to serve a role in maintaining chronic inflammation in PS. Indeed, highly expressed IL-17, IL-22 and IL-23 have been demonstrated in skin biopsies from patients with PS (57,58). IL-22 is also known to be essential for maintaining the immune barrier within the epidermis and is able to induce the release of antimicrobial agents and β-defensins from keratinocytes and promote epidermal hyperplasia (57). In the recruitment of Th17 cells to local tissues, the CCL20/CCR6 axis has been demonstrated to serve a crucial role (59). Finally, several other factors associated to the Th17 response also engage in the vascular inflammatory pathway by recruiting leukocytes, activating B cells and producing autoantibodies, and therefore may contribute to the occurrence and development of SLE and PS (60,61). The current data indicates the factors that are common between SLE and PS are an increase in the number of Th17 lymphocytes and an increase in the serum levels of IL-17 and IL-23, in which IL-17 is a main proinflammatory cytokine that serves a crucial role in the pathogenesis of various inflammatory diseases, including PS and SLE (62-64).

Patients with SLE have higher serum levels of IL-17 and IL-23 compared with healthy controls (65). Furthermore, IL-17 levels in the plasma are correlated with the severity of SLE (66). Compared with a healthy control group, the concentration of IL-17 in the serum of patients with SLE and the expression of IL-17 mRNA in activated peripheral blood mononuclear cells were increased, which were positively correlated with the Systemic Lupus Erythematosus Disease Activity Index (67-69). The skin biopsy examination of patients with SLE and skin involvement demonstrated that the expression level of IL-17 was increased compared with that of normal individuals, confirming that IL-17 is involved in the immune pathogenesis of SLE (70). IL-17 promotes inflammation and tissue damage in the context of SLE by recruiting neutrophils and monocytes, facilitating T-cell tissue infiltration and promoting antibody production (71). By contrast, IL-17 also facilitates T-cell activation and infiltration into the tissues along with increased expression levels of intercellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase (MMPs) (72,73).

The IL-23/Th17 axis has previously been suggested to be essential in developing lupus nephritis, both in mice models and in patients with SLE (74,75). In mouse models, IL-17 is associated not only to T cell-mediated tissue injury, but also to the production of pathogenic autoantibodies and it was demonstrated that Th17 cells were increased in a MRL/lpr lupus nephritis mouse model (76). The IL-23/IL-17 axis is involved in the pathogenesis of SLE where activated DCs produce the inflammatory cytokines IL-6 and IL-23, which then stimulate Th17 cells to produce IL-17(77). In two in vitro studies, T cells from patients with SLE increased their IL-17 production and concomitantly limited production of the regulatory cytokine IL-2 in the presence of IL-23, leading to exacerbated inflammation (56,57). Additionally, an attenuated inflammation with a striking decrease in the accumulation of double-negative T cells were revealed in the kidneys and secondary lymphoid organs when a IL-23 receptor deficient MRL/lpr mouse SLE model was used (78,79).

It is well known that B cells and autoantibodies directed against numerous nuclear and cell surface antigens serve roles in SLE immunopathogenesis. Given the fact that SLE-derived B cells would increase anti-DNA production in the presence of IL-17(66), an extensive body of data obtained in mice models and humans in terms of the T cell-B cell interactions have revealed that T cells aid the activation of the autoantibody-producing B cells in SLE (80-82). However, the exact function of IL-17 that leads to SLE remains unknown. In the SLE development process, B lymphocyte stimulator (BLyS) can become upregulated and it may act as a survival factor to inhibit B cell apoptosis, to stimulate B cell proliferation and differentiation through an interaction with IL-17, and ultimately to increase the production of autoantibodies (83,84). In addition, increased levels of BLyS would promote the proliferation of Th17 cells leading to increased levels of IL-17, which in turn could act in conjunction with BAFF to promote the survival and proliferation of human B cells and their differentiation into antibody-producing cells (81). In addition to IL-17, the roles of other cytokines in the T cell-B cell interaction have been noted with regard to SLE pathogenesis. For example, IL-21, produced by Th17 cells, stimulates CD8⁺ T cell proliferation and B cell differentiation for immunoglobulin production (66,85,86). These roles of IL-21 have been validated in a lupus-prone mouse model, in which the IL-21/IL-21 receptor pathway was blocked by the administration of a fusion protein, resulting in an alleviated disease progression (87,88). Finally, the production of autoantibodies by activated B cells leads to the activation of DCs and the secreted IL-23 can increase production of IL-17(89) (Fig. 1).

Collectively, this data indicates that the multifarious functions of the Th17 cells and B cells as well as the inflammatory environment created by the T cell-B cell interaction all function together to lead to SLE, as demonstrated in other human IMIDs.

Treg cells are a distinct lineage of T-cell subsets (90) and control the immune responses to self- and non-self-antigens (91). Under normal physiological conditions, Treg cells serve a critical role in maintaining a balance in the immune homeostasis, and abnormalities in the function Treg cells have been associated with the pathogenesis of autoimmune disorders, allergic diseases and even cancer, such as PS, asthma, prostatic carcinoma and lymphoma (92). For autoimmune diseases, low volume or inactivated Treg cells fail to suppress self-reactive T cell proliferation and cytokine production, leading to the imbalanced activities of other effector immune cells such as Th1 and Th17. The suppressive functions of the Treg cells occur mainly through direct contact and/or through its secretion of suppressive cytokines, such as IL-10 and transforming growth factor (TGF)-β (93). In addition, Treg cells reduce the differentiation of cytotoxic CD8⁺ T cells and inactivate B cells (94). Furthermore, the suppressive function of Treg cells is impaired in patients with PS and an altered Th17/Treg ratio in the peripheral blood of patients with PS is due to a decreased number of Treg cells and an increased number of Th1 and Th17 cells (95). The imbalance in the Th17/Treg ratio promotes inflammation due to the production of inflammatory cytokines such as IFN-γ or IL-17 (96,97). Similar phenotypic effector cells and Treg cells are also considered to contribute to SLE pathogenesis (98-100). Therefore, it is possible that the inflammatory environment of PS could be conducive to the development and deterioration of SLE. Although IL-10 is the key cytokine that is produced by Treg cells (CD4⁺CD25⁺FOXP3⁺), it has also been revealed that the D4⁺CD25⁺FOXP3^-Treg cells could also secrete high levels of IL-10 (in a FOXP3⁺ independent manner) to inhibit the in vitro proliferation of CD4⁺CD25^- T cells with a similar efficiency to that of FOXP3⁺ Tregs (91). However, no matter the origin of IL-10 in PS and SLE, the increased levels of IL-10 are associated with the increased levels of antibodies in patients with SLE (101). The increased levels of IL-10 has been hypothesized to stimulate the proliferation of B cells (102,103) and to promote their synthesis of IgG through the upregulation of the interactions between cytokines and B cell receptors (102,104). In addition to secreting IL-10, Treg cells collected from patients with SLE were demonstrated to directly suppress the B cell-mediated antibody production in an in vitro experiment (105), in which Treg cells induced a contact-dependent apoptosis of the B cells through the perforin- and granzyme-pathways (106). Therefore, functional defects in Treg cells, or a lack of Treg cells and IL-10 are considered to contribute to SLE pathogenesis (98-100).

TNF-α is a pleiotropic cytokine that affects the activities of variant cell types in various physiological and pathological conditions, such as in the development of T cells, B cells and DCs. This cytokine is a potent inflammatory mediator and also an apoptosis inducer. Overexpression of TNF-α has been observed in patients with PS for two decades and it was revealed to be distributed throughout the epidermis and specifically localized to the upper dermal blood vessels (107).

The significance of the involvement of TNF-α in the pathogenesis of SLE remains controversial. Previous evidence has suggested that this cytokine serves a dualistic, proinflammatory, and an immune- or disease suppressive role in SLE progress (108). TNF-α was reported to be increased in patients with SLE and was correlated with disease course, and the immunopathogenesis of SLE (109,110). Anti-TNF-α administration also demonstrated that this treatment can suppress the inflammatory responses in an experimental SLE model, which was induced by the injection of human anti-DNA autoantibodies in mice (111). However, the use of an anti-TNF-α agent can also lead to increased levels of autoantibodies for double-stranded DNA (dsDNA) and cardiolipin (112). Higher levels of TNF-α have been reported in patients with PS than in healthy individuals (113); therefore, the pathogenic roles of TNF-α in both diseases should be further classified.

Different subpopulations of T cells (Th1, Th2, Th9, Th17, Th22 and Treg cells) and their corresponding proinflammatory cytokines are all involved in the pathophysiology of PS and SLE (114). Activated T cells secrete proinflammatory cytokines, which in turn stimulate the resident tissue cells to recruit immune cells and further increase the secretion of IL-2, IL-4, IL-9, IL-17 A, IL-22, TNF-α, IFN-γ and GM-CSF in perivascular and renal systems of affected patients with PS or SLE (84,115-118). Nevertheless, chronic inflammation due to abnormal immune responses is the pathogenic bases of SLE and PS. In addition to the aforementioned cytokines and effector cells, other inflammatory mediators, such as those from fibroblast-like synoviocytes (FLSs), could also crosstalk with these factors to lead to pathophysiological conditions and to accelerate inflammation in PS and SLE. Previously, local stromal cells, such as FLSs, have been revealed as inflammatory effectors that affect the phenotype and function of different organs, such as kidney, gastrointestinal tract, and joints, in autoimmune disease (119). For example, the involvement of FLS in inflammation and cartilage destruction has been observed in PsA; however, how activated T cells modulate the release of the inflammatory mediators is not fully understood in both diseases.

In the lupus-induced mouse model, IL-17 production was positively associated with disease progression since the manifestation could be eliminated by reducing IL-17 production and IL 17^-/- mice did not develop anti-dsDNA, anti-single stranded DNA, anti-nuclear ribonucleoprotein and anti-chromatin autoantibodies (78). In mouse models, overexpression of IL-17 using an adenovirus increased the severity of lupus nephritis, while inhibition of IL-17 using neutralizing antibodies resulted in a reduced severity of lupus nephritis (142). These results suggest that IL-17 is involved in the pathogenesis of SLE (71). Currently, a number of IL-17 inhibitors, including the anti-IL-17 monoclonal antibodies secukinumab, ixekizumab and bimekizumab, and the anti-IL-17 receptor A monoclonal antibody brodalumab, have been demonstrated to be effective as PS treatments (143-145). Furthermore, a case report described the efficacy of an IL-17 inhibitor, secukinumab, in a patient with SLE (146). The use of an IL-17 monoclonal antibody to treat lupus was approved by the US Food and Drug Administration. Additionally, a double-blind phase II study has demonstrated the efficacy and safety of ustekinumab (an IL-12 and IL-23 antagonist) in patients with active SLE (147). Ustekinumab has been demonstrated to improve a number of mucocutaneous and musculoskeletal diseases, such as atopic dermatitis, Crohn's disease and ankylosing spondylitis, perhaps by decreasing the levels of anti-dsDNA titers and complement 3. It was also revealed to improve the renal function of the patients with SLE (146,148). After receiving secukinumab treatment, a patient with PsA combined with SLE had improved clinical symptoms along with decreased levels of IL-17 in the serum and renal tissue (149). The success in treating this patient with both SLE and PsA suggests that the IL-17/IL-23 axis is the common immunogenic mechanism for developing both diseases.

Cytokines that activate B cells and promote the interaction between B and T cells contribute to the production of autoantibodies (150,151). Inhibition of B cell-associated molecules should downregulate the overactive immune responses in SLE. B-lymphocyte antigen (126,127) (called CD20) is highly expressed on the surface of all B-cells and also serves critical roles in cell cycle progression during human B cell proliferation and activation. Anti-CD20 antibodies have been employed in treatment of a number of diseases (152). In patients with rheumatic arthritis, anti-CD20 therapy achieved a rapid and almost complete B-cell depletion in the peripheral blood and suppressed the generation of plasma blasts, sustainable for at least 6 months (153,154). The disappearance of the anti-neutrophilscytoplasmic antibody (ANCA) in ANCA-associated vasculitis or anti-desmoglein antibodies in pemphigus confirmed the efficacy of the anti-CD20 monoclonal antibody (155,156). In addition, a study revealed that an anti-CD20 antibody, Rituximab, can reduce the expression levels of RORγt and IL-22 and decrease the numbers of Th17-positive cells (157). In a case report of palmoplantar pustulosis, a less severe and localized variant of pustular PS, after treatment failure with an TNF-α blocker, an improvement was demonstrated with rituximab treatment (158). The present review considered that rituximab might reverse the effects of TNF-α via the antigen-antibody complex. However, contradictory effects of anti-CD20 are also observed in the literaturs. For example, the use of anti-CD20 therapy (Rituximab) for autoimmune diseases such as SLE may be the cause of the development of PS (159,160). It is likely that the depletion of B-lymphocytes in these patients caused an imbalance between the T and B cells and this interaction may promote a hyperactive T cells response.

Unlike Th17 antagonists, the efficacy of IFN-α antagonists on PS is uncertain. Collamer et al (161) found that the number of patients with new onset or exacerbation of preexisting PS is increasing due to TNF therapy. This does not seem to be consistence with the fact that IFN-α is a key element in the early phase of psoriatic skin lesion induction (46). It was suspected that an IFN-α antagonist may also be involved in other mechanisms for PS induction (161), and inhibition of TNF-α has been demonstrated in turn to induce the overexpression of IFN-α (162). Increased expression levels of IFN-α in the psoriatic lesions of patients that have been administered with anti-TNF-α therapeutics were also reported (163). The increased production of IFN-α will stimulate myeloid DCs, promote the polarization of Th1 cells and lead to an excessive proliferation of keratinocytes via IL-15(164).

Likely acting via the same mechanism, treatment with anti-TNF-α agents is controversial in SLE as well, since it may further induce antinuclear antibodies, anti-dsDNA and anticardiolipin antibodies. Indeed, cases of drug-induced lupus have been observed in patients with rheumatoid arthritis (165).

Treatment of patients with both PS and SLE or prevention of the occurrence of comorbidity is challenging. The onset of PS and SLE could appear in a different order of precedence, which may not only affect the profiles of the inflammatory cytokines (such as IL-17, IL-10 and IL-23) but also may change the efficacy of the treatment in each individual patient. For example, phototherapy for PS can exacerbate SLE and hydroxychloroquine or systemic corticosteroids for SLE treatment would exacerbate PS (42).

When ultraviolet (UV) light is used to control PS through triggering keratinocyte apoptosis, it also promotes an immunopathogenesis in lupus (166). As a result, nucleoprotein autoantigens will be transported to the surface of keratinocytes to stimulate the release of further inflammatory cytokines, including IFN-γ, TNF-α, IL-1, IL-6, IL-8, IL-10 and IL-17 (167-170). The accumulation of these apoptotic keratinocytes would increase the aforementioned changes to cause a secondary necrotic process and to amplify the release of proinflammatory cytokines and potential autoantigens (171). These factors would recruit inflammatory cells into the skin and cause tissue inflammation.

By contrast, after the patients with a genetic predisposition to PS and lupus receive UV treatment, the skin cells of the patients will be more likely to have thymine dimmers in their DNA (172). The photo-induced thymine-dimmers in the DNA are then the target antigens of the autoimmune response, thus causing lupus. However, the pathophysiology of induced lupus is still poorly understood. In addition, the mechanism of drug-induced PS is not completely understood. A study concluded that hydroxychloroquine disrupts the barrier of the epidermis by inhibiting transglutaminase activity (173,174). Following this initial break in the skin barrier, the epidermis undergoes a physiological proliferation in an attempt to restore the integrity of the barrier. In a genetically predisposed individual, this damage to the skin barrier may be sufficient to initiate a non-specific stimulus-induced epidermal proliferation (173).

At present, TNF-α inhibitors have been widely investigated for the treatment of PS (175), and anti-TNF-α drugs are frequently reported to induce systemic drug-induced lupus erythematosus (176,177). A number of hypotheses have been proposed for the mechanism of autoantibody induction by anti-TNF-α agents as follows: i) An imbalance between IFN-α and TNF-α induces an apoptosis in inflammatory cells; ii) decreased expression levels of CD44 causes nucleosome accumulation in apoptotic cells and leads to the production of DNA and other nuclear antigens; iii) infections in patients receiving anti-TNF-α can lead to lymphocyte activation and subsequently to polyclonal B lymphocytes production; and iv) suppression of the Th1 response caused by the anti-TNF-α and Th2 response, IL-10, and INF-α, promotes humoral autoimmunity and autoantibody production and suppresses cytotoxic T-lymphocytes (178-181) (Fig. 2).

In a case report, the symptoms of lupus nephritis in patients with both PS and SLE diseases worsened after secukinumab treatment (182). Certainly, caution is necessary when administering drugs to patients with PS and SLE, since it may effective for one of these diseases but it may not be effective for the other disease, particularly when TNF-α antagonists are used. As aforementioned, TNF-α inhibitors have well been documented to cause lupus-like syndromes with the onset of antinuclear antibodies and anti-dsDNA, as well as an exacerbation of PS. Therefore, when treating patients with biological agents, their immunological profiles and family history should be evaluated in detail in order to avoid a deterioration in the inflammation of both diseases.