Psoriatic arthritis (PsA) is a complex and chronic inflammatory disease characterized by an association of psoriasis and arthritis in which different manifestations run together during the disease course [1, 2]. Recent GRAPPA and EULAR recommendations [3, 4] were published on the treatment management of PsA, based on over 20 years of active research that have led to the development of efficacious and effective drugs to treat all disease domains. Biologic DMARDs (anti-TNF, anti-IL-12/23, anti-IL-23, anti-IL-17) and the new targeted synthetic DMARDs (JAK inhibitors- JAKi such as tofacitinib, upadacitinib and PDE4 inhibitor—apremilast) revolutionized the treatment of PsA with proved efficacy and effectiveness in the achievement of remission, low disease activity and in a “comprehensive” disease control (efficacy on almost all disease domains) [3].

Due to the increasing number of drugs, the possibility to implement a “precision” medicine approach has become more real: in fact, some differences in mechanism of action exist between the different drugs, based on their capability to inhibit one target cytokine (anti-TNF, anti-IL-23, anti-IL-17A), two cytokines (IL-12/23 inhibitors, IL-17A/F) or more cytokines (apremilast and JAKi, which leads to different cytokines expression reduction such as IL-22, IL-23, IL-6, IFNy and other, or new dual variable domains drugs that inhibits TNF and IL-17). In this view, a tailored approach based on disease domains and pathogenetic aspects may be real in the future [5].

However, despite the different mechanism of action, differences in clinical efficacy for the different disease domains are more faded, with a general similar efficacy, mainly in the context of articular domains [6]. JAKi (in particular, upadacitinib at 30-mg dose in the SELECT-PsA 1 trial) potentially may be superior on the achievement of ACR20 in respect to anti-TNF [7] but head-to-head trials are still scarce and evidence should be further amplified. On the other hand, anti-IL-12/23, anti-IL-17, and anti-IL-23 agents are more efficacious on skin disease than anti-TNF [8, 9].

Finally, some agents showed direct (anti-IL-17, MAXIMIZE study) and indirect evidence of efficacy (JAKi, anti-TNF) on axial disease, while for other drugs, the evidence is still insufficient [10].

In this context, and for the reasons stated ahead, the recent GRAPPA recommendation allows for the treatment of PsA all those agents without a hierarchical scheme [3], but with some differences in respect to the presence of peculiar clinical manifestations (e.g., extra-articular manifestations) or comorbidities/contraindications for the single drug class (e.g., Crohn’s or ulcerative colitis for anti-IL-17, heart failure/demielinization for anti-TNF) following the strength of recommendation after a review of the literature (GRADE) [3]. In this context, the first b/ts DMARDs choice for PsA patients could be based on clinical judgment or restrictions/potential adverse events of single drug class, or based on costs for the health system.

Another important aspect is the probability of response to a certain drug in naïve PsA patients: in clinical trial and clinical practice, about 1/3–1/4 of patients (naïve to b/tsDMARDs) lack to respond to a first b/tsDMARDs or may have a loss of response/side effects (with only about 20% of patients remained on any particular biologic agent after 5 years of treatment [11]. This percentage is further reduced if our aim is to induce a condition of minimal disease activity or remission, as stated by the recent recommendations. Thus, the implementation of strategies aiming to improve the probability of having a good response is of particular interest. Furthermore, the choice of which drug/mechanism of action to be implemented after failure of previous treatments is not based on strong evidence and a “trial-and-error” approach is usually used, in the absence of accurate biomarkers. Moreover, the treatment responses in those patients are generally reduced in respect to naïve patients.

Recently, the availability of different drugs has led to the concept of “switching” (change between drugs within the same mechanism of action) or “swapping” (change with other drugs with different mechanism of action). The concept of switching was introduced when the only available drugs were different anti-TNF [12], but it raises the attention in the last years when different IL-17 inhibitors and JAKi were indicated for the treatment of PsA.

The effectiveness of these two strategies (switching/swapping) is an interesting and actual field of research, with some evidence arising from new articles, in which the two strategies seem to have the same effectiveness. Ariani et al. recently compared the cycling and swapping strategies in a real-life cohort of PsA patients. They did not observe any statistical difference between cycling and swap strategy. However, the swapping strategy showed an effectiveness not dissimilar to that one observed in the group of patients receiving first line treatment. It is, therefore, possible that the change in mechanism of action can bring some minimal improvement in treatment effectiveness, but the amount of the evidence on this topic is still scarce [13].

Finally, as in rheumatoid arthritis, a significant proportion of patients with PsA could be considered as difficult-to-treat [14], with lack/loss of response to more than two b/ts DMARDs and a moderate-to-high disease activity leading to reduced quality of life.

In this context, in an intriguing disease like PsA, some clinical questions arise: which is the best possible treatment strategy in PsA in terms of the achievement of the best treatment goal (remission/low disease activity) considering the multidomain involvement, the peculiar combination of comorbidities/extra-articular manifestations, the possible different effectiveness of treatments in each disease domains and the availability of a large number of active drugs? How can one improve the choice of the subsequent treatment after failure of the first line agent?

Furthermore, would it be ideal to implement a “sequential” strategy or sequencing of b/tsDMARDs to further improve an “optimal” personalized treatment approach?

To better respond to those questions, further clinical studies are needed. However, in recent years, in-depth characterization of the synovial tissue in PsA is bringing new insights to matching the use of specific agents to the specific target pathways in PsA [15].

Some interesting approaches come from other rheumatological diseases: sequential treatment approach was recently proposed for the treatment of systemic lupus erythematosus, in which the B-cell depleting treatment followed by BLys inhibition may lead to better outcomes [16].

These could be translated in PsA and, in general, in the management of inflammatory arthritis, in which the availability of different drugs with different mechanism of actions and effective on the different phenotype expressions of the disease should lead to sequencing biologic therapy, with the aim to improve patients’ outcomes.

In this light, sequential targeting of “effector” cytokine such as TNF, “enhancer” cytokine such as IL-17, or “inducer” cytokine like IL-23 may be an interesting future research topic [17]. Of note, the availability of small molecules targeting intracellular pathways and leading to the reduction of different cytokines further amplify, or simplify, our choices.

In PsA, preliminary clues are coming from a recent paper, aimed to assess the possibility of a sequential approach, based on IL-17/IL-23 sequential inhibition, in treatment of refractory PsA. This approach conceptualizes observations that IL-23 and IL-17 inhibition share a low infection risk, can act independently from each other, and that IL-23 inhibition may have long-standing effects that may condition patients to IL-17 inhibition [18]. In this small case series, authors demonstrated improved outcomes in severe PsA patients with moderate-to-severe psoriasis based on this innovative approach [18]. This finding could be of particular importance in PsA, in which the different clinical manifestations seem to be driven to specific cells activation and cytokines expression.

On the other hand, sequencing may be implemented in clinical practice, based on a target-to-treat viewpoint [19]: achievement of the best treatment response in the predominant domain with a greater impact on disease activity by using more efficacious drugs (e.g., for skin, axial, peripheral joint, enthesis). Then, when the target is achieved, swap to another agent with less side effects/better safety/tolerability or with better effectiveness in other disease domains less predominant. In this view, it would be possible to improve our patient’s management even in those patients with residual disease activity (RDA) in one or more domains [20,21,22]. In fact, sequential treatment strategy may be applied for patients with RDA occurring during treatment, which can be defined as the activity already present at the beginning of the treatment but not completely controlled. In this scenario, some domains, such as joint, skin, etc. could be still residual and inducing a treatment re-evaluation. Therefore, in the Box 1 a possible sequencing of drugs in clinical practice for PsA patients based on treatment response, residual disease activity and, eventually economic restrictions (i.e., usage of only available biosimilar as first line biologic therapy) is shown as a proposal. This approach is based on initial anti-TNF treatment in patients with active PsA, which is the usual first-line treatment after failure of conventional therapy in PsA patients without limitation/restriction to anti-TNF and with non-extensive skin involvement.

Box 1
figure 1

Possible sequencing of drugs in clinical practice for PsA patients based on treatment response, residual disease activity and, eventually economic restrictions (i.e., usage of only available biosimilar as first line biologic therapy. Legend: *Usually first-line treatment anti-TNF biosimilars. In case of extensive skin psoriasis, it would be possible to consider IL-23/Il-17 inhibitors. MDA Minimal disease activity, GE gastroenterologist, OF ofthalmologist

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Finally, related conditions such as inflammatory bowel disease or uveitis should be taken into account. In this context, the treatment choice is often shared with gastroenterologists and ophthalmologists with limited drug availability [23]. A sequential treatment strategy may be more difficult to apply, but with the development of effective drugs in the near future, it would be possible to implement.

An intriguing aspect is the management of patients that did not achieve minimal disease activity or are potential “difficult-to-treat”. However, to date, there are no evidence-based criteria to assess how switch or swap should be operated. A possible sequential treatment strategy has been used in the above-mentioned paper [18] but further clinical studies are needed. In particular, the understanding of the underlying molecular mechanism, cytokine expression, and clinical aspects such as the presence of comorbidities possibly leading to “difficult-to-treat” patients could further improve our patient’s management.

Conclusions

In this context, and waiting for new clinical trials based on sequencing of b/ts DMARDs and precision medicine which could also set up algorithm and machine learning, an optimal personalized approach using sequencing together with non-pharmacological approaches is needed [24].