A complex and not fully understood pathogenesis is exhibited in psoriasis. External factors can trigger an interaction between skin cells, pro-inflammatory immunocytes (i.e., tumor necrosis factor (TNF)-α and interferon (IFN)-α), and biologic signaling molecules in genetically predisposed individuals [7,8]. This interaction stimulates the myeloid dendritic cells (mDC) in the lymph nodes to release interleukin (IL)-12 and IL-23 to promote the cellular immune response of T helper lymphocytes (Th) type 1 (Th1), 17 (Th17), and 22 (Th22) T cells. Activated Th migrate to the skin guided by a gradient of chemokine and produce abundant psoriatic cytokines (i.e., IL-17, IFN-γ, TNF-α, and IL-22). The cytokine-mediated effects on keratinocytes influence typical psoriatic inflammation [9,10,11,12,13]. Molecular and genetic studies in specific psoriasis phenotypes have identified different inflammatory pathways that may coexist and evolve over time. The identification of the main inflammatory pathways through individual molecular descriptors represents a future step to guide personalized therapy [14]. In this sense, different classes of possible biomarkers have been explored in psoriasis (Figure 1), but further replication and validation are required [15,16,17].

The severity of psoriasis will be determined by the extent of the disease, the location of the lesions, the degree of inflammation, and the impact on quality of life. According to the most important clinical guidelines (Figure 1), the evaluation of psoriasis severity and the levels of its treatment responses is generally based on the percentage of the total Body Surface Area (BSA) affected, Psoriasis Area Severity Index (PASI), Physician Global Assessment (PGA), and Dermatologic Life Quality Index (DLQI) [18,19].

Monoclonal antibodies are heterodimeric glycoprotein macromolecules of type-G immunoglobulin recognizing a single epitope on a target antigen in a bivalent manner [25]. They are produced and engineered by hybridoma technology, developed for the first time by Köhler and Milstein in 1975 [26]. Due to their molecular size and their three-dimensional conformation, the PK and PD properties of mAbs are considerably different compared with those related to small-molecule drugs (SDM) [27].

The low permeability and high degradation of mAbs throughout the gastrointestinal tract lead to intravenous, subcutaneous, or intramuscular administration [28], and no significant improvement has been published to overcome the limitations of the oral administration of mAbs. Consequently, the most frequent routes of the administration of mAb in psoriasis follow intravenous (IV) or subcutaneous (SC) injections [29]. Regarding the distribution and tissue infiltration, mAbs can easily move from the SC space most probably via diffusion and/or convection through lymphatic capillaries, and they can be able to reach the intracellular space of targets beyond systemic circulation by pinocytosis or by receptor-mediated endocytosis [30].

The large size and physicochemical properties (charge and hydrophobicity) explain the distribution of mAbs mainly in the vascular and interstitial fluids. Usually, tissue distribution represents 5 to 15% of the total amount of mAb, and distribution into the brain is quite restricted (0.1%) [31]. A significant fraction of mAb in the body may be found if mAb-tissue target binding occurs with high affinity. Therefore, large apparent volumes of distribution in steady state (Vss) could be estimated for mAbs. In cases where the binding capacity of tissue is limited, nonlinear distribution is more probable and Vss decreases in a dose or concentration-dependent manner [32].

In regard to mAbs metabolism and excretion, the impacts of the renal and biliary pathways are insignificant [33]. Due to the null role of enzymatic processes related to the metabolism and excretion of mAb, the interaction with other substrates of these enzymes is negligible [34,35,36,37]. mAbs exhibit specific and non-specific types of binding, depending on the fragment of the antibody. The first one occurs when the antigen-binding fragment (Fab) attaches to the target antigen. The second one appears after the fragment crystallizable (Fc) region binds to cell surface receptors, such as the Fcγ receptor (FcγR) on the immune effector cells and the neonatal Fc receptor (FcRn) on different cell types, as well as components of the complement system (i.e., complement C1q) [25]. For such reasons, mAb distribution can be directly influenced by the density and expression of the target antigen. The two parallel metabolic pathways, i.e., specific and non-specific. are involved in mAb disposition, and their impact changes over time based on the available free mAb in the plasma and the dose administered. Metabolism through the reticuloendothelial system via pinocytosis/proteolysis represents the linear and non-specific clearance, which may be relevant at certain dose levels due to the larger endothelial surface area in the gut, muscle, and skin [38]. The specific pathway is initiated after the internalization of the receptor–drug complex, which allows the drug to enter the cell and then be inactivated by cytoplasmic endosomes. However, FcRn can bind IgG and mAbs at the acidic pH conditions of the lysosome, escape from proteolysis, and be directed back to the cell membrane [39,40,41]. Both pathways have been mechanistically described in population PK models through a target-mediated drug disposition (TMDD) approach and its quasi-equilibrium or rapid binding approximations, quasi-steady-state approximation, and even simpler Michaelis–Menten kinetics.

One more key aspect in the PK of mAb is the rescue from lysosomal degradation by binding to FcRn in endothelial cells, which is crucial for the long half-life and low clearance rate reported for most therapeutic mAbs [42,43]. These mechanisms result in clearance values of mAbs for psoriasis that range from 90 to 560 mL/day, leading to half-lives between 11 and 30 days. Several covariates have been identified in PK studies to partially explain inter-individual differences in mAb exposure, such as FcRn and FcγR gene expression, genetic polymorphism, target properties, and covariates associated with increased clearance, such as the generation of antidrug antibodies (ADA), low serum albumin and high serum C-reactive protein levels (CRP), gender, and high body weight (BW) [27,30].

The mAbs for treating psoriasis are designed to block either the specific receptors or soluble mediators of the main pathways in the progress and chronicity of psoriasis, including TNF-α, IL-12/23, and IL-17 [11] (Figure 2). The PD effect of mAb is delayed to the time course of its plasma concentrations, which has been described using PK/PD models, such as indirect responses and transduction models, in order to describe the exposure–response (E–R) relationship [44,45]. The following parameters are mostly determined: kin, formation rate of psoriatic skin lesions; kout, remission rate of psoriatic skin lesions; Emax, maximum mAb effect; and EC₅₀ or IC₅₀, serum mAb concentration causing 50% of the maximum effect.

Compared with SDM, mAbs offer therapeutic exclusivity, a higher safety profile, and an increase in clinical efficacy [46,47]. The relative change in the PASI of patients receiving novel mAbs (guselkumab and brodalumab) has reached 90–100% PASI reduction, which has led to an adjustment of the primary endpoint of PASI75 to PASI90 or PASI100 in clinical trials [48].

3. Monoclonal Antibody Approved for Psoriasis

The selection of the optimal treatment for psoriasis depends on the severity of the disease [67]. Mild or limited-extent psoriasis is managed by topical treatment, while the moderate to severe types usually require a combination of phototherapy and systemic therapies [68]. Biological agents, such as mAb, have been the most successful approach in the management of this disease in the last decade.

The use of mAbs is indicated in psoriasis when (i) effective control of psoriasis is not achieved with oral and phototherapy treatments, (ii) in patients who have rapid regrowth (3 months or less) after suspending any treatment, (iii) when higher doses of conventional systemic drugs are required with the increased associated risk of adverse effects, (iv) in patients with comorbidities for which the use of systemic agents, such as methotrexate or cyclosporine, are contraindicated, (v) when a patient is unable to tolerate the traditional systemic therapy, or (vi) the patient is at high risk of toxicity with methotrexate, cyclosporine, acitretin, or phototherapy, even in the absence of analytical alterations [23].

4. Therapeutic Drug Monitoring of Monoclonal Antibodies in Psoriasis

Treatments for an immune-mediated inflammatory disease, such as psoriasis, have been enhanced with the development of biologics. However, some patients are not able to achieve an adequate clinical response to mAb-based therapy. Some patients present an insufficient response in the induction phase of the treatment, which is called primary non-response, or after initial clinical benefit, they lose the ability to respond, which is called secondary non-response [115,116]. The IIV of the clinical response to standard biologic doses in patients with psoriasis may be explained by differences in the amount of drug available at the target tissue, which in turn is induced by adherence, physiological and genetic mechanisms, and PK covariates, such as BW and drug immunogenicity [117,118]. Increasing evidence indicates that a way to explain all these concerns about mAb could be TDM.

The term TDM was defined in 1997 by Watson et al. as the measurement of a prescribed xenobiotic in serum or biological fluids at a single or multiple time points, with a view to influencing prescription and individualizing the dosage regimen to achieve maximal clinical efficacy and minimize adverse effects [119]. Distinction should be made between reactive and proactive TDM. Reactive TDM is performed in patients failing treatment in order to guide decision-making, whereas proactive TDM is performed in responding patients to optimize therapy and potentially prevent future flare-ups and loss–of–response [120]. The implementation of TDM is essential to define the optimal dose ranges for each patient for a given biologic in psoriasis. The TDM for biological agents in immune-mediated inflammatory diseases involves the measurement of drug levels and ADA. Dose increase, interval shortening, and/or the addition of an immunomodulator are proposed, with subsequent re-evaluation of the drug concentration until the therapeutic goals are achieved [41].

In the last decade, the data in favor of TDM in psoriasis are growing. Based on the distribution of a survey among dermatologists who participated in Belgian Dermatology Days 2019 and Skin Inflammation & Psoriasis International Network Congress 2019, Schots et al. [121] indicated that 70% of the total study cohort admitted the need for TDM, implying the necessity in the daily dermatology routine for active interaction about the accessibility, utility, and application of TDM assays. However, over the years, there has been much confusion about what exposure metrics are informative in patients with psoriasis. Most of the studies reported in the literature have measured drug levels, but very little information has been used to evaluate the relationship between the mAb levels and clinical response to treatment [122]. Therefore, the selection of TDM in mAb for psoriasis may be beneficial due to the large IIV observed in clinical trials, its chronic administration that leads to the appearance of time-dependent changes in PK or PD parameters, and the role of disease progression in the increase of clearance and decrease in the response over time.

The attempts to establish therapeutic ranges and the incidence of ADA of some mAbs employed for the treatment of psoriasis are shown in Table 5. Takahashi et al. [123] identified the infliximab C_trough for responder patients at 0.92 μg/mL. Recently, the NORwegian DRUg Monitoring study was published [124] to assess the efficacy of TDM in patients on infliximab treatment regarding the achievement of remission, as well as to maintain immune-mediated inflammatory disease control. Additionally, among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening [125]. For adalimumab, Menting et al. [113] defined a window based on C_trough from 3.51 to 7.00 μg/mL corresponding to the optimal clinical response. This window was confirmed by the Psoriasis Stratification to Optimize Relevant Therapy (PSORT) consortium in a large multicenter prospective study [122]. Other studies have shown how early measurement of the adalimumab C_trough levels could help to predict the possibilities of responses [122,126,127].

A pilot study estimated a negative correlation between PASI and the trough secukinumab concentrations during maintenance therapy, suggesting no clinically relevant relationship between C_trough and PASI. On the other hand, a minimal effective C_trough of 33.2 μm/mL for achieving PASI ≤ 2 was proposed based on receiver operating characteristic curve analysis [128]. Menting et al. [129] reported low and variable trough concentration levels of ustekinumab, which were not correlated with clinical response. However, the studies by Toro-Montecinos et al. [130] and Van Den Berghe et al. [131] found an inverse correlation between the absolute PASI score and ustekinumab serum concentrations measured at week six and week four, respectively. These contradictory results have not made it possible to reach a consensus for the ustekinumab concentration–response relationship. Nevertheless, it has been demonstrated how early serum ustekinumab levels post-injection monitoring contribute to timely identifying under-exposed patients who might benefit from treatment optimization [77,131,132]. E–R association data in psoriasis is limited for certolizumab pegol, brodalumab, ixekizumab [87,88,133], guselkumab [96], tildrakizumab [102], and risankizumab [134].