Psoriatic Arthritis

Chapter 47

Psoriatic Arthritis Francesco Caso, Luisa Costa, Rosario Peluso, Antonio Del Puente, Raffaele Scarpa Rheumatology Unit, Department of Clinical Medicine and Surgery, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy

INTRODUCTION PsA represents an inflammatory arthropathy associated with psoriasis or its familiarity, belonging to the spondyloarthritis (SpAs) group [1,2]. Psoriatic skin lesions generally show as inflammatory hyperproliferative and erythematous cutaneous manifestations usually located on the extensor surfaces of the knees and elbows and other areas, more commonly represented by the scalp, intergluteal, and umbilical areas [3]. In addition, nails can be involved by inflammatory processes leading to psoriatic onychopathy [3]. Psoriasis occurs in 1%–3% of the population, and about 10%–40% of patients with psoriasis can develop PsA [3]. The average age at PsA onset is around the fourth decade, men and women can be affected equally [1]. Articular inflammatory processes can involve axial skeleton (spondylitis), peripheral joints (peripheral arthritis), insertion sites of tendons and ligaments into bone (enthesitis), and PIP and DIP joints, and soft tissue of digits (dactylitis). Any of these manifestations can occur alone or in any of the possible combinations [1–6]. PsA represents a significant health issue because of its high worldwide prevalence and implications both in terms of survival and social costs [2]. These are mainly correlated to alteration of functional status, disability, and negative impacts on patients’ function and QOL and psychosocial aspects [7–12]. Diagnosis in early phases and immediate and effective therapy may be able to reduce disease severity, improving cutaneous, articular, QoL, and psychosocial outcomes [1,13].

ETIOPATHOGENESIS Etiopathogenetic hypothesis of PsA includes a complex interaction of genetic, environmental, and immunological factors [14]. In the etiology of the disease, the familial aggregation of PsA supports a key role of genetic factors, most likely with a multifactorial inherited mechanism [14]. Environmental factors, particularly infections and trauma, have been called in cause as possible elements in triggering arthritis in genetically predisposed subjects [14]. The largest reported genetic association of psoriasis and PsA is represented by genetic loci localized within the major histocompatibility complex region [15–17]. The HLA allele, B27, has been reported as a PsA risk factor and key predictor of disease progression [18,19]. Frequency of HLA-Cw*0602 is higher in psoriasis patients than among PsA ones [15–17,19]. In patients carrying HLA-B*27 allele, PsA occurs more early and the temporal interval between psoriasis and arthritis is longer than in those without it. In patients with PsA carrying the HLA-C*06 allele, the interval between the psoriasis and arthritis is longer than in those without it [20]. The pathogenic action of class I molecules belonging to the HLA complex remains unclarified. Among hypotheses, the pathogenetic role of HLA-B27 has been considered potentially linked to its possible ability of acting as a molecule presenting arthritogenic peptides to cytotoxic T cells [21–24]. Another mechanism provides a potential HLA-B27 misfolding with consequent endoplasmic reticulum accumulation, unfolded response, stress, and autophagy [21–24]. Furthermore, at level of cell surface, the binding of homodimers, constituted by β2-microglobulin-free HLA-B27 heavy chains, with immunoglobulin-like receptors on lymphocytes leads to inflammatory response [20–24]. Multiple and genome-wide association studies have investigated other genetic regions. Among numerous identified potential susceptible genes, the killer cell Ig-like receptors (KIR), KIR2DS2, expressed on natural killer cells, have been found to be significantly associated to PsA [24,25]. Mosaic of Autoimmunity. https://doi.org/10.1016/B978-0-12-814307-0.00047-5 Copyright © 2019 Elsevier Inc. All rights reserved.

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Different studies have reported that different cytokines, especially TNF-α, interleukin (IL)-17, and IL-23, represent crucial proinflammatory molecules upregulated in peripheral blood, skin lesions, synovial membrane, and fluid of PsA patients [26–29]. TNF-α, expressed in the form of soluble cytokine (sTNF) and type II membrane-associated TNF (mTNF) protein, is a crucial molecule in pathogenesis of PsA [30–33]. TNF-α binds the TNF receptors, TNFR1 and TNFR2, present on various immune cell types. TNFR leads to activation of different kinases, phosphor-proteins and nuclear factor kappa B (NF-kB), proinflammatory genes transcription with consequent cytokines secretion, cytotoxic effects, and peripheral differentiation of T helper (Th) cell subsets [34]. In course of synovitis, overexpression of TNF-α by macrophages and other immune cells is able to promote unbalanced inflammatory response and articular damage [31–33]. Notably, the improved understanding of TNF-α mechanisms of action has represented the main factor in influencing the recent therapeutic approach to PsA patients by use of biological disease-modifying antirheumatic drugs (bDMARDs) [35,36]. Other proinflammatory molecules involved in the pathogenesis of the disease and representing therapeutic targets of new bDMARDs are represented by IL-12 and IL-23 produced by antigen-presenting cells. These cytokines are able to induce and activate Th1 and Th17 cells leading to the synthesis of type 1 cytokines [37]. In addition, Th-17 responses include dysregulation of the IL-17 axis cytokines. Among those, the proinflammatory cytokine, IL-17A, is crucial in the regulation of different innate and adaptive immune pathways [38–40]. It is produced by Th-17 cells and other innate immune cells as neutrophils, mast cells, CD8+, and T lymphocytes at sites of skin plaques and inflamed entheses, representing another pharmacologic target [38–40]. IL-17A, acting with other proinflammatory cytokines, including TNF-α, leads to upregulation of expression of different genes associated to inflammatory response in different cells, as well as keratinocytes and fibroblasts, leading to increased synthesis of proinflammatory molecules [38–41]. In the recent years, different studies have evidenced the important pathogenetic role of dysfunction of several regulating steps involving intracellular molecules [42–47]. They are represented by the signaling pathways involving transcription factors or enzymes, the JAK–signal transducer of activators of transcription (STAT) pathway [26,27], and PDE4 [42–47]. These represent also the target of several drugs known as tsDMARDs [35]. JAK/STAT molecules are activated by growth factors and interleukins and regulate intracellular inflammatory pathways and immune cell response by activation of proinflammatory genes [48]. PDE4 hydrolyzes cyclic adenosine monophosphate, leading to intracellular adenosine monophosphate increase [45–47] and consequent activation of protein kinase A, inhibition of antiinflammatory IL-10 and increased synthesis of proinflammatory molecules, including leukotriene B4, different chemokines (CXCL9, CXCL10, and CCL4), and the interleukins interferon-γ, TNF-α, IL-2, IL-8, IL-12, and IL-23 [45–47].

CLINICAL ASPECTS Involvement of several domains represented by joints, entheses, digit, tendons, axial skeleton, skin, and nails leads to the wide heterogeneity of the disease [49–52]. Inflammatory involvement of sacroiliac joints and spine (axial pattern), asymmetrical oligoarthritis, DIP arthritis, symmetrical polyarthritis, dactylitis, enthesitis, and more rarely the mutilans form, in concomitance of psoriasis or its familial history, represent key clinical findings for addressing PsA diagnosis [49–52]. High specific (98.7%) and sensitive (91.4%) Classification Criteria for Psoriatic Arthritis (CASPAR) criteria are used to categorize research cohorts [53,54]. Laboratory evaluation shows usually negative serological test for rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPAs) [1]. Inflammatory markers, erythrocyte sedimentation rate (ESR), and C-reactive protein are found elevated in above half of PsA patients [1]. Diagnosis of PsA relies mainly on clinical aspects and imaging techniques can represent additional tools useful for addressing the diagnosis and are essential for monitoring joint involvement [55]. Plain radiography can detect erosive and bone proliferative changes in advanced phases and represents a key instrument for monitoring articular damage [55]. Main radiological findings can be represented by articular erosions, exuberant new bone formations, osteolysis, periostitis, enthesitis, nonmarginal syndesmophytes, and ankylosis [55]. In early and active phases of the disease, inflammatory aspects can be detected by use of MRI and ultrasonography, able to evidence active signs and staging articular and periarticular involvement (soft tissue and bone marrow) [56–61]. According to Moll and Wright classification, PsA can be divided into five subsets: axial PsA, symmetrical polyarthritis, asymmetrical oligoarthritis, DIP arthritis, and arthritis mutilans (Table 47.1) [14]. These subsets have been reported significantly different in terms of frequency and characteristics in several populations [62–65]. Additionally, PsA phenotypes

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TABLE 47.1  Main Manifestations of the Five Psoriatic Arthritis (PsA) Subsets Main Articular Aspects

Possible Subset Overlap

Main X-Ray Findings

Axial involvement

Spondylitis; bilateral or more often unilateral sacroiliitis.

Peripheral arthritis.

Nonmarginal syndesmophytes distributed asymmetrically along the spine; bilateral or unilateral sacroiliitis.

Symmetrical polyarthritis

Symmetrical inflammatory involvement of ≥4 peripheral joints, resembling RA. Unlike RA, there is seronegativity for RF and ACPAs, involvement of DIP joints, concomitance of enthesopathies, dactylitis, spondylitis, and sacroiliitis.

Axial involvement; DIP arthritis.

Erosions are often associated with exuberant ankylosis, periostitis, and syndesmophytes.

Asymmetrical oligoarthritis

Oligoarthritis is characterized by asymmetrical involvement of less than four joints and dactylitis may represent a clinical expression. It can represent the onset phase of a symmetric polyarthritis.

Axial involvement; DIP arthritis.

Erosions are often associated with exuberant ankylosis, periostitis, and syndesmophytes.

DIP arthritis

Symmetrical or asymmetrical DIP arthritis can occur in more than 50% of patients with PsA. It can be associated with onychopathy and may occur more frequently in advanced phases.

DIP arthritis may occur as a single or combined manifestation of PsA both with axial involvement and with prevalent peripheral involvement (in course of symmetrical polyarthritis, asymmetrical oligoarthritis, and arthritis mutilans).

Presence of marginal erosions associated with adjacent bone proliferation; erosive modifications at first involve the margins of DIP joint and then centrally; lack of prominent juxtaarticular osteoporosis; resorption of the tufts of terminal phalanx both of hands and feet.

Arthritis mutilans

Digital shortening characterized by osteolysis of phalanx and metacarpals (opera glass).

It occurs in less than 1% of patients and generally as an isolated articular subset.

Osteolysis of phalangeal, metacarpal, and metatarsal bone (telescoping digits); periarticular and shaft periostitis; pencil-in-cup deformity.

ACPAs, anticitrullinated peptide antibodies; DIP, distal interphalangeal; PsA, psoriatic arthritis; RA, rheumatoid arthritis; RF, rheumatoid factor.

can change over time and peripheral arthritis, in particular polyarthritis and DIP arthritis may often occur in concomitance with axial involvement [62–65]. Furthermore, on the basis of the cutaneous manifestation, a PsA subset classified as “sine psoriasis” is recognized. It involves patients who have never suffered from psoriasis, but who present to the anamnesis psoriasis familiarity [66].

Axial Involvement Axial involvement can show as spondylitis and bilateral or more often unilateral sacroiliitis. It can interest up to 70% of PsA, being associated or less with peripheral arthritis. Criteria match those used for ankylosing spondylitis (AS) [67–69]. PsA shows radiologic features which differentiate it from other SpAs, including AS [70–73]. Axial X-rays permit to identify peculiar nonmarginal syndesmophytes distributed asymmetrically along the spine. Syndesmophytes seem to emerge from spinal ligament and it is possible to detect an equal frequency of bulky marginal and paramarginal vertical syndesmophytes [70–73]. On the other hand, in AS, syndesmophytes are marginal, bridge the intervertebral discs, and are symmetric, progressing caudal to cranial [70–73].

Symmetrical Polyarthritis Occurrence of symmetrical polyarthritis in PsA resembles that of rheumatoid arthritis (RA), and in the past, it has been recognized as rheumatoid-like form [64,74]. Findings characterizing psoriatic polyarthritis and useful in differentiating it from RA are mainly represented by RF and APCAs seronegativity, DIP involvement, concomitance of enthesopathies, dactylitis, spondylitis, and sacroiliitis [64,74].

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In RA, progressive and bilateral involvement of small, medium, and large joints tends to be symmetric, differently from PsA. Furthermore, in RA, the involvement of DIP and of the spine is uncommon, except for cervical tract [75–78]. In addition, despite occasional detection in PsA of RF and APCAs, these are peculiar and specific markers of RA [79]. In PsA, APCAs seem to be correlated with severe polyarticular subset with a more and erosive disease course and more often in female patients [79]. Not at last, while in RA osteoporosis can represent a frequent finding both at a systemic level and at level of involved joints, and in PsA, mechanisms of bone loss are accompanied by bone formation with ankylosis, periostitis, and exuberant syndesmophytes [80,81].

Asymmetrical Oligoarthritis Oligoarthritis is characterized by asymmetrical involvement of less than four joints and dactylitis may represent a typical clinical expression [74]. Oligoarthritis, as polyarthritis pattern, can occur isolated or less frequently in concomitance of axial involvement. Furthermore, it can represent the onset phases of a future symmetric polyarthritis [63,64,82,83]. Oligoarthritis, especially associated with inflammatory back pain, needs ruling out of other SpAs, such as enteroarthritis and reactive arthritis, mainly by the investigation on presence of inflammatory bowel diseases and recent gastrointestinal or urogenital infection by 1–6 weeks [84,85].

Distal Interphalangeal Arthritis Symmetrical or asymmetrical DIP arthritis can be associated with onychopathy and may occur more frequently in advanced phases [52,86]. Erosive modifications at first involve the margins of DIP joint and then centrally [86]. DIP arthritis may occur as a single or combined manifestation of PsA [64,87]. In several cases, inflammatory DIP joints involvement occurring in PsA needs ruling out the erosive form of OA [88–91]. In uncertain cases, inflamed entheses with diffuse bone edema can address the PsA diagnosis and exclude OA, in which entheses are thickened and associated with osteophytes, cartilage loss and joint space narrowing [92].

Arthritis Mutilans Arthritis mutilans represents a severe PsA phenotype in which osteolysis of phalanx and metacarpals represent the prominent findings (opera glass) [64,87]. It occurs in less than 1% of patients and generally as an isolated articular subset [64,87,93–95].

Psoriatic Arthritis Sine Psoriasis PsA sine psoriasis is characterized by the presence of dactylitis and DIP arthritis and more rarely enthesitis, tenosynovitis, and axial involvement, in the absence of an overt skin and/or nail psoriasis and in presence of a familial history of psoriasis in first- and/or second-grade relatives [65,66]. HLA haplotypes showing HLA-Cw*6 positivity can be useful for addressing the diagnosis [66].

LABORATORY AND INSTRUMENTAL FINDINGS Markers of inflammation, such as ESR, show to be elevated up to 50% of the patients [96,97], and a peculiar finding is represented by the usual absence of RF, playing a significant role in cases where clinical aspects mime RA [98]. Although rarely, positivity of APCAs, a characteristic RA marker, can also be found in PsA and can correlate with a severe and erosive polyarthritis [99–103]. Main PsA indices measuring disease activity and remission are represented by minimal disease activity criteria, Composite Psoriatic Disease Activity Index, Psoriatic Arthritis Disease Activity Score, and Disease Activity Index for Psoriatic Arthritis [104]. In the routine practice, follow-up of axial involvement can be performed by the use of Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index, whereas the count of swollen and tender joints, the tender entheseal count, and the Leeds Dactylitis Index represent PsA indices useful for monitoring of peripheral and entheseal involvement [104].

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FIGURE 47.1  T2 weighted magnetic resonance imaging of the sacroiliac joints on coronal view shows a moderate increased signal intensity in joint space of the right sacroiliac joint and marrow edema, such as sacroiliitis (red circle).

With regard to skin, Psoriasis Area Severity Index (PASI) or body surface area and Nail Psoriasis Severity Index are used for the evaluation of the activity and extension of cutaneous involvement [104]. Plain film radiography has markedly contributed in describing PsA as a pathological entity different from RA [55,73]. Characteristic aspects are represented by the frequent asymmetric joint involvement, the involvement of DIP joints of fingers and toes; the presence of marginal erosions associated with adjacent bone proliferation; the lack of prominent juxtaarticular osteoporosis; the resorption of the tufts of terminal phalanx both of hands and feet; the osteolysis of phalangeal, metacarpal, and metatarsal bone (telescoping digits), in the case of arthritis mutilans; the periarticular and shaft periostitis; and pencil-in-cup deformity [55,73]. High-resolution ultrasonography, ultrasound combined with power Doppler, and MRI (Fig. 47.1) have been validated as sensitive techniques not only to detect the involvement of synovial membrane but also for the study of adjacent soft structures [55,73,105–109].

EXTRA-ARTICULAR MANIFESTATIONS PsA has long been considered a disease with a low inflammatory profile, but recent studies have provided growing evidence of its multisystemic nature and association with extra-articular involvement in the form of colitis, uveitis, metabolic syndrome (MetS), and atherosclerosis [1,110]. Today, PsA, as well as psoriasis, is recognized under the most general term of psoriatic disease. It originated from a better understanding of pathogenetic mechanisms and systemic clinical manifestations of the disease [110]. Subclinical gut inflammation in patients with PsA has been reported as characterized by a specific histologic and immunologic signature represented by pronounced Paneth cell hyperplasia and Th17 and Th9 responses [111]. Th9 responses have been reported to be a specific PsA signature when compared with AS and Crohn’s disease [111]. A possible link has also been hypothesized between intestinal and synovial inflammation through IL-9 overexpression and Th9 polarization that occur in synovitis and in the peripheral blood of patients with PsA. This could suggest a potential existence of a bowel joint migratory axis [111]. PsA can be characterized by ocular involvement [112]. Ophthalmic findings occur in 10% of patients with psoriasis [112,113] and in 31% of patients with PsA [114,115]. In PsA, recurrent acute anterior uveitis represents the most frequent manifestation of ocular involvement and it shows frequently bilateral [116]. In comparison with other spondyloarthropathies, PsA-associated uveitis has been reported more insidious in initial phases and chronic in duration [117]. Other ocular manifestations have been reported in course of PsA and among those conjunctivitis, followed by episcleritis, scleritis, keratitis, cystoid macular edema, glaucoma, and cataract [113–117]. In comparison with the general population, PsA patients show an increased risk of cardiovascular (CV) risk factors and CV events, in particular coronary heart disease (myocardial angina and infarction) and stroke [118–120].

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PsA patients have been reported to have higher CV risk than those with psoriasis alone. Despite the significant contribution to CV morbidity and mortality of traditional risk factors, such as metabolic and lipid alterations, PsA per se should be considered as an independent CV risk factor [121]. An important role could be played by PsA inflammatory activity, metabolic components such as hypertension, dyslipidemia, and diabetes and the grade of systemic inflammation leading to accelerated atherosclerosis [122–129].

THERAPY Inhibition of the structural radiological damage, clinical remission, and improvement of the patients’ QOL represent the main aim of the treatment, as defined by international guidelines by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and the European League Against Rheumatism (EULAR) [130–132]. The current treatment for nonsevere articular form consists initially of NSAIDs and intraarticular steroids injections, when these are appropriate [130–132]. csDMARDs, mainly methotrexate (MTX), sulfasalazine, and leflunomide, represent therapeutic options in refractory cases, but biologic agents (bDMARDs) are then recommended in resistant patients (Table 47.2) [130–134]. bDMARDs have been shown to be effective on all the clinical domains of the disease, including psoriasis, axial involvement enthesitis, dactylitis, joint pain, and swelling [130–132]. Inhibition of radiographic progression has been also reported under biological therapies [130–132]. The five anti-TNF-α agents available are infliximab, adalimumab, etanercept, golimumab, and certolizumab pegol (Table 47.2) [135–143]. In comparison with NSAIDs, glucocorticoids, and csDMARDs, a higher level of evidence has been reported on the efficacy of anti-TNF-α agents in treating both clinical aspects and in reducing radiographic progression [144,145]. The concomitant use of MTX has been reported well tolerated and able to prolong TNF inhibitor drug survival [146,147]. Combined therapy with MTX can be significantly useful to decrease prevalence of neutralizing antibodies to anti-TNF-α, and for this reason, MTX use should be strongly considered in patients with PsA under anti-TNF-α therapy [148–150]. With regard to anti-TNF safety profile, these agents have also been demonstrated to be reasonably safe in PsA [135,144,145]. A large metanalysis on anti-TNF-α has recently shown that the overall malignancy rates for PsA patients treated resulted similar to those expected from the general population and death rates are lower than, or equivalent to, those expected in the general population [151]. Randomized controlled trials (RCTs) safety data are confirmed by real-life studies and registries [152–155]. With regard to infectious risk, latent, acute, and chronic infections represent always a contraindication to use a biological therapy. In cases of Latent tuberculosis infection (LTBI), antitubercular prophylaxis can be considered in experienced and specialized rheumatologic units and in strong collaboration with related specialists [156–160]. In PsA patients, all related conditions need to be carefully evaluated to avoid microbial reactivation [161,162]. Several data have generally shown that switching to a second anti-TNF is safe and efficacious in patients with failure and inadequate response to the use of a previous TNF-α agent [163–165]. Fewer data are available about switching to a third anti-TNF-α [163–165]. Different mechanisms of blocking inflammatory pathways by therapy on mechanisms other than those TNF-α driven are important in patients refractory or developing loss of response to anti-TNF-α [166–168]. Among therapies able to inhibit precise cytokines other than TNF-α, ustekinumab (UST), a fully human monoclonal antibody blocking the common p40 chain shared by IL-12 and IL-23 (anti-IL-12p40), has been reported as an efficacious treatment for moderate-to-severe plaque psoriasis and active PsA (Table 47.2) [169,170]. Reports on two large phase III trials have shown that UST at dosage of 45 or 90 mg resulted more effective than placebo on cutaneous, articular, and radiological aspects as determined by significant improvement of PASI ≥75% response, American College of Rheumatology 20/50/70 rates, enthesitis and dactylitis scores, radiographic progression, and Health Assessment Questionnaire scores [171–174]. UST was generally safe and well tolerated, showing occasionally rare serious infections or CV events [171–174]. In addition to IL-12p40 and IL-23 blockage, targeting on IL-17 has been reported as a valid therapeutic option for PsA. IL-17A, acting with other proinflammatory cytokines, including TNF-α, leads to increased inflammatory response and its role in PsA seems to be significant [166,175,176]. Several direct and receptorial IL-17A inhibitors have shown promising results in several phase 2 clinical studies, and more recently in phase 3 RCTs on psoriasis and PsA [177–180].

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TABLE 47.2  Structures and Administration Dosage of Disease-Modifying Antirheumatic Drugs Used in Psoriatic Arthritis (PsA) Therapy DMARD

Drug Structure and Mechanism

Dose and Route Administration

MTX

Folate analog with inhibitory effects on proliferation and stimulation of apoptosis in immune and inflammatory cells

15–25 mg/wk; oral, or IM or SC

SSZ

Combined acetylsalicylic acid and sulfapyridine molecule with inhibitory effects on 5-lipoxygenase pathway

1–3 g/d; oral

LFN

Selective pyrimidine synthesis inhibitor

20 mg/d; oral

ADA

Fully human IgG1 anti-TNF-α monoclonal antibody

40 mg biweekly; SC

CTZ-PEG

Human anti-TNF-α antibody Fab fragment linked to 40 kDa PEG

200 mg biweekly; SC

ETN

Recombinant fusion protein consisting of the extracellular ligand-binding domain of the soluble 75 kD receptor (p75) for TNF-α and the Fc portion of human IgG1

50 mg weekly in a single administration or in two 25 mg administration; SC

GOL

Fully human IgG1 kappa anti-TNF monoclonal antibody

50 mg, every 4 wks; SC

IFX

Chimeric (human/murine) IgG1 anti-TNF-α monoclonal antibody

5 mg/kg at 2 and 6 wks after the first infusion and then every 8 wks; IV

Anti-IL12/23 agent

UST

Anti-IL-12/23 p40 fully human monoclonal antibody

45 mg/kg (for body weight of <100 kg) or 90 mg/kg (for body weight of ≥100 kg) at 0, 4, and 12 wk, then every 12 wks; SC

Anti-IL17 agent

SEC

Anti-IL-17A fully humanized IgG1k monoclonal antibody

150 mg weekly from 0 to 4 wk, then monthly; SC

Phosphodiesterase 4 inhibitor

30 mg twice per day; oral

csDMARDs

bDMARDs Anti-TNF-α agents

tsDMARDs APR

ADA, adalimumab; APR, apremilast; bDMARDs, biologic disease-modifying antirheumatic drugs; csDMARDs, conventional synthetic disease-modifying antirheumatic drugs; CTZ-PEG, certolizumab pegol; ETN, etanercept; GOL, golimumab; IFX, infliximab; IG, immunoglobulin; IL, interleukin; IM, intramuscular; IV, intravenously; LFN, leflunomide; MTX, methotrexate; PEbG, polyethylene glycol; PsA, psoriatic arthritis; SEC, secukinumab; SC, subcutaneously; SSZ, sulfasalazine; TNF, tumor necrosis factor; tsDMARDs, targeted synthetic disease-modifying antirheumatic drugs; UST, ustekinumab.

The IL-17A inhibitor in PsA secukinumab (SEC) represents a fully human IgG1κ monoclonal antibody, which selectively neutralizes IL-17A. SEC has shown efficacy on skin manifestations and is significantly able to improve physical function in PsA patients (Table 47.2) [177–180]. The most frequently reported adverse events for agents targeting IL-17 are represented by upper respiratory tract infection, nasopharyngitis, and injection site erythema and neutropenia [177–180]. Among the emerging tsDMARDs, APR represents an oral molecule that inhibits the activity of PDE4, and data from clinical trials indicate its antiinflammatory effects (Table 47.2) [181–184]. Several trials both in psoriasis and PsA have shown APR as a safe and efficacious therapeutic option in the therapy of moderate-to-severe psoriasis and active PsA [181–184]. Furthermore, APR resulted well tolerated with an acceptable safety profile, while the most frequent adverse effects were represented by early onset of mild gastrointestinal complaints resolving with time, such as diarrhea, nausea, headache, upper respiratory tract infection, and nasopharyngitis [181–184]. With regard to APR position in the algorithm of the treatment of PsA, GRAPPA recommends its use for patients with peripheral PsA after failure of csDMARDs or if csDMARDs are contraindicated [130–132]. Furthermore, in the GRAPPA recommendations even if the effect on structural progression for APR is not established, it is taken into consideration before csDMARDs in definite cases with peripheral PsA, given its safety profile and ease of use [130–132].

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On the other hand, because of lack of data on radiographic progression, moderate effect of APR on most disease outcomes, and the cost ratio benefit, the EULAR group recommends APR to patients who do not achieve targets with csDMARDs and for whom bDMARDs are contraindicated [130–132]. Among the emerging tsDMARDs, tofacitinib represents an oral JAK inhibitor [185]. A recent study has highlighted that tofacitinib regulates synovial inflammation in PsA, inhibiting activation of STAT molecules [186]. Several studies have shown that JAK inhibition by tofacitinib is able to suppress arthritic joint structural damage through decreased RANKL synthesis and inhibition of production of several proinflammatory cytokines [187–189]. In PsA, a coordinate increase of JAK1, STAT1, STAT3, and STAT5 phosphoproteins has been found in synovial fluid T cells [42]. Recent data have reported that the efficacy of tofacitinib was superior to that of placebo at month 3 in PsA patients who previously had an inadequate response to csDMARDs [190,191].

CONCLUSIONS PsA represents a relevant health issue, being highly prevalent in worldwide population with severe implications both in terms of survival and of social costs [1]. Globally, psoriasis shows a high prevalence and arthritis can occur in about one-third of the affected patients [2–6]. PsA has been reported to be a disease that negatively impacts on patients’ function and QOL; psychosocial expression of QOL and life satisfaction have been shown to be comparable to RA [11,12]. However, when diagnosed in early phases, PsA can show a less disabling arthropathy than early or established RA [13]. Anti-TNF-α therapies still represent the cornerstone for the treatment of moderate and severe PsA, making possible its adequate clinical control. These treatments have been shown to be effective on inhibition of radiographic progression and on all the clinical domains of the disease, including enthesitis, dactylitis, joint pain and swelling, axial involvement, and psoriasis [130–132]. Biologic therapies targeting molecules other than TNF-α and tsDMARDs have opened a large space in the therapeutic scenario of PsA, mainly both as first-line and in cases of primary nonresponse, loss of efficacy with time, intolerance, side effects, and contraindication to anti-TNF-α agents [192,193]. In the last years, progress in understanding pathogenetic mechanisms of PsA has contributed to better define the heterogeneous clinical expression of the disease. Furthermore, today it is also evident that in the pathogenesis of the disease, several cytokines and different inflammatory pathways likely contribute to induce and maintain PsA, and it is unlikely that blocking a single cytokine or a specific pathway or a defined cell line will resolve all cases of such a complex condition. The increasing development of agents targeting molecular pathways has never been more stimulating in PsA. The clinical heterogeneity of the disease and the complexity of the pathogenetic aspects involving multiple cytokines, cell lines, and molecules need to be further investigated with a collaborative and translational effort for improving outcomes of patients affected by PsA.

KEY POINTS PsA represents an inflammatory arthropathy associated with psoriasis in which recently it has been recognized by its multisystemic nature and association with extra-articular involvement in the form of colitis, uveitis, metabolic syndrome, and atherosclerosis. l In susceptible subjects through a complex interaction of a predisposing genetic background, an altered immune response, mainly mediated by proinflammatory cytokines, induces the inflammatory state. l Articular inflammatory processes can involve axial skeleton (spondylitis), peripheral joints (peripheral arthritis), insertion sites of tendons and ligaments into bone (enthesitis), PIP and DIP joints, and soft tissue of digits (dactylitis). Any of these manifestations can occur alone or in any of the possible combinations. l Inhibition of the structural radiological damage, clinical remission, and improvement of the patients’ QOL represent the main aim of the treatment. l  The current treatment for nonsevere articular form consists initially of NSAIDs. csDMARDs represent therapeutic options in refractory cases, but biologic agents (bDMARDs), represented by TNF-α, IL-12/23R, and IL-17 inhibitors, are then recommended in resistant patients. Among the emerging tsDMARDs, APR, an inhibitor of PDE4, and tofacitinib, a Janus kinase inhibitor, have shown antiinflammatory effects. l

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Psoriatic Arthritis Chapter | 47  539

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Sustained clinical response in psoriatic arthritis patients treated with anti-TNF agents: a 5-year open-label observational cohort study. Semin Arthritis Rheum 2011;40:398–406. [144] Ramiro S, Smolen JS, Landewé R, van der Heijde D, Dougados M, Emery P, et al. Pharmacological treatment of psoriatic arthritis: a systematic literature review for the 2015 update of the EULAR recommendations for the management of psoriatic arthritis. Ann Rheum Dis 2016;75:490–8. [145] Braun J. New targets in psoriatic arthritis. Rheumatology 2016;55. ii30-ii37. [146] Behrens F, Cañete JD, Olivieri I, van Kuijk AW, McHugh N, Combe B. Tumour necrosis factor inhibitor monotherapy vs combination with MTX in the treatment of PsA: a systematic review of the literature. Rheumatology (Oxford) 2015;54:915–26. [147] Costa L, Perricone C, Chimenti MS, Del Puente A, Caso P, Peluso R, Bottiglieri P, Scarpa R, Caso F. Switching between biological treatments in psoriatic arthritis: a review of the evidence. 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Incidence of malignancies in a cohort of psoriatic arthritis patients taking traditional disease modifying antirheumatic drug and tumor necrosis factor inhibitor therapy: an observational study. J Rheumatol 2016;43:2149–54. [153] Saad AA, Ashcroft DM, Watson KD, Symmons DP, Noyce PR, Hyrich KL. BSRBR. Efficacy and safety of anti-TNF therapies in psoriatic arthritis: an observational study from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 2010;49:697–705. [154] Mariette X, Tubach F, Bagheri H, Bardet M, Berthelot JM, Gaudin P, et al. Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry. Ann Rheum Dis 2010;69:400–8. [155] Carmona L, Abasolo L, Descalzo MA, Pérez-Zafrilla B, Sellas A, de Abajo F, Gomez-Reino JJ. BIOBADASER Study Group; EMECAR Study Group. Cancer in patients with rheumatic diseases exposed to TNF antagonists. Semin Arthritis Rheum 2011;41:71–80. [156] Adelzadeh L, Jourabchi N, Wu JJ. The risk of herpes zoster during biological therapy for psoriasis and other inflammatory conditions. J Eur Acad Dermatol Venereol 2014;28:846–52. [157] Jung SM, Ju JH, Park MS, Kwok SK, Park KS, Kim HY, et al. Risk of tuberculosis in patients treated with anti-tumor necrosis factor therapy: a nationwide study in South Korea, a country with an intermediate tuberculosis burden. Int J Rheum Dis 2015;18:323–30. [158] Kim YJ, Kim YG, Shim TS, Koo BS, Hong S, Lee CK, Yoo B. Safety of resuming tumour necrosis factor inhibitors in patients who developed tuberculosis as a complication of previous TNF inhibitors. Rheumatology (Oxford) 2014;53:1477–81. [159] Atteno M, Costa L, Matarese A, Caso F, Del Puente A, Cantarini L, et al. The use of TNF-α blockers in psoriatic arthritis patients with latent tuberculosis infection. Clin Rheumatol 2014;33:543–7. [160] Mongey AB, Doran JP, Kleinerova J, Fitzgerald O, McDonnell TJ. Late onset tuberculosis infection in patients receiving anti-TNFα therapy. QJM 2014;107:69–71. [161] Caso F, Cantarini L, Morisco F, Del Puente A, Ramonda R, Fiocco U, et al. Current evidence in the field of the management with TNF-α inhibitors in psoriatic arthritis and concomitant hepatitis C virus infection. Expert Opin Biol Ther 2015;15:641–50. [162] Costa L, Caso F, Atteno M, Giannitti C, Spadaro A, Ramonda R, et al. Long-term safety of anti-TNF-α in PsA patients with concomitant HCV infection: a retrospective observational multicenter study on 15 patients. Clin Rheumatol 2014;33:273–6. [163] Rudwaleit M, Van den Bosch F, Kron M, Kary S, Kupper H. Effectiveness and safety of adalimumab in patients with ankylosing spondylitis or psoriatic arthritis and history of anti-tumor necrosis factor therapy. Arthritis Res Ther 2010;12. R117. [164] Jani M, Macphie E, Rao C, Moore S, Mirjafari H, McLoughlin Y, et al. Effectiveness of switching between biologics in psoriatic arthritis- results of a large regional survey. Clin Med (Lond) 2014;14:95–6. [165] Ohshima Y, Kinoshita Y, Akita Y, Tamada Y, Watanabe D. Psoriatic arthritis that responded dramatically when infliximab was switched to adalimumab. Ann Dermatol 2013;25:496–7. [166] Caso F, Lubrano E, Del Puente A, Caso P, Peluso R, Foglia F, et al. Progress in understanding and utilizing TNF-α inhibition for the treatment of psoriatic arthritis. Expert Rev Clin Immunol 2016;12:315–31. [167] Caso F, Del Puente A, Peluso R, Caso P, Girolimetto N, Del Puente A, et al. Emerging drugs for psoriatic arthritis. Expert Opin Emerg Drugs 2016;21:69–79. [168] Costa L, Del Puente A, Peluso R, Tasso M, Caso P, Chimenti MS, et al. Small molecule therapy for managing moderate to severe psoriatic arthritis. Expert Opin Pharmacother 2017;18:1557–67.

540  SECTION | IX  Classical Autoimmune Diseases

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