Mitigation of disease- and treatment-related risks in patients with psoriatic arthritis

Early diagnosis and treatment of PsA is important because the disease not only causes functional impairment over time, but also may increase the risk of mortality in affected patients [15]. Unfortunately, early detection methods for PsA remain limited and the disease is often underdiagnosed due to symptoms going unrecognized [15]. Common initial symptoms include arthritis in the upper and lower limbs (Table 2).

For proper treatment of PsA, it is necessary to consider all aspects of the disease, including clinical pathology and psychological issues [15]. Further, worse outcomes in patients with PsA are associated with a delay in diagnosis, disability, and joint damage, whereas male sex and lower burden of inflammation at presentation were predictors of improved patient outcomes [17‐19]. The presence of specific HLA alleles can also identify patients likely to sustain joint damage [19].

Maintaining good functional status is the primary aim of pharmacologic treatment in patients with PsA. Although the recommended approaches to the diagnosis, therapy, and follow-up of patients with PsA have changed numerous times over the past decade, the goal of treatment is remission or, alternatively, low disease activity or minimal disease activity (MDA) if remission is not attainable [20, 21]. Loss of physical functioning directly impairs patient quality of life (QoL) and results in increased direct and indirect costs associated with the disease [22]. For example, decreased functional status can prevent patients from performing daily activities of living, such as washing and dressing [23].

Clinicians should be aware of the relevant extra-articular manifestations of PsA and its associated comorbidities, which result in considerable morbidity and mortality [24]. At least 1 extra-articular immune-mediated inflammatory disease is present in 94.7% of patients with PsA and the most common of these are psoriasis (94%), uveitis (1.3%), and inflammatory bowel disease (0.7%) [25]. The extra-articular manifestations and comorbidities associated with PsA can also significantly impact QoL and must be considered in the management of PsA [23].

Patients with PsA have a higher prevalence and incidence of cardiovascular (CV) disease than the general population [24, 26]. This increased risk is due to both a higher prevalence of traditional risk factors such as hypertension, obesity, diabetes, and hyperlipidemia, and also to nonconventional risk factors, for example, those related to chronic systemic inflammation, including higher levels of C-reactive protein and erythrocyte sedimentation rate [24, 27]. Interestingly, suppression of inflammation in patients with PsA has been linked with improvements in surrogate markers of CV risk, such as increased carotid intima media thickness and endothelial dysfunction [28]. Further, the presence of metabolic syndrome and insulin resistance, which are also more common in patients with PsA, are associated with increased severity of PsA and increased risk of CV disease [29, 30]. These findings suggest that systemic inflammation may play an important role in driving CV risk in patients with PsA.

Obesity is reported in 35% of patients with PsA and has been suggested as a potential risk factor for developing PsA [31, 32]. Obesity may also impact disease activity and response to therapy, possibly through increased production of inflammatory cytokines [33]. For instance, irrespective of the kind of therapy used, obesity is associated a lower probability of achieving MDA and it is speculated that the chronic pro-inflammatory state, the biomechanical effect of heavy weight on the joints, and the altered pain threshold associated with obesity may be factors responsible preventing achievement of MDA [32].

PsA is associated with diabetes mellitus and the rate of diabetes mellitus is significantly higher in patients with PsA than in those with RA (odds ratio 1.56; 95% confidence interval [CI] 1.07–2.28; P = 0.02) [34]. Caution should be used if prescribing glucocorticoids because they are associated with an approximately 30% increase in the risk for developing diabetes mellitus in patients with psoriasis or PsA [35]. Some dermatologists consider psoriasis as a contraindication for use of corticosteroids, due to concerns of converting plaque psoriasis into pustular psoriasis. However, corticosteroids are still often used across various practice settings, including dermatology.

A strong relationship has been noted between gastrointestinal (GI) inflammation and joint inflammation in various forms of SpA [36]. However, the prevalence of inflammatory bowel disease in patients with PsA is less clearly defined [24]. Of note, there is a significantly increased risk of Crohn’s disease in women with psoriasis (relative risk [RR] 3.86, 95% CI 2.23–6.67) that is further increased in women with both psoriasis and PsA (RR 6.43, 95% CI 2.04–20.32) [37].

Patients with PsA also suffer from sleep disturbances and diminished sleep quality that are associated with generalized pain, anxiety, enthesitis, increased levels of C-reactive protein, and increased erythrocyte sedimentation rate [38]. The prevalence of depression in patients with PsA is 22.2%, compared with 9.6% in patients with psoriasis alone, and the estimated prevalence in the general population (9%) [39]. Similarly, the prevalence of anxiety among patients with PsA is reported as 36.6%, compared with 24.4% in patients with psoriasis alone [39].

Mitigation and evaluation of disease-specific risks is dependent upon prompt and accurate diagnosis. Currently, the primary objectives in clinical rheumatology are early diagnosis and initiation of treatment because diagnostic delays are a significant contributor to poor patient outcomes [4, 15]. Even short delays (6 months) from symptom onset to first visit with a rheumatologist have been observed to contribute to development of peripheral joint erosions and worse long-term physical function [40]. To this end, remission in PsA has been attributed to early diagnosis and treatment.

Disease-related risks should be evaluated through good patient history and use of metrics specific to PsA [41]. These include evaluation of physical function and skin involvement, as well as joint examination (tender joint count, swollen joint count, entheseal assessment). Additionally, physicians should be aware of the possibility of PsA when diagnosing and treating patients who suffer from pre-existing psoriasis. Tracking of metrics over time should be undertaken to detect whether medications are ameliorating disease severity. Imaging may be used for diagnosis and following disease progression over time [41]. In recent years, magnetic resonance imaging (MRI) and ultrasonography have been increasingly used for assessment of PsA and have provided additional information on the pathogenesis of PsA [15].

Treatment with drugs is necessary for patients with PsA and recommended treatment guidelines tailored to individual PsA characteristics are shown in Fig. 1 [16]. Although it is important for patients with PsA to remain active, it is typically not possible to manage disease symptoms through physical therapy alone.

Early recognition and intervention with therapy is key to controlling disease progression in patients with PsA [15]. The tumor necrosis factor (TNF) inhibitors etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol have been shown to improve signs and symptoms of PsA [42‐46]. Additionally, apremilast (an oral phosphodiesterase-4 inhibitor), abatacept (a T cell selective costimulation modulator), ustekinumab (an interleukin- [IL-] 12/23 inhibitor), and secukinumab (an IL-17A inhibitor) have also shown varying degrees of efficacy in the treatment of PsA [47‐53]. Approved agents are discussed in more detail in the following section.

Treat-to-target is a therapeutic concept derived from RA and other diseases [54, 55], which has been proposed for all forms of SpA [20, 41, 54, 56]. With this approach, a clear target, such as remission or low disease activity, is identified and the goal is to sustain this response over time, with an understanding of the need to treat flares and keep tight control of disease activity [55]. A universal definition of the target (e.g., remission, prevention of flare of disease) is required for the treat-to-target approach and, in SpA, remission and sustained low disease activity have been suggested as possible targets [20, 55]. Although definitions of remission or MDA in SpA have been proposed, none have been widely accepted or endorsed and given the multifaceted nature of SpA, a composite of outcome measures may be most useful [54, 57].

The Tight Control of Psoriatic Arthritis (TICOPA) trial, an open-label, randomized, controlled study, has recently provided evidence on the benefit of treating-to-target in PsA [58]. This study compared treat-to-target versus standard of care in newly diagnosed patients with PsA receiving methotrexate (MTX), a combination of disease-modifying antirheumatic drugs (DMARDs), or TNF inhibitors. Results from TICOPA demonstrated that tight control of disease activity using a step-up dosing regimen to achieve MDA (reviewed and adjusted, if necessary, every 4 weeks) significantly improved joint outcomes compared with standard of care (per the treating physician, reviewed every 12 weeks). After 48 weeks, the odds of achieving an American College of Rheumatology (ACR) 20% criteria for improvement (ACR20 response) nearly doubled (odds ratio 1.91; 95% CI, 1.03–3.55; P = 0.0392) without any unexpected serious adverse events (AEs) [58].

The complexities of PsA pathology suggest the need to identify suitable therapies to address the different combinations of clinical manifestations [21]. Traditional treatments for PsA include nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, and synthetic DMARDs [59]. NSAIDs are effective for relieving musculoskeletal symptoms due to joint inflammation, but have no efficacy on psoriatic skin lesions and are associated with AEs including renal toxicity, gastrointestinal toxicity, and the risk of developing CV events [59]. Traditional DMARD treatment options for PsA include sulfasalazine and MTX [16, 59, 60]. There is debate over the efficacy of MTX and randomized trials have generally been unable to show efficacy [59, 61, 62]. Additionally, MTX is ineffective in treating axial inflammation and there is little evidence to support its use for other symptoms such as enthesitis [59, 62]. However, in the placebo-controlled Methotrexate in Psoriatic Arthritis (MIPA) trial (that showed no benefit with respect to the primary endpoint of PsA response criteria), treatment with MTX resulted in a significant improvement over placebo in both patient and physician global assessments, as well as Psoriasis Area and Severity Index (PASI) scores at 6 months [61, 62]. Nonetheless, the MIPA authors asserted that their findings questioned the classification of MTX as a DMARD in the setting of PsA, with recognition that there are safety concerns associated with MTX therapy [61]. In particular, the use of MTX in obese patients may lead to potential liver damage [63]. Alcohol abuse and the high prevalence of fatty liver in obese patients may contribute to the development of liver damage and the presence of fatty liver can also impede monitoring for liver damage.

Current targeted treatment options approved for PsA include biologics (TNF inhibitors, ustekinumab, and secukinumab) and the small molecule apremilast [3, 59]. These therapies are typically recommended for use after inadequate response to at least one DMARD but early escalation can be considered, especially for patients with poor prognostic factors such as raised inflammatory markers or high active-disease joint counts [16]. For patients who fail a biologic therapy, the GRAPPA guidelines provide a conditional recommendation for switching to a different biologic agent within a drug class or to a drug with a different mode of action [16]. While switching TNF inhibitors can be effective, response rates tend to diminish with successive TNF inhibitor use [64]. There has been investigation of combining TNF inhibitors with a DMARD to prolong biologic persistence but a clear benefit of combination therapy was not observed [65]. There are currently two biologics (secukinumab and ustekinumab) available for treatment of PsA with a different mechanisms of action than TNF inhibition [50, 51, 53]. A concern with all biologic therapies for PsA is an increased risk for infections and patients should be monitored for the development of serious infections that would necessitate discontinuation of treatment until the infection resolves. Reactivation of tuberculosis has been observed with TNF inhibitors and patients must be monitored for active tuberculosis while receiving these agents.

Additionally, response to biologic agents can be limited by immunogenicity and the development of antidrug antibodies [66]. Antidrug antibodies have been observed in 29% of patients receiving adalimumab and 21% of patients receiving infliximab and their presence was significantly correlated with low drug levels and high levels of disease activity [66]. This study also reported that MTX significantly decreased the prevalence of antidrug antibodies, and use of MTX should be considered for patients treated with TNF inhibitors. With secukinumab and ustekinumab, treatment-emergent antidrug antibodies were reported in 0.2% to 0.3% and 9.3%, respectively, of patients from phase 3 trials [49, 52, 53]. In patients receiving ustekinumab and MTX, antidrug antibodies were less common (6.4%) than in those only receiving ustekinumab (12.3%) [52].

Treatment of skin disease associated with PsA can include phototherapy such as ultraviolet B or oral psoralen followed by ultraviolet A (PUVA) [67]. PUVA therapy carries an increased risk of skin cancer compared with other forms of ultraviolet light treatment and patients receiving this treatment should be monitored for skin cancer [67, 68].

Patient compliance to therapy is an underlying concern in the management of PsA. In patients treated with TNF inhibitors, age has been associated with increased compliance and female sex, comorbidity, and poor clinical condition at baseline have been associated with decreased compliance [69]. Poor adherence can reduce therapeutic efficacy and increase medical costs due to the need for more aggressive treatments [69, 70]. In general, there is the potential for reduced compliance if a patient cannot observe their disease directly, although this is less likely in patients with PsA because skin involvement is more common.