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Saturday 19 January 2019
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Challenges in the management of psoriatic arthritis

Psoriatic disease is a chronic inflammatory systemic condition affecting up to 3% of the general population, characterised by skin psoriasis, and in about 20–40% of patients, characterised by psoriatic arthritis (PsA), which may also be diagnosed in the absence of a personal history of psoriasis.1 PsA, different from rheumatoid arthritis, affects both sexes with equal frequency, albeit with differences in clinical manifestations.2 The incidence of PsA is of approximately 6 per 100,000 per year and the prevalence is approximately 6–25 per 10,000 in the general population.3
The peak of incidence is around 30–50 years, with skin psoriasis in the majority of cases preceding the arthritis by an average of five years; although in 15% of cases, psoriasis and PsA occur simultaneously, or PsA precedes the skin manifestation, while, more importantly, psoriasis is diagnosed simultaneously with PsA in over 25% of patients.4 While the diagnosis and management of other forms of arthritis, particularly rheumatoid arthritis, are well characterised, taking care of patients with psoriatic disease in general, and PsA in particular, manifests numerous challenges and the major ones are discussed here.
Unmet needs in PsA

Diagnostic delay

Due to variable manifestations, suspecting and timely diagnosis of PsA is a major issue in daily practice. In fact, the diverse clinical features of PsA often result in delayed diagnosis and treatment, ultimately leading to reduced quality of life and elevated risk of cardiovascular disease, and depression.5 The major clinical manifestations can be separated into different phenotypes: distal arthritis; asymmetric arthritis; symmetric polyarthritis; dactylitis; enthesitis; and arthritis mutilans and axial involvement, which can coexist in the same patient along with skin and nail psoriasis.6 PsA can lead to bone erosions in up to 45% of patients within the first two years. Spontaneous remission of PsA is extremely rare, and relapse rates are high when treatment is discontinued. 
The diagnosis of PsA can be only supported by the CASPAR classification criteria,7 and is based on clinical and imaging features that reflect a later stage of the disease. Unlike rheumatoid arthritis, there are no known autoantibodies.8 Thus, a significant diagnostic delay in PsA can be observed,9 which can lead to irreversible damage and permanent disability; therefore establishing an early diagnosis as one of the key challenges in the management of PsA. Unfortunately, only human leukocyte antigen (HLA)-B27 and and HLA-Cw6 are important markers to identify patients at higher risk of PsA.8 However, HLA-B27 is positive in 25% of PsA cases, and increases in levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) can be observed in 40% of patients. By contrast, several studies are investigating PsA biomarkers, and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has launched a biomarker initiative.10 Recently, serum proteins (CD5L, ITGB5, M2BP, MPO, MMP3 and CRP) have been found to differentiate PsA from controls, whereas CD5L, M2BP and MPO were independently associated with psoriasis only.11
To increase the detection of PsA, ideally every psoriasis case complaining of musculoskeletal pain should undergo a rheumatological evaluation; however, this approach is not feasible in every setting. Therefore, in the past years, a number of screening tools have been developed to improve PsA early diagnosis among dermatologists and primary care physicians.12 These screening tools are questionnaires that are feasible in daily practice and include, among others, the Psoriatic Arthritis Screening and Evaluation (PASE), the Psoriasis Epidemiology Screening Tool (PEST), and the Toronto Psoriatic Arthritis Screening (ToPAS), which have been shown to have similar sensitivities and specificities.13

Comorbidities and associated conditions

PsA patients often manifest an increased prevalence of comorbidities, in particular metabolic and psychiatric diseases (Table 1), which impair daily activity, disability, treatment response and impose an economic burden.14,15 Moreover, psoriatic disease, due to chronic inflammation, can be considered an additional risk factor, as arterial hypertension, and therefore should be taken into account when managing patients. There are no biomarkers currently available to identify patients at higher risk of developing comorbidities or other chronic inflammatory conditions, such as inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, and uveitis.16 Therefore, it is crucial to detect and treat comorbid conditions early, and refer to the appropriate specialist for other inflammatory diseases. Experts’ checklists have been proposed to screen patients for cardiovascular disease, which however may not be practical in real-life or might underestimate patients’ risks.17,18 With this is mind, the European League against Rheumatism (EULAR) has issued recommendations for cardiovascular risk management in inflammatory arthritis (Table 2).19
Table 1: Prevalence of PsA-associated comorbidities
Table 2: EULAR recommendations for cardiovascular risk management in inflammatory arthritis
Furthermore, PsA is associated in particular with psychiatric comorbidities and depression, while only psoriasis has been associated with suicidal ideation,20 and depression increases PsA risk in psoriasis patients.21 Given the importance of depression, it is critical to diagnose and refer patients, and questionnaires have been developed especially for research purposes.22 Collaboration with a psychologist/psychiatrist, if feasible, might have an impact on the management of psoriatic disease.23
Ultimately, the co-occurrence of multiple chronic inflammatory diseases should be suspected in the presence of certain red flags that, for example, have been proposed for IBD detection. In particular, a diagnosis of IBD should be suspected in patients with a family history of IBD, or in the presence of: chronic diarrhoea, chronic abdominal pain, rectal bleeding. weight loss, persistent fever, history or evidence of perianal fistula/abscess and/or anaemia.16 The converse is also important, that is, IBD patients complaining about musculoskeletal pain. In fact, multidisciplinary evaluation in IBD patients led to a diagnosis of an inflammatory arthritis in up to 50% of patients with musculoskeletal complaints.24 Uveitis affecting the anterior and posterior poles of the eye occurs in 8% of PsA patients. 

Choosing the appropriate treatment in each patient

The current treatment armamentarium for PsA encompasses different drug classes, including non-steroidal anti-inflammatory (NSAIDs), conventional disease modifying anti-rheumatic rugs (cDMARDs) and biologics (bDMARDs), as well as small molecules. However, despite the increasing availability of therapeutic strategies, we rely on PsA clinical features to choose the most appropriate treatment,25 there are few objective measurements, that is, CRP, to measure its efficacy.8 For patients with mild oligoarticular presentation, NSAIDs and intra-articular injections can be effective, but in patients with more severe symptoms, cDMARDs are typically prescribed as the initial treatment. Unfortunately, there are limited data from randomised clinical trials for cDMARDs in PsA, and their efficacy is mostly suggested by rheumatoid arthritis studies. 
A small real-life study suggested that methotrexate (MTX), sulfasalazine (SSZ), and leflunomide are effective in reducing peripheral arthritis and enthesitis, while SSZ use is associated with the greatest improvements.26 Moreover, a randomised clinical trial on MTX did not show a significant treatment effect, but that could have been a result of the low doses prescribed,27 as in real-life it is the most frequently used cDMARD.28
The treatment of PsA is complicated by the heterogeneous clinical manifestations, on which cDMARDs are poorly effective, while bDMARDs suppress both skin and joint disease, retard radiographic progression, and are effective for enthesitis, dactylitis and axial involvement. Therefore, up to 40% of PsA patients are treated with bDMARDs in real-life, with etanercept, directed towards tumour necrosis alpha (TNFa) being the most frequently prescribed according to a large epidemiological study.28 Beyond TNFa inhibitors, bDMARDs with other mechanisms of action (targeting interleukin (IL)-17 and IL-12/23) are effective and safe in PsA. Moreover, in the past, small molecules, or medications inhibiting intracellular signalling pathways (Janus kinase or phosphodiesterase 4) have supplemented the therapeutic armamentarium for PsA.  
In addition to pharmacotherapy, patient education and physical activity are crucial in the management of PsA, in particular, lifestyle modifications including smoking cessation, weight reduction and stress management. 
Finally, recommendation on the treat-to-target strategy for PsA have been made, since it has been demonstrated that a target-driven approach in rheumatoid arthritis is superior to usual care for clinical, functional and structural outcomes. According to the most recent recommendations, remission/inactive disease of musculoskeletal and extra-articular manifestations should be the treatment target; however low/minimal disease activity might be an alternative target. It is important therefore to measure disease activity based on clinical signs and symptoms, as well as acute phase reactants. We have numerous tools to measure disease activity, of which some have been specifically developed and validated for PsA. In particular, for PsA, DAPSA (disease activity index for psoriatic arthritis) and MDA (minimal disease activity) should be considered to define the target.29


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