Psoriasis and systemic inflammation: underdiagnosed enthesopathy

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1 DOI: /j x JEADV Blackwell Publishing Ltd REVIEW ARTICLE Psoriasis and systemic inflammation: underdiagnosed enthesopathy G Girolomoni*, P Gisondi Section of Dermatology and Venereology, Department of Biomedical and Surgical Sciences University of Verona, Verona, Italy *Correspondence: G Girolomoni. giampiero.girolomoni@univr.it Abstract Our understanding of the pathogenesis of psoriasis is changing rapidly and the traditional view that it is a disease limited to the skin continues to be challenged. Indeed, there is convincing evidence that psoriasis patients have a higher prevalence of comorbid disease, particularly cardio-metabolic disorders and psoriatic arthritis (PsA). The results of recent investigations into psoriasis and cardiovascular or metabolic comorbidities provide increasing evidence for a possible shared pathogenic mechanism for these disorders, linked by an underlying chronic systemic inflammatory state. This highlights the importance of investigating associated comorbidities beyond skin manifestations. Psoriatic arthritis is a chronic inflammatory arthropathy that can occur in association with psoriasis and most commonly affects the distal joints in the hands and feet. Skin lesions precede arthritic symptoms in approximately 75% of cases; typically, the cutaneous manifestations of the disease develop 10 years prior to the onset of joint symptoms. This disease course, therefore, provides a potential window of opportunity to initiate effective and aggressive therapies to prevent long-term damage, if symptoms of PsA can be detected early. One of the major features of PsA is enthesitis, yet clinically asymptomatic cases of entheseal abnormalities are likely to go undiagnosed. This concept was evaluated in a prospective study in which entheseal changes in clinically asymptomatic psoriasis patients were compared with findings from a control group. Ultrasonography detected a significantly higher incidence of entheseal abnormalities in patients with psoriasis, despite the absence of clinical symptoms of arthropathy. Ongoing monitoring of these patients has also revealed that a higher baseline score for enthesitis may be associated with a more severe psoriasis outcome. These findings demonstrate that detecting early signs of PsA in asymptomatic patients with psoriasis may have the potential to positively influence disease prognosis and ultimately clinical outcome. Dermatologists can, therefore, play a key role in the early detection and management of PsA. Received: 30 April 2009; Accepted: 28 May 2009 Keywords enthesitis, psoriasis, psoriatic arthritis, systemic inflammation Conflicts of interest None declared. Introduction Our understanding of the pathogenesis of psoriasis has changed rapidly over the past decade. Initially considered an inflammatory disease of the skin, increasing evidence indicates that the inflammation associated with psoriasis may also have systemic consequences. Patients with psoriasis have a higher prevalence of comorbid disease, particularly cardio-metabolic disorders and psoriatic arthritis (PsA), which may reflect a common underlying disease pathogenesis or be the systemic consequences of severe and persistent inflammation. To reflect this, the term psoriatic disease is emerging to cover the various signs and symptoms of tissue and organ involvement that are now recognized in patients with psoriasis. 1 Indeed, the more prominent role of systemic inflammation in psoriasis is demonstrated by the greater importance given to the assessment of associated comorbidities beyond the skin manifestations of the disease. The evidence for a chronic systemic inflammatory disease process in patients with psoriasis, and the importance of early detection of psoriatic inflammation with particular focus on a study of lower limb enthesopathy in clinically asymptomatic patients, are the focus of this review. Psoriasis: metabolic and cardiovascular comorbidities Epidemiological studies have shown that patients with psoriasis have an increased risk of cardiovascular disease, which is an

2 4 Girolomoni and Gisondi important cause of significant morbidity and mortality in psoriasis as well as in other systemic autoimmune disorders. 2 5 In particular, recent studies have shown that there is an association between psoriasis and metabolic syndrome and its components, including hypertension, obesity, dyslipidaemia and insulin resistance. A case-control study of 338 patients with chronic plaque psoriasis found a significantly higher incidence of metabolic syndrome in psoriatic patients compared with controls (30.1% vs. 20.6%; P = 0.005), as well as a higher prevalence of hypertriglyceridaemia and abdominal obesity. 6 A similar study in 581 patients also demonstrated a significant association between psoriasis and the metabolic syndrome (OR 5.29), as well as with individual components of the metabolic syndrome such as hypertension and hyperlipidaemia. 7 A large population-based study in the UK, which utilized the General Practice Research Database to identify patients with severe (n = 3854) or mild (n = ) psoriasis, also found that multiple cardiovascular risk factors were associated with psoriasis, including diabetes, hypertension, hyperlipidaemia and obesity. 8 In addition, diabetes and obesity were more prevalent in patients with severe psoriasis than in those with mild disease. 8 The role of inflammation in the pathogenesis of metabolic and vascular disorders is increasingly well recognized, and there are many common pathogenic features between systemic inflammatory diseases and conditions such as atherosclerosis and insulin resistance. 9 Pro-inflammatory cytokines such as interleukin-6 (IL-6) can stimulate the hypothalamus pituitary axis, which is known to be associated with central obesity, hypertension and insulin resistance. 10 IL-6 may also induce hepatic synthesis of C-reactive protein and, along with TNF-α, alter insulin sensitivity via the insulin signalling pathway. 11 Psoriasis and atherosclerosis also share inflammatory and histological features: pro-inflammatory cytokines are involved in the development of psoriatic lesions as well as having an important role in the breakdown of atherosclerotic plaques, while the two conditions are both characterized by the extravasation of T cells through the epithelium. 12 A recent study examined traditional and novel (Apo A1 and Apo B) risk factors for cardiovascular disease in patients with PsA compared with age- and sex-matched controls, and correlated these risk factors with a marker of inflammation (high-sensitivity C-reactive protein). Inflammation was associated with a higher BMI, waist circumference, waist hip ratio, systolic and diastolic blood pressure, sugar and insulin resistance and dyslipidaemia (lower HDL cholesterol and Apo A1 levels; higher total cholesterol : HDL and Apo B : Apo A1 ratios). 13 The authors concluded that these data support the hypothesis that a shared inflammatory pathway links PsA with common risk factors for cardiovascular disease. Taken together, the results of recent investigations into psoriasis and cardiovascular or metabolic comorbidities provide increasing evidence for a shared pathogenic mechanism for these disorders, linked by the underlying chronic, systemic inflammatory state associated with psoriasis or PsA. Psoriatic arthritis PsA is a chronic inflammatory arthropathy that can occur in association with psoriasis, and is classified as part of the spondyloarthritis complex along with primary ankylosing spondylitis, reactive arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthritis. The prevalence of PsA in patients with psoriasis has ranged widely over the years, the wide range reflecting methodological differences in the various epidemiology studies and the lack of standardized diagnostic criteria for this disease. More recent figures, such as those from national surveys, estimate the incidence to be between 20% and 30%. 19,20 In the general population, the prevalence of PsA is 0.05% to 0.1%, approaching that of rheumatoid arthritis. 21,22 The peak onset of PsA occurs between the ages late 20s to the 40s, with a similar prevalence in men and women. 18 Like arthritis, PsA can cause stiffness, pain and lack of movement in affected areas. It most commonly affects the distal joints in the hands and feet, but can also cause inflammation, swelling and pain in larger joints, including the knees, elbows, hips and the spine. PsA presents with a wide spectrum of clinical symptoms including morning stiffness, dactylitis, distal interphalangeal (DIP) joint disease, enthesitis, actively inflamed joints, and joint deformities. 18,23 PsA was previously considered a mild disease. However, studies conducted over the past two decades have shown that it is in fact an erosive and deforming condition; 40 60% of patients develop joint damage within the first few years of disease onset, and 20% of patients experience a very destructive and disabling disease course Another major feature of PsA is enthesitis, and fingernails and toenails are also commonly affected by signs of nail psoriasis such as pitting, loosening of the nail bed, splinter haemorrhages and onycholysis. PsA: early detection is key Skin lesions precede arthritic symptoms in approximately 75% of cases; typically, the cutaneous manifestations of the disease develop 10 years prior to the onset of joint symptoms. This natural history of disease progression provides a potential window of opportunity for early diagnosis of PsA and the initiation of effective and aggressive therapies to alleviate pain and prevent longer term damage. However, there are several unresolved questions relating to the early diagnosis of PsA. Firstly, what time period covers the early disease phase? Current chronological definitions, extrapolated from early rheumatoid arthritis, range from 6 24 months but specific definitions for PsA are required. Standardized, validated diagnostic criteria are also needed. Disease classification criteria exist, but there are currently no diagnostic criteria for PsA. Early classification criteria were developed by Moll and Wright over 30 years ago and categorize the disease as an inflammatory arthritis, in the presence of psoriasis, and in the absence of rheumatoid factor. 28 Five subgroups of PsA were identified: predominant DIP joint disease, asymmetrical oligoarthritis, polyarthritis, spondylitis, and arthritis mutilans. However, these

3 Psoriatic enthesopathy 5 criteria poorly differentiate between psoriatic and rheumatoid arthritis. 29 More recently, a global group of investigators developed the CASPAR classification (Classification Criteria for Psoriatic Arthritis), which was based upon observed clinical data from > 500 patients with PsA and compared with findings from > 500 control cases (rheumatoid arthritis, ankylosing spondylitis, undifferentiated arthritis and connective tissue disorders). 30 To meet these criteria, a patient must have established inflammatory articular disease (joint, spine or entheseal) and a score of at least 3 based on the following categories: current psoriasis (assigned a score of 2; all other features assigned a score of 1), a history of psoriasis (unless current psoriasis was present), a family history of psoriasis (unless current psoriasis was present or there was a history of psoriasis), dactylitis, radiographic evidence of juxtaarticular new bone formation, a negative test for rheumatoid factor, and typical psoriasis nail dystrophy. From these criteria, it can be seen that the CASPAR classification has the advantage of enabling PsA to be diagnosed in the presence of rheumatoid factor and the absence of psoriasis, providing typical findings of PsA are present. The CASPAR classification is easy to use and has been shown to be highly specific for PsA, with a specificity of 98.7%, and it has been proposed that it is adopted for use in future clinical studies of PsA. 30 A recent study has also demonstrated that CASPAR criteria have high sensitivity in early PsA and may, therefore, be used to classify patients with early-onset disease. 31 In addition to disease classification and diagnostic criteria, the most appropriate diagnostic imaging approach for use in PsA must be clarified. The utility of ultrasonography or magnetic resonance imaging (MRI) in detecting inflammatory and destructive changes in finger and toe joints, tendons and entheses compared with radiography or clinical assessment in patients with PsA was recently assessed. 32 The study enrolled 15 patients with PsA, 5 patients with rheumatoid arthritis and 5 healthy control subjects. Each joint of the second to fifth finger (metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints) and first to fifth metatarsophalangeal joints of both hands and feet were assessed for the presence of synovitis, bone erosions, and bone proliferations using ultrasonography. The second to fifth flexor and extensor tendons of the fingers were also assessed for insertional changes and tenosynovitis. These changes were also assessed in one hand using MRI. X-rays of both hands and feet were assessed for bone erosions and proliferations. Results showed that both ultrasonography and MRI were more sensitive to inflammatory and destructive changes compared with X-ray or clinical examination. Patients with PsA had more changes to the distal interphalangeal joint than patients with rheumatoid arthritis; in particular, bone changes in this joint were detected exclusively in PsA patients. The authors of the study concluded that, in comparison with X-rays, ultrasonography and MRI offer the potential for major improvement in the assessment of inflammatory or destructive changes to joints, tendons, and entheses in the fingers and toes of patients with PsA. An additional complicating factor in the diagnosis of early PsA is that a minority of patients (3 8%) with psoriasis report articular symptoms, including arthralgia, morning stiffness and paresthesia, in the absence of other symptoms required for the diagnosis of PsA. 14 It is, therefore, possible that early sites of inflammation such as the entheses could be missed during clinical evaluation if the patient exhibits no other overt signs of PsA. As a result, it is likely that enthesitis is underdiagnosed in a number of patients with psoriasis. Indeed, several studies have been published that demonstrate asymptomatic joint or entheseal involvement in patients with psoriasis. Entheseal abnormalities were detected using ultrasonography in 33% of patients with psoriasis in whom abnormalities were not identified during routine clinical evaluation. 33 Ultrasonography was also used to detect thickening of the Achilles tendon in patients with psoriasis who had no clinical signs of enthesitis, 34 a similar study that included a subset of patients with symptomatic PsA reported Achilles tendon abnormalities in 59% of patients. 35 Bone scintigraphy has also been used to identify subclinical joint involvement in patients without clinical arthropathy, detecting joint involvement in 35 of 50 patients (70%) in a recent study. 36 The value of bone scintigraphy in refining the diagnostic accuracy of entheso articular involvement was also demonstrated in a recently published study of patients with early PsA. 37 The study included 47 patients with definite PsA (n = 29) or sine psoriasis (n = 18) with articular and/or entheseal involvement for a duration less than or equal to 12 weeks. Clinical examination indicated that early PsA was an oligoenthesoarthritis in > 75% of cases. However, bone scintigraphy revealed that the number of joints and/or entheses with inflammatory involvement was three times greater than that observed on clinical examination. These findings suggest that clinical presentation of oligoenthesoarthritis in early PsA may in fact represent a polyarticular condition in which patients are at increased risk for clinical progression, underscoring the importance of accurate diagnostic imaging in early disease stage. Review of a study of lower limb enthesopathy in asymptomatic patients with psoriasis The presence of entheseal abnormalities in patients with psoriasis who did not have clinical signs of PsA was investigated in a hospitalbased case-control study. 38 Thirty patients with chronic plaque psoriasis were enrolled. Inclusion criteria were disease duration > 1 year; no clinical signs and symptoms of articular involvement (including axial and peripheral involvement); no clinical signs and symptoms of enthesopathy; no radiological signs of spinal hyperostosis; and no systemic treatment for psoriasis in previous 3 months. Patients who had received previous treatment with retinoids were also excluded from the study. Results from patients with psoriasis were compared with findings from a control group of subjects (n = 30) who were being treated at the same hospital for other dermatological conditions including skin carcinomas, atopic or contact eczema or chronic urticaria.

4 6 Girolomoni and Gisondi Patients underwent ultrasonographic evaluation of the Achilles, quadriceps and patellar entheses, and of the plantar aponeurosis. Ultrasonography was performed by both a radiologist and a rheumatologist who were unaware of the patient s disease status, and assessments of structure, thickness, and the presence or absence of bony erosions, enthesophytes and bursitis were made at each site. The ultrasonographic findings were then scored using the Glasgow Ultrasound Enthesitis Scoring System (GUESS). 39 Radiography of the spine, knee and foot was also performed in order to detect hyperostosis, calcifications, bone erosions and bone apposition. The number of calcifications detected by radiography was used to derive a modified GUESS score, in which calcifications were excluded, thereby taking into account only those enthesophytes caused by inflammatory processes. Patients and case controls were well matched for baseline characteristics, with no significant differences observed between the two groups in terms of sex distribution, mean age, BMI, waist circumference, and plasma levels of glucose, cholesterol, triglycerides or uric acid. The severity of plaque psoriasis ranged from mild to severe, with a median Psoriasis Area and Severity Index (PASI) score of 7.54 and a mean Nail Psoriasis Severity Index (NAPSI) score of Despite having no clinical signs of arthropathy, patients with psoriasis had significantly higher mean GUESS scores compared with controls (7.9 vs. 2.9; P < ) (Fig. 1A). Significant differences between the two groups remained when comparing modified GUESS scores, taking into account only inflammatory enthesophytes (5.0 vs. 2.8; P < 0.01) (Fig. 1B). Patients with psoriasis also had a significantly higher number of enthesophytes and significantly increased tendon thickness in all sites examined compared with controls (Table 1; Fig. 2). Six patients with psoriasis had retrocalcaneal bursitis, whereas no cases were found in controls (P < ). In both patients and controls, GUESS scores were directly correlated with age, BMI and waist circumference. Figure 1 (A) Mean GUESS scores in patients with psoriasis compared with case controls (t-test P < ); (B) Modified GUESS scores in patients with psoriasis compared with case controls (excluding enthesophytes due to degenerative disease processes as detected by radiography) (t-test P < ). Reprinted with permission of the BMJ Group. 38 However, no correlation was found between GUESS scores and either the duration or severity of psoriasis, BSA involvement, or severity of nail psoriasis. These findings confirm that patients with psoriasis commonly exhibit entheseal abnormalities, even in the absence of clinical signs of articular involvement. Potentially confounding risk factors, such as BMI, diabetes or familial hypercholesterolaemia, were excluded or controlled for suggesting that the observed entheseal abnormalities were caused by subclinical psoriatic Table 1 Ultrasonographic examination results with abnormal findings in 30 patients with psoriasis and 30 controls 38 Cases Controls P value Quadriceps tendon thickness > 6.1 mm; N* (%) 18 (30) 2 (3.3) Suprapatellar bursitis; N (%) 1 (1.6) Superior pole of patellar enthesophyte; N (%) 41 (68.3) 24 (40) Patellar ligament thickness > 4 mm (inferior pole of patella); N (%) 22 (36.6) 14 (23.3) 0.02 Inferior pole of patella enthesophyte; N (%) 20 (33.3) 12 (20) 0.01 Patellar ligament thickness > 4 mm (insertion at the tibial tuberosity); N (%) 21 (35) 10 (16.7) 0.01 Tibial tuberosity enthesophyte; N (%) 14 (23.3) 1 (1.6) Achilles tendon thickness > 5.29 mm; N (%) 10 (16.6) 1 (1.6) Retrocalcaneal bursitis; N (%) 6 (10) Posterior pole of calcaneus enthesophyte; N (%) 54 (90) 20 (33.3) Plantar aponeurosis thickness > 4.4 mm; N (%) 3 (5) Inferior pole of calcaneus enthesophyte; N (%) 23 (38.3) 22 (36.6) 0.8 *N is the number of entheseal sites categorised as abnormal according to the GUESS score. (%) is the prevalence of entheseal sites abnormalities in the case and control population, respectively.

5 Psoriatic enthesopathy 7 Table 2 Retrospective analysis showing the association between baseline GUESS score and a worse clinical outcome in patients with psoriasis. A more severe outcome was defined as PASI score of > 10, non-response to first-line conventional therapies, biological therapy required, or change in biological therapy required. (Personal communication) Baseline Good outcome Worse outcome P Number of patients GUESS score 4.25 ± ± PASI 3.8 ± ± Psoriasis duration (years) Age (years) Waist circumference (cm) BMI (kg/m 2 ) Male sex 35% 65% Diabetes 2% 3% 0.8 Figure 2 (A) Ultrasonographic image of normal Achilles tendon (3.8 mm) in a case control subject. (B) Ultrasonographic image of a thickened Achilles tendon (7.1 mm) and enthesophyte in a patient with psoriasis. (C) Ultrasonographic image of a thickened Achilles tendon (6.8 mm) associated with a retrocalcaneal bursa in a patient with psoriasis. (AT: Achilles tendon, B: retrocalcaneal bursa, CA: calcaneus, E: enthesophyte). Reprinted with permission of the BMJ Group. 38 inflammation. The presence of asymptomatic enthesopathy in patients with psoriasis raises several unresolved questions. Firstly, does the enthesopathy represent a consequence of the chronic systemic inflammation of the psoriatic disease? Secondly, is the association between cutaneous and joint psoriasis much more frequent than previously believed? Thirdly, is enthesopathy a risk factor for developing PsA? And finally, could lower limb enthesopathy represent a type of entheseal Koebner phenomenon due to biomechanical stress, as proposed by McGonagle and colleagues? 40 To address at least the first two questions regarding the prognosis of these subclinical entheseal abnormalities, patients in the study are being prospectively monitored. A recent analysis assessed disease status after a 2-year follow-up period, from April 2006 to March There was no significant change in mean GUESS scores over this period, although it should be noted that patients were receiving systemic treatment for psoriasis during this time. However, three of the 30 patients developed PsA, all of whom had a baseline GUESS score of > 9. Two of these patients developed hand dactylitis and, subsequently, plantar fasciitis and oligoarticular peripheral arthritis, while one patient developed oligoarticular peripheral arthritis only. These preliminary results suggest that a baseline GUESS score of > 9 may be associated with a more aggressive clinical course with an increased risk of developing PsA. This finding clearly requires evaluation in larger prospective clinical studies. The relationship between entheseal abnormalities and disease progression was further evaluated by analysing the association between baseline GUESS score and a more severe psoriasis outcome (defined as PASI score of > 10, non-response to first-line conventional therapies, biological therapy required, or change in biological therapy required). This retrospective analysis revealed that, according to these criteria, nine of the 30 patients had a more severe clinical outcome compared with the remaining 21 patients. These nine patients had a significantly higher baseline GUESS score (9.29 vs. 4.25; P < 0.001) and a significantly higher baseline PASI score (14.5 vs. 3.8; P < 0.002) compared with the patients who had a good clinical outcome (Table 2). No significant differences between the two groups were found for disease duration, age, waist circumference, BMI, or comorbid diabetes. Patients with more severe psoriasis were also significantly more likely to be male (65% vs. 35%), although this may be a chance finding based on the small number of patients included in this study. These results demonstrate that early detection of PsA in clinically asymptomatic patients with psoriasis has the potential to positively influence disease prognosis and patient outcomes. Dermatologists can therefore play a key role in the early detection and management of PsA. Since there is preliminary evidence that more severe entheseal involvement may be associated with poorer clinical outcomes in psoriasis patients, ultrasonography may prove useful in the future by helping to diagnose enthesopathy earlier. Conclusion There is now increasing evidence from a number of imaging studies, including the one described in detail above, which provide

6 8 Girolomoni and Gisondi a new insight into the link between skin and joint disease in patients with psoriasis. Results from these studies show that clinically asymptomatic patients with psoriasis often exhibit entheseal changes, which could be related to subclinical entheseal psoriatic inflammation. Since clinical examination commonly fails to detect enthesopathies, ultrasonography may prove useful for identifying such abnormalities early in the course of psoriasis. Preliminary analyses suggest that the presence of entheseal disease may help to predict which patients are more likely to develop PsA in the future. However, these results need to be confirmed in a longitudinal study involving a large cohort of patients with and without entheseal abnormalities. Finally, two clinically important questions at this stage are: what evidence is available to assist physicians in deciding the best therapeutic approach for patients, and will early intervention help prevent progression of joint damage in individuals with signs of subclinical psoriatic inflammatory disease? References 1 Ritchlin C. Psoriatic disease from skin to bone. Nat Clin Pract Rheumatol 2007; 3: Azfar RS, Gelfand JM. Psoriasis and metabolic disease: epidemiology and pathophysiology. Curr Opin Rheumatol 2008; 20: Federman DG, Shelling M, Prodanovich S et al. Psoriasis: an opportunity to identify cardiovascular risk. Br J Dermatol 2009; 160: Gelfand JM, Neimann AL, Shin DG et al. Risk of myocardial infarction in patients with psoriasis. JAMA 2006; 296: Wu Y, Mills D, Bala M. Psoriasis: cardiovascular risk factors and other disease comorbidities. J Drugs Dermatol 2008; 7: Gisondi P, Tessari G, Conti A et al. 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