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Abstract
Objective Enthesopathy is a major feature of psoriatic arthritis (PsA), which is supported by imaging studies. Given that nail disease often predates PsA and that the nail is directly anchored to entheses, the authors asked whether nail involvement in psoriasis equates with a systemic enthesopathy.
Methods Forty-six patients with psoriasis (31 with nail disease) and 21 matched healthy controls (HC) were recruited. 804 entheses of upper and lower limbs were scanned by an ultrasonographer blinded to clinical details.
Results Psoriasis patients had higher enthesitis scores than HC (median (range) 21 (0–65) vs 11 (3–39), p=0.005). Enthesopathy scores were higher in patients with nail disease (23 (0–65)) than in patients without nail disease (15 (5–26), p=0.02) and HC (11 (3–39), p=0.003). Inflammation scores of patients with nail disease (13 (0–34)) were higher than patients without nail disease (8 (2–15), p=0.02) and HC (5 (0–19), p<0.001). Modified nail psoriasis severity index scores were correlated to both inflammation (r2=0.45, p=0.005) and chronicity scores (r2=0.35, p=0.04). No link between the psoriasis area and severity index and enthesitis was evident.
Conclusion The link between nail disease and contemporaneous subclinical enthesopathy offers a novel anatomical basis for the predictive value of nail psoriasis for PsA evolution.
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Psoriasis affects approximately 2% of the population and up to 30% of these will develop psoriatic arthritis (PsA).1,–,4 As dermatologists usually see patients with psoriasis before arthritis develops they are well placed to diagnose PsA early. Now that effective therapies for the suppression of PsA exist, the early recognition of PsA has important consequences for optimal patient management. Currently, the conceptual basis for the link between psoriasis and nail disease and subsequent PsA is poorly understood.
It has been suggested that enthesitis is the primary lesion that underscores the diverse skeletal manifestations of PsA.5 It has also been demonstrated that subclinical enthesopathy and associated osteitis is present in up to 50% of patients with psoriasis with no arthritis.6 7 Another stream of research has shown that the presence of nail disease is a harbinger for the future development of PsA.8 These findings are noteworthy because we have shown that psoriatic nail disease in PsA is intimately associated with enthesopathy of the distal interphalangeal joint and that the nail is functionally integrated with the enthesis.9,–,11
These combined clinical and imaging observations suggest that there may be a link between systemic enthesopathy and psoriatic nail disease. Therefore, we posed the question as to whether nail disease in psoriasis is linked to a greater degree of systemic enthesopathy compared with psoriasis patients without nail disease. Such a link would offer a novel unifying concept for nail disease, systemic enthesopathy and the future development of PsA.
Methods
The study was carried out in two European populations (Leeds, UK and Verona, Italy). Ethical approval for the study was obtained in both countries.
Patient groups and clinical assessment
Forty-six patients with psoriasis (31 with nail disease) and 21 healthy controls (HC) were included. Any patients with PsA according to the classification of psoriatic arthritis (CASPAR) criteria, patients with evidence of osteoarthritis, and those with arthralgia or articular symptoms were excluded.12 The clinical assessment, including a psoriasis area and severity index (PASI) score, was performed by a clinician blinded to ultrasound data. Modified nail psoriasis severity index (NAPSI) scores for all fingernails were recorded for patients recruited in the UK.13 For HC recruitment, adults aged between 18 and 64 years who were accompanying patients were approached in the outpatient clinical waiting area. People without a history of arthritis and psoriasis were recruited.
Ultrasonography
Ultrasonography was performed by three rheumatologists fully trained in musculoskeletal ultrasound and with a special interest in scanning enthesitis (SZA and CC in the UK, IT in Italy) using a Logiq E9 machine in the UK and a Logiq 5 machine in Italy (General Electric, Wauwatosa, Wisconsin, USA) both with a linear probe at 9–14 MHz.
Ultrasound of the lower limbs entheses (Achilles, plantar fascia insertion, quadriceps insertions, patellar tendon origins and insertions) and common extensor tendon origins of the upper limbs was performed blinded to the presence of psoriasis or nail disease. To enable blinding, patients were asked not to communicate with the ultrasonographer about their disease during the ultrasound assessment. The sonographer did not perform a physical examination, therefore sites other than those involved in the ultrasound scan were not seen by the sonographer. The room was completely darkened starting from the beginning of the ultrasound assessment. The light of the ultrasound machine alone is not enough for the sonographer to see the nails clearly.
The patients were placed in a supine position to assess the entheses around the knee (extended to assess the presence of Doppler signal and semiflexed to 30° to assess the grey scale changes), and in a prone position with the feet over the end of the examination table for visualisation of the entheses around the heel. To assess the common extensor tendon, patients were placed in a sitting position with the elbow flexed to 90° (see supplementary table 1, available online only).
Total number of ultrasound findings including all sites
The power Doppler settings were standardised with a pulse repetition frequency of 750 Hz, a colour mode frequency of 9.1 MHz and low wall filters. The colour gain was increased to the maximum level not generating power Doppler signals under the bony cortex. All ultrasound assessments were performed using a multiplanar scanning technique.
Ultrasound image interpretation
The outcome measures in rheumatoid arthritis clinical trials (OMERACT) definition of enthesopathy was used to interpret ultrasound images: ‘abnormally hypoechoic (loss of normal fibrillar architecture) and/or thickened tendon or ligament at its bony attachment (may occasionally contain hyperechoic foci consistent with calcification), seen in two perpendicular planes that may exhibit Doppler signal and/or bony changes including enthesophytes, erosions, or irregularity’.14 Bursal enlargement was also scored. Thickness measurements and erosions were scored quantitatively, except the thickness of the common extensor tendon which was assessed semi-quantitatively. The thickness of the entheses was measured at the level of insertions in longitudinal scans. Normal values for each insertion were accepted as reported in the literature15 and additionally less than 1 mm of increase exceeding the threshold was scored as grade 1, 1 mm or more but less than 2 mm of increase was scored as grade 2 and 2 mm or more was scored as grade 3. Erosions were also scored quantitatively (maximum diameter of the erosion >0, <2 mm: grade 1; ≥2, <3 mm: grade 3; ≥3 mm: grade 3). The rest of the assessments were performed on a semiquantitative basis (mild changes grade 1, moderate grade 2 and severe grade 3).
Ultrasound findings were categorised according to the following: the grey scale changes related to inflammation (entheseal hypoechogenicity, thickening and bursal enlargement) and the power Doppler scores were added up to create an ‘inflammation score’ (range 0–156). The grey scale changes related to chronic findings (calcifications, erosions and enthesophytes) were added up to calculate a ‘chronicity score’ (range 0–108). A total score (by adding up all findings) had a possible range of 0–264.
Statistics
Categorical data are expressed as frequencies, and continuous variables are given as means (SD) or medians (range) (depending on the distribution). The prevalence of each individual lesion by ultrasound in patients with or without nail disease was compared by using a χ2 test. The Mann–Whitney U test was used in order to compare ultrasound scores between groups.
Correlations between clinical parameters (modified NAPSI, PASI and disease duration) and ultrasound scores (separately for ultrasound scores related to inflammation, damage and total) were analysed by the Pearson correlation test. Statistical analysis was performed using SPSS version 11.5.
For agreement between sonographers, all investigators agreed on definitions and the scoring system before the study both on saved images and while acquiring sample images. One thousand and twenty stored images of 21 patients for grey scale and power Doppler for all entheses included in the study were scored by all three investigators and intraclass correlation coefficient (ICC) values were calculated for each pair of investigators.
Results
Inter-observer agreement
A moderate to excellent agreement between both investigator pairs was calculated for different ultrasound scores: for grey scale inflammation the ICC values were 0.91–0.93 (95% CI 0.79 to 0.97), for power Doppler inflammation 0.74–0.95 (95% CI 0.45 to 0.98), for chronicity scores 0.89–0.93 (95% CI 0.76 to 0.98) and for total ultrasound scores 0.92–0.95 (95% CI 0.81 to 0.98).
Patient characteristics
The distribution of key characteristics of patients and HC did not differ significantly (for age mean (SD) 44.2 (15.5) vs 50.5 (10), respectively, p=NS), (for body mass index 26.7 (5.1) vs 24.9 (2.7), respectively, p=NS), (female percentage 50% in psoriasis vs 52.4 % in HC). PASI scores of psoriasis patients with (5.6 (4.1)) or without (6.3 (5)) nail disease were similar. They also had similar disease durations (19.1 (10) years for nail disease and 14.1 (12.6) years for psoriasis, p=0.06). Nail findings within the nail disease group were as follows: 104/310 nails had onycholysis; 165/310 had pitting and 41/310 had crumbling. Although no patients reported joint symptoms and none had clinically evident joint swelling, four cases had mild entheseal tenderness on physical examination (three with nail disease, one without nail disease). Three of these patients had tenderness only at one site (two lateral epicondyle and one patellar ligament insertion) and one patient had tenderness at multiple sites.
Soft tissue changes at insertions
Patients with psoriasis had higher inflammation scores than HC (med (range): 12 (0–34) vs 5 (0–19), p<0.001). The inflammation scores of psoriasis patients with nail disease (13 (0–34)) were higher than both patients without nail disease (8 (2–15), p=0.02) and HC (5 (0–19), p<0.001) (figures 1 and 2). Hypoechogenicity and thickening were more frequent in patients with nail disease compared with patients without nail disease (table 1).
Comparison of median ultrasound (US) scores related to inflammation and chronicity in psoriasis patients with and without nail disease and healthy controls.
(A) Photograph of thumb nail of a patient with psoriasis, showing onycholysis and an oil drop spot. (B) Longitudinal ultrasound scan of the origin of patellar tendon of the same patient showing severe thickening (white line 0.7 mm), hypoechogenicity (*) and a large enthesophyte (e).
Bone erosion and spur formation
Patients with psoriasis had similar chronic changes to HC (8.5 (0–31) vs 7 (1–24), p=0.08) (figure 1). When patients with nail disease were compared separately, the nail disease group had considerably higher enthesopathy chronicity scores than HC (10 (0–31) vs 7 (1–24), p=0.04). Patients with nail disease had more enthesophytes than patients without nail disease (table 1).
Total ultrasound scores
Patients with nail disease had higher total ultrasound scores (23 (0–65)) compared with patients without nail disease (15 (5–26), p=0.02) and HC (11 (3–39), p=0.005). A detailed list of ultrasound findings depending on the site can be seen in supplementary table 2 (available online only).
Link between clinical assessments and ultrasound findings
We explored the link between the overall burden of nail disease extent and severity using the modified NAPSI scores in 36 patients. The severity of nail disease correlated with the inflammation (r2=0.45, p=0.005) and chronicity scores (r2=0.35, p=0.04).
The duration of psoriasis also tended to correlate with entheseal inflammation (r2=0.29, p=0.05), whereas no link between PASI and ultrasound scores was evident.
We performed a further analysis to exclude the effect of tenderness on physical examination and compared the ultrasound scores by excluding four patients with mild entheseal tenderness. We noted that the ultrasound scores showed the same statistical associations with nail disease (data not given).
Discussion
Given that nail disease is a predictor for PsA evolution and that the nail is functionally integrated with a network of entheses about the distal interphalangeal joints, we tested the hypothesis that nail involvement in psoriasis was linked to a more extensive subclinical enthesopathy. Our findings confirm that subclinical enthesopathy was common and was specifically related to nail disease. We also found that more extensive nail involvement correlated with more severe enthesopathy scores.
What is the pathophysiological basis for these findings? It has recently been shown that nail disease in psoriasis most typically affects the dominant hand thumb nail and then other nails that are most associated with hand function.16 This points towards tissue-specific factors rather than autoimmunity in general as being key drivers in the psoriatic onychopathy process. Given that Koebnerisation responses in the skin occur in the presence of tissue trauma or an aberrant repair response to it, then it is possible that much of the nail disease process is linked to joint mechanics and/or trauma.17 18 The genetic basis for these changes awaits elucidation.
There is also a clear epidemiological link between PsA and joint trauma, and perhaps of even greater relevance is the observation that normal entheses have evidence of microscopic damage and associated inflammatory changes that probably represent part of the normal healing process.19,–,21 Therefore, the subclinical enthesopathy noted in psoriasis cases with nail disease may point towards an aberrant response to tissue micro damage at diverse sites. However, it may be that the genetic factors that predispose to nail disease may also help switch subclinical enthesopathy into a manifesting inflammatory enthesitis. At this point, it must be accepted that the actual basis for the link between nail disease and distant enthesopathy awaits elucidation and that other putative mechanisms may exist.
In conclusion, this study confirms that enthesopathy is common in psoriasis patients without clinical arthritis. Moreover, subclinical enthesopathy is especially associated with nail involvement in a cross-sectional analysis. These findings suggest that nail disease is in some way linked to the expression of enthesitis including subclinical disease.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Web Only Data - This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
- Web Only Data - This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Web Only Data - This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
- Web Only Data - This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
The first two authors contributed equally to this study.
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Funding This study was supported by an unrestricted educational grant from Merck Sharp & Dohme Ltd with part funding also from the National Institute for Health Research. SZA had a grant from the Society for Education and Research in Rheumatology in Turkey. CCG was funded by EULAR and the Spanish Foundation of Rheumatology grants.
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Competing interests None.
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Ethics approval Ethics approval for the study was obtained from the ethics committees in Leeds and Verona.
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Provenance and peer review Not commissioned; externally peer reviewed.