Modification of a sonographic enthesitis score to differentiate between psoriatic arthritis and young healthy volunteers

Objectives: We aimed to describe sonographic structural and inflammatory changes in entheses of patients with recently diagnosed psoriatic arthritis (PsA), patients with established PsA, and young healthy volunteers, and to investigate whether the MAdrid Sonographic Enthesitis Index (MASEI) enables us to distinguish these groups in an extreme comparison. Method: New and established PsA patients and healthy volunteers (aged 20–30 years) were recruited. The triceps, quadriceps, patellar, Achilles and elbow extensor tendon insertion, and plantar fascia entheses were investigated sonographically for structural changes, erosions, calcifications, increased thickness, bursitis, and power Doppler (PD) signal according to the MASEI. Results: The study included 25 new and 25 established PsA patients, and 25 healthy volunteers. Increased thickness and PD signal in knee entheses were common for patients and healthy volunteers, while changes at other locations predominantly occurred in patients only. PD was recoded (1, one spot; 1.5, two or three spots; 2, confluent signal; 3, severe confluent signal) and thickness of knee entheses excluded. This resulted in different modified MASEI scores between PsA patients and young healthy controls: median (interquartile range) modified MASEI of 13 (10–22.5) in new PsA, 13.5 (9.5–18) in established PsA, and 3 (1–8.5) in healthy volunteers (p = 0.002). Conclusions: Structural ultrasound changes and PD in entheses are common in both new and established PsA and healthy controls. MASEI score did not differentiate PsA patients from young healthy volu

Measuring Disease Activity and Outcomes in Early Psoriatic Arthritis

Psoriatic Arthritis (PsA) is a heterogeneous disease, characterized by manifestations of peripheral arthritis, dactylitis, enthesitis, spondylitis, and psoriasis. Patients with PsA experience the impact of disease as loss of functional ability, decreased health-related quality of life (HRQOL) and loss of productivity. Treatment is aimed at preventing these consequences. It is recommended that treatment is given as early as possible, with all manifestations taken into account, and in a treat-to-target strategy. In a treat-to-target strategy, treatment is intensified if a certain target – a composite disease activity measure – has not been achieved. Good measures of disease activity are needed to improve outcomes for patients with PsA. For this purpose, more information is needed on disease activity and outcomes early in the disease course. These are studied in the Dutch southwest Early Psoriatic Arthritis cohoRt (DEPAR) and related sub-studies. This thesis aims to investigate the following four aspects of disease activity and outcomes in early PsA: ultrasound abnormalities of the entheses, burden of disease at time of diagnosis and its relation with disease manifestations, the relation between time to minimal disease activity and outcomes, and the performance of disease activity measures

Decision Making with Ultrasound in Rheumatology

The _first aim_ of this thesis was to evaluate the added value of ultrasound in clinical decision making in patients with arthralgia, patients with psoriasis and monitoring RA patients. Our _second aim_ was to increase sensitivity of power Doppler ultrasound for MCP joints. Early diagnosis of rheumatoid arthritis and thereby facilitating early initiation of effective disease-modifying drugs can slow down disease progression and diminish joint damage. With the introduction of the 2010 ACR/EULAR classification criteria for RA we are able to classify patients as having RA at an earlier stage. We described which cut point of the 2010 criteria would enable us to earlier identify RA patients among recent onset inflammatory arthritis patients. _Part one – Ultrasound in clinical practice_ Since physical examination reached its maximum to identify synovitis, the first chapters of this thesis focus on the added value of ultrasound in daily clinical practice. Firstly, we described the association of ultrasound inflammation and the development of inflammatory arthritis in an early arthralgia cohort. Secondly, the frequency of ultrasound enthesitis in primary care psoriasis patients with musculoskeletal complaints was explored. The course of ultrasound inflammation and clinical findings in the feet in newly diagnosed RA patients was investigated next. In addition, the association of the presence of ultrasound synovitis and health status in RA patients who are in clinical remission was studied. And last we evaluated if ultrasound synovitis is a biomarker for clinical flare in RA patients who are tapering their medication. _Part two – Experimental technical research_ The performance of the power Doppler modality of several ultrasound machines was compared by a flow phantom. The same flow phantom was used to compare conventional ultrasound with high-frame rate Doppler ultrasound. And we also give the results of high-frame rate Doppler ultrasound imaging in RA patients to evaluate whether it was possible to detect higher levels of vascularisation than with conventional ultrasound

Early Recognition of Spondyloarthritis in Patients at Risk

Spondyloarthritis(SpA) is an umbrella term for a group of rheumatic diseases. It can manifest with pain and stiffness of the joints, tendons or lower back. Patients who suffer from psoriasis or inflammatory bowel disease (IBD) are at increased risk of developing SpA. In patients with psoriasis this is called psoriatic arthritis and in patients with IBD it is called IBD-related SpA. In __Part I__ of this thesis the prevalence and impact of SpA in these risk groups is described. We set up the SENSOR study to establish the prevalence of psoriatic arthritis in primary care. A special form of psoriatic arthritis is enthesitis, where the entheses are inflamed. We describe the results of an ultrasound study in enthesitis as well. For IBD-related SpA a systematic review was performed to establish the prevalence. We also looked at the impact of musculoskeletal complaints in patients with IBD. __Part II__ of this thesis focusses on awareness and screening. SpA should be recognized as early as possible to initiate adequate treatment early on. In order to achieve timely recognition, physicians should be aware of the increased risk in patients with psoriasis and IBD. The AppSpA study describes the current awareness in both general practitioners and patients themselves. Besides awareness, screening could also contribute to early recognition. For psoriatic arthritis multiple screeningtools have been developed. We tested these screeningtools in a primary care setting and compared the different screeningtools with each other

Epidermal Growth Factor Receptor in Joint Health and Osteoarthritis

Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases in the world. Our laboratory has shown that epidermal growth factor receptor (EGFR) signalling is involved in the process of cartilage degeneration in OA. Regulation of EGFR signalling by mitogen-inducible gene 6 (Mig-6) and dual specificity phosphatase 1 (DUSP-1) allows for signal modulation, and mouse models have linked these proteins to joint pathologies. Failure to control EGFR signalling may be involved in OA progression leading to my overarching hypothesis: regulation of EGFR signalling is essential for maintenance of joint health. I initially tested the role of Mig-6 in cartilage health using cartilage-specific deletion of Mig-6 in a mouse model. Using various histological and imaging techniques, we demonstrated that these animals show increased anabolic activity in articular cartilage, as well as the formation of chondro-osseous nodules in their knee joints within the first 3 months. These mice did not develop severe OA as I predicted, however, there were early signs of developing articular cartilage pathology. To assess the role of Mig-6 in elderly cartilage, we employed the same mouse model but aged these animals to 21 months, near the end of their life span. These KO animals exhibited similar knee phenotypes, however, no abnormal growths were observed in the ankle and elbow joints which showed enhanced cartilage thickness. Only minor signs of OA were noted. Using an inducible system to delete Mig-6 from cartilage of 3 week old mice, we found limited evidence of increased anabolic activity at 12 weeks. These studies demonstrate that Mig-6 may be playing an important role during development and that loss of Mig-6 may positively impact cartilage health. Finally, I examined the knee joints of whole body Dusp1 null mice at 21 months of age for signs of OA. Both Dusp1 null and control mice showed similar signs of OA, indicating that DUSP-1 mediated regulation of signalling downstream of EGFR is not essential to prevent spontaneous OA progression. Taken together, these data demonstrate that EGFR signalling regulated by both Mig-6 and DUSP-1 is important in joint homeostasis, and has revealed a potential target in Mig-6 for future cartilage regenerative treatments

More Than Skin Deep: Detection of subclinical enthesopathy and early psoriatic arthritis in patients with psoriasis in primary and secondary care and assessment of the response to anti-IL-12/IL-23p40 monoclonal antibody skin-directed therapy using ultrasound and whole-body MRI

Objectives: Primary care cohort: To determine the rates of undiagnosed psoriatic arthritis (PsA) amongst patients with psoriasis using clinical examination and screening questionnaires, and test the performance a new PsA screening questionnaire alongside the current standard (Psoriasis Epidemiology Screening Tool, PEST). Secondary care cohort: To develop novel ultrasound and whole body magnetic resonance imaging (WBMRI) protocols to facilitate the comprehensive assessment of subclinical abnormalities within the peripheral and axial skeleton of immunomodulatory therapy-naïve patients with psoriasis referred to secondary care, and to use these protocols to assess the imaging response of abnormalities over 52 weeks of skin- directed treatment with a licensed IL-12/23p40 inhibitor (ustekinumab). Methods: Primary care cohort: 932 patients, across five diverse primary care practices, who were coded as having a diagnosis of psoriasis, were invited by their General Practitioner to attend an evening appointment at their surgery for a consultation with a dermatologist and a rheumatologist. Half of patients were sent an educational leaflet regarding PsA with their invitation letter. Attendees were examined and asked to complete a PEST questionnaire and a new PsA screening questionnaire (CONTEST). Secondary care cohort: 73 immunomodulatory therapy-naive patients, without musculoskeletal disease or symptoms, who were referred to dermatology for treatment of moderate to severe psoriasis were screened using an extensive ultrasound protocol to assess for the presence of subclinical enthesitis. Patients who had at least one inflammatory abnormality, and in whom biologic therapy was not contraindicated, were invited to receive standard-dose skin directed therapy with ustekinumab for 52 weeks. Ultrasound examination of 13 entheses and structures within the adjacent synovio- entheseal complex were performed at weeks 0, 12, 24 and 52. WBMRI was performed at week 0, 24 and 52, to assess the axial skeleton and sites in the peripheral skeleton inaccessible by ultrasound. 23 healthy volunteers had one ultrasound scan and WBMRI using the same protocols, for comparison. Results: Primary care cohort: 20.5% of patients invited for screening attended. The provision of an educational leaflet did not have an impact on attendance for screening, except in the most deprived areas. 191 patients were examined, of which 169 had current or previous psoriasis (11.5% misdiagnosis rate). 17 patients were newly diagnosed with PsA (10.1%). The best sensitivity and specificity of the CONTEST questionnaires were 76.5% and 56.5% respectively, without the joint mannequin (cut off 33), and 70.6% and 63.3% respectively, with the joint mannequin (cut off 34). The sensitivity and specificity of the PEST questionnaire in this cohort, using the validated cut off 33, was 52.9% and 66.0%. Lowering the cut off 32, the sensitivity improved to 82.4% with a specificity of 44.9%. Secondary care cohort: 36 patients (49.3%) had at least inflammatory subclinical abnormality on screening ultrasound. 28 of these 36 were eligible for a biologic therapy and agreed to undergo a more detailed ultrasound scan and WBMRI. 5 patients subsequently chose conventional therapy, and 23 patients consented to treatment with ustekinumab and long-term review. 23 patients reached the primary end point of week 24, and 20 reached week 52. Inflammatory and chronic damage abnormalities were seen with greater frequency in the peripheral rather than axial skeleton, mostly involving the larger entheses of the knee, foot, ankle and elbows. Healthy volunteers exhibited a similar pattern of abnormalities but at a significantly lower frequency (inflammatory lesions 4.5% vs. 31.1%, chronic damage lesions 6.0% vs. 27.0%, both p<0.00001). Synovitis was seen in 82.1% of patients, while bursitis and tenosynovitis were uncommon. Following treatment with ustekinumab, ultrasound inflammation scores reduced by 42.2% at the primary end point (week 24, p<0.001), and by 51.5% after 52 weeks (p=0.01). Chronic damage scores remain unchanged (p=0.082 week 24, p=0.512 week 52). In the axial skeleton, more patients than volunteers had vertebral unit bone marrow oedema (64.3% vs. 30.4%, p<0.00001). Sacroiliac joint inflammation was minimal in both groups. Axial structural changes occurred in 14.3% in patients and were absent in volunteers. No significant change in spine or SIJ osteitis (p=0.656 week 24, p=0.627 week 52), or structural abnormalities were observed after ustekinumab therapy. Conclusions: A proportion of patients with psoriasis have undiagnosed PsA in primary care, even with signs and symptoms of inflammatory arthritis. Screening questionnaires are useful to detect some, but not all patients and further measures are required to capture all cases of PsA. Early identification and treatment is essential to prevent future pain, functional limitation and disability. Treating patients for psoriasis with a therapeutic agent that is effective at reducing the development of PsA is one means of addressing the failings of clinical examination and screening questionnaires, although the evolution from subclinical enthesitis (a common finding in patients with psoriasis) to PsA is not understood. This thesis provides preliminary data to suggest that anti-IL-12/23p40 therapy may reduce the burden of subclinical inflammation at the primary site of lesion development in PsA (the enthesis), and further longitudinal studies are now encouraged to confirm these observations with ustekinumab and other immunomodulatory therapies

Modification of a sonographic enthesitis score to differentiate between psoriatic arthritis and young healthy volunteers

<p><b>Objectives</b>: We aimed to describe sonographic structural and inflammatory changes in entheses of patients with recently diagnosed psoriatic arthritis (PsA), patients with established PsA, and young healthy volunteers, and to investigate whether the MAdrid Sonographic Enthesitis Index (MASEI) enables us to distinguish these groups in an extreme comparison.</p> <p><b>Method</b>: New and established PsA patients and healthy volunteers (aged 20–30 years) were recruited. The triceps, quadriceps, patellar, Achilles and elbow extensor tendon insertion, and plantar fascia entheses were investigated sonographically for structural changes, erosions, calcifications, increased thickness, bursitis, and power Doppler (PD) signal according to the MASEI.</p> <p><b>Results</b>: The study included 25 new and 25 established PsA patients, and 25 healthy volunteers. Increased thickness and PD signal in knee entheses were common for patients and healthy volunteers, while changes at other locations predominantly occurred in patients only. PD was recoded (1, one spot; 1.5, two or three spots; 2, confluent signal; 3, severe confluent signal) and thickness of knee entheses excluded. This resulted in different modified MASEI scores between PsA patients and young healthy controls: median (interquartile range) modified MASEI of 13 (10–22.5) in new PsA, 13.5 (9.5–18) in established PsA, and 3 (1–8.5) in healthy volunteers (p = 0.002).</p> <p><b>Conclusions</b>: Structural ultrasound changes and PD in entheses are common in both new and established PsA and healthy controls. MASEI score did not differentiate PsA patients from young healthy volunteers. After recoding of PD severity and excluding thickness of knee entheses, marked differences between PsA patients and healthy controls were observed.</p