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-naive 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.