Title: Treating to target in psoriatic arthritis: assessing real-world outcomes and optimising therapeutic strategy for individuals.
Funder: Department of Health and Social Care

Abstract: BACKGROUND Psoriatic arthritis (PsA) accounts for 20% of inflammatory arthritis affecting ~150,000 people in the UK. Direct costs to healthcare are estimated at 2,400 per patient with indirect costs of over 8,000 annually. There are limited data guiding therapy in PsA. The Tight Control of PsA (TICOPA) randomised controlled trial (RCT) confirmed improved clinical outcomes with a treat to target' strategy compared to standard care. This consisted of 4-weekly review and escalation of step up' therapy (one disease modifying therapy (DMARD), combinations of DMARDs and then biologics) based on achievement of minimal disease activity (MDA) criteria. As a result, this approach is supported by European treatment recommendations but it is not implemented in most centres due to feasibility and cost concerns.PsA is a highly heterogenous condition but no studies have tailored which drugs are used depending on disease severity. Studies in oligoarthritis ( AIMS The hypothesis is that management of PsA can be optimised by implementing a pragmatic treat to target' approach in clinical practice and testing different therapies tailored to disease severity. The aims are (1) To provide clinical effectiveness data and costings for a feasible model of treat to target' step-up' therapy. (2) To determine feasibility and design a future definitive trial addressing whether patients with mild PsA can be managed without DMARDs. (3) To establish in a full RCT whether initial intensive therapy with either combination DMARDs or early biologics is superior to a step up treatment approach in moderate/severe PsA. METHODS This programme of work utilises a Trials within Cohorts (TWiCs) design (see figure).WP1 The cohort where clinical outcomes and costs will be assessed every 12 weeks in newly diagnosed PsA patients (n200) treated using a pragmatic step up' treat to target' regime. Treatment will be guided by MDA criteria every 4-12 weeks.These patients will also be asked if they are willing to consider alternative therapies. For both trials (WP2/3) within the cohort (WP1), subsets of patients willing to consider alternative therapies are chosen randomly to be offered different treatment. These groups are compared to those who met the inclusion criteria but were randomly chosen not to be offered them. WP2 This feasibility study (n=60) will invite patients with mild PsA (oligoarticular, no adverse prognostic factors, low patient-reported impact) to receive analgesia/intra-articular steroids delaying DMARD therapy. It will assess the proportion eligible, acceptability to patients and clinical outcomes to inform the design of a definitive future trial evaluating treatment of mild PsA.WP3 This RCT will recruit 315 patients with polyarticular disease (5 inflamed joints) or oligoarticular disease with poor prognostic factors to receive either initial combination DMARD or six months of biologic therapy compared to standard step up' therapy, to establish whether early intensive therapy for moderate/severe PsA is superior. POTENTIAL BENEFITS This programme of work will establish treat to target' strategy in PsA and develop evidence for which therapies should be used. WP1 will establish a pragmatic treat to target' approach within an NHS clinic establishing real-life clinical outcomes and costs. WP2 will provide feasibility data for a definitive trial addressing conservative management of mild PsA. WP3 will provide definitive RCT evidence establishing the optimal management of moderate/severe PsA assessing two different intensive treatment regimes (combination DMARDs/biologics) against standard step up' therapy. The TWiCs design allows robust generalizability to routine healthcare, avoids disappointment bias, aids recruitment and in future will allow assessment of longer term outcomes.

Lay abstract: Background Psoriatic arthritis (PsA) is a type of arthritis that develops in around 15% of people with the skin condition psoriasis, causing swollen and painful joints. It affects around 150,000 people in the UK but there is little research on the best way to treat them. One of the first studies compared normal care with a new Treat to Target' approach where patients were reviewed every four weeks and their treatment increased until a target was achieved. They reported improved arthritis, psoriasis, quality of life, pain and function. However, this approach is not widely used due to worries about increased hospital visits and costs. There are no studies looking at which drugs work best in this Treat to Target' strategy. We currently use a step-up' approach for all patients, whether they have mild or severe disease. This means at first one standard arthritis drug is used, then two standard drugs together and finally newer stronger biologic drugs for patients not responding to the other drugs. It is possible that patients with mild disease may not need any of these treatments, suffering unnecessary side effects such as sickness, stomach upsets, infections and liver problems. Previous studies in patients with severe disease suggested they may do better if they are treated with stronger drugs earlier. Both these issues need examining properly. Aims (1) To see if a more practical version of treat to target' approach can be run successfully in a routine NHS Clinic that is beneficial to patients and sustainable (2) To see if it would be possible to run a trial looking at whether patients with mild disease can be treated successfully without being put onto more powerful arthritis drugs. (3) To see if patients with severe PsA do better if they start on stronger arthritis drugs. Design and Methods Study 1 (Aim 1) will set up a more practical version of the Treat to Target' approach in a routine NHS out-patient clinic. Patients will be regularly monitored with treatment increased using the step-up' approach described above until the target is achieved. However, the clinic will use telephone consultations where possible, and fewer visits once their disease is well controlled. I am hoping that this reduced treat to target' approach will be more acceptable to patients and more affordable to the NHS, whilst providing a similar level of disease control to the original study. Studies 2 and 3 will also run within the routine NHS out-patient clinic. Study 2 (Aim 2) will assess whether a trial is feasible for patients with mild disease to go without standard arthritis drugs. I will do this by running a small study where some patients receive the usual drugs, and others are only given painkillers and steroid injections into swollen joints. If any joint needs more than two injections in six months, patients will start on the standard arthritis drugs. The study will look at how many patients in the clinic have mild disease, how many agree to delay treatment and how many require repeated steroid injections and need to start the standard arthritis drugs anyway. This will help us to design a future trial to see whether patients with mild disease can manage with less treatment. This may reduce the number of patients suffering side effects when they don't need to.Study 3 (Aim 3) will look at whether patients with more severe disease would do better if they have stronger arthritis drugs at the beginning of their treatment. Patients will be allocated to one of three treatment groups receiving: (1) two standard arthritis drugs together; (2) stronger biologic therapy at the start or (3) the standard step-up' of arthritis drugs receiving the standard drugs before the stronger biologics. I will see which is best in terms of arthritis, skin psoriasis, quality of life, pain and function, and compare the costs of the different treatment options. Patient and Public Involvement Patients involved in research internationally reviewed the project and advised on the design of the three studies including who should be included and how the treatment should be given. Patients will continue to advise throughout the project, reviewing study information for patients, interpreting the results and sharing results with doctors and patients. Dissemination Our results will be presented at international research meetings and published in medical journals so that they can then be incorporated into international treatment recommendations. Results will be communicated to rheumatology doctors and nurses via educational meetings and to patients via local and national patient support groups.

Research activity codes: 6.1 PHARMACEUTICALS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: SKIN;INFLAMMATORY AND IMMUNE SYSTEM