This is a trial to find out how weight loss (achieved by the use of tirzepatide) or ixekizumab treatment affects the characteristics of skin, joint and fat tissues in patients with Psoriatic Arthritis, Psoriasis and obesity/overweight BMI >=27.

Participants will be allocated either Tirzepatide, Ixekizumab or both. Samples of joint tissue, fat and skin will be taken at the start of the study and week 12. Blood and urine samples will also be taken.

The primary objective will be to assess the changes seen in the joint, fat and skin tissue samples 12 weeks after starting the medications (additional analysis will be done on the optional 36 week samples).

Secondary objectives will be

• To assess the changes seen in blood 4, 12, 36 and 52 weeks after starting the medication.
• To compare the changes seen in tissue and blood between Ixekizumab and Tirzepatide/Weight loss.
• To see how the changes seen in the tissue relate to weight loss.

This is a trial to find out how weight loss (achieved by the use of tirzepatide) or ixekizumab treatment affects the characteristics of skin, joint and adipose tissues in patients with Psoriatic Arthritis, Psoriasis and obesity/overweight BMI >=27.

Patients will be randomised to three groups- tirzeparatide only, ixekizumab only or both drugs.

They will have an ultrasound guided synovial biopsy, a 4mm punch skin biopsy, alea skin tape sampling and a needle aspiration fat biopsy at baseline, and then be followed up for 52 weeks.

Disease activity will be monitored throughout the trial (both examination and clinical questionnaires), and participants in the tirzepatide only group not in PsA minimal disease activity (with > 1 swollen joint, >1 tender entheseal point or PASI >1/BSA >3%) at weeks 12, 24 or 36 will be offered the addition of Ixekizumab.

As well as the biopsies, bloods and urine will be taken at weeks 0, 4, 12, 24, and 52; urine samples taken at weeks 0, 12 and 36; and an additional alea skin tape sample at week 4.

Participants have the option to have additional synovial, adipose or skin biopsies at 36 weeks.

The primary objective will be to evaluate the molecular changes in repeated synovial, skin and adipose biopsies, and alea skin tape sampling associated with weight loss at 12 weeks (with additional analysis at 36 weeks if patients consent for optional biopsy.

The secondary objectives will be :

• To evaluate the molecular changes in blood samples associated with weight loss at weeks 4, 12, 36 and 52.
• To evaluate how the molecular changes associated with weight loss differ and/or complement those associated with immunomodulation in PsA
• To evaluate how the molecular changes associated with weight loss (with/without immunomodulation) relate to disease activity measures.

Inclusion Criteria:

1. Age >= 18 years and <=75 years
2. Have a documented diagnosis of PsA for at least 6 months AND fulfil the CASPAR criteria (Defined as >=3 points)
3. Have active PsA defined as >=3 swollen and >=3 tender joints (dactylitis counts as a swollen joint).
4. Have a BMI >= 27 kg/m^2
5. Have at least one affected joint amenable to ultrasound-guided synovial biopsy (and must undergo successful synovial biopsy prior to randomisation)
6. Have at least one psoriatic plaque amenable to biopsy (up to a maximum of 5 participants per treatment arm can be recruited without skin biopsy if no suitable lesion
7. Capable of giving signed informed consent
8. Willing and able to participate in the study and undergo synovial, adipose and skin (if appropriate) biopsies (under local anaesthetic) on at least 2 occasions

Exclusion Criteria:

Prior/Concomitant Therapy:

1. Previous treatment with tirzepatide or any GLP-1 receptor agonist.

2. Previous treatment with Ixekizumab.

3. Previous treatment with BOTH secukinumab AND Bimekizumab. [note: Previous treatment with one of EITHER secukinumab OR Bimekizumab for PsA/psoriasis is allowed PROVIDED: i) Last dose was >6months before baseline AND ii) Therapy was not stopped due to an IL-17-related side effect OR due to complete primary lack of response.

4. Previous treatment with rituximab.

5. Failed >3 classes of advanced therapies (regardless of given for PsA or psoriasis), including but not limited to:

   • TNF inhibitors (adalimumab, etanercept, certolizumab, golimumab, and infliximab)
   • IL-12/23 inhibitors (ustekinumab)
   • IL-23 inhibitors (guselkumab and risankizumab)
   • IL-17 Inhibitors (secukinumab or bimekizumab)
   • Selective co-stimulation modulators (abatacept)
   • Janus Kinase or tyrosine kinase 2 inhibitors (tofacitinib, upadacitinib and deucravacitinib) Note: Prior exposure to phosphodiesterase-4 inhibitors, such as apremilast and conventional synthetic DMARDs, such as methotrexate, are not considered as advanced therapies.

6. If currently receiving conventional DMARDs, or apremilast, must have been treated for at least 12 weeks prior to first biopsy visit and on a stable dose for at least 8 weeks prior to first biopsy visit.

7. Use or oral, intra-articular, IM or IV corticosteroids 4 weeks prior to first biopsy visit or anticipated/planned prior to the week 12 biopsy visit.

8. Topical steroids within 2 weeks of first biopsy visit (participants on topical corticosteroids at baseline willing to leave these off 2 weeks prior to biopsy will be eligible).

9. Live, attenuated or recombinant vaccination within 1 month prior to screening visit or planned before the 12 week visit.

10. Contraindication to local anaesthetics (lidocaine/similar) used for biopsies

11. Antiplatelet or anticoagulant therapy that cannot be safely interrupted:

    1. Clopidogrel or other antiplatelet therapies (note: aspirin is not an exclusion)
    2. Vitamin K antagonists (including but not limited to warfarin)
    3. Direct inhibitors of thrombin (e.g. dabigatran)
    4. Factor Xa inhibitors (e.g. rivaroxaban, apixaban)
    5. Heparins (including low-molecular weight heparins (LMWH)

12. Previous treatment with insulin (exception: Use of insulin for gestational diabetes or short-term use (less than 14 days) for acute conditions, such as acute illness, hospitalisation or elective surgery).

    Medical Conditions:

13. Diagnosis of type 1 diabetes or insulin treated type 2 diabetes.

14. History of severe hypoglycaemia and/or hypoglycaemia unawareness within the 6 months prior to screening.

15. History of ketoacidosis or hyperosmolar state or coma in the last year

16. Any current or past diagnosis of:

    • proliferative diabetic retinopathy, or
    • diabetic maculopathy, or
    • non-proliferative diabetic retinopathy that requires treatment.

17. Have a self-reported change in body weight greater than 5% (gain or loss) within 3 months prior to screening.

18. Prior or planned surgical treatment for obesity, such as gastric bypass (bariatric) surgery or restrictive bariatric surgery (excluding liposuction or abdominoplasty if performed more than 1 year prior to screening).

19. Have a family or personal history of medullary thyroid carcinoma or multiple endocrine neoplasia (MEN) syndrome type 2.

20. History of IBD (Crohn's disease or ulcerative colitis).

21. Known clinically significant gastric emptying abnormality (for example, severe gastroparesis or gastric outlet obstruction); or chronically take drugs that directly effect gastroparesis.

22. History of chronic or acute pancreatitis.

23. Renal Impairment with estimated glomerular filtration rate (GFR) of less than or equal to 30ml/min/1.73m^2.

24. A diagnosis or history of malignant disease within 5 years prior to baseline visit, with the following exceptions:

    • Basal cell and squamous epithelial carcinomas of the skin that have been resected, with no evidence of metastatic disease for 3 years and 2 years, respectively.
    • cervical carcinoma in situ, with no evidence of recurrence within 3 years.

25. History of any other condition (such as known drug, alcohol abuse, or psychiatric disorder) that, in the opinion of the investigator, may preclude the participant from following and completing the study.

26. History of significant active or unstable major depressive disorder (MDD), suicidal ideation, or other severe psychiatric disorder (for example, schizophrenia, bipolar disorder, or other serious mood or anxiety disorder) within the last 2 years.

    Note: Participants with MDD or generalised anxiety disorder whose disease state is considered stable for the past year and expected to remain stable throughout the course of the study, in the opinion of the investigator, may be considered for inclusion if they are not on excluded medications.

27. Are, in the judgement of the investigator, actively suicidal or deemed to be at significant risk for suicide.

28. Diagnosis of other inflammatory arthritis, such as rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, gout, or enteropathic arthritis.

29. Active infection at screening.

30. Have had any of the following types of infection within 3 months prior to screening or develops any of the following infections before the baseline visit:

    • Serious (requiring hospitalisation, or intravenous or equivalent oral antibiotic treatment, or both).
    • Opportunistic. Note: Herpes Zoster is considered active and ongoing until all vesicles are dry and crusted over).
    • Chronic (duration of symptoms, signs and/or treatment of 6 weeks or longer).
    • recurring (including, but not limited to, herpes simplex, herpes zoster, recurring cellulitis, and chronic osteomyelitis).

31. Have evidence or suspicion of active or latent TB (unless screened previously, all will be evaluated for TB prior to initiating treatment) or had latent TB infection that has not been treated with a complete course of appropriate therapy as per local guidelines, unless such therapy is currently underway.

32. Current HIV infection.

33. Current infection with hepatitis B virus (HBV) (i.e. positive for HBsAg and/or PCR positive for HBV DNA).

34. Current infection with hepatitis C virus (HCV) (i.e. positive for HCV RNA).

35. History of recurrent or chronic infection which in the opinion of the investigator might place a participant at unacceptable risk for participation in the study.

36. Major surgery witing 8 weeks prior to screening or planned within 12 weeks from baseline visit.

37. Any other condition that is a contraindication to ixekizumab or tirzepatide.

    Laboratory results:

38. If type 2 diabetic, laboratory evidence of poorly controlled diabetes, including HbA1c >80mmol/mol (>9.5%).

39. Clinical laboratory test results at screening that are outside the normal reference range for the population and are considered clinically significant, or have any of the following specific abnormalities:

    • Absolute neutrophil count <1.5 x 10^3/microlitre
    • Lymphocyte count <0.80 x 10^3/microlitre
    • Platelet count <100 x 10^3/microlitre
    • Total WBC count <3.00 x 10^3/microlitre
    • Haemoglobin <85 g/L (males) or <80g/L (females)
    • AST or ALT levels >3 x upper limit of local normal range
    • Serum creatinine levels >2.0omg/dL (equivalent to >176.8 micromol/L Participants who fail screening as a result of a minor blood test abnormality/abnormalities may be re-screened and have the test(s) repeated, within 14 days of the previous blood test, at the investigators discretion. If the tests meet the trial entry criteria on the second occasion, then the participant will be deemed to meet the entry criteria for the trial.

    In women of child bearing potential(WOCBP):

40. Are Pregnant, breastfeeding or planning to become pregnant during the course of the study.

41. Not established, or unwilling to use a method of contraception considered highly effective for the duration of the study and at least 4 weeks after the study if they receive tirzepatide, or 10 weeks if they receive ixekizumab. Tirzepatide may decrease the effectiveness of oral contraceptives, so it is advised that WOCBP using an oral contraceptive should add a barrier method of contraception or switch to a non-oral contraceptive method for the first 4 weeks of treatment, and for 4 weeks after each dose increase.

    Other exclusions:

42. Have participated, within the last 30 days prior to trial entry, in a clinical study involving an investigational study intervention. If the previous investigational study intervention has a long half life, then 5 half lives or 30 days (whichever is longer), should have passed prior to screening.

43. Are currently enrolled in any other clinical study involving an investigational study intervention or any other type of medical research judged not to be scientifically or medically compatible with this study.

44. Unable or unwilling to provide informed consent.

45. Are unsuitable for inclusion in the study, in the opinion of the investigator or sponsor, for any reason that may compromise the participant's safety or confound data interpretation.

46. Any other contra-indications to biopsies (including anti-coagulants) in the opinion of the investigator.](streamdown:incomplete-link)

After the study ends, anonymous information and samples may also be shared with other trusted researchers, such as universities, the NHS, or healthcare research groups in the UK or other countries. Any request to use this resource will be carefully checked by a special review group, including experienced researchers, doctors, and patient representatives, to make sure it is appropriate and used only for bona fide research.

The IPD and supporting information will be available for 10 years after the study report is completed, which is expected in June 2028.

After study closure, baseline (pre-treatment) samples in the Immune Mediated Inflammatory Diseases Research Tissue Bank may be accessed and used for future studies by researchers in the University of Glasgow, Eli Lilly or third-party academic institutions. Access to surplus follow-up (post-treatment) samples held in the IMID RTB is restricted to researchers in the University of Glasgow or Eli Lilly for internal research purposes only. All requests for access must be submitted through the established application process of the Research Tissue Bank, which ensures appropriate governance and ethical oversight of the use of research samples, including that use is in line with the existing study contracts

No masking is involved