Evaluating the Role of IL-17 as an Orchestrator of Peripheral-central Cross Talk in Depressive Symptoms

Evaluating the Role of IL-17 as an Orchestrator of Peripheral-central Cross Talk in Depressive Symptoms

The investigators seek clinically actionable understanding of the mechanisms that underlie depression in the context of immune mediated inflammatory diseases (IMIDs), delivered by a focused immune intervention study examining brain circuitry using state of the art imaging in the context of exquisitely specific therapeutic immune interception in human immune disease.

Glutamate concentration in the NAcc will be positively correlated with the magnitude of the inflammatory response and will be attenuated by IL-17A inhibition. Ultimately, this will be associated with an improvement in depressive symptoms.

The strength of coupling between early and late systems will be attenuated in the context of IL-17A-driven inflammation and will be correlated with less frequent switching behaviour following negative outcomes and ultimately depressive symptoms. This coupling will be re-established following IL-17 antagonism.

Patients whose depressive symptoms benefit most from IL-17A antagonism will exhibit greatest resting-state and task-specific functional connectivity between Th-NAcc.

Approximately 30-40% of patients with immune-mediated inflammatory diseases (IMIDs), such as psoriatic disease, experience depression. These symptoms negatively affect clinical outcomes, quality of life and treatment adherence. There is accumulating evidence that peripheral inflammation may contribute to the origins of depression. In particular, a) stimulation of active phase inflammation results in remitting-relapsing depressive symptoms b) abnormal neural connectivity linked to this depression is correlated with peripheral inflammation and c) biologic therapies targeting specific peripheral inflammation components (cytokines) improve depressive symptoms.

In this proposal, psoriatic disease (PsD), encompassing both psoriasis and PsA, will be our IMID exemplar. In this condition, the IL-23/IL-17 cytokine axis is central to pathogenesis, as proven by successful application of inhibitors to this pathway. Moreover, this axis has also recently been implicated in the neurobiology of depression in both preclinical and clinical studies.

The investigators aim to uncover the mechanisms that underlie depression in the context of IMIDs, delivered by a focused immune intervention study examining brain circuitry using state of the art imaging in the context of exquisitely specific therapeutic immune interception in human immune disease.

The rationale for this study is to use this specific therapeutic immune intervention to leverage mechanistic understanding of brain changes that drive depressive symptoms. Prior animal studies have clearly demonstrated the deleterious effects of proinflammatory cytokines on neural functioning. The investigators will integrate current therapy with innovative neuroimaging technologies to obtain data for the first time in humans that have hitherto only been possible in animal studies.

The intervention tools proposed herein (secukinumab, bimekizumab or Ixekizumab) are IL-17 inhibitors licensed for treatment of active PsO and PsA. Secukinumab, bimekizumab and Ixekizumab are widely used in clinical practice globally and across the UK as a first/second-line biologic disease modifying antirheumatic drug (DMARD), in line with national/international NICE (TA350, TA445, TA723, TA916, TA442, TA537) treatment recommendations. Secukinumab is given by self-administered subcutaneous injection weekly for the first five weeks of treatment and thereafter by monthly maintenance injections. Bimekizumab is given by self-administered subcutaneous injection 4 weekly, Ixekizumab is given by self -administered subcutaneous injection either 2 or 4 weekly. Typically, depressive symptoms are attenuated within weeks of therapeutic initiation. Prior study data indicate a beneficial effect of IL17 antagonism on depressive symptoms, but the mechanism of action has not yet been explored.

Inclusion Criteria:

• Adults ≥18 years < 75years
• Diagnosis of PsO or PsA, made by a dermatologist or rheumatologist.
• Selected to start secukinumab/ bimekizumab/ Ixekizumab as part of their standard clinical care by their usual dermatology team for PsO or rheumatology clinical team for PsA in line with the license for secukinumab/ bimekizumab/ Ixekizumab and NICE/SMC criteria.
• No contraindications to MRI (for example metal fragments or implantable devices not compatible with MRI. (no extra x-ray images will be obtained to check placement of metal fragments or clips insitu. Existing images may be used to check for possible contraindications)
• Satisfactory completion of standard pre-biologic safety screening (including, but not limited to, exclusion of latent TB infection according to local protocol, chest X-ray, negative HIV screen, negative Hepatitis screen antibody, negative Hepatitis B surface antigen [Hep B sAg] and negative Hepatitis B anti-core antibody [Hep B cAb])
• Recent (but not within 4 weeks prior baseline) use of intra-muscular or intra-articular steroid injections
• Women of Child-Bearing Potential (WoCBP) must be willing to use effective contraception for study duration. Further information is provided in appendix 1.
• Willing to participate and give informed consent

Exclusion Criteria:

• Inability to provide written informed consent
• Severe physical impairment (e.g., blindness, deafness, paraplegia).
• Clinically important, active infections e.g. active TB
• History of inflammatory bowel disease
• Pregnant or breast feeding
• Severe claustrophobia precluding MRI
• Contraindications to 7T MRI (metal implants in the ears, head or neck, microbladed/ tattooed eyebrows, metal fragments in the eyes)
• Confounding neurological disease including MS, Stroke, Traumatic Brain Injury
• Previous exposure to IL-17A, IL-17A/F, IL-17R inhibitors or IL-23 p19/p40 inhibitors in the last 6 months
• Hypersensitivity to any of the excipients in secukinumab/ bimekizumab/ ixekizumab.
• Any reason which, at the investigator's discretion, would make them unsuitable to take part in the study.