De Marco, G

FitzGerald, O

Goodfield, M

Magee, C

Marzo-Ortega, H

Mathieson, HR

McGonagle, D

Merashli, M

White Rose Research Online

Combined inhibition of tumour necrosis factor-alpha and interleukin-12/23 for long-standing, refractory psoriatic disease: a differential role for cytokine pathways?

This is a repository copy of Combined inhibition of tumour necrosis factor-alpha and interleukin-12/23 for long-standing, refractory psoriatic disease: a differential role for cytokine pathways?.White Rose Research Online URL for this paper:http://eprints.whiterose.ac.uk/134324/Version: Accepted VersionArticle:De Marco, G, McGonagle, D, Mathieson, HR et al. (5 more authors) (2018) Combined inhibition of tumour necrosis factor-alpha and interleukin-12/23 for long-standing, refractorypsoriatic disease: a differential role for cytokine pathways? Rheumatology, 57 (11). pp. 2053-2055. ISSN 1462-0324 https://doi.org/10.1093/rheumatology/key199© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. This is an author produced version of a paper published in Rheumatology. Uploaded in accordance with the publisher's self-archiving policy.eprints@whiterose.ac.ukhttps://eprints.whiterose.ac.uk/Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request.  Version 12 Page 1 of 10   COVER PAGE TITLE Combined inhibition of TNFα and IL-12/23 for long-standing, refractory Psoriatic disease: a differential role for cytokines pathways?  Gabriele De Marco1,2, Dennis McGonagle1,2, Hannah R. Mathieson1,2 , Mira Merashli3 , Conor Magee4, Oliver FitzGerald4, Mark Goodfield5, Helena Marzo-Ortega1,2   1) NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom 2) Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom 3) Division of Rheumatology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon 4) St Vincent’s University Hospital and Conway Institute for Biomolecular Research, University College Dublin, Ireland  5) Department of Dermatology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom   Address for correspondence Helena Marzo-Ortega LIRMM, Second floor,  Chapel Allerton Hospital,  Chapeltown Road,  Leeds LS7 4SA, United Kingdom.  Telephone:  +44 (0) 113 392 4884 Fax:   +44 (0) 113 392 4991 E-mail:  medhmo@leeds.ac.uk      Word count: 714. Tables: 1; Figures: 1; References: 8     Version 12 Page 2 of 10   Sir, Psoriatic arthritis (PsA) and psoriasis are closely related chronic inflammatory conditions leading to multi-tissue involvement. Polymorphisms in genes regulating Tumour Necrosis Factor alpha (TNFα) and the interleukin-23 and -17 axis (IL-23/17) are risk factors for both musculoskeletal and cutaneous phenotypes (1). Biological drugs are effective at the population level with significant overlap in clinical response between both cutaneous and musculoskeletal involvement. Unfortunately, some patients are refractory or intolerant to TNFα inhibitors (TNFi) or to biologics targeting the IL23/17 axis. The clinical practitioner may, on occasions, encounter affected individuals showing an excellent response from one tissue target, i.e. the skin, and incomplete response or even deterioration in others, such as the joints, the uvea or bowel.  Here, we report six cases of long-lasting, complex PsA refractory and/or intolerant to several conventional synthetic and biologic disease-modifying anti-rheumatic drugs (csDMARDs and bDMARDs, respectively) who were exposed to a combination of an anti-IL-12/23 and a TNFi (Table 1). Dual targeting inhibition was considered in all cases as the TNFi worked on articular disease whereas the anti-IL12/23 only worked on skin. While combination therapy with differential cytokine inhibition mechanism showed some mild and subjective effects, it appeared to be associated with increased risk of infections.  Beyond the advent of bDMARDs, the main therapeutic challenge in real life remains the lack of response-biomarkers to support stratified intervention. Because of this, and through a trial-and-error approach, we found that some patients required dual inhibition of both TNFα and IL-12/23 to address disease activity at both the articular and the cutaneous level. This is suggestive of a TNFα-dependent arthropathy concomitant to an IL-23/17-axis-dependent psoriasis occurring in a subset of cases (2) (Figure 1). To our knowledge, there are only a few reports (3, 4) on the combination of bDMARDs in severe, refractory PsA. In our series, single-targeted inhibition was inadequate to gain full control on disease activity, triggering the decision to trial a bDMARDs combination to selectively inhibit different cytokines. The rationale behind this is partly due to the synergistic effect of the modulation of the lymphoid stress surveillance response through IL-23/IL-17 axis (1).   Version 12 Page 3 of 10   The small number, diverse clinical features and uncontrolled nature of these cases and different drug combinations preclude any definitive scientific conclusions being drawn regarding evidence of clinical improvement. Further, in most cases toxicity precluded treatment continuation which also carried significant cost considerations. From a mechanistic viewpoint, although there appears to be strong overlap between TNFi and anti-IL12/23 at the population level, our findings suggest a differential role of TNFα and IL-23/17 pathways in the immunopathology of articular and cutaneous involvement in some psoriatic disease cases. Despite common tissue-specific factors in the skin and joint including Köebner responses (figure 1), some data suggest a differential involvement of pivotal innate immune cytokines, with the IL-23 pathway playing a greater role in the skin and TNFα pathway playing a greater role in the joints. We hypothesize that in some extreme cases such a polarisation may occur. Theoretical support for this comes from four strands. First, the IL-23 pathway genetics appears to be greater in psoriasis than in PsA(5). Secondly, animal models with IL-23 dysregulation develop both psoriasiform skin inflammation and arthritis, whereas TNFα transgenic models develop enthesitis, synovitis and colitis but not skin disease(6). Human immunology studies, although limited in regards of the enthesis, point towards diverse and comparatively abundant IL-23R positive cells in the skin compared to the enthesis (7). Moreover, deficiency in IL-17 pathway leads to cutaneous fungal infection, but not arthritis, suggesting an important role of the IL-23/17 axis pathway in normal skin homeostasis. Finally, these and other case series (3, 4) consistently report on the effect of TNFi on arthritis and of IL-23 inhibitor on skin disease. No reports of bDMARDs combination therapy showing TNFi efficacy in skin disease and IL-23i efficacy for joint disease exist. Thus, despite common inciting factors including cutaneous or articular micro-damage and shared cytokine networks, there may be a differential innate immune cytokine hierarchy between skin and joints in a subset of cases.  Drug development programmes confirmed the safety and efficacy of dual cytokine inhibition without superiority to conventional TNFi(8). Whereas this may apply to the population level, the need remains for single molecules with safe, dual targeting properties to be developed in PsA and psoriasis cases showing divergent therapy responses.    Version 12 Page 4 of 10   Key message We hypothesize a differential cutaneous/articular cytokine hierarchy in a subset of psoriatic disease cases.     Version 12 Page 5 of 10   References   1. McGonagle D, Aydin SZ, Gul A, Mahr A, Direskeneli H. 'MHC-I-opathy'-unified concept for spondyloarthritis and Behcet disease. Nat Rev Rheumatol. 2015;11(12):731-40. 2. Belasco J, Louie JS, Gulati N, Wei N, Nograles K, Fuentes-Duculan J, et al. Comparative Genomic Profiling of Synovium Versus Skin Lesions in Psoriatic Arthritis. Arthritis Rheumatol. 2015;67(4):934-44. 3. Cuchacovich R, Garcia-Valladares I, Espinoza LR. Combination biologic treatment of refractory psoriasis and psoriatic arthritis. J Rheumatol. 2012;39(1):187-93. 4. Gniadecki R, Bang B, Sand C. Combination of antitumour necrosis factor-alpha and anti-interleukin-12/23 antibodies in refractory psoriasis and psoriatic arthritis: a long-term case-series observational study. Brit J Dermatol. 2016;174(5):1145-6. 5. Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappa B pathways. Nat Genet. 2009;41(2):199-204. 6. Armaka M, Apostolaki M, Jacques P, Kontoyiannis DL, Elewaut D, Kollias G. Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases. J Exp Med. 2008;205(2):331-7. 7. Cuthbert RJ, Fragkakis EM, Dunsmuir R, Li Z, Coles M, Marzo-Ortega H, et al. Group 3 Innate Lymphoid Cells in Human Enthesis. Arthritis Rheumatol. 2017;69(9):1816-22. 8. Mease P, Genovese M, Weinblatt M, Peloso P, Chen K, Li Y. Safety and efficacy of ABT-122, a TNF and IL-17–targeted dual variable domain (DVD)–Ig™, in psoriatic arthritis patients with inadequate response to methotrexate: results from a phase 2 trial. Arthritis Rheumatol. 2016;68(Suppl 10):958.     Version 12 Page 6 of 10   Acknowledgements The authors would like to thank the patients for agreeing to share their experience for this report and Dr. Sayam Dubash for his suggestions regarding manuscript editing. This research is supported by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.  Author Disclosures HMO has received grants and/or honoraria from Abbvie, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, UCB. DMG has received grants and/or honoraria from Abbvie, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, UCB. OF has received grants and/or honoraria from Abbvie, BMS, Celgene, Janssen, Lilly, Novartis Pfizer and UCB. MG has received grants and/or honoraria from AbbVie, Amgen, Biogen, Celgene, Galderma, Janssen, Leo Pharma, Lilly, Novartis and Pfizer. GDM, HM, CM and MM have no disclosures.  Patients consent All patients described in this report have provided written consent as per Rheumatology journal guidelines.  Ethics approval Not applicable.      Version 12 Page 7 of 10   Table 1. Main clinical characteristics and treatment history of the clinical series.    Case 1 41 year old female Case 2 50 year old female Case 3 63 year old female Case 4 32 year old male Case 5 49 year old female Case 6 45 year old male Primary disease phenotype (duration to presentation) Polyarticular (13 years)  Polyarticular (12 years) Axial and polyarticular (20 years) Polyarticular (17 years) Polyarticular (24 years) Axial and oligoarticular (20 years) Psoriasis (phenotype)  Plaque Plaque Flexural Plaque Plaque Plaque, “paradoxical”* Other extra-articular manifestations None Uveitis Uveitis; Crohn’s disease None Uveitis Uveitis (likely secondary to ETN**) SpA-related characteristics   HLA-B27+ve HLA-B27+ve Family history of AS HLA-B27+ve  Co-morbidities Morbid obesity  Obesity; Essential arterial hypertension Bronchial asthma; COPD; Liver cirrhosis Dyslipidaemia; Essential arterial hypertension Obesity; Essential arterial hypertension None Previous csDMARDs SSZ, MTX, HCQ, AZT, LEF SSZ, MTX AZT (for bowel) MTX Tacrolimus, MTX, Cyclosporin A, oral steroids MTX, MMF, Tacrolimus, oral steroids Previous bDMARDs ADA (2006) (for joints): non-specific neurologic side effects (MS excluded) INF: 2nd NR initially effective on skin and eyes; ADA: 1NR; INF (2004) (for joints): 2nd NR; ADA (2012) (for joints and skin)  2nd NR on both joints and skin; INF (for joints): 2nd NR; GOL (for joints): 2nd NR **ETN: stopped due to development of uveitis;  Version 12 Page 8 of 10   GOL: 2nd NR ; UST (for skin) - LEF added for joints at this point, but stopped in 2014 (1NR) ETN (2005-8) (for joints): stopped due to uveitis flare INF (for joints and skin): effective on joints, 2 nd NR in skin  *ADA: developed Psoriasis; GOL: 2nd NR; INF: 2NR Most recent bDMARD UST (excellent control of skin, but not of joints) UST (no control of joints)  ADA (2008-2017) (for bowel and joints), led to new flare of Psoriasis UST (2013) (for skin) UST helped skin but not joints CZP prescribed for joints Biologic co-prescribed and purpose ETN successfully added (Feb 2014) to UST to regain control of joints CZP (Jan 2015) successfully added to UST to regain control of joints UST (2016) successfully added to ADA to regain control of skin ETN (2015) added to UST to regain control of articular disease First ETN added to UST to regain control of articular disease (not tolerated due to uveitis); Then UST+ADA (not effective on joints); Then UST+CTZ UST added onto CZP to regain control of skin Overall duration of exposure to bDMARDs combination 15 months 6 months 3 months 24 months 15 months 12 months Reason for discontinuation of bDMARDs combination  Developed severe skin infection Discontinued because of 2 chest infections Respiratory failure with recurrent chest infections Developed chest sarcoidosis mediastinal and hilar lymphadenopathy 2nd NR (joints) followed by bout of uveitis  Lack of significant response from skin and joints  Version 12 Page 9 of 10   Therapy subsequent to bDMARDs combination  APR started in October 2015, regained control of synovitis and skin Chronic pain syndrome   Ixekizumab (dramatic skin improvement, mild articular improvement) SEC (Good improvement in skin only) PsA = psoriatic arthritis; AS = ankylosing spondylitis; SpA = Spondyloarthritis; COPD = chronic obstructive pulmonary disease; bDMARDs = biologic disease-modifying anti-rheumatic drugs; sDMARDs = synthetic disease-modifying anti-rheumatic drugs; SSZ = sulphasalazine; MTX = methotrexate; HCQ = hydroxychloroquine; AZT = azathioprine; MMF = mofetil mycophenolate; ADA = adalimumab; MS = multiple sclerosis; INF = infliximab; 2nd NR = secondary non-response; 1NR = primary non-response; GOL = golimumab; ETN = etanercept; UST = ustekinumab; CZP = certolizumab pegol; APR = apremilast; SEC = secukinumab.    Version 12 Page 10 of 10   Figure 1   Legend Suggestions for a differential involvement of innate immune cytokines in psoriatic disease. The IL-23 pathway may play a greater role in the skin, while the TNFα pathway may retain a greater role in the joints. 

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Combined inhibition of tumour necrosis factor-alpha and interleukin-12/23 for long-standing, refractory psoriatic disease: a differential role for cytokine pathways?

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