1. Faculty of Medicine and Health
  2. School of Medicine
  3. Research groups
  4. Autoimmune Connective Tissue Diseases

Autoimmune Connective Tissue Diseases

  • Group summary: The Autoimmune Connective Tissue Diseases Group’s research focuses on a series of overlapping systemic diseases which result in inflammation of multiple organs. Through the use of laboratory studies, clinical trials and outcome measures research this group’s research topics cover a broad range of themes, from novel imaging tools to elucidating the role type I interferons play in the pathogenesis of a range of autoimmune diseases.

What we do

Autoimmune connective tissue diseases are an overlapping set of systemic diseases that cause inflammation in multiple organs. We are a group of investigators with diverse interests in these conditions that range from basic laboratory science through to clinical trials and outcome measures research.

The ANA-associated diseases include systemic lupus erythematosus, Sjogren’s Syndrome, inflammatory myopathies, mixed and undifferentiated connective tissue diseases and research is led by Ed Vital, Miriam Wittmann and Paul Emery. The research programme in scleroderma and related diseases is led by Francesco Del Galdo, Maya Buch and Paul Emery). These diseases may affect many organs of the obody including the skin, joints, kidneys, lungs and brain. They are uncommon but unmet needs for treatment are severe with marked morbidity and mortality despite best therapy. More than 2000 patients with these conditions have been enrolled into local registries and observational studies with rich clinical phenotyping and sample collections. ANCA vasculitis is another multisystem autoimmune disease with therapeutic and mechanistic similarities.

Polymyalgia Rheumatica and Large vessel vasculitis are related diseases that occur predominantly in older people. This programme is led by Sarah Mackie. The predominant therapy for these diseases is glucocorticoids, which have significant toxicity. The use, minimisation and toxicity of glucocorticoids is a related theme of this research programme.

Research themes

These diverse areas of research are linked by several cross-cutting themes. Further details on individual projects can be found below.

Pre-clinical and early disease

The mainstay of treatment for autoimmune connective tissue diseases is immunosuppression but this seldom leads to cure and may cause long term toxicity. The initiation of diseases like SLE and scleroderma are now recognised to occur in a stepwise manner over many years. A key focus of research is in the prediction of disease in individuals “at risk” so that disease can be predicted, diagnosed before clinical features begin, and to allow future disease prevention trials.

Skin Disease

Diseases like discoid lupus, SLE and scleroderma all have prominent involvement of the skin. Linked to the dermatorheumatology theme in LIRMM, we have substantial research programmes investigating basic and translational immunology in the skin, mechanisms of scarring and novel non-invasive biomarkers and novel locally directed therapeutics.

Imaging

Novel imaging tools are a strength of research in LIRMM. Musculoskeletal imaging with ultrasound and MRI, such as in the phenotyping of lupus arthritis, linked to the LIRMM imaging group. In scleroderma, tools such as optical coherence tomography, capillaroscopy and laser Doppler imaging allow insights in early stages of disease, clinical outcomes and mechanism.

B cell therapies and biomarkers

B cell targeted therapies, such as rituximab, belimumab and humanised anti-CD20 molecules, are used across the spectrum of ANA- and ANCA-associated disease. LIRMM has the largest single-centre cohort of rituximab-treated patients in the world across all indications. We pioneered the use of flow cytometry to understand responses and develop novel therapeutic strategies in clinical trials.

Type I interferons and other biomarkers

Type I interferons play a crucial role in the pathogenesis of a range of autoimmune diseases. We have developed novel biomarkers to characterise interferon status in blood and tissue and shown how these can be used for prediction of disease and other clinical outcomes. These projects are linked to translational immunology studying the regulation of interferon production in blood and tissue. Our large cohorts and sample collections are ideal for the study of other biomarkers. For example, novel serum fibrosis biomarkers to predict outcomes in scleroderma.

Collaborative and student opportunities

Work with industry includes investigator-initiated clinical trials of novel therapies and strategies, early phase and proof of concept studies. Through our clinical cohorts and translational immunology we are ideally place to work in biomarker development and validation. We have developed both imaging and clinical endpoints for use in clinical trials as well as stratifying populations to determine optimal target populations for interventions in trials and routine clinical practice.

Postgraduate student opportunities include lab based and clinical research fellow projects. Previous PhD and MSc students have been successful in obtaining fellowships from the NIHR, industry, charities, Leeds Teaching Hospitals and the University of Leeds.

Collaborative research projects include MRC stratified medicine consortia and multicentre academic and industry-sponsored clinical trials.

Funding

Key publications

Vital EM

  1. Responsiveness of clinical and ultrasound outcome measures in musculoskeletal systemic lupus erythematosus.
    Mahmoud K, Zayat AS, Md Yusof MY, Hensor EM, Conaghan PG, Emery P, Vital EM.
    Rheumatology 2018 (In press).
     
  2. Defining inflammatory musculoskeletal manifestations in systemic lupus erythematosus.
    Zayat AS, Mahmoud K, Md Yusof MY, Mukherjee S, D'Agostino MA, Hensor EMA, Wakefield RJ, Conaghan PG, Edwards CJ, Emery P, Vital EM.
    Rheumatology (Oxford). 2018 Sep 27. doi: 10.1093/rheumatology/key277.
     
  3. Prediction of autoimmune connective tissue disease in an at-risk cohort: prognostic value of a novel two-score system for interferon status.
    Md Yusof MY, Psarras A, El-Sherbiny YM, Hensor EMA, Dutton K, Ul-Hassan S, Zayat AS, Shalbaf M, Alase A, Wittmann M, Emery P, Vital EM.
    Ann Rheum Dis. 2018 Oct;77(10):1432-1439. doi: 10.1136/annrheumdis-2018-213386. Epub 2018 Jun 21.
     
  4. A novel two-score system for interferon status segregates autoimmune diseases and correlates with clinical features.
    El-Sherbiny YM, Psarras A, Md Yusof MY, Hensor EMA, Tooze R, Doody G, Mohamed AAA, McGonagle D, Wittmann M, Emery P, Vital EM.
    Sci Rep. 2018 Apr 11;8(1):5793. doi: 10.1038/s41598-018-24198-1. Erratum in: Sci Rep. 2018 Oct 1;8(1):14846.
     
  5. Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus.
    Md Yusof MY, Shaw D, El-Sherbiny YM, Dunn E, Rawstron AC, Emery P, Vital EM.
    Ann Rheum Dis. 2017 Nov;76(11):1829-1836. doi: 10.1136/annrheumdis-2017-211191. Epub 2017 Jul 6.
     
  6. The role of ultrasound in assessing musculoskeletal symptoms of systemic lupus erythematosus: a systematic literature review.
    Zayat AS, Md Yusof MY, Wakefield RJ, Conaghan PG, Emery P, Vital EM.
    Rheumatology (Oxford). 2016 Mar;55(3):485-94. doi: 10.1093/rheumatology/kev343. Epub 2015 Oct 7. Review.
     
  7. IFNλ Stimulates MxA Production in Human Dermal Fibroblasts via a MAPK-Dependent STAT1-Independent Mechanism.
    Alase AA, El-Sherbiny YM, Vital EM, Tobin DJ, Turner NA, Wittmann M.
    J Invest Dermatol. 2015 Dec;135(12):2935-2943. doi: 10.1038/jid.2015.317. Epub 2015 Aug 19.
     
  8. Repeat cycles of rituximab on clinical relapse in ANCA-associated vasculitis: identifying B cell biomarkers for relapse to guide retreatment decisions.
    Md Yusof MY, Vital EM, Das S, Dass S, Arumugakani G, Savic S, Rawstron AC, Emery P.
    Ann Rheum Dis. 2015 Sep;74(9):1734-8. doi: 10.1136/annrheumdis-2014-206496. Epub 2015 Apr 8.
     
  9. Brief report: responses to rituximab suggest B cell-independent inflammation in cutaneous systemic lupus erythematosus.
    Vital EM, Wittmann M, Edward S, Md Yusof MY, MacIver H, Pease CT, Goodfield M, Emery P.
    Arthritis Rheumatol. 2015 Jun;67(6):1586-91. doi: 10.1002/art.39085.
     
  10. B cell biomarkers of rituximab responses in systemic lupus erythematosus.
    Vital EM, Dass S, Buch MH, Henshaw K, Pease CT, Martin MF, Ponchel F, Rawstron AC, Emery P.
    Arthritis Rheum. 2011 Oct;63(10):3038-47. doi: 10.1002/art.30466.
     
  11. Type I interferon-mediated autoimmune diseases: pathogenesis, diagnosis and targeted therapy.
    Psarras A, Emery P, Vital EM.
    Rheumatology (Oxford). 2017 Oct 1;56(10):1662-1675. doi: 10.1093/rheumatology/kew431. Review.
     
  12. Musculoskeletal manifestations of systemic lupus erythmatosus.
    Mahmoud K, Zayat A, Vital EM.
    Curr Opin Rheumatol. 2017 Sep;29(5):486-492. doi: 10.1097/BOR.0000000000000421. Review.
     
  13. The initiation of autoimmunity at epithelial surfaces: a focus on rheumatoid arthritis and systemic lupus erythematosus.
    Pentony P, Duquenne L, Dutton K, Mankia K, Gul H, Vital E, Emery P.
    Discov Med. 2017 Nov;24(133):191-200. Review.

Wittmann M

  1. Human keratinocytes release high levels of inducible heat shock protein 70 that enhances peptide uptake.
    Wang D, Eiz-Vesper B, Zeitvogel J, Dressel R, Werfel T, Wittmann M.
    Exp Dermatol. 2011 Aug;20(8):637-41. doi: 10.1111/j.1600-0625.2011.01287.x. Epub 2011 May 4.
     
  2. Human plasmacytoid dendritic cells express receptors for anaphylatoxins C3a and C5a and are chemoattracted to C3a and C5a.
    Gutzmer R, Köther B, Zwirner J, Dijkstra D, Purwar R, Wittmann M, Werfel T.
    J Invest Dermatol. 2006 Nov;126(11):2422-9. Epub 2006 Jun 15.
     
  3. Evidence for a pathogenetic role of interleukin-18 in cutaneous lupus erythematosus.
    Wang D, Drenker M, Eiz-Vesper B, Werfel T, Wittmann M.
    Arthritis Rheum. 2008 Oct;58(10):3205-15. doi: 10.1002/art.23868.

Buch MH

  1. Consensus best practice pathway of the UK Systemic Sclerosis Study group: management of cardiac disease in systemic sclerosis.
    Bissell LA, Anderson M, Burgess M, Chakravarty K, Coghlan G, Dumitru RB, Graham L, Ong V, Pauling JD, Plein S, Schlosshan D, Woolfson P, Buch MH.
    Rheumatology (Oxford). 2017 Jun 1;56(6):912-921. doi: 10.1093/rheumatology/kew488.
     
  2. Does high-dose extended course cyclophosphamide and methylprednisolone pulse therapy have a role in the management of systemic sclerosis-related interstitial lung disease?
    Abignano G, Bissell LA, Emery P, Del Galdo F, Buch MH.
    Rheumatology (Oxford). 2016 Dec;55(12):2273-2275. Epub 2016 Oct 15. No abstract available.
     
  3. Primary myocardial disease in scleroderma-a comprehensive review of the literature to inform the UK Systemic Sclerosis Study Group cardiac working group.
    Bissell LA, Md Yusof MY, Buch MH.
    Rheumatology (Oxford). 2017 Jun 1;56(6):882-895. doi: 10.1093/rheumatology/kew364. Review.
     
  4. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European SclerodermaObservational Study (ESOS).
    Herrick AL, Pan X, Peytrignet S, Lunt M, Hesselstrand R, Mouthon L, Silman A, Brown E, Czirják L, Distler JHW, Distler O, Fligelstone K, Gregory WJ, Ochiel R, Vonk M, Ancuţa C, Ong VH, Farge D, Hudson M, Matucci-Cerinic M, Balbir-Gurman A, Midtvedt Ø, Jordan AC, Jobanputra P, Stevens W, Moinzadeh P, Hall FC, Agard C, Anderson ME, Diot E, Madhok R, Akil M, Buch MH, Chung L, Damjanov N, Gunawardena H, Lanyon P, Ahmad Y, Chakravarty K, Jacobsen S, MacGregor AJ, McHugh N, Müller-Ladner U, Riemekasten G, Becker M, Roddy J, Carreira PE, Fauchais AL, Hachulla E, Hamilton J, İnanç M, McLaren JS, van Laar JM, Pathare S, Proudman S, Rudin A, Sahhar J, Coppere B, Serratrice C, Sheeran T, Veale DJ, Grange C, Trad GS, Denton CP.
    Ann Rheum Dis. 2017 Jul;76(7):1207-1218. doi: 10.1136/annrheumdis-2016-210503. Epub 2017 Feb 10.
     
  5. Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study.
    Herrick AL, Peytrignet S, Lunt M, Pan X, Hesselstrand R, Mouthon L, Silman AJ, Dinsdale G, Brown E, Czirják L, Distler JHW, Distler O, Fligelstone K, Gregory WJ, Ochiel R, Vonk MC, Ancuţa C, Ong VH, Farge D, Hudson M, Matucci-Cerinic M, Balbir-Gurman A, Midtvedt Ø, Jobanputra P, Jordan AC, Stevens W, Moinzadeh P, Hall FC, Agard C, Anderson ME, Diot E, Madhok R, Akil M, Buch MH, Chung L, Damjanov NS, Gunawardena H, Lanyon P, Ahmad Y, Chakravarty K, Jacobsen S, MacGregor AJ, McHugh N, Müller-Ladner U, Riemekasten G, Becker M, Roddy J, Carreira PE, Fauchais AL, Hachulla E, Hamilton J, İnanç M, McLaren JS, van Laar JM, Pathare S, Proudman SM, Rudin A, Sahhar J, Coppere B, Serratrice C, Sheeran T, Veale DJ, Grange C, Trad GS, Denton CP.
    Ann Rheum Dis. 2018 Apr;77(4):563-570. doi: 10.1136/annrheumdis-2017-211912. Epub 2018 Jan 6.
     
  6. A Multicenter Study of the Validity and Reliability of Responses to Hand Cold Challenge as Measured by Laser Speckle Contrast Imaging and Thermography: Outcome Measures for Systemic Sclerosis-Related Raynaud's Phenomenon.
    Wilkinson JD, Leggett SA, Marjanovic EJ, Moore TL, Allen J, Anderson ME, Britton J, Buch MH, Del Galdo F, Denton CP, Dinsdale G, Griffiths B, Hall F, Howell K, MacDonald A, McHugh NJ, Manning JB, Pauling JD, Roberts C, Shipley JA, Herrick AL, Murray AK.
    Arthritis Rheumatol. 2018 Jun;70(6):903-911. doi: 10.1002/art.40457. Epub 2018 Apr 23.

Del Galdo F

  1. Transforming Growth Factor β Activation Primes Canonical Wnt Signaling Through Down-Regulation of Axin-2.
    Gillespie J, Ross RL, Corinaldesi C, Esteves F, Derrett-Smith E, McDermott MF, Doody GM, Denton CP, Emery P, Del Galdo F.
    Arthritis Rheumatol. 2018 Jun;70(6):932-942. doi: 10.1002/art.40437. Epub 2018 Apr 23.
  2. Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor.
    Liakouli V, Elies J, El-Sherbiny YM, Scarcia M, Grant G, Abignano G, Derrett-Smith EC, Esteves F, Cipriani P, Emery P, Denton CP, Giacomelli R, Mavria G, Del Galdo F.
    Ann Rheum Dis. 2018 Mar;77(3):431-440. doi: 10.1136/annrheumdis-2017-212120. Epub 2017 Dec 19.
  3. The enhanced liver fibrosis test: a clinical grade, validated serum test, biomarker of overall fibrosis in systemic sclerosis.
    Abignano G, Cuomo G, Buch MH, Rosenberg WM, Valentini G, Emery P, Del Galdo F.
    Ann Rheum Dis. 2014 Feb;73(2):420-7. doi: 10.1136/annrheumdis-2012-202843. Epub 2013 Mar 19.
  4. Virtual skin biopsy by optical coherence tomography: the first quantitative imaging biomarker for scleroderma.
    Abignano G, Aydin SZ, Castillo-Gallego C, Liakouli V, Woods D, Meekings A, Wakefield RJ, McGonagle DG, Emery P, Del Galdo F.
    Ann Rheum Dis. 2013 Nov;72(11):1845-51. doi: 10.1136/annrheumdis-2012-202682. Epub 2013 Feb 20.

Mackie SL

  1. A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility.
    Carmona FD, Mackie SL, Martín JE, Taylor JC, Vaglio A, Eyre S, Bossini-Castillo L, Castañeda S, Cid MC, Hernández-Rodríguez J, Prieto-González S, Solans R, Ramentol-Sintas M, González-Escribano MF, Ortiz-Fernández L, Morado IC, Narváez J, Miranda-Filloy JA; Spanish GCA Group, Beretta L, Lunardi C, Cimmino MA, Gianfreda D, Santilli D, Ramirez GA, Soriano A, Muratore F, Pazzola G, Addimanda O, Wijmenga C, Witte T, Schirmer JH, Moosig F, Schönau V, Franke A, Palm Ø, Molberg Ø, Diamantopoulos AP, Carette S, Cuthbertson D, Forbess LJ, Hoffman GS, Khalidi NA, Koening CL, Langford CA, McAlear CA, Moreland L, Monach PA, Pagnoux C, Seo P, Spiera R, Sreih AG, Warrington KJ, Ytterberg SR, Gregersen PK, Pease CT, Gough A, Green M, Hordon L, Jarrett S, Watts R, Levy S, Patel Y, Kamath S, Dasgupta B, Worthington J, Koeleman BP, de Bakker PI, Barrett JH, Salvarani C, Merkel PA, González-Gay MA, Morgan AW, Martín J.
    Am J Hum Genet. 2015 Apr 2;96(4):565-80. doi: 10.1016/j.ajhg.2015.02.009. Epub 2015 Mar 26.
     
  2. HLA allele variation as a potential explanation for the geographical distribution of granulomatosis with polyangiitis.
    Watts RA, MacGregor AJ, Mackie SL.
    Rheumatology (Oxford). 2015 Feb;54(2):359-62. doi: 10.1093/rheumatology/keu321. Epub 2014 Aug 28. Review.
     
  3. Whole-body MRI of patients with polymyalgia rheumatica identifies a distinct subset with complete patient-reported response to glucocorticoids.
    Mackie SL, Pease CT, Fukuba E, Harris E, Emery P, Hodgson R, Freeston J, McGonagle D.
    Ann Rheum Dis. 2015 Dec;74(12):2188-92. doi: 10.1136/annrheumdis-2015-207395. Epub 2015 Sep 16.
     
  4. Current evidence for therapeutic interventions and prognostic factors in polymyalgia rheumatica: a systematic literature review informing the 2015 European League Against Rheumatism/American College of Rheumatology recommendations for the management of polymyalgia rheumatica.
    Dejaco C, Singh YP, Perel P, Hutchings A, Camellino D, Mackie S, Matteson EL, Dasgupta B.
    Ann Rheum Dis. 2015 Oct;74(10):1808-17. doi: 10.1136/annrheumdis-2015-207578. Review.
     
  5. 2015 Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative.
    Dejaco C, Singh YP, Perel P, Hutchings A, Camellino D, Mackie S, Abril A, Bachta A, Balint P, Barraclough K, Bianconi L, Buttgereit F, Carsons S, Ching D, Cid M, Cimmino M, Diamantopoulos A, Docken W, Duftner C, Fashanu B, Gilbert K, Hildreth P, Hollywood J, Jayne D, Lima M, Maharaj A, Mallen C, Martinez-Taboada V, Maz M, Merry S, Miller J, Mori S, Neill L, Nordborg E, Nott J, Padbury H, Pease C, Salvarani C, Schirmer M, Schmidt W, Spiera R, Tronnier D, Wagner A, Whitlock M, Matteson EL, Dasgupta B; European League Against Rheumatism; American College of Rheumatology.
    Ann Rheum Dis. 2015 Oct;74(10):1799-807. doi: 10.1136/annrheumdis-2015-207492.

 

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Professor Maya Buch

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