Research and publications from the Rheumatology department

Research by the Rheumatology department at Great Ormond Street Hospital (GOSH) focuses on childhood arthritis, dermatomyositis and vasculitis.

Many of these complex diseases are still hard to treat and we have few ways to tell parents how severe or mild their child’s illness will be.

Our clinical and research teams collaborate closely with one another and are constantly improving the treatment that we provide as well as the patients' experiences. All our work, from basic science right through to patient-centred work, is informed by patient need and the need for better ways to understand, diagnose and treat these conditions.

Examples of our work that have direct benefit to patients include our leading role in drug trials of new medicines, for example for arthritis and the rare fever syndromes of childhood. These are medications such as Anakinra and Toculizumab. Some of the key basic science work that led up to the use of Toculizumab in childhood arthritis was carried out by our team at GOSH/University College London.

A major effort has been our study to understand the mechanisms of response (or failure) to first line drugs used to treat arthritis, like Methotrexate (MTX) and anti-TNF medicines. Our CHARMS study (Childhood Arthritis Response to Medication Study) has collected the experiences of more than 250 families and built a family website, now under testing, to help parents manage their life with a child with arthritis.

In parallel we have undertaken the largest study of genetics of the response to MTX to help us to understand what controls children’s response to these drugs. We are the host centre for the UK-wide Cohort study of Juvenile Dermatomyositis (JDM) which is an invaluable resource both for researchers and also families with children with JDM.

The research expertise in the Rheumatology department is wide, with active research programmes on arthritis, myositis, vasculitis, juvenile systemic lupus erythematosus (JSLE) and hypermobility.

Our current work ranges from:

• Basic science laboratory work (which includes immunology, genetics and vascular biology).

• Translational work - such as finding out ways to measure the activity of these rare diseases, including developing biomarkers, or predict how a child’s disease will develop.

• Our family-centred work such as our juvenile idiopathic arthritis (JIA) family website project.

We are working to understand what has changed in a child’s immune system when arthritis develops and how we can help the immune system to restore its balance to make arthritis go into remission

The large CHARMS includes more than 800 children and aims to understand immunological, genetic and psychological factors that control response to drugs in JIA.

The key aims of the vasculitis research are to further understand the pathogenesis of vasculitis in the young, develop novel diagnostic and treatments and systematic documentation of different types of childhood vasculitis.

We are custodians of the UK-wide JDM Cohort study, now the largest of its kind in the world, which supports many clinical/research studies and now has its own Juvenile Dermatomyositis Research Group website.

We are involved in many clinical trials including POPS (Prevention and treatment of steroid induced OsteoPenia Study) and SYCAMORE, a new trial of Adalimumab in uveitis. Many of our studies are carried out in the GOSH Clinical Research Facility and are supported by the Medicines for Children Research Network. We play an active role in the UK Arthritis Research Clinical Studies Group for Paediatric Rheumatology.

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Chinoy H, Payne D, Poulton KV, Fertig N, Betteridge Z, Gunawardena H, Davidson JE, Oddis CV, McHugh NJ, Wedderburn LR, Ollier WE, Cooper RG, UK Adult Onset Myositis Immunogenetic Collaboration & UK Juvenile Dermatomyositis Research Group (2009) HLA-DPB1 associations differ between DRB1*03 positive anti-Jo-1 and anti-PM-Scl antibody positive idiopathic inflammatory myopathy. Rheumatology (Oxford) 48 (10): 1213-7

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Giles I, Pericleous C, Liu X, Ehsanullah J, Clarke L, Brogan P, Newton-West M, Swerlick R, Lambrianides A, Chen P, Latchman D, Isenberg D, Pierangeli S, Rahman A (2009) Thrombin binding predicts the effects of sequence changes in a human monoclonal antiphospholipid antibody on its in vivo biologic actions. J Immunol 182 (8): 4836-43

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Hall S, Brogan P, Haworth SG, Klein N (2009) Contribution of inflammation to the pathology of idiopathic pulmonary arterial hypertension in children. Thorax 64 (9): 778-83

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Howell KJ, Lavorato A, Visentin MT, Smith RE, Schaefer G, Jones CD, Weibel L, Denton CP, Harper JI, Woo P (2009) Validation of a protocol for the assessment of skin temperature and blood flow in childhood localised scleroderma. Skin Res Technol 15 (3): 346-56

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Huber AM, Giannini EH, Bowyer SL, Kim S, Lang B, Lindsley CB, Pachman LM, Pilkington C, Reed AM, Rennebohm RM, Rider LG, Wallace CA, Feldman BM (2010) Protocols for the initial treatment of moderately severe juvenile dermatomyositis: results of a Children's Arthritis and Rheumatology Research Alliance Consensus Conference. Arthritis Care Res (Hoboken) 62 (2): 219-25

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Hunter PJ, Nistala K, Jina N, Eddaoudi A, Thomson W, Hubank M, Wedderburn LR (2010) Biologic predictors of extension of oligoarticular juvenile idiopathic arthritis as determined from synovial fluid cellular composition and gene expression. Arthritis Rheum 62 (3): 896-907

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Hunter PJ, Wedderburn LR (2009) Pediatric rheumatic disease: can molecular profiling predict the future in JIA?. Nat Rev Rheumatol 5 (11): 593-4

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Hyrich KL, Lal SD, Foster HE, Thornton J, Adib N, Baildam E, Gardner-Medwin J, Wedderburn LR, Chieng A, Davidson J, Thomson W (2010) Disease activity and disability in children with juvenile idiopathic arthritis one year following presentation to paediatric rheumatology. Results from the Childhood Arthritis Prospective Study. Rheumatology (Oxford) 49 (1): 116-22

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Jones RB, Ferraro AJ, Chaudhry AN, Brogan P, Salama AD, Smith KG, Savage CO, Jayne DR (2009) A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 60 (7): 2156-68

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Li CK, Knopp P, Moncrieffe H, Singh B, Shah S, Nagaraju K, Varsani H, Gao B, Wedderburn LR (2009) Overexpression of MHC class I heavy chain protein in young skeletal muscle leads to severe myositis: implications for juvenile myositis. Am J Pathol 175 (3): 1030-40

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Liu C, Walter TS, Huang P, Zhang S, Zhu X, Wu Y, Wedderburn LR, Tang P, Owens RJ, Stuart DI, Ren J, Gao B (2010) Structural and functional insights of RANKL-RANK interaction and signaling. J Immunol 184 (12): 6910-9

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Lowry CA, Pilkington CA (2009) Juvenile dermatomyositis: extramuscular manifestations and their management. Curr Opin Rheumatol 21 (6): 575-80

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Marks SD, Shah V, Pilkington C, Tullus K (2010) Urinary monocyte chemoattractant protein-1 correlates with disease activity in lupus nephritis. Pediatr Nephrol 25 (11): 2283-8

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Moncrieffe H, Hinks A, Ursu S, Kassoumeri L, Etheridge A, Hubank M, Martin P, Weiler T, Glass DN, Thompson SD, Thomson W, Wedderburn LR (2010) Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype. Pharmacogenet Genomics 20 (11): 665-76

Reference 18
Moncrieffe H, Nistala K, Kamhieh Y, Evans J, Eddaoudi A, Eaton S, Wedderburn LR (2010) High expression of the ectonucleotidase CD39 on T cells from the inflamed site identifies two distinct populations, one regulatory and one memory T cell population. J Immunol 185 (1): 134-43

Reference 19
Moncrieffe H, Hinks A, Ursu S, Kassoumeri L, Etheridge A, Hubank M, Martin P, Weiler T, Glass DN, Thompson SD, Thomson W, Wedderburn LR (2010) Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype. Pharmacogenet Genomics 20 (11): 665-76

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Mukhtyar C, Brogan P, Luqmani R (2009) Cardiovascular involvement in primary systemic vasculitis. Best Pract Res Clin Rheumatol 23 (3): 419-28

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Mulligan K, Etheridge A, Kassoumeri L, Wedderburn LR, Newman S (2009) Do mothers and fathers hold similar views about their child's arthritis?. Arthritis Rheum 61 (12): 1712-8 

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Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, de Jager W, Evans JG, Cimaz R, Bajaj-Elliott M, Wedderburn LR (2010) Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci U S A 107 (33): 14751-6

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Nistala K, Wedderburn LR (2009) Th17 and regulatory T cells: rebalancing pro- and anti-inflammatory forces in autoimmune arthritis. Rheumatology (Oxford) 48 (6): 602-6

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Ravelli A, Trail L, Ferrari C, Ruperto N, Pistorio A, Pilkington C, Maillard S, Oliveira SK, Sztajnbok F, Cuttica R, Beltramelli M, Corona F, Katsicas MM, Russo R, Ferriani V, Burgos-Vargas R, Magni-Manzoni S, Solis-Valleoj E, Bandeira M, Zulian F, Baca V, Cortis E, Falcini F, Alessio M, Alpigiani MG, Gerloni V, Saad-Magalhaes C, Podda R, Silva CA, Lepore L, Felici E, Rossi F, Sala E, Martini A (2010) Long-term outcome and prognostic factors of juvenile dermatomyositis: a multinational, multicenter study of 490 patients. Arthritis Care Res (Hoboken) 62 (1): 63-72

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Reference 28
Ruperto N, Pistorio A, Ravelli A, Rider LG, Pilkington C, Oliveira S, Wulffraat N, Espada G, Garay S, Cuttica R, Hofer M, Quartier P, Melo-Gomes J, Reed AM, Wierzbowska M, Feldman BM, Harjacek M, Huppertz HI, Nielsen S, Flato B, Lahdenne P, Michels H, Murray KJ, Punaro L, Rennebohm R, Russo R, Balogh Z, Rooney M, Pachman LM, Wallace C, Hashkes P, Lovell DJ, Giannini EH, Gare BA, Martini A, Paediatric Rheumatology International Trials Organisation (PRINTO), Pediatric Rheumatology Collaborative Study Group (PRCSG) (2010) The Paediatric Rheumatology International Trials Organisation provisional criteria for the evaluation of response to therapy in juvenile dermatomyositis. Arthritis Care Res (Hoboken) 62 (11): 1533-41

Reference 29
Salomonsson S, Grundtman C, Zhang SJ, Lanner JT, Li C, Katz A, Wedderburn LR, Nagaraju K, Lundberg IE, Westerblad H (2009) Upregulation of MHC class I in transgenic mice results in reduced force-generating capacity in slow-twitch muscle. Muscle Nerve 39 (5): 674-82

Reference 30
Stringer E, Bohnsack J, Bowyer SL, Griffin TA, Huber AM, Lang B, Lindsley CB, Ota S, Pilkington C, Reed AM, Scuccimarri R, Feldman BM (2010) Treatment approaches to juvenile dermatomyositis (JDM) across North America: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM Treatment Survey. J Rheumatol 37 (9): 1953-61

Reference 31
Visvanathan S, Wagner C, Marini JC, Lovell DJ, Martini A, Petty R, Cuttica R, Woo P, Espada G, Gattorno M, Apaz MT, Baildam E, Fasth A, Gerloni V, Lahdenne P, Quartier P, Saurenmann R, Travers S, Mendelsohn A, Xu S, Giannini EH, Ruperto N, the Paediatric Rheumatology INternational Trials Organization (PRINTO), the Pediatric Rheumatology Collaborative Study Group (PRCSG) (2010) The effect of infliximab plus methotrexate on the modulation of inflammatory disease markers in juvenile idiopathic arthritis: analyses from a randomized, placebo-controlled trial. Pediatr Rheumatol Online J 8 (1): 24

Reference 32
Walter TS, Liu C, Huang P, Zhang S, Wedderburn LR, Gao B, Owens RJ, Stuart DI, Tang P, Ren J (2009) Crystallization and preliminary X-ray analysis of mouse RANK and its complex with RANKL. Acta Crystallogr Sect F Struct Biol Cryst Commun 65 (Pt 6): 597-600

Reference 33
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Reference 34
Williams B, Neth O, Shingadia D, Dixon G, Jupp RS, Rosendahl K, Eastwood D, Klein N, Brogan P (2010) Mycobacterium kansasii causing septic arthritis and osteomyelitis in a child. Pediatr Infect Dis J 29 (1): 88-9

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Reference 36
Abinun M, Flood TJ, Cant AJ, Veys P, Gennery AR, Foster HE, Friswell M, Baildam E, Davidson J, Southwood TR, Livermore P, Wedderburn LR (2009) Autologous T cell depleted haematopoietic stem cell transplantation in children with severe juvenile idiopathic arthritis in the UK (2000-2007). Mol Immunol 47 (1): 46-51

Reference 37
Basu N, Watts R, Bajema I, Baslund B, Bley T, Boers M, Brogan P, Calabrese L, Cid MC, Cohen-Tervaert JW, Flores-Suarez LF, Fujimoto S, de Groot K, Guillevin L, Hatemi G, Hauser T, Jayne D, Jennette C, Kallenberg CG, Kobayashi S, Little MA, Mahr A, McLaren J, Merkel PA, Ozen S, Puechal X, Rasmussen N, Salama A, Salvarani C, Savage C, Scott DG, Segelmark M, Specks U, Sunderköetter C, Suzuki K, Tesar V, Wiik A, Yazici H, Luqmani R (2010) EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis. Ann Rheum Dis 69 (10): 1744-50

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Brogan P, Eleftheriou D, Dillon M (2010) Small vessel vasculitis. Pediatr Nephrol 25 (6): 1025-35

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Reference 44
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Fu H, Liu C, Flutter B, Tao H, Gao B (2009) Calreticulin maintains the low threshold of peptide required for efficient antigen presentation. Mol Immunol 46 (16): 3198-206

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Gunawardena H, Wedderburn LR, Chinoy H, Betteridge ZE, North J, Ollier WE, Cooper RG, Oddis CV, Ramanan AV, Davidson JE, McHugh NJ, Juvenile Dermatomyositis Research Group, UK and Ireland (2009) Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis. Arthritis Rheum 60 (6): 1807-14

Reference 47
Hinks A, Barton A, Shephard N, Eyre S, Bowes J, Cargill M, Wang E, Ke X, Kennedy GC, John S, Worthington J, Thomson W, British Society of Paediatric and Adolescent Rheumatology Study Group (2009) Identification of a novel susceptibility locus for juvenile idiopathic arthritis by genome-wide association analysis. Arthritis Rheum 60 (1): 258-63

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