Here is the first Abstract section together with the Basic Science section and the Conclusion. Together with all the different sections on SLE, APS, Scleroderma, Myositis and PSS, you have the whole article.
Latest Advances In Connective Tissue Disorders
Simon Bowman, PhD, FRCP, Vijay Rao, MRCPDisclosures
Ther Adv Musculoskel Dis. 2013;5(4):234-249.
The connective tissue disorders comprise a number of related conditions that include systemic lupus erythematosus (SLE) and the antiphospholipid (Hughes) syndrome, scleroderma, myositis and Sjögren's syndrome. They are characterized by autoantibody production and other immune-mediated dysfunction. There are common clinical and serological features with some patients having multiple overlapping connective tissue disorders. The latest advances include new approaches to therapy, including more focused utilization of existing therapies and the introduction of biological therapies in SLE, more precise protocols for assessment of severe disease manifestations such as in interstitial lung disease and pulmonary artery hypertension in scleroderma, new antibodies for disease characterization in myositis and new approaches to patient assessment in Sjögren's syndrome. B cells have a critical role in most, if not all of these disorders such that B-cell depletion or suppression of B-cell activating cytokines improves disease in many patients. In particular, the introduction of rituximab, a monoclonal antibody targeting the CD20 molecule on B cells, into clinical practice for rheumatoid arthritis and B-cell lymphoma has been a key driver of experimental approaches to therapy in connective tissue disorders. Genetic studies also suggest a role for the innate immune system in disease pathogenesis, suggesting further future targets for biological therapies over the next few years.
Looking back over the past decade one of the main themes has been the role of B cells and B-cell cytokines in the pathogenesis of many of the autoimmune connective tissue disorders and the use of anti-B-cell/anti-B-cell cytokine agents in their therapy (see above). Looking forwards, a number of themes are emerging, in particular, the potential role of the innate immune system, particularly of type I interferons and toll-like receptors (TLRs) in the triggering and maintenance of these conditions. A second related theme is the insight that high-throughput genome-wide association screening (GWAS), 'next-generation' screening and functional genomics will provide into the pathogenesis of these conditions.
TLRs are a group of receptor proteins that recognize structurally conserved molecules shared by many microbial pathogens [Mills, 2011]. The name is derived from the Toll gene of Drosophila. TLRs are key molecules that alert the immune system to the presence of foreign microorganisms. They can be triggered by a range of bacterial molecules, including lipopolysaccharides, flagella proteins and also some DNA and RNA species. The latter in particular offer a potential mechanism for autoimmunity, since many human autoantigens are either nucleic acids or nucleic acid binding proteins. TLRs then activate a number of signalling pathways, including the activation of type I interferons [Biggioggero et al. 2010; Pascual et al. 2010; Sozzani et al. 2010].
There has been a substantial amount of work over the past few years exploring the relationships between the innate immune system, TLRs, the type I interferon 'signature' [pattern of upregulation of downstream molecules such as the interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) genes following interferon activation] in SLE [Banchereau and Pascual, 2006], PSS [Nordmark et al. 2012; Brkic et al. 2012], myositis [Suber et al. 2008] and scleroderma [Lafyatis and York, 2009; Higgs et al. 2011]. Sifalimumab, an anti-interferon antibody, is now being studied in SLE [Merrill et al. 2011] and potentially could be investigated in other autoimmune diseases over the next few years.
Genome-wide Screening and Genomic Approaches
In parallel with hypothesis-driven research (e.g. investigating the role of the innate immune system in autoimmune disease), another powerful technique over the past decade has been the use of GWAS to examine the association of common genetic variants with particular diseases. These studies take advantage of several technical developments. The first is the identification of a large number of single-nucleotide polymorphisms (SNPs) covering the entire human genome [Sherry et al. 2001; Gibbs et al. 2003]. By demonstrating statistical linkage between the presence of these variants and a particular disease it has been possible to then identify possible genes in the location of the relevant SNPs that could be involved in disease pathogenesis. The second technical development has been of automated 'chip' or 'microarray' technology that allows millions of SNPs from thousands of individuals to be examined in a short space of time.
A number of GWAS have been performed to date in SLE and scleroderma. They have perhaps been easier to study than some of the rarer connective tissue disorders due to access to large, established cohorts of patients. A number of SNP linkages have been identified in both of these diseases but the human leukocyte antigen region and the regions of the IRF5 and STAT4 genes have emerged as common areas of interest both in SLE [Moser et al. 2009; Deng and Tsao, 2010; Sandling et al. 2011; Ramos et al. 2011] and scleroderma [Allanore et al. 2011; Gorlova et al. 2011; Radstake et al. 2010; Broen et al. 2012], again supporting the potential role of the type I interferon system as important in the pathogenesis of these connective tissue disorders and as a potential target for therapy. Early studies in PSS have demonstrated similar data [Lessard et al. 2011].
These studies are still at a relatively early stage and it is likely that other potential genes of interest will emerge for hypothesis-driven evaluation over the next decade as will new insights from other next-generation sequencing technologies and functional genomic studies [Cho and Gregersen, 2011; Scofield and Kaufman, 2012].
The past few years have seen significant changes in clinical practice, for example the increasing use of renal biopsy-driven choices of therapy in lupus nephritis and the introduction of biological therapy in SLE. In scleroderma, closer assessment of patients and the introduction of therapies such as bosentan have improved the outlook for patients with PAH. Challenges still remain, however, particularly to find effective therapies for scleroderma, myositis and Sjögren's syndrome and to reduce the usage of toxic therapies such as corticosteroids and cyclophosphamide wherever possible. With new oral anticoagulants and a broad range of new biological therapies becoming available, the next few years should also be a period of potentially rapid progress in the therapy of these disorders.
Aggarwal, R. and Oddis, C. (2012) Therapeutic advances in myositis. Curr Opin Rheumatol 24: 635–641.
Allanore, Y., Saad, M., Dieude, P., Avouac, J., Distler, J., Amouyel, P. et al. (2011) Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genet 7: e1002091.
American College of Obstetricians and Gynaecologists Committee on Practice Bulletins – Obstetrics (2011) ACOG Practice Bulletin No. 118: Antiphospholipid syndrome. Obstet Gynaecol 117: 192–199.
Appel, G., Contreras, G., Dooley, M., Ginzler, E., Isenberg, D., Jayne, D. et al. (2009) Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. Am Soc Nephrol 20: 1103–1112.
Ballou, S., Khan, M. and Kushner, I. (1982) Clinical features of systemic lupus erythematosus: differences related to race and age of onset. Arthritis Rheum 25: 55–60.
Banchereau, J. and Pascual, V. (2006) Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 25: 383–392.
Baron, M., Hudson, M. and Steele, R.; Canadian Scleroderma Research Group (2009) Malnutrition is common in systemic sclerosis: results from the Canadian scleroderma research group database. J Rheumatol 36: 2737–2743.
Barry, R., Sutcliffe, N., Isenberg, D., Price, E., Goldblatt, F., Adler, M. et al. (2008) The Sjögren's syndrome damage index: a damage index for use in clinical trials and observational studies in primary Sjögren's syndrome. Rheumatology (Oxford) 47: 1193–1198.
Batal, I., Domsic, R., Medsger, T. and Bastacky, S. (2010) Scleroderma renal crisis: a pathology perspective. Int J Rheumatol 2010: 543704.
Batal, I., Domsic, R., Shafer, A., Medsger, T. Jr, Kiss, L., Randhawa, P. et al. (2009) Renal biopsy findings predicting outcome in scleroderma renal crisis. Hum Pathol 40: 332–340.
Bello, K.J., Fang, H., Magder, L.S. and Petri, M (2012) Increase in vitamin D improves disease activity and systolic blood pressure in systemic lupus erythematosus. 2012 ACR/ARHP Annual Meeting, Washington, DC, November 2012. Abstract 1710.
Bertsias, G., Tektonidou, M., Amoura, Z., Aringer, M., Bajema, I., Berden, J. et al. (2012) Joint European League against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 71: 1771–1782.
Betteridge, Z., Gunawardena, H., Chinoy, H., North, J., Ollier, W., Cooper, R. et al. (2009) Clinical and human leucocyte antigen class II haplotype associations of autoantibodies to small ubiquitin-like modifier enzyme, a dermatomyositis-specific autoantigen target, in UK Caucasian adult-onset myositis. Ann Rheum Dis 68: 1621–1625.
Betteridge, Z., Gunawardena, H. and McHugh, N. (2011) Novel autoantibodies and clinical phenotypes in adult and juvenile myositis. Arthritis Res Ther 13: 209.
Biggioggero, M., Gabbriellini, L. and Meroni, P. (2010) Type I interferon therapy and its role in autoimmunity. Autoimmunity 43: 248–254.
Boumpas, D., Austin, H. 3rd, Vaughn, E., Klippel, J., Steinberg, A., Yarboro, C. et al. (1992) Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 340: 741–745.
Bowman, S., Hamburger, J., Richards, A., Barry, R. and Rauz, S. (2009) Patient-reported outcomes in primary Sjögren's syndrome: comparison of the long and short versions of the Profile of Fatigue and Discomfort – SICCA Symptoms Inventory. Rheumatology (Oxford) 48: 140–143.
Bowman, S., Sutcliffe, N., Isenberg, D., Goldblatt, F., Adler, M., Price, E. et al (2007) Sjögren's Systemic Clinical Activity Index (SCAI): a systemic disease activity measure for use in clinical trials in primary Sjögren's syndrome. Rheumatology (Oxford) 46: 1845–1851.
Bramham, K., Thomas, M., Nelson-Piercy, C., Khamashta, M. and Hunt, B. (2011) First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood 117: 6948–6951.
Brkic, Z., Maria, N., Van Helden-Meeuwsen, C., Van De Merwe, J., Van Daele, P., Dalm, V. et al. (2012) Prevalence of interferon type I signature in CD14 monocytes of patients with Sjögren's syndrome and association with disease activity and BAFF gene expression. Ann Rheum Dis 26 June (Epub ahead of print).
Broen, J., Coenen, M. and Radstake, T. (2012) Genetics of systemic sclerosis: an update. Curr Rheumatol Rep 14: 11–21.
Brueckner, C., Becker, M., Kroencke, T., Huscher, D., Scherer, H., Worm, M. et al. (2010) Effect of sildenafil on digital ulcers in systemic sclerosis: analysis from a single centre pilot study. Ann Rheum Dis 69: 1475–1478.
Callen, J. (1994) Relationship of cancer to inflammatory muscle diseases. Dermatomyositis, polymyositis, and inclusion body myositis. Rheum Dis Clin North Am 20: 943–953.
Cavagna, L., Caporali, R., Klersy, C., Ghio, S., Albertini, R., Scelsi, L. et al. (2010) Comparison of brain natriuretic peptide (BNP) and NT-proBNP in screening for pulmonary arterial hypertension in patients with systemic sclerosis. J Rheumatol 37: 2064–2070.
Cervera, R., Bucciarelli, S., Plasín, M., Gómez-Puerta, J., Plaza, J., Pons-Estel, G. et al. Catastrophic Antiphospholipid Syndrome (CAPS) Registry Project Group (European Forum On Antiphospholipid Antibodies) (2009) Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the 'CAPS Registry'. J Autoimmun 32: 240–245.
Cheema, G., Roschke, V., Hilbert, D. and Stohl, W. (2001) Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum 44: 1313–1319.
Cho, J. and Gregersen, P. (2011) Genomics and the multifactorial nature of human autoimmune disease. N Engl J Med 365: 1612–1623.
Christopher-Stine, L., Casciola-Rosen, L., Hong, G., Chung, T., Corse, A. and Mammen, A. (2010) A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 62: 2757–2766.
Chung, L., Liu, J., Parsons, L., Hassoun, P., McGoon, M., Badesch, D. et al. (2010) Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL identifying systemic sclerosis as a unique phenotype. Chest 138: 1383–1394.
Cohen, H. and Machin, S. (2010) Antithrombotic treatment failures in antiphospholipid syndrome: the new anticoagulants? Lupus 19: 486–491.
Colaci, M., Giuggioli, D., Sebastiani, M., Manfredi, A., Vacchi, C., Spagnolo, P. et al. (2013) Lung cancer in scleroderma: results from an Italian rheumatologic center and review of the literature. Autoimmun Rev 12: 374–379.
Crowther, M., Ginsberg, J., Julian, J., Denburg, J., Hirsh, J., Douketis, J. et al. (2003) A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 349: 1133–1138.
Dalakas, M. (2010) Immunotherapy of myositis: issues, concerns and future prospects. Nat Rev Rheumatol 6: 129–137.
Daniels, T., Criswell, L., Shiboski, C., Shiboski, S., Lanfranchi, H., Dong, Y. et al. (2009) An early view of the international Sjögren's syndrome registry. Arthritis Rheum 61: 711–714.
Danza, A., Ruiz-Irastorza, G. and Khamashta, M. (2012) Antiphospholipid syndrome in obstetrics. Best Pract Res Clin Obstet Gynaecol 26: 65–76.
Dastmalchi, M., Grundtman, C., Alexanderson, H., Maragani, C.P., Einarsdottir, H., Helmers, S.B., et al. (2008) A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies. Ann Rheum Dis 67(12): 1670–1677.
Deng, Y. and Tsao, B. (2010) Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat Rev Rheumatol 6: 683–692.
Denton, C., Lapadula, G., Mouthon, L. and Müller-Ladner, U. (2009) Renal complications and scleroderma renal crisis. Rheumatology 48(Suppl. 3): iii32–iii35.
Dooley, M., Jayne, D., Ginzler, E., Isenberg, D., Olsen, N., Wofsy, D. et al. (2011) Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 365: 1886–1895.
Empson, M., Lassere, M., Craig, J. and Scott, J. (2005) Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 18: CD002859.
Erkan, D., Harrison, M., Levy, R., Peterson, M., Petri, M., Sammaritano, L. et al. (2007) Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody-positive individuals. Arthritis Rheum 56: 2382–2391.
Espada, G., Maldonado Cocco, J., Fertig, N. and Oddis, C. (2009) Clinical and serologic characterization of an Argentine pediatric myositis cohort: identification of a novel autoantibody (anti-MJ) to a 142-kDa protein. J Rheumatol 36: 2547–2551.
Fertig, N., Domsic, R., Rodriguez-Reyna, T., Kuwana, M., Lucas, M., Medsger, T. Jr et al. (2009) Anti-U11/U12 RNP antibodies in systemic sclerosis: a new serologic marker associated with pulmonary fibrosis. Arthritis Rheum 61: 958–965.
Finazzi, G., Marchioli, R., Brancaccio, V., Schinco, P., Wisloff, F., Musial, J. et al. (2005) A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 3: 848–853.
Fischer, A., Bull, T. and Steen, V. (2012) Practical approach to screening for scleroderma-associated pulmonary arterial hypertension. Arthritis Care Res 64: 303–310.
Furie, R., Petri, M., Zamani, O., Cervera, R., Wallace, D., Tegzova, D. et al. (2011) A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 63: 3918–3930.
Galli, M., Luciani, D. and Bertolini, G. (2003) Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 101: 1827–1832.
Garcia, D., Libby, E. and Crowther, M. (2010) The new oral anticoagulants. Blood 115: 15–20.
Gibbs, R., Belmont, J., Hardenbol, P., Willis, T., Yu, F., Yang, H. et al. (2003) The International HapMap Project. Nature 426: 789–796.
Gliddon, A., Doré, C., Black, C., McHugh, N., Moots, R., Denton, C. et al. (2007) Prevention of vascular damage in scleroderma and autoimmune Raynaud's phenomenon: a multicentre, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril. Arthritis Rheum 56: 3837–3846.
Goh, N., Desai, S., Veeraraghavan, S., Hansell, D., Copley, S., Maher, T. et al. (2008) Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med: 177: 1248–1254.
Gordon, P., Winer, J., Hoogendijk, J. and Choy, E. (2012) Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis. Cochrane Database Syst Rev 8: CD003643.
Gorlova, O., Martin, J., Rueda, B., Koeleman, B., Ying, J. and Teruel, M. (2011) Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genet 7: e1002178.
Gregersen, J. and Jayne, D. (2012) B-cell depletion in the treatment of lupus nephritis. Nat Rev Nephrol 8: 505–514.
Gunawardena, H., Wedderburn, L., Chinoy, H., Betteridge, Z., North, J., Ollier, W. et al. (2009) Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis. Arthritis Rheum 60: 1807–1814.
Hahn, B., McMahon, M., Wilkinson, A., Wallace, W., Daikh, D., Fitzgerald, J. et al. (2012) American College of Rheumatology guidelines for screening, treatment and management of lupus nephritis. Arthritis Care Res 64: 797–808.
Harris, E., Chan, J., Asherson, R., Aber, V., Gharavi, A. and Hughes, G. (1986) Thrombosis, recurrent fetal loss, and thrombocytopenia. Predictive value of the anticardiolipin antibody test. Arch Intern Med 146: 2153–2156.
Henness, S. and Wigley, F. (2007) Current drug therapy for scleroderma and secondary Raynaud's phenomenon: evidence-based review. Curr Opin Rheumatol 19: 611–618.
Hickman, R. and Gordon, C. (2011) Causes and management of infertility in systemic lupus erythematosus. Rheumatology 50: 1551–1558.
Higgs, B., Liu, Z., White, B., Zhu, W., White, W., Morehouse, C. et al. (2011) Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Ann Rheum Dis 70: 2029–2036.
Houssiau, F., Vasconcelos, C., D'Cruz, D., Sebastiani, G., Garrido, E., Danieli, M. et al. (2002) Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomised trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 46: 2121–2131.
Houssiau, F., D'Cruz, D., Sangle, S., Remy, P., Vasconcelos, C., Petrovic, R. et al. (2010) Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN nephritis trial. Ann Rheum Dis 69: 2083–2089.
Hoyles, R., Ellis, R., Wellsbury, J., Lees, B., Newlands, P., Goh, N. et al. (2006) A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 54: 3962–3970.
Ingraham, K., O'Brien, M., Shenin, M., Derk, C. and Steen, V. (2010) Gastric antral vascular ectasia in systemic sclerosis: demographics and disease predictors. J Rheumatol 37: 603–607.
Isenberg, D. (2012) Rituximab – it was the best of times, it was the worst of times. Autoimmun Rev 11: 790–791.
Ittah, M., Miceli-Richard, C., Gottenberg, J., Lavie, F., Lazure, T., Ba, N. et al. (2006) B cell-activating factor of the tumour necrosis factor family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in primary Sjögren's syndrome. Arthritis Res Ther 8: R51.
Jajoria, P., Murthy, V., Papalardo, E., Romay-Penabad, Z., Gleason, C. and Pierangeli, S. (2009) Statins for the treatment of antiphospholipid syndrome? Ann N Y Acad Sci 1173: 736–745.
Khamashta, M., Cuadrado, M., Mujic, F., Taub, N., Hunt, B. and Hughes, G. (1995) The management of thrombosis in the antiphosphlipid-antibody syndrome. N Engl J Med 332: 993–997.
Khanna, D. and Denton, C. (2010) Evidence-based management of rapidly progressing systemic sclerosis. Best Pract Res Clin Rheumatol 24: 387–400.
Khattri, S., Zandman-Goddard, G. and Peeva, E. (2012) B-cell directed therapies in antiphospholipid antibody syndrome – New directions based on murine and human data. Autoimmun Rev 11: 717–722.
Koga, T., Fujikawa, K., Horai, Y., Okada, A., Kawashiri, S., Iwamoto, N. et al. (2012) The diagnostic utility of anti-melanoma differentiation-associated gene 5 antibody testing for predicting the prognosis of Japanese patients with DM. Rheumatology 51: 1278–1284.
Korn, J., Mayes, M., Matucci-Cerinic, M., Rainisio, M., Pope, J., Hachulla, E. et al. for the RAPIDS-1 Study Group (2004) Digital ulcers in systemic sclerosis. prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 50: 3985–3993.
Labirua-Iturburu, A., Selva-O'Callaghan, A., Vincze, M., Danko, K., Vencovsky, J., Fisher, B. et al. (2012) Anti-PL-7 (anti-threonyl-tRNA synthetase) antisynthetase syndrome: clinical manifestations in a series of patients from a European multicenter study (EUMYONET) and review of the literature. Medicine (Baltimore) 91: 206–211.
Lafyatis, R. and York, M. (2009) Innate immunity and inflammation in systemic sclerosis. Curr Opin Rheumatol 21: 617–622.
Laskin, C., Bombardier, C., Hannah, M., Mandel, F., Ritchie, J. and Farewell, V. (1997) Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. New Eng J Med 337: 148–153.
Laskin, C., Spitzer, K., Clark, C., Crowther, M., Ginsberg, J., Hawker, G. et al. (2009) Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA trial. J Rheumatol 36: 279–287.
Lavie, F., Miceli-Richard, C., Ittah, M., Sellam, J., Gottenberg, J. and Mariette, X. (2007) Increase of B cell-activating factor of the TNF family (BAFF) after rituximab treatment: insights into a new regulating system of BAFF production. Ann Rheum Dis 66: 700–703.
Lessard, C., Ice, J., Adrianto, I., Kelly, J., Jonsson, R., Illei, G. et al (2011) A high-density genome-wide association study by the Sjögren's Genetics Network identifies five novel susceptibility loci for primary Sjögren's syndrome and confirms association with MHC, IRF5, and BLK. Arthritis Rheum 63: S184.
Lightstone, L. (2010) Lupus nephritis: where are we now? Curr Opin Rheumatol 22: 252–256.
Lockshin, M., Kim, M., Laskin, C., Guerra, M., Branch, D., Merrill, J. et al. (2012) Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant but not anticardiolipin antibody in patients with antiphospholipid antibodies. Arthritis Rheum 64: 2311–2318.
Mak, A., Cheung, M., Cheak, A. and Ho, R. (2010) Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology 49: 281–288.
Mammen, A., Chung, T., Christopher-Stine, L., Rosen, P., Rosen, A., Doering, K. et al. (2011) Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 63: 713–721.
Manzi, S., Sanchez-Guerrero, J., Merrill, J., Furie, R., Gladman, D., Navarra, S. et al. (2012) Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann Rheum Dis 71: 1833–1838.
Marie, I. (2012) Morbidity and mortality in adult polymyositis and dermatomyositis. Clin Rheumatol Rep 14: 275–285.
Mariette, X., Ravaud, P., Steinfeld, S., Baron, G., Goetz, J., Hachulla, E. et al. (2004) Inefficacy of infliximab in primary Sjögren's syndrome: results of the randomised, controlled trial of Remicade in Primary Sjögren's syndrome (TRIPSS). Arthritis Rheum 50: 1270–1276.
Matucci-Cerinic, M., Denton, C., Furst, D., Mayes, M., Hsu, V., Carpentier, P. et al. (2011) Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 70: 32–38.
Mehndiratta, P., Mehta, S., Manjila, S., Kammer, G., Cohen, M. and Preston, D. (2012) Isolated necrotizing myopathy associated with ANTI-PL12 antibody. Muscle Nerve 46: 282–286.
Merrill, J., Neuwelt, C., Wallace, D., Shanahan, J., Latinis, K., Oates, J. et al. (2010) Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomised, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 62: 222–233.
Merrill, J., Wallace, D., Petri, M., Kirou, K., Yao, Y., White, W. et al. (2011) Safety profile and clinical activity of sifalimumab, a fully human anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study. Ann Rheum Dis 70: 1905–1913.
Milic, V., Petrovic, R., Boricic, I., Radunovic, G., Marinkovic-Eric, J., Jeremic, P. et al. (2012) Ultrasonography of major salivary glands could be an alternative tool to sialoscintigraphy in the American-European classification criteria for primary Sjögren's syndrome. Rheumatology (Oxford) 51: 1081–1085.
Miller, F. (2012) New approaches to the assessment and treatment of the idiopathic inflammatory myopathies. Ann Rheum Dis 71(Suppl. 2): i82–i85.
Mills, K. (2011) TLR-dependent T cell activation in autoimmunity. Nat Rev Immunol 11: 807–822.
Moser, K., Kelly, J., Lessard, C. and Harley, J. (2009) Recent insights into the genetic basis of systemic lupus erythematosus. Genes Immun 10: 373–379.
Mouthon, L., Berezné, A., Brauner, M., Kambouchner, M., Guillevin, L. and Valeyre, D. (2007) Interstitial lung disease in systemic sclerosis. Rev Mal Respir 24: 1035–1046.
Muro, Y., Ishikawa, A., Sugiura, K. and Akiyama, M. (2012) Clinical features of anti-TIF1-α antibody-positive dermatomyositis patients are closely associated with coexistent dermatomyositis-specific autoantibodies and anti-TIF1-γ or anti-Mi-2 autoantibodies. Rheumatology 51: 1508–1513.
Navarra, S., Guzman, R., Gallacher, A., Hall, A., Levy, R., Jiminez, R. et al. (2011) Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised placebo-controlled, phase 3 trial. Lancet 377: 721–731.
Ng, W. and Bowman, S. (2011) Biological therapies in primary Sjögren's syndrome. Expert Opin Biol Ther 11: 921–936.
Ng, W., Bowman, S. and Griffiths, B; UKPSSR Study Group (2011) United Kingdom Primary Sjögren's syndrome registry: a united effort to tackle an orphan rheumatic disease. Rheumatology (Oxford) 50: 32–39.
Nordmark, G., Eloranta, M. and Ronnblom, L. (2012) Primary Sjögren's syndrome and the type I interferon system. Curr Pharm Biotechnol 13: 2054–2062.
Pascual, V., Chaussabel, D. and Banchereau, J. (2010) A genomic approach to human autoimmune diseases. Annu Rev Immunol 28: 535–571.
Pengo, V., Ruiz-Irastorza, G., Denas, G., Andreoli, L., Khamashta, M. and Tincani, A. (2012) High intensity anticoagulation in the prevention of the recurrence of arterial thrombosis in antiphospholipid syndrome: 'PROS' and 'CONS'. Autoimmun Rev 11: 577–580.
Pepper, R., Griffith, M., Kirwan, C., Levy, J., Taube, D., Pusey, C. et al. (2009) Rituximab is an effective therapy for lupus nephritis and allows a reduction in maintenance steroids. Nephrol Dial Transplant 24: 3717–3723.
Petri, M. (1996) Thrombosis and systemic lupus erythematosus: the Hopkins Lupus Cohort perspective. Scand J Rheumatol 25: 191–193.
Petri, M., Orbai, A., Alarcon, G., Gordon, C., Merrill, J., Fortin, P. et al. (2012a) Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 64: 2677–2686.
Petri, M., Purvey, S., Fang, H. and Magder, L. (2012b) Predictors of organ damage in systemic lupus erythematosus. The Hopkins Lupus Cohort. Arthritis Rheum 64: 4021–4028.
Pope, J., Harding, S., Khimdas, S. and Bonner, A.; Canadian Scleroderma Research Group, Baron, M. (2012) Agreement with guidelines from a large database for management of systemic sclerosis: results from the Canadian Scleroderma Research Group. J Rheumatol 39: 524–531.
Radstake, T., Gorlova, O., Rueda, B., Martin, J., Alizadeh, B., Palomino-Morales, R. et al. (2010) Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet 42: 426–429.
Ramos, P., Criswell, L., Moser, K., Comeau, M., Williams, A. and Pajewski, N. (2011) A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap. PLoS Genet 7: e1002406.
Regier, M., Ries, T., Arndt, C., Cramer, M., Graessner, J., Reitmeier, F. et al. (2009) Sjögren's syndrome of the parotid gland: value of diffusion-weighted echo-planar MRI for diagnosis at an early stage based on MR sialography grading in comparison with healthy volunteers. Rofo 181: 242–248.
Rider, L., Werth, V., Huber, A., Alexanderson, H., Rao, A., Ruperto, N. et al. (2011) Measures of adult and juvenile dermatomyositis, polymyositis and inclusion body myositis. Arthritis Care Res 63: S118-S157.
Rovin, B., Furie, R., Latinis, K., Looney, R., Fervenza, F., Sanchez-Guerrero, J. et al. (2012) Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 64: 1215–1226.
Rubin, L., Badesch, D., Barst, R., Galie, N., Black, C., Keogh, A. et al. (2002) Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 346: 896–903.
Ruiz-Irastorza, G., Danza, A. and Khamashta, M. (2012) Glucocorticoid use and abuse in SLE. Rheumatology 51: 1145–1153.
Ruiz-Irastorza, G., Hunt, B. and Khamashta, M. (2007) A systematic review of secondary thromboprophyllaxis in patients with antiphospholipid antibodies. Arthritis Care Res 57: 1487–1495.
Sandling, J., Garnier, S., Sigurdsson, S., Wang, C., Nordmark, G. and Gunnarsson, I. (2011) A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE. Eur J Hum Genet 19: 479–484.
Saroh, M., Chan, J., Ross, S., Li, Y., Yamasaki, Y., Yamada, H. et al. (2012) Autoantibodies to transcription intermediary factor (TIF)1β associated with dermatomyositis. Arthritis Res Ther 14: R79.
Sato, S., Kuwana, M., Fujita, T. and Suzuki, Y. (2012) Anti-CADM-140/MDA5 autoantibody titer correlates with disease activity and predicts disease outcome in patients with dermatomyositis and rapidly progressive interstitial lung disease. Mod Rheumatol 29 May (Epub ahead of print).
Schermuly, R., Janssen, W., Weissmann, N., Stasch, J., Grimminger, F. and Ghofrani, H. (2011) Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs 20: 567–576.
Scoble, T., Wijetilleka, S. and Khamashta, A. (2011) Management of refractory anti-phospholipid syndrome. Autoimmun Rev 10: 669–673.
Scofield, R. and Kaufman, K. (2012) Mapping susceptibility gene in systemic lupus erythematosus. Methods Mol Biol 900: 11–24.
Seror, R., Mariette, X., Bowman, S., Baron, G., Gottenberg, J., Boostma, H. et al. (2010a) Accurate detection of changes in disease activity in primary Sjögren's syndrome by the European League Against Rheumatism Sjogren's Syndrome Disease Activity Index. Arthritis Care Res 62: 551–558.
Seror, R., Ravaud, P., Bowman, S., Baron, G., Tzioufas, A., Theander, E. et al. (2010b) EULAR Sjögren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjögren's syndrome. Ann Rheum Dis 69: 1103–1109.
Seror, R., Ravaud, P., Mariette, X., Bootsma, H., Theander, E., Hansen, A. et al. (2011) EULAR Sjögren's syndrome patient reported index (ESSPRI): development of a consensus patient index for primary Sjögren's syndrome. Ann Rheum Dis 70: 968–972.
Sherry, S., Ward, M., Kholodov, M., Baker, J., Phan, L., Smigielski, E. et al. (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29: 308–311.
Shiboski, S., Shiboski, C., Criswell, L., Baer, A., Challacombe, S., Lanfranchi, H. et al. (2012) American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjogren's International Collaborative Clinical Alliance cohort. Arthritis Care Res 64: 475–487.
Sozzani, S., Bosisio, D., Scarsi, M. and Tincani, A. (2010) Type I interferons in systemic autoimmunity. Autoimmunity 43: 196–203.
Stewart, M. and Morling, J. (2012) Oral vasodilators for primary Raynaud's phenomenon. Cochrane Database Syst Rev 7:CD006687.
Suber, T., Casciola-Rosen, L. and Rosen, A. (2008) Mechanisms of disease: autoantigens as clues to the pathogenesis of myositis. Nature Clin Prac Rheumatol 4: 201–209.
Suzuki, S., Hayashi, Y., Kuwana, M., Tsuburaya, R., Suzuki, N. and Nishino, I. (2012) Myopathy associated with antibodies to signal recognition particle: disease progression and neurological outcome. Arch Neurol 69: 728–732.
Takagi, Y., Kimura, Y., Nakamura, H., Sasaki, M., Eguchi, K. and Nakamura, T. (2010) Salivary gland ultrasonography: can it be an alternative to sialography as an imaging modality for Sjögren's syndrome? Ann Rheum Dis 69: 1321–1324.
Targoff, I. and Reichlin, M. (1985) The association between Mi-2 antibodies and dermatomyositis. Arthritis Rheum 28: 796–803.
Tashkin, D., Elashoff, R., Clements, P., Goldin, J., Roth, M., Furst, D. et al. (2006) Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 354: 2655–2666.
Theander, E., Vasaitis, L., Baecklund, E., Nordmark, G., Warfvinge, G., Liedholm R., et al. (2011) Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjogren's syndrome. Ann Rheum Dis 70(8):1363–1368.
Trallero-Araguás, E., Rodrigo-Pendás, J., Selva-O'Callaghan, A., Martínez-Gómez, X., Bosch, X., Labrador-Horrillo, M. et al. (2012) Usefulness of anti-p155 autoantibody for diagnosing cancer-associated dermatomyositis: a systematic review and meta-analysis. Arthritis Rheum 64: 523–532.
Tzouvelekis, A., Galanopoulos, N., Bouros, E., Kolios, G., Zacharis, G., Ntolios, P. et al. (2012) Effect and safety of mycophenolate mofetil or sodium in systemic sclerosis-associated interstitial lung disease: a meta-analysis. Pulm Med 2012: 143637.
Urowitz, M., Gladman, D., Tom, B., Ibanez, D. and Farewell, V. (2008) Changing patterns in mortality and disease outcomes for patients with systemic lupus erythematosus. J Rheumatol 35: 2152–2158.
Van Vollenhoven, R., Petri, M., Cervera, R., Roth, D., Ji, B., Kleoudis, C. et al. (2012) Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis 71: 1343–1349.
Vargas-Hitos, J., Ateka-Barrutia, O., Sangle, S. and Khamashta, M. (2011) Efficacy and safety of long term low molecular weight heparin in patients with antiphospholipid syndrome. Ann Rheum Dis 70: 1652–1654.
Vitali, C., Bombardieri, S., Jonsson, R., Moutsopoulos, H., Alexander, E., Carsons, S. et al.; European Study Group on Classification Criteria for Sjögren's Syndrome (2002) Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61: 554–558.
Vitali, C., Palombi, G., Baldini, C., Benucci, M., Bombardieri, S., Covelli, M. et al. (2007) Sjögren's syndrome disease damage index and disease activity index: scoring systems for the assessment of disease damage and disease activity in Sjögren's syndrome, derived from an analysis of a cohort of Italian patients. Arthritis Rheum 56: 2223–2231.
Vivino, F., Al-Hashimi, I., Khan, Z., LeVeque, F., Salisbury, P. 3rd, Tran-Johnson, T. et al. (1999) Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren's syndrome: a randomised, placebo-controlled, fixed-dose, multicenter trial. P92–01 Study Group. Arch Intern Med 159: 174–181.
Voulgarelis, M., Ziakas, P., Papageorgiou, A., Baimpa, E., Tzioufas, A. and Moutsopoulos, H. (2012) Prognosis and outcome of non-Hodgkins lymphoma in primary Sjögren's syndrome. Medicine (Baltimore) 91: 1–9.
Walker, K. and Pope, J. for the Scleroderma Clinical Trials Consortium; Canadian Scleroderma Research Group (2011) Expert agreement on EULAR/EUSTAR recommendations for the management of systemic sclerosis. J Rheumatol 38: 1326–1328.
Walker, K. and Pope, J. for the participating members of the Scleroderma Clinical Trials Consortium (SCTC): Canadian Scleroderma Research Group (CSRG) (2012) Treatment of systemic sclerosis complications: what to use when first-line treatment fails: a consensus of systemic sclerosis experts. Semin Arthritis Rheum 42: 42–55.
Wang, D., Shu, X., Tian, X., Chen, F., Zu, N., Ma, L. et al. (2012) Intravenous immunoglobulin therapy in adult patients with polymyositis/dermatomyositis: a systemic literature review. Clin Rheumatol 31: 801–806.
Weidenbusch, M., Rommele, C., Schrottle, A. and Anders, H. (2012) Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis. Nephrol Dial Transplant 28: 106-111.
Whitcher, J., Shiboski, C., Shiboski, S., Heidenreich, A., Kitagawa, K., Zhang, S. et al. (2010) A simplified quantitative method for assessing keratoconjunctivitis SICCA from the Sjögren's syndrome international registry. Am J Ophthalmol 149: 405–415.
Zhang, J., Roschke, V., Baker, K., Wang, Z., Alarcon, G., Fessler, B. et al. (2001) Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol 166: 6–10.