Latest Advances In Connective Tissue Disorders: Abstract, Basic Science and Conclusion

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.

Basic Science

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.

Innate Immunity

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.


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2 Replies

  • Wow, thank you for that detailed interesting report! :)

    I will add it also onto my facebook Hughie site for added information to others. xx

  • Hi, APSnotFab,

    Excellent. Thank you so much for sharing. May I please translate it and share it to the Portuguese spoken public? It is very important for people to know these matters.

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