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21st December 2018
17th December 2018
Connective tissue diseases (CTD) are a group of disorders involving the protein-rich tissue that supports organs and other parts of the body. However, more commonly the acronym CTD identifies systemic autoimmune rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and SLE-like diseases, Sjogren syndrome (SS), scleroderma (SSc), inflammatory autoimmune myopathies (AM), systemic autoimmune vasculitides (AV), mixed or undifferentiated connective tissue disease (MCTD/UCTD), and anti-phospholipid syndrome (APS).
All these disorders are also defined as systemic autoimmune rheumatic diseases (SARD) and are characterised by an autoimmune response against self-antigens that ends in chronic inflammation and irreversible tissue damage if untreated, with high direct and indirect costs for the social/health systems. SARD can affect several organs and tissues of the body; as a consequence, different specialists may see these patients but ultimately, rheumatologists or clinical immunologists are the main physicians providing care for SARD.
Classification and diagnosis
The classification and the diagnosis of SARD are based on clinical signs and symptoms, however laboratory and instrumental parameters are also required.1 These tools improved our classification/diagnostic power; this is the case, for example, for RA with the new anti-citrullinated peptide antibodies and joint magnetic resonance and/or ultrasound Doppler evaluation.2 In addition, the histology or immune-phenotyping of the damaged tissues help in diagnosis but, unfortunately, are not always feasible or specific because of overlapping pathogenic pathways.3
Although each disease displays peculiar clinical pictures, some manifestations are not specific at all (such as thrombosis in APS) or frequently overlapping among different diseases (for example, inflammatory arthritis). Moreover, the clinical manifestations are non-specific particularly at the beginning of the clinical history making difficult the correct diagnosis. Consequently, biological biomarkers play a crucial role in directing physicians towards the right diagnosis. In particular, autoantibodies are offering the most reliable tools nowadays (Table 1). Additional tools, such as cytokines or genetic biomarkers (including non-coding RNA/DNA) are quite promising but not useful in practice at the moment.
Table 1. Autoantibodies in SARD
|Rheumatoid factor (RF)
Anti-citrullinated protein antibodies (ACPA)
|Anti-nuclear antibodies (ANA)
Anti-double stranded DNA antibodies (anti-dsDNA)
Anti-Sm antibodies (anti-Sm)
Lupus anticoagulant (LA)
Anti-cardiolipin antibodies (anti-CL)
|Systemic lupus erythematosus|
Anti-centromere A,B,C (anti-CENP A,B,C)
Anti-RNA polymerase III
|Anti-U1 ribonucleoprotein (anti-U1 RNP)||Mixed connective tissue disease|
|ANA||Undifferentiated connective tissue disease|
Anti-beta2-glycoprotein I antibodies (anti-b2GPI)
Proteinase 3 (PR3)
Autoantibodies represent well-accepted classification criteria and, in some cases, they are also entry classification criteria; the most recent examples are represented by anti-phospholipid antibodies (aPL) for APS and anti-nuclear antibodies detectable by indirect immunofluorescence or equivalent solid phase assays for SLE.4,5 From this point of view, they represent mandatory inclusion criteria for clinical trials.
Autoantibodies in diagnosis
SARD are chronically evolving disorders characterised by the production of autoantibodies, even years before the appearance of the clinical manifestations. Because of the non-specific clinical symptoms at the beginning of the SARD, the detection of autoantibodies is a useful diagnostic tool. By contrast, early diagnosis is mandatory in order to start treatment before irreversible tissue damage takes place. This approach results in a better prognosis (that is, less organ damage) and in the reduction of the costs of the disease. The most common approach is the use of screening assays (for example, ANA detection) for supporting the suspect of the autoimmune origin of the disease and then the request for autoantibody profiles for identifying autoantibodies associated to SLE-, SSc-, SS- or AM-like disorders6 (Table 2).
Table 2. Autoantibodies and their associations with clinical manifestations in SARD
|Autoantibody||Disease association||Clinical manifestations|
|anti-topoisomerase I||SSc||ILD, digital ulcers, diffuse skin involvement, heart involvement|
|anti-CENP A, B, C||SSc||PAH, bowel involvement, digital ulcers, limited skin involvement|
|anti-RNA polymerase III||SSc||SRC, tendon friction rubs, severe diffuse skin involvement|
|anti-U3 RNP||SSc||PAH, myositis, heart involvement, diffuse skin involvement|
|anti-U1 RNP||SSc, SSc/PM overlap, SLE, MCTD||Myositis, PAH, arthritis, limited skin involvement|
|anti-PM-Scl||PM/DM, SSc/myositis overlap, SSc||Myositis, limited skin involvement|
|anti-Th/To||SSc||PAH, ILD, bowel involvement, limited skin involvement|
|anti-mitochondria||PBC/lcSSc and PBC/SS overlap||Cholestatic liver disease|
|anti-Ku||SLE, SSc, SLE/PM/SSc and PM/SSc overlap||Myositis, arthritis|
|anti-dsDNA||SLE||Nephritis, disease activity|
|anti-Ro/SSA||SLE, SS, SCLE||Haematologic disorder, photosensitivity, neonatal lupus, C2 deficiency|
-PL12, -EJ, -OJ,
-KS, -Zo, -YRS)
|PM/DM||Myositis, ILD, mechanic’s hands|
|anti-ribosomal P protein||SLE||Neuropsychiatric manifestations|
|anti-nucleosomes||SLE, APS||Drug-induced lupus, nephritis, disease activity|
|anti-C1q||SLE||Active renal disease|
|anti-citrullinated proteins||RA||Severe disease|
|LA, anti-CL, anti-b2GPI||APS||Thrombosis, miscarriages|
Autoantibodies are also widely used for disease subgrouping. For example, SSc patients sub grouped according to the presence of anti-topoisomerase or anti-centromere autoantibodies display different clinical picture and evolution.7,8 The same is also the case for the autoantibodies detectable in a different AM.9
The presence of different autoantibody profiles is useful for risk stratification in some diseases. The best example is represented by APS, in which the number of tests positive for aPL (that is, lupus anticoagulant, anti-cardiolipin, anti-b2 glycoprotein) or the aPL titres are risk factors. In other words, the higher the number of positive tests (triple or double versus single positivity) or the antibody titres, the higher the risk for thrombosis or miscarriages.10
SARD subgrouping and risk profiling allow a better disease characterisation and ultimately the best treatment approach according to precision (or personalised) medicine.
In addition to their defined role in the diagnosis of AID, a number of autoantibodies represent biomarkers for damage or involvement of particular tissues or organs, making them important in defining relevant comorbidities. This is the case for anti-C1q antibodies closely associated with active renal disease in SLE11 (Table 2).
The presence of an autoantibody might be the determining factor for starting primary prophylactic therapy, even in the absence of overt clinical signs, in order to reduce the risk of the clinical manifestations. Anti-phospholipid antibodies are the most popular example, justifying antiplatelet therapy even in asymptomatic aPL-positive carriers or low-dose aspirin and heparin in pregnant women at high risk for miscarriages.10
Nowadays, autoantibody detection is performed by automated assays in high-throughput routine service laboratories. The availability of the new assays has uncovered many problems, including quality control, quality assurance, standardisation, analytical sensitivity/specificity, within and between laboratory reproducibility and clinical sensitivity. These aspects are all relevant to the overall clinical interpretation of the tests and several international standardisation initiatives are currently ongoing.12,13
13th December 2018
12th December 2018
The Government has chosen England’s chief pharmacist to look into “problematic” overprescribing in the NHS, it has announced.
Health and Social care secretary Matt Hancock revealed last week (8 December) that the Government will look into overprescribing to address “problematic polypharmacy” and ensure patients receive the treatment they need.
The review will be conducted by England’s chief pharmaceutical officer Dr Keith Ridge, the Government said.
The review will mainly focus on addressing “problematic polypharmacy”, where needed, and reducing overprescribing, the Government said.
Dr Ridge will be tasked with ensuring pharmacists and doctors receive the support they need to review prescriptions and provide patients with “the most appropriate treatment for their needs”, the Government said.
He will look in particular at situations where there is a potential overlap of multiple medicines prescribed to treat the same condition and where people are subject to repeat prescriptions without being reviewed.
Mr Hancock said: “Recent advances in medicine have led to fantastic developments in managing and treating certain conditions, but poorly managed prescribing can lead to serious issues for patients such as increased admissions to hospital or antibiotic resistance.
“As we invest an extra £20.5bn a year into our NHS, we want to empower doctors and pharmacists to use the data available to ensure patients get the medicines they need and stop taking those that no longer benefit them.”
According to the Government, NHS spending on medicines has risen by 5% a year between 2010 and 2018, from £13bn to £18.2bn.
11th December 2018