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An idiopathic, chronic, systemic inflammatory condition with persistent symmetrical poly-arthropathy, the aetiology and pathophysiology of rheumatoid arthritis (RA) remains elusive, continuing to evade modern medicine, despite significant advances in molecular science.
With a worldwide prevalence of approximately 1 per cent, the burdens of RA in terms of patient morbidity as well as overall economic costs are by no means news headlines to healthcare professionals. Like the manifestations of disease, the impact on quality of life in sufferers is also a spectrum but is hugely significant.
While it affects all populations, RA is more prevalent among certain ethnicities. However, like an increasing number of other disease processes, it appears nature and nurture play integral roles in the pathophysiology of this disease. While concordance among monozygotic twins is only approximately 15-to-20 per cent, there is an estimated two- to three-fold higher risk in first-degree relatives, clearly demonstrating strong genetic associations.
Carrying subtypes of certain specific human leukocyte antigen (HLA) (eg, the HLA-DR4 cluster) confers increased risk, eg, certain HLA-DR4 beta subtypes. The genetic relevance pertains largely to the major histocompatibility complex (MHC) genes on chromosome 6 that have long been associated with RA in this regard. Divided into three regions, certain HLA class genes are associated with the class 1 region, while the HLA DR subset are associated with the class 2 region. The potential relevance of these loci is with regard to the immune-regulatory functions they fulfil, once transcribed.
Like many other autoimmune diseases, infectious agents have been implicated as potential aetiologies of RA, including Epstein-Barr virus, bacterial oral flora and mycoplasma organisms. Despite infectious aetiologies having been proposed, given the relatively ubiquitous global frequency, women remain affected more than men by a factor of three. This has prompted studies focusing on reproductive correlations.
A Danish study reported a higher rate in women who had given birth to just one child when compared to those who had delivered two or three. The study also suggested there was an association between the times elapsed since pregnancy with those in the one- to five-year postpartum period showing a lower risk of RA. Pre-eclampsia, hyperemesis during pregnancy and gestational hypertension were cited as risk factors for women, possibly as a result of maladaptive immune responses to pregnancy.
In practice, patients can present with arthropathy of any joint that is lined by a synovial membrane, although hands and feet are the classically-affected joints at presentation. The onset of RA is usually insidious, often beginning with mild systemic manifestations in advance of joint-based complaints but again, presentations vary. The American College of Rheumatology (ACR) published new recommendations in 2012 for measuring disease activity. These comprised of various composite tools, ranging from patient-driven to patient- and provider-driven as well as patient, provider and laboratory combinations. Determination of disease progression is made on the basis of both clinical and radiologic criteria.
While spontaneous remission is rare, the disease may become less aggressive in some patients over time. Cardiovascular risk is a well-recognised association, while multi-system involvement in general remains a well-worn path for this disease, as is the case with other autoimmune diseases. Despite the apparent but elusive environmental inputs with regard to pathophysiology, there seems to be little that can be done from a primary prevention point of view. Nevertheless, early treatment within six months of the onset of symptoms followed by instigation of treatment with disease-modifying anti-rheumatic drugs (DMARDs) has shown to be most effective in disease control and the preservation of affected joints. The diagnostic considerations are varied, with many falling under the umbrella of rheumatology disease subtypes. These include degenerative joint disease, osteoarthritis, myelodysplastic syndrome, Sjogren’s syndrome, rheumatic fever and polymyalgia rheumatica, although patients with the latter usually demonstrate proximal myalgia and are negative for rheumatoid factor (RF). However, as always, the first priority should be to assess for potentially life/limb threatening conditions. These can mimic arthropathies and are in some cases themselves arthropathies, eg, septic arthritis.
Septic arthritis is an orthopaedic emergency requiring immediate joint aspiration and joint washout. C reactive protein (CRP) is not always elevated in such patients and such a differential diagnosis should not be dismissed or excluded on the basis of a normal CRP.
If there is a clinical suspicion of septic arthritis for any reason, an immediate orthopaedic consultation should be sought. As such, anyone presenting with an inflamed monoarticular arthropathy should undergo joint aspiration. Likewise, cellulitis can also be confused with arthropathy when it occurs over a joint. Falling victim to such a misinterpretation and failing to treat accordingly can be catastrophic, as the complications in this regard include septicaemia and necrotising fasciitis, both of which confer significant morbidity and mortality.
There is no single test for RA. Just as it is a multi-system disease, diagnosis is also multifaceted and based on a combination of clinical, laboratory and radiological components. Treatment considerations are made using an integrated multidisciplinary approach, which includes an array of medical options, both in terms of analgesia and disease-targeted drugs. Physiotherapists and occupational health practitioners are often at the forefront of therapeutic intervention, while surgical interventions including tendon realignment, synovectomy and arthrodesis remain options for certain patients.
However, medical DMARD therapy remains the mainstay in the successful treatment of RA. With the potential to slow and prevent disease and concomitant loss of function, successful therapeutic intervention in this regard with DMARDs may avoid the necessity to use other classes of drugs, thus limiting deleterious iatrogenic outcomes. With an increasing array of medications available, extending from NSAIDs to newer monoclonal antibodies, it is a promising era for progress to be made in treatment of RA.
A recent arrival on to the therapeutic stage is in the form of REGN88/SAR153191 (sarilumab), an IL-6 receptor inhibitor, which is the first fully-humanised monoclonal antibody directed against the IL-6 receptor. Data has demonstrated significantly better responses when methotrexate (MTX) is used in combination with sarilumab than when MTX is used alone.
On 21 May this year, Regeneron and Sanofi announced that a Phase 3 study of REGN88/SAR153191 met its co-primary efficacy endpoints of a greater improvement in signs and symptoms of RA at 24 weeks and physical function at 12 weeks, compared to placebo. The study, called SARIL-RA-TARGET, evaluated the efficacy and safety of two subcutaneous sarilumab doses vs placebo, added to DMARD therapy in RA patients who were inadequate responders to or intolerant of TNF-alpha inhibitors (TNF-IR).
The SARIL-RA-TARGET trial enrolled 546 TNF-IR patients who were randomised to one of three treatment groups self-administered subcutaneously (SC) every other week (Q2W): sarilumab 200mg, sarilumab 150mg, or placebo, in addition to DMARD therapy.
Both sarilumab groups showed clinically-relevant and statistically-significant improvements compared to the placebo group in both co-primary endpoints (p greater than 0.001):
- Improvement in signs and symptoms of RA at 24 weeks, as measured by the ACR score of 20 per cent improvement (ACR20), were as follows: 61 per cent in the sarilumab 200mg group; 56 per cent in the sarilumab 150mg group; and 34 per cent in the placebo group, all in combination with DMARD therapy.
- Improvement in physical function, as measured by change from baseline in the Health Assessment Question-Disability Index (HAQ-DI) at week 12.
The most frequently reported adverse events included infections (30, 22 and 27 per cent in the 200mg, 150mg and placebo groups respectively) and injection site reactions. Serious infections were uncommon (1, 0.6 and 1 per cent in the 200mg, 150mg and placebo groups, respectively). Reduction in neutrophil count was the most common lab abnormality. No unexpected safety findings were observed.
Two additional trials from the Phase 3 programme, SARIL-RA-EASY and SARIL-RA-ASCERTAIN, also met their primary endpoints:
- SARIL-RA-EASY enrolled 217 patients and was designed to evaluate the technical performance and usability of the sarilumab autoinjector device. There were no product technical failures with the autoinjector, the primary endpoint of the study.
- SARIL-RA-ASCERTAIN was a 202-patient safety calibrator study, designed to assess the safety of two subcutaneous doses of sarilumab and tocilizumab infusion in combination with DMARDs in patients with RA who were TNF-IR. There were no clinically meaningful differences between the treatment groups in serious adverse events and serious infections.
Detailed results from all three SARIL-RA trials will be presented at future medical congresses.
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References on request
- There is an association between RA and periodonopathic viral infection?
- Boutonnière deformity is a result of synovitis disrupting the DIP joint through the central extensor tendon?
- Both anti-cyclic citrullinated peptide (anti-CCP) and anti-mutated citrullinated vimentin (anti-MCV) assays have been recommended by the ACR and EULAR classification criteria as useful laboratory studies?
- Over time, anti-CCP correlates with radiographic progression of disease?
- Rheumatoid factor is a non-specific immunoglobulin (IgG) directed against the Fc fragment of IgM?
- NSAIDs can be used after the first and second trimester in pregnant women with active RA?
- MTX is a DNA gyrase inhibitor and as such, is contraindicated in pregnancy?
- Being male in the context of RA is a poor prognostic indicator, even though RA more commonly affects women?
- Poor prognosis is dependent on the number of joints involved?
- Radiographic erosion is typically fastest in the second year of disease?
- False. Antibodies to oral anaerobic bacteria found in periodontal infection have been demonstrated in high levels in the synovial fluid of RA patients, leading these organisms to be cited as potential aetiologies of RA.
- False. It is the PIP joint.
- False. CRP and ESR are routine laboratory tests associated with disease activity with CRP, correlating with radiographic progression of disease over time.
- False. RF is an IgM directed at the Fc fragment of IgG.
- False. NSAIDs are contraindicated in the third trimester of pregnancy, as they help induce premature closure of the ductus arteriosus, which leads to foetal pulmonary hypertension.
- False. MTX is a folic acid antagonist, it is an abortifacient and is teratogenic and therefore contraindicated in pregnancy.
- False. Female sex is a poor prognostic indicator.
- True. Poor prognosis is proportional to the number of joints involved.
- False. Radiographic erosion is typically fastest in the first year of disease.