Associate Professor David Bossingham, James Cook University
Rheumatoid arthritis is common, the prevalence is 1.5 -1.8% with a 3:1 female preponderance. It can begin at any age but is rare before puberty and most common between 30 and 45, with an increased risk postpartum. There is a strong familial association with a five amino acid sequence motif common to residues 70–74 of the DR chain coded by several HLA-DRB1 alleles, called the ‘common epitope’, there is a high risk in smokers and those with common autoimmune diseases, hypothyroidism, pernicious anaemia, vitiligo, type 1 diabetes and Addison’s disease.
The pathology is that of inflammation with a systemic response to the citrullinated peptides, a post translational change where valine is replaced by citrulline. With time the immune response becomes more varied with elements of abnormal T and B cell function together with cell mediated responses, it is not a simple autoimmune disease.
The recent finding of antibodies to cyclic citrullinated peptides (CCPAb’s or ACPA) has enabled us to define two distinct groups. The former, making some 70%+ of the population, carries the common epitope and are more likely to be smokers and have positive antibody tests. The second group are phenotypically similar but a definable immunological abnormality has yet to be found. It is very likely that there is a long “pre-disease” seropositive latent period possibly of many years.
The consequences of untreated Rheumatoid Arthritis are pain, joint deformity and premature death from arterial disease the result of cytokine damage to endothelium, research has shown that after 5 years of disease >50% will be unemployed and after 12 years up to 17% will be dead. These figures are equivalent to the prognosis for stage 3 Hodgkin’s disease.
It has been shown that early diagnosis and prompt disease modification can reduce disease complications. This ‘Window of Opportunity’ may be only a few months long, after which changes in immune response make disease control more problematic.
The differential diagnosis for early polyarticular inflammatory arthritis is wide the onset can be sudden and symmetrical peripheral polyarthritis is more likely;
|Infection||particularly viral, Human Parvovirus especially, consider Hepatitis B or C and HIV, all the paediatric exanthema especially rubella|
|Malignancy||Joint pain can be an early sign particularly for bone marrow diseases|
|Rheumatic Fever||In the indigenous population where RA is rare|
|SLE||Consider other system involvement|
|Spondyloarthropathy||psoriasis, reactive etc, diagnosis often made from the family history|
Gout pseudogout, haemochromatosis etc are unusual as polyarticlar presentations.
The best method for diagnostic tool are the criteria of Aletaha et al (A&R 2010 62; 2569-81)
|Inflammation 1 Large Joint||0||Low Positive Serology||2|
|2-10 Large Joints||1||High Positive Serology||3|
|1-3 Small Joints||2||Normal ESR/CRP||0|
|4-10 Small Joints||3||Raised ESR/CRP||1|
|> 10 Joints||5||Symptoms < 6 weeks||0|
|Negative Serology (CCP/RhF)||0||Symptoms > 6 weeks||1|
SCORE > 6 is strongly indicative of RA
Once a presumptive diagnosis is made disease modification should be commenced, after discussion with a rheumatologist. Treatment with single or multiple agents is required, methotrexate alone or in combination with hydroxychloroquine and sulfasalazine. The aim is to reduce or abolish joint tenderness and return acute phase measurements to normal.
This “Treat to target” approach has been shown effective with additions to treatment over monthly periods and then reduction in treatment once remission has been achieved. With early intervention many will remit entirely some may even be able to stop some or all medications however some will not and then treatment with novel biologic agents may be required.
The doses of methotrexate are modest starting at 20mg weekly and if possible, reducing. This requires normal renal and hepatic function and these tests along with a blood count are required at regular intervals whilst treatment continues, initially then at up to 2 monthly intervals. Nausea can be a problem which can be reduced by taking folic acid 5mg the day before or by using drug by subcutaneous injection. Leflunomide requires similar monitoring, sulfasalazine can cause neutropenia and this needs to besought early on, hydroxychloroquine has a reputation for causing retinopathy but in the doses used 2-400mg daily this is agreed to be miniscule.
The patient who fails to respond to conventional DMARD’s may be eligible for treatment with one of the biologic agents whose effects have made such an impression on rheumatology practice and workload.
The discovery of the details in inflammatory cytokine cascade enabled the production of specific monoclonal antibodies initially to tumour necrosis factor alpha (TNF-α), the effects have been profound for many individuals but their use is not without complication. Il-1 which appeared important in animal studies is of little value in RA but has a place in other rheumatic diseases.
The problems of biological treatment are the possible presence of underlying chronic infection and all patients must be extensively screened for tuberculosis, hepatitis B, C and HIV. It advisable not to treat any patient who has undergone successful treatment for a malignancy (excluding non-melanoma skin cancers) in the prior 5 years and treatment should be stopped should a malignancy be diagnosed. Alternatives are available especially in the form of Rituximab.
The next generation treatment is the use of oral inhibitors of the JAK-STAT determinants on lymphocytes, they are effective and offer an alternative to conventional biologic drugs.
In the past a regular problem were ‘flares’ of symptoms, now we consider the recurrence of symptoms or the acute phase response to be an indication of treatment failure and a search for alternatives is necessary. Oral corticosteroids were widely used but they are now considered inappropriate as their disease modifying potential is very limited and their side effect profile is too damning.
The introduction of energetic early intervention, the treat to target mantra and the development of the biologic agents has made a huge difference for patients with RA. The number of patients with severe deformities has plummeted, those requiring surgery have dwindled to a mere trickle and life expectancy has improved as a result of controlling inflammation and its comorbidities.