Rheumatoid arthritis (RA)
The principal symptom of rheumatoid arthritis (RA) is inflammation of the joints. Inflammation may also occur in other tissues, including, for example, the heart, lungs, kidneys and pleura. The cause is currently unknown, but may involve climate, working conditions and gender, because it is more prevalent in women (F: M approximately 2.5: 1.0).
RA is diagnosed through its distinctive effects on the joints and in skin, and the diagnosis is reinforced by the presence in serum of the rheumatoid factor (RF), although its presence is not mandatory for diagnosis of RA. RA is systemic in that it may attack several different joints, and in many cases appears to affect different joints at different times, hence the term ‘migratory or flitting polyarthritis’ used by some authorities.
Over time, irreparable damage is done to the joint due to inflammation of the synovial membrane, which forms the lining of the tendon sheaths and the joints. As the disease progresses, it destroys the joint tissues and reduces joint mobility through, for example, erosion and tethering of the tendons.
This means that the tendon becomes fixed to adjacent tissues, which restricts its movement. Eventually, use of joints in the hands and limbs is lost, and fingers and toes may become severely deformed. In the skin, subcutaneous nodules form, and vasculitis may also be diagnosed, which is the chronic destruction of blood vessels. Several other haematological, radiological and biochemical tests are used to confirm the diagnosis but are not dealt with here. RA has traditionally been associated with morbidity and significantly earlier mortality.
Important environmental and biological factors associated with or possibly contributory to the pathogenesis of RA
* Cigarette smoking.
* Tumour necrosis factor (TNF)-α activity.
* Abnormal and inappropriate B-lymphocyte activity, i.e. abnormal antibody production.
* Detection of circulating autoantibodies against Ig Fc; these autoantibodies have been termed ‘rheumatoid factor’, and they may be involved in the inappropriate presentation of antigens to T cells by B cells.
* Abnormal activity of certain signaling pathways in synovial tissue, e.g. the Wnt signaling pathway, which is involved in embryonic development and cell renewal. In patients with RA, it has been reported that the synovial cells have abnormally high activity of the Wnt gene, as well as a number of other genes for several of the cytokines, cell adhesion molecules and chemokines. At present, it is not known whether these abnormalities are causative or a result of the more fundamental abnormalities.
Diagnosis of rheumatoid arthritis – clinical criteria
The criteria listed below are those published by the American College of Rheumatology in 1987. Any four of the criteria listed below must be identified for positive diagnosis of RA:
* Detection of serum RF
* Morning stiffness for 1 hour or longer for 6 weeks or more
* Arthritis in three or more joints persisting for 6 weeks or more
* Persistence for 6 weeks or more of symmetrical arthritis
* Persistence for 6 weeks or more of arthritis of the hand joints
* Rheumatoid nodules
* Observation, using hand radiographs, of changes, erosion or unequivocal bony decalcification.
Current aims of treatment of RA
* Slow the rate of disease progression.
* Control inflammation and pain; ideally the patients should be as free as possible from pain.
* Design the appropriate treatment regimen for each patient.
* Regular appointments with the clinic and the rheumatologist.
* Regular patient monitoring for adverse effects of treatments.
* Regular blood tests.
* Monitor patient compliance.
Several drugs, e.g. methotrexate, penicillamine, gold and azathioprine, commonly known as DMARDs, or disease-modifying anti-rheumatic drugs, have been used for several years. These may provide symptomatic relief and slow the progression of the disease, but are associated with serious adverse effects and are relatively non-specific in their actions.
The biological DMARDs have been developed thanks to the advances made in molecular biology, and especially with regard to the identification of key cellular mediators of inflammation. Essentially, these are monoclonal antibodies (MAbs) directed against chemical mediators of inflammation, notably TNF-α, and interleukins IL-1 and IL-6.
These MAbs compete with the endogenous ligands at their receptor sites on cells, e.g. CD20 and CD22, some of which have no identified endogenous ligand (at the time of writing).
The introduction of the biological drugs, also termed ‘biological DMARDs’, seems set to bring more benefit to patients in this respect but they too may have serious adverse effects due to the lowering of resistance to infection through their powerful inhibition of the immune system.
Methotrexate is prescribed alone as a DMARD for RA. It does take down tissue swelling and reduces pain, and will slow the rate of progression of joint damage and degeneration. It is prescribed together with the biological DMARDs in order to attenuate any immune reaction to the latter.
The drug needs to be used with caution because it is a folic acid antagonist, and it is recommended that a dose of 5mg folic acid be taken with each weekly dose of methotrexate (usually 7.5–20 mg weekly). Regular blood cell counts are strongly recommended for patients who take methotrexate.
Many of the biological drugs, e.g. infliximab and rituximab, are administered by intravenous infusion and are therefore given under clinical supervision in hospital. A nurse, doctor or other carer, on the other hand, may administer etanercept to the patient in hospital or at home.
Abatacept (Orencia) is a soluble fusion protein, prepared by fusing the extracellular domain of the human cytotoxic T-lymphocyte-associated antigen (hCTLA-4) to a modified human G1 immunoglobulin. When abatacept binds to its target receptors, namely CD80 and CD86 on the T cell, it prevents endogenous ligands from binding and blocks the inflammatory cascade.
Abatacept is prescribed together with methotrexate, another DMARD. This is because abatacept, as with the other biological DMARDs, is a foreign protein and may elicit an immune response by the host immune system. Methotrexate is a relatively small molecule that limits the immune response, thus sparing the foreign protein so that it can attenuate the host immune system’s response.
Adalimumab (Humira) is a completely human MAb that exhibits high affinity and specificity for TNF-α, blocking binding to its receptors. Adalimumab is supplied as a prefilled syringe containing 40 mg adalimumab, or as an autoinjector system and self-administered as a subcutaneous injection every other week. In some patients who do not respond satisfactorily to this dose it has been prescribed for once-weekly injection
Anakinra (Kineret) is a recombinant antagonist at the IL-1 receptor. Chemically it is based on the structure of the IL-1RA receptor. It blocks the inflammatory actions of IL-1 by binding to it, thus blocking the cartilage degradation and inflammation caused by IL-1.
Etanercept (Enbrel) consists of a fully human amino acid sequence p75 TNFR11 dimer linked to the Fc of human IgG. It acts by blocking the binding of TNF-α to its receptor. It was the first biological approved by the US Food and Drug Administration (FDA) for the treatment of psoriatic arthritis. It is a dimer that can bind to two TNF-α receptors, whether free or cell bound, with very high affinity. As with several other MAb treatments, etanercept is often prescribed together with methotrexate.