1. Compare the features of rheumatoid and osteoarthritis. How do the disease processes
differ?
Introduction
Rheumatoid and osteoarthritis each affect a significant number of people in the UK.
They are capable of causing considerable disability leading to loss of working days as
well as healthcare expenditure. Understanding their disease processes better, in order
to develop more effective treatments, is clearly important. Here I will examine the
differences between the two diseases.
Features
While osteoarthritis is more common with age, rheumatoid arthritis tends to occur
at an earlier age, although females are more prone to both. Osteoarthritis is
characterised by pain, stiffness and swelling as is rheumatoid arthritis, but the joints
typically affected differ. Rheumatoid arthritis starts in the small joints of the hands
and feet (particularly the metacarpophalangeal joints) while in the hands osteoarthritis
is more common in the distal interphalangeal joint, but also occurs typically in the
knees and hips.
In osteoarthritis there is age related focal damage of the articular surface and a
reaction with the underlying bone. There may be irregular thickening of
subchondral bone, possibly with cysts and sclerosis, while the capsule can also be
thickened, distorted and fibrosed. Osteophytosis also occurs leading to the growth of
bony nodules (known as Heberden’s nodes on the DIP joints) and there is also soft
tissue growth.
In contrast rheumatoid arthritis is characterised by a hyperproliferative synovial
membrane, that may invade the underlying bone, forming a pannus. There are
typically enlarged villi, the occasional giant multinucleated cell and an
inflammatory cell infiltrate. These cells are mostly CD4+ T cells, but also include
dendritic cells, macrophages, fibroblasts, endothelial cells and neutrophils. A
vasculitis is also present. Approximately one third of patients will also have extra-
articular disease – fibrosing alveolitis, vasculitis or granuloma formation
Osteoarthritis patients are usually negative for rheumatoid factor with an
ESR<40mm/hour, while rheumatoid patients are generally rheumatoid factor positive
and have an elevated ESR, reflecting immune system activation. Rheumatoid patients
also often have decreased serum metals (Cu, Zn, Fe) and the anaemia of chronic
disease
Disease process
Although patients may present with similar symptoms the joint environment is clearly
histopathologically different. This reflects the fact that osteoarthritis is not a disease
of immune system activation or origin while rheumatoid arhtiritis is thought to be
both initiated and maintained by the bodys own immune system. I will now examine
the disease processes of each in more detail.
Osteoarthritis

2. Insight may be gained into the pathogenesis of osteoarthritis by looking at the risk
factors. These are age, obesity, female, osteoporosis, smoking and hypermobility,
of which the most important is age.
Repeated insults to the joint throughout life cause damage to accumulate. When
coupled with the repair senescence seen in aging, this causes wear and tear of the
articular surface. Neuromuscular function also declines with age, so the joint is less
protected and more likely to acquire injuries. Hypermobility also increases the risk of
causing joint damage, by pushing it beyond its normal range of motion, and obesity
causes more stress to be placed on weight bearing joints such as the knees and hips.
Acute injuries that damage the cartilage can also result in the development of
osteoarthritis
Rheumatoid arthritis
The pathogenesis of rheumatoid arthritis has not yet been fully elucidated but many
mechanisms have been implicated.
It is thought that individuals with rheumatoid arthritis may have higher levels of an
enzyme called PADI. PADI converts arginine to citrulline which can then bind to
proteins created citrullinated proteins. This leads to the generation of neo-epitopes
that may be recognised by T and B cells. Why this should lead specifically to T cells
attacking joints is unclear, but may be because collagen contains unique epitopes
that are similar to these neo-epitopes generated.
It also has been found that there are reduced levels of glutathione in patients with
rheumatoid arthritis so they are less protected against free radical mediated damage.
Free radicals can depolymerise hyaluronic acid, fragment collagen and activate
MMPs, all of which would contribute to tissue damage.
It is not yet determined whether T cells simply initiate the disease and it is then
maintained by mesenchymal cells, or if they are responsible for the ongoing
inflammation. However there is strong evidence for the involvement of T cells. They
are found within the joint itself and have been shown to transfer disease in animals.
The inflammation is antigen driven which suggests a role for the recognition of
arthritogenic peptide by T cell receptors. Additionally anti T cell therapies are at
least partially successful in ameliorating disease.
There may also be a part to play in the initiation of disease by infectious agents.
Infection may lead to the generation of cytokines that could allow autoreactive T cells
to break tolerance, or it may be that epitopes in the joint have shared sequences with
infectious agents (molecular mimicry). However infection does not appear to be
present chronically in rheumatoid joints and so can only be involved in initiation.
Auto-antibodies are seen against type II collagen in 10% and also against
proteoglycans (not expressed in the thymus so central tolerance to these cannot be
present). Proteolysis of glycoaminoglycan caps on the proteoglycans could reveal
epitopes to autoreactive T cells, thus activating them. Rheumatoid factor is an IgG
Fc, that inhibits capstatin. Capastatin usually inhibits calpain, which degrades the
extracellular matrix, and so rheumatoid factor helps to promote this degradation.

3. Joint injury may also be important as reperfusion injury could cause the release of
cytokines, activating inflammatory processes within the joint, which is usually a
relatively immune privileged site. Cytokines are secreted by a variety of cells
including T cells, macrophages and fibroblasts. Fibroblasts are also important in
the disease as synovial fibroblasts transplanted into SCID mice invade bone,
suggesting that the immune system is involved in keeping them in check. Elevated
cytokines is rheumatoid arthritis include IL-1, IL-6, IL-8 and importantly TNFa.
TNFa promotes the expression of other pro-inflammatory cytokines as well as its
own receptor thereby generating positive feedback. It leads to the expression of
adhesion molecules, increased vascular permeability, inflammatory cell activation
and angiogenesis. In fact many of the cytokines elevated in rheumatoid arthritis are
pro-angiogenic (Feldman et al, 1996)
There is also a role for genetics in rheumatoid arthritis. Those with HLA DR4 are
predisposed to the disease possibly because of a shared sequence with an EBV
glycoprotein, or because DR4 may be able to bind citrullinated proteins better.
Conclusion
The pathogenesis of osteoarthritis is primarily age related and is not related to
immune system activation. In contrast a great many components of the immune
system are involved in rheumatoid arthritis, emphasising its inflammatory (rather than
degenerative as in osteoarthritis) nature.