Rheumatoid arthritis, other inflammatory arthritides and osteoarthritis

Rheumatoid arthritis

Rheumatoid arthritis is a chronic systemic inflammatory autoimmune condition to which some people are genetically predisposed. The symptoms of rheumatoid arthritis usually appear gradually and most often involve the proximal interphalangeal joints of the fingers, metacarpophalangeal joints and wrists. Inflammation of other joints such as the ankles and hips may be the presenting complaint, or they may become involved later. The affected joints are warm, swollen and painful. Stiffness is troublesome, particularly in the morning, as a result of an increase in extracellular fluid in and around the joint. Systemic disturbance is common, including general fatigue, malaise and weight loss, while extra-articular manifestations such as vasculitis and neuropathy can occur.

Autoimmune processes contribute to the maintenance of the rheumatoid arthritis, but it is uncertain whether it is initiated by an autoimmune reaction or by an exogenous antigen. Two autoantibodies, rheumatoid factor (IgM autoantibodies reactive with IgG) and anti-citrullinated protein antibodies, may be detected, but are absent in about one-third of cases. The initiating antigen is believed to bind to Toll-like receptors (TLRs) – pattern-recognition molecules that bind to both foreign and self structures – on dendritic cells and macrophages, which then initiate a response by the innate immune system (Ch. 38). The primary response is lymphoid cell infiltration of the synovium around the joint, formation of new blood vessels and a proliferation of the synovial membrane. The synovium becomes locally invasive (pannus) and osteoclasts destroy joint cartilage and bone. Apart from psoriatic arthritis, other forms of inflammatory arthritis do not produce erosive changes in periarticular bone or marked joint destruction to the same degree.

The chronic inflammatory process is initiated by T-helper 1 (Th1) lymphocytes that migrate into the joint. Failure of suppression of Th1 cells by regulatory T-cells may be important in the pathogenesis of the disease. Activated T-cells produce a gamut of pro-inflammatory cytokines, including tumour necrosis factor α (TNFα) and interleukin-1 (IL-1). These cytokines stimulate B-lymphocytes, macrophages, fibroblasts, chondrocytes and osteoclasts (Fig. 30.1). B-cells play an important role in the pathology of rheumatoid arthritis. They act as antigen-presenting cells that co-stimulate T-cells, generate inflammatory cytokines such as TNFα and produce rheumatoid factor antibody. Antigen-presenting cells express CD20, CD80 and CD86 surface markers and are involved in the activation of T-cells (Fig. 30.1). TNFα has a prominent role in orchestrating the production of other inflammatory mediators and the recruitment of further immune and inflammatory cells into the joint. This pattern of inflammation differs from most other immune-mediated diseases. The ubiquitous gene transcription factor nuclear factor κB (NF-κB) is also thought to be involved at many steps in cell activation and cytokine production in the destructive cycle of events.

TNFα and IL-1 aid the recruitment of inflammatory cells such as leucocytes by increasing the expression of adhesion molecules (integrins) on vascular endothelial cells. These cytokines also stimulate synovial fibroblasts, osteoclasts and chondrocytes to release tissue-destroying matrix metalloproteinases (MMPs) and to express chemokine receptors. Activated macrophages, lymphocytes and fibroblasts stimulate angiogenesis in the synovium.

Antibodies are produced to the collagen exposed in the damaged cartilage. Rheumatoid factor forms complexes with collagen in damaged cartilage, which then activate the complement pathway. The relevance of this to joint damage is not known. The activated osteoclasts increase bone resorption. The result of this complex inflammatory process is irreversible destruction of cartilage and erosion of periarticular bone.

The plethora of cells that enter the synovium, and the bewildering array of cytokines that are involved, provide a large number of potential targets for disease-modifying antirheumatic drugs affecting the immune system (Fig. 30.1).

Other types of inflammatory arthritis: the spondyloarthritides

There are many types of inflammatory arthritis that have a pattern of joint involvement different from that of rheumatoid arthritis. They involve the sacroiliac joints and can affect small or large joints peripherally. Collectively they are called the spondyloarthritides, and include ankylosing spondylitis, psoriatic arthritis, arthritis associated with inflammatory bowel disease and some juvenile idiopathic arthritis. There is a genetic predisposition to this type of arthritis, varying from a single genetic risk factor such as HLA-B27 in ankylosing spondylitis to polygenic influences in other disorders.

Spondyloarthritides are considered to be autoinflammatory syndromes and probably arise from activation of innate immune processes in response to bacterial or mechanical stress. This distinguishes them from autoimmune conditions that are triggered by activation of the adaptive immune system (Ch. 38). A variety of cytokines appear to be involved in the inflammatory response, including TNFα, and various interleukins such as IL-1, IL-6, IL-17 and IL-23. The inflammation is characteristically associated with enthesopathy (inflammation at the bone insertion of tendons and ligaments) and formation of new endochondral bone.

The presence of different pathophysiological mechanisms in rheumatoid arthritis and the spondyloarthritides explains the different responses to treatments designed to modify disease progression.

Conventional disease-modifying antirheumatic drugs for rheumatoid arthritis

Non-steroidal anti-inflammatory drugs (NSAIDs; Ch. 29) provide symptomatic relief but do not alter the long-term progression of joint destruction in rheumatoid arthritis. A diverse group of compounds can reduce the rate of progression of joint erosion and destruction, leading to improvement both in symptoms and in the clinical and serological markers of rheumatoid arthritis activity. These drugs produce long-term depression of the inflammatory response even though they have little direct anti-inflammatory effect. They all have a slow onset of action, with many producing little improvement until about 3 months after starting treatment. Such drugs are grouped together and known as disease-modifying antirheumatic drugs (DMARDs).

Biological drugs for rheumatoid arthritis

Management of rheumatoid arthritis

Progressive joint damage is common in rheumatoid arthritis. There is now a substantial body of evidence that early use of DMARDs (within three months of the onset of symptoms) leads to a better long-term outcome.

DMARDs do not have significant anti-inflammatory action and require 2–3 months before an effect is established. Therefore, they are almost always used initially in combination with a corticosteroid or an NSAID. Methotrexate, given with folic acid supplementation, is the first-choice DMARD. It is usually taken orally, but parenteral use can be considered if gastrointestinal tolerability is a problem. A combination of two DMARDs is now recommended as standard first-line therapy and is more effective than a single drug. Sulfasalazine, leflunomide or hydroxychloroquine are most frequently used in combination with methotrexate. Immunosuppressant drugs such as ciclosporin or azathioprine are generally reserved as third-line agents. Gold and penicillamine are less widely used due to toxicity and, in the case of penicillamine, limited efficacy. If disease activity cannot be suppressed by two DMARDs then a combination of three DMARDs (such as methotrexate, sulfasalazine and hydroxychloroquine) can be tried. Cyclophosphamide is useful for the management of extra-articular manifestations of rheumatoid disease, such as vasculitis, pericarditis or pleurisy.

Intra-articular injections of corticosteroid are used for individual inflamed joints (especially knee and shoulder). Pulsed intramuscular corticosteroid therapy can be given for disease flares, or to ameliorate symptoms in the first few weeks after initiating DMARD therapy (because of the slow response). In early rheumatoid disease a low dose of corticosteroid, given for six months in combination with DMARDs, retards bone destruction and slows disease progression. Intramuscular methylprednisone is often used and is preferred to oral prednisolone, which can be difficult to withdraw (Ch. 44).

Anti-TNFα drugs such as etanercept (the most frequently used biological agents for rheumatoid arthritis) are usually reserved for those who fail to respond to combination therapy with DMARDs, or who are intolerant of several DMARDs. They are typically used in combination with methotrexate, or leflunomide if methotrexate is not tolerated, which produces a better response than the biological agent given alone. The combination produces remission and halts disease progression in up to 60% of people who are treated. If one anti-TNFα drug is ineffective or poorly tolerated, then a different drug from the same class should be tried. Abatacept, tocilizumab and rituximab have been shown to be effective for people with rheumatoid arthritis who fail to respond to, or who cannot tolerate, TNFα blockers. Anakinra is less effective than anti-TNFα drugs and is currently not recommended in the UK.

NSAIDs (Ch. 29) are useful for symptomatic treatment of all types of inflammatory arthritis since they reduce both pain and stiffness. However, they do not affect the long-term course of the disease, and DMARDs have superseded them as the mainstay of treatment of rheumatoid arthritis. There is considerable variation in responses to different NSAIDs, and there is no way of predicting effectiveness in an individual. Propionic acid derivatives, such as ibuprofen, are often used first. They have a weaker anti-inflammatory activity than other classes of NSAID, but generally have fewer unwanted effects. More powerful drugs such as naproxen can be used when ibuprofen fails to control symptoms, although the increased risk of gastrointestinal irritation and cardiovascular events limit their use, especially in the elderly. Morning stiffness is often disabling in inflammatory arthritis. This is helped by giving a late-evening dose of an NSAID with a long half-life, a modified-release formulation of a compound with a short half-life or an NSAID suppository. Topical NSAIDs applied over the affected joint(s) are not usually recommended. Selective cyclo-oxygenase (COX)-2 inhibitors are usually reserved for people who are intolerant of NSAIDs, or who have a higher risk of serious gastrointestinal complications with an NSAID (Ch. 29).

Physical aids such as splinting and bed rest can help acute flares of joint inflammation. There is an increased risk of cardiovascular disease in people with rheumatoid arthritis, and attention to the conventional risk factors for prevention of atherosclerosis is important (Ch. 5).

Management of spondyloarthritides

NSAIDs remain the first-line treatment for this group of disorders, and will relieve pain and improve function. This should be combined with a tailored exercise regimen. Although most evidence for the use of DMARDs has been obtained in the treatment of rheumatoid arthritis, there is limited evidence for their efficacy in the seronegative spondyloarthritides. Sulfasalazine and methotrexate give some benefit for peripheral joint disease in these forms of inflammatory arthritis, but do not improve axial joint inflammation or enthesitis. Anti-TNFα agents can produce remission of disease in ankylosing spondylitis and psoriatic arthritis in about one-third of those treated, with considerable symptomatic benefit in others. Unlike DMARDs, these agents can help most aspects of the disease, with the exception of new bone formation. If treatment with an anti-TNFα agent is stopped after remission is achieved then relapse usually occurs within 6–12 months. The efficacy of biological agents that block other cytokines is unproven, and T- or B-lymphocyte targeted therapies are ineffective.

Osteoarthritis

Osteoarthritis is the clinical manifestation of joint degeneration that results from loss of articular cartilage and becomes more common with increasing age. Most osteoarthritis is idiopathic (when it can be localised or generalised) but a small proportion is secondary to other conditions such as joint injury or chondrocalcinosis. The cardinal symptom of osteoarthritis is pain in the affected joint during physical activity, which is relieved by rest. Pain also occurs at rest with advanced disease. Stiffness may be troublesome for a few minutes after rest. Various small joints can be involved, particularly the distal interphalangeal joints of the fingers and the carpometacarpal joint of the thumb. Large joints such as the knee, hip, elbow and shoulder are often asymmetrically affected.

The integrity of articular cartilage depends on the balance of synthetic and catabolic activity of the chondrocytes embedded in the cartilage matrix. Mechanical compression of cartilage produces many physical and biochemical stimuli that influence chondrocyte metabolism. Mechanical overload, the principal cause of secondary osteoarthritis, produces changes that promote matrix destruction and apoptotic chondrocyte death. Osteoarthritis is caused by an imbalance of cartilage degradation compared to synthesis of cartilage, with loss of the normal cartilage matrix. Synovial inflammation results from release of cartilage debris into the joint accompanied by catabolic mediators and results in joint swelling.

Synthesis of cartilage is promoted by the expression of growth factors by chondrocytes, particularly insulin-like growth factor 1 and transforming growth factor β (TGFβ). Degradation of cartilage proteins is carried out by matrix metalloproteinases (MMPs), particularly stromelysin 1 (MMP-3) in early osteoarthritis and gelatinase A (MMP-2) and MMP-13 in late disease. MMPs are synthesised by chondrocytes in response to stimulation by the pro-inflammatory cytokines IL-1β and TNFα released by inflammatory cells. Synovial inflammation often occurs adjacent to the damaged cartilage. Chondrocytes produce a chemokine, RANTES (regulated upon activation, normal T-cell expressed and secreted), and synovial fluid cells express chemokine receptors including CXC chemokine receptor type 4 (CXCR4), which may have a role in recruiting inflammatory cells to the joint.

Loss of matrix leads to disruption of the cartilage, with swelling and fissuring of the surface. Subchondral bone becomes increasingly vascular and new bone is laid down. It is uncertain whether the initiating factors for osteoarthritis originate in the articular cartilage or subchondral bone. However, recent evidence suggests that stiffening of subchondral bone, with less effective shock absorption, may be the trigger for cartilage loss.

Management of osteoarthritis

Treatment of osteoarthritis currently remains symptomatic. Non-pharmacological therapy such as weight loss, exercise, physical therapy and orthotics is often useful. Glucosamine sulphate or chondroitin sulphate supplements (over-the-counter preparations in the UK) are often used by people with osteoarthritis, but there is conflicting evidence of benefit. If pain is troublesome, simple analgesics such as paracetamol should usually be considered as first-line treatment. NSAIDs may be helpful for inflammatory episodes or if paracetamol is ineffective. In vitro studies suggest that some NSAIDs may accelerate the loss of articular cartilage in osteoarthritis. Clinical studies are inconclusive, but avoidance of powerful NSAIDs is probably desirable. The risks of gastrointestinal and cardiac toxicity may also limit the value of NSAIDs.

Intra-articular or periarticular injection of a corticosteroid (Ch. 44) can provide short-term symptomatic relief in osteoarthritis, even if there is little clinical evidence of joint inflammation. Corticosteroids inhibit pro-inflammatory mediators in synovial tissue, such as IL-1 and TNFα. Joint injection with hyaluronic acid remains a controversial treatment, with conflicting evidence of efficacy from clinical trials.

The recognition that osteoarthritis involves inflammatory flares and that cartilage repair can occur has opened up potential new approaches to management. However, there is no proven disease-modifying therapy currently available for the treatment of osteoarthritis. Long-term management of osteoarthritis may eventually require surgical joint replacement.

Further reading