Fig. 30.1 The biology of rheumatoid arthritis and sites of drug action.
The affected synovial joint is characterised by inflamed and swollen synovium with angiogenesis and increased presence of fibroblasts, osteoclasts, plasma cells, mast cells and B-lymphocytes. The synovial fluid contains increased numbers of neutrophil leucocytes and there is erosion of cartilage and adjacent bone. The cascade of self-perpetuating inflammatory events involves many factors, including upregulation of the ubiquitous nuclear transcription factor NF-κB and generation of cytokines including IL-1, IL-6 and TNFα. Some of the drugs shown act at multiple sites. APCs, antigen-presenting cells; IFN, interferon; IL, interleukin; NF-κB, nuclear factor κB; TLR, Toll-like receptor; TNFα, tumour necrosis factor α.
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).
Sulfasalazine
The action of sulfasalazine in arthritis is poorly understood. It is cleaved in the colon by bacterial enzymes to 5-aminosalicylic acid (which is not believed to contribute to the antirheumatic action) and sulfapyridine. Sulfapyridine in the colon may reduce the absorption of antigens that promote joint inflammation. However, sulfasalazine and sulfapyridine are both absorbed and are found at similar concentrations in synovial fluid. Sulfasalazine can suppress several signal transduction pathways involved in the synthesis of pro-inflammatory cytokines, which may contribute to its efficacy.
High doses of sulfasalazine are required for the treatment of rheumatoid arthritis and these often produce gastrointestinal upset. This can be minimised by increasing the dose slowly and by using an enteric-coated formulation. Other problems include reversible oligospermia (therefore sulfasalazine should be avoided in males who wish to have a family) and blood dyscrasias. Sulfasalazine is discussed more fully in Chapter 34.
Antimalarials
Hydroxychloroquine is weakly basic, which permits its uptake and concentration in a non-ionised form within cells. Having entered the lysosomes inside the cell, the acidic environment traps and concentrates the drug in its ionised state. Macrophages depend on acid proteases in their lysosomes for digestion of phagocytosed protein. Hydroxychloroquine slightly increases the pH inside the macrophage lysosomes, which alters the processing of peptide antigens and reduces their subsequent presentation on the cell surface. Thus, the interaction between T-helper cells and antigen-presenting macrophages responsible for joint inflammation is reduced, with a reduction in the inflammatory response. Hydroxychloroquine also reduces the activation of plasmacytoid dendritic cells by blocking Toll-like receptors on their cell membrane.
Retinal toxicity is a potential problem due to selective binding to photoreceptor cells in the macula and subsequent disruption of lysosomal function. It is rare with recommended doses of hydroxychloroquine, but specialist assessment of the eyes is recommended before treatment and again during treatment if there is a change in visual acuity or blurring of vision or if treatment continues for more than five years. The pharmacokinetics and other unwanted effects of hydroxychloroquine can be found in Chapter 51.
Leflunomide
Leflunomide is an isoxazole derivative that inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme in the de novo synthesis of the pyrimidine ribonucleotide uridine monophosphate (UMP). Activated lymphocytes require an eightfold increase in their pyrimidine pool to proliferate. Inadequate provision of UMP increases the expression of the tumour-suppressor molecule p53 which translocates to the cell nucleus and arrests the cell cycle in the G1 phase. This cytostatic action reduces the expansion of the activated autoimmune T- and B-lymphocyte pool, thereby suppressing immunoglobulin production and cellular immune processes. Other dividing cells can obtain adequate pyrimidines from a separate salvage pathway that reuses existing ribonucleotides and is not affected by leflunomide.
There are other potential mechanisms of immunomodulation by leflunomide, such as inhibition of tyrosine kinases and suppression of transcription factors that stimulate osteoclast formation, but they are probably of lesser importance.
Pharmacokinetics
Leflunomide is a prodrug. It is well absorbed from the gut and is converted non-enzymatically, mainly in the intestinal mucosa and plasma, to its active metabolite. The metabolite is excreted via the bile, and enterohepatic circulation contributes to its very long plasma half-life (15 days).
Prevention and management of unwanted effects
Monitoring of full blood count and liver function should be carried out regularly during treatment. If serious unwanted effects occur, elimination of the drug can be increased by the use of colestyramine (Ch. 48) or activated charcoal to bind the active metabolite present in the gut after biliary excretion, thereby interrupting its enterohepatic circulation (Ch. 2).
Immunosuppressant drugs
Several drugs with immunosuppressant actions have been shown to be effective in rheumatoid arthritis. These include:
Methotrexate is one of the most effective antirheumatic drugs. Although its primary mechanism of action is by folate antagonism, co-administration of folic acid supplements prevents much of the mucosal and gastrointestinal toxicity of the drug but does not reduce its immunomodulatory effect. A possible additional mechanism of action to explain the effect of methotrexate in arthritis is inhibition of the deamination of adenosine, causing its accumulation. Adenosine is an intermediate in purine biosynthesis and a potent anti-inflammatory mediator. It suppresses neutrophil adhesion and cytokine production, reduces macrophage function and impairs the expression of endothelial adhesion molecules. Methotrexate is usually given orally once a week for the treatment of inflammatory arthritis. It can be given intramuscularly if oral use produces intractable gastrointestinal symptoms or if absorption by the oral route is inadequate.
Gold
Mechanism of action
The precise mechanism by which gold compounds act is unknown. A popular concept is that the compound is taken up by mononuclear cells and inhibits their phagocytic function. This will reduce the release of inflammatory mediators and inhibit inflammatory cell proliferation. Production of inflammatory cytokines such as IL-1, IL-6 and TNFα is inhibited, and superoxide generation by neutrophils is reduced. There is also evidence for inhibition of other cell signalling pathways involved in inflammation, including NF-κB.
The advent of more effective and less toxic drugs has reduced the use of gold salts in current clinical practice.
Pharmacokinetics
Sodium aurothiomalate is given by deep intramuscular injection. An initial test dose is given to screen for acute toxicity (see below), followed by injections at weekly intervals to gradually achieve a therapeutic concentration in the tissues. Subsequently, a smaller dose is used to maintain remission. Gold binds readily to albumin and several tissue proteins and accumulates in many tissues such as the liver, kidney, bone marrow, lymph nodes and spleen. Accumulation also occurs in the synovium of inflamed joints. Elimination is largely renal. Gold has a half-life of several weeks, probably as a result of its extensive tissue binding.
Unwanted effects
The unwanted effects can be serious and all but the most minor effects should lead to immediate cessation of treatment:
Prevention and management of unwanted effects
Urine should be checked for protein and a full blood count obtained before each injection of gold, and regularly during oral therapy. Major complications may require treatment with dimercaprol or penicillamine to chelate the gold (Ch. 53) and increase its elimination. Corticosteroids can be helpful to treat blood dyscrasias. Gold should not be used if there is a history of renal or hepatic disease, blood dyscrasias or severe rashes. Gold should be stopped if stomatitis, a pruritic rash, neutropenia, thrombocytopenia or significant proteinuria (>1 g in 24 h) develops.
Penicillamine
The mechanisms of action of penicillamine are uncertain. Modulation of the immune system is believed to be important, including a reduction in the number of activated lymphocytes, reduced synthesis of immunoglobulins and stabilisation of lysosomal membranes in inflammatory cells. Penicillamine has not been shown to slow the progression of joint erosions and is no longer widely used for rheumatoid arthritis.
Penicillamine is a thiol compound that can chelate many metals. This is probably of little relevance to its use in arthritis but has given the drug a role in the management of poisoning (Ch. 53) and in Wilson’s disease, a genetically determined illness that is associated with copper overload.
Pharmacokinetics
Penicillamine is well absorbed from the gut, although oral iron supplements substantially reduce its absorption.
Unwanted effects
Unwanted effects occur frequently and are responsible for cessation of treatment in about 30% of people. They can be reduced by slow increases in dose. Many unwanted effects resemble those of gold:
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