Many leucocytes, including mast cells and macrophages, as well as endothelial cells, synthesise pro-inflammatory eicosanoids and platelet-activating factor (PAF) (Fig. 16.1). These are 20-carbon unsaturated fatty acids derived from phospholipid substrates in the plasma membrane by the enzymes phospholipase A₂, cyclo-oxygenase (COX) and lipo-oxygenase (which are induced by IL-1). The prostaglandins, thromboxanes and leukotrienes have diverse pro-inflammatory roles. Leukotrienes promote the activation and accumulation of leucocytes at sites of inflammation. Prostaglandins induce vasodilatation of the microcirculation and are important in pain signalling from locally inflamed tissue. Platelet-activating factor and thromboxane A₂ affect the coagulation and fibrinolytic cascades. Non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, inhibit COX and hence prostaglandin and thromboxane synthesis. Glucocorticoids act by inducing the synthesis of lipocortin-1, a polypeptide that inhibits phospholipase A₂, and thereby exert a broad anti-inflammatory effect. The leukotriene receptor antagonists montelukast and zafirlukast cause bronchodilatation and are used to treat asthma.

Fig. 16.1 Synthesis of eicosanoids and platelet-activating factor, and drugs acting on this pathway. The enzymes phospholipase A₂, cyclo-oxygenase and lipo-oxygenase are involved in the synthesis of prostaglandins, thromboxanes, leukotrienes and platelet-activating factor, all of which are derived from phospholipid substrates in plasma membranes. Glucocorticoids induce lipocortin 1, which inhibits phospholipase A_2. NSAIDs inhibit cyclo-oxygenases 1 and 2, preventing formation of prostaglandins and thromboxanes.

The adaptive immune response

The adaptive immune response, although integrated into the process of inflammation, becomes active at later stages. Its key properties are (1) specificity: each B and T lymphocyte recognises a single specific peptide sequence; and (2) memory: when an invading pathogen has been recognised once, a small number of specific cells remain dormant within the lymph tissue for many years. If that pathogen is detected again, a very rapid response is mounted to eradicate it before the development of clinical symptoms.

An adaptive immune response is initiated when a helper T cell recognises a peptide antigen presented on the surface of an antigen-presenting cell (APC) and is activated (Fig. 16.2). The activated helper T cell is then able to activate other types of T cell and B cells. This results in the proliferation of adaptive cellular effectors, the generation and release of antibodies by plasma cells and the production of a range of cytokines by the participating leucocytes. On occasion, amplification loops may become self-perpetuating, leading to chronic autoimmune disease.

Fig. 16.2 Three general mechanisms of action of glucocorticoids and the glucocorticoid receptor in the inhibition of inflammation. TNFα, tumour necrosis factor α; HSP, heat-shock protein; mRNA, messenger RNA; P, phosphate. The three mechanisms are non-genomic activation, DNA-dependent regulation, and protein interference mechanisms (e.g. NF-KB elements). Black arrows denote activation, the red line inhibition, the red dashed arrow repression, and the red X lack of product (i.e. no mRNA).

Many immunomodulatory drugs, such as the calcineurin inhibitors, seek to break these loops by inhibiting lymphocyte proliferation. Other newer approaches target specific components of the immune system. For example, rituximab binds CD20, a cell surface molecule found only on B lymphocytes and not memory cells. It is used to treat diseases in which pathogenic autoantibody production is prominent, such as rheumatoid arthritis and SLE. Abatacept blocks co-stimulatory signals, which are required when a helper T cell is activated, by recognising bound antigen presented by an APC. This is a central process in the pathogenesis of rheumatoid arthritis, and abatacept is licensed to treat this.

Pharmacological manipulation of inflammatory mediators

Glucocorticoids

Glucocorticoids (GCs) are among the most widely prescribed anti-inflammatory drugs, due to their profound efficacy, long history of use and familiarity. Besides their anti-inflammatory actions they exert effects on carbohydrate, protein and lipid metabolism, some of which contribute to their substantial adverse effect profile.

GCs are used in acute and chronic settings to treat inflammatory conditions ranging from asthma and allergy, to prevention of allograft rejection, to rheumatoid arthritis and systemic vasculitis. Because of their rapid onset of action (less than 24 h) and potency, they remain the preferred acute treatment for severe inflammatory disease in a wide variety of settings despite their adverse effects. In chronic disease the aim now is to minimise cumulative exposure by using other immunomodulatory ‘steroid-sparing’ drugs, and proactively to manage potential long-term side-effects such as osteoporosis.

Mode of action

GCs, being lipophilic, diffuse across the cell membrane and bind the cytosolic glucocorticoid receptor (GR) (Fig. 16.3). Receptor polymorphisms influence the strength of the receptor interaction, and represent one source of variation in sensitivity to exogenous steroids. Once bound, the GC-GR complex translocates to the nucleus where it acts in at least two ways to alter gene transcription:

1. The GC-GR complex binds to the glucocorticoid response element within target gene promoters, increasing transcription of various anti-inflammatory genes. These include I-κB, which inhibits the activation of nuclear factor (NF)-κB, and the cytokines IL-4, IL-10, IL-13 and transforming growth factor (TGF)β, which have immunosuppressive and anti-inflammatory activity.

2. The GC-GR complex interferes with the binding of the transcription factors activating protein (AP)-1 and NF-κB to their response elements. This action decreases the transcription of a range of pro-inflammatory mediators. These include IL-1β and TNFα; IL-2, which stimulates T-cell proliferation; a range of chemokines and cellular adhesion molecules; metalloproteinases; COX-2; and inducible nitric oxide synthase.

3. GCs increase synthesis of the polypeptide lipocortin-1, which inhibits phospholipase A₂ and thereby the synthesis of prostaglandins, thromboxane A₂ and PAF (see Fig. 16.1).

Fig. 16.3 Mechanisms of glucocorticoid anti-inflammatory effects. Glucocorticoids exert pleiotropic effects on cellular metabolism. They increase transcription of a number of genes encoding anti-inflammatory proteins and decrease transcription of pro-inflammatory genes. AP-1, activating protein-1; COX, cyclo-oxygenase; GR, glucocorticoid receptor; GRE, glucocorticoid response element; IL, interleukin; iNOS, inducible nitric oxide synthase; NF, nuclear factor; TGF, transforming growth factor.

At the cellular level, GCs reduce the numbers of circulating lymphocytes, eosinophils and monocytes. This is maximal 4–6 hours after administration and is achieved by a combination of apoptosis induction and inhibition of proliferation. Chronic administration of GC is associated with a neutrophilia caused by release of neutrophils from the bone marrow and reduced adherence to vascular walls.

In inflammatory disease, the choice of GC preparation will reflect the site and the extent of inflamed tissue, e.g. oral or parenteral for systemic disease, inhaled in asthma, topical in cutaneous, ocular, oral or rectal disease. Different corticosteroid preparations, their pharmacokinetics, modes of delivery and adverse effects are discussed elsewhere, except for the management of steroid-induced osteoporosis, which is found in the section on management of rheumatoid arthritis at the end of this chapter.

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are an extremely widely prescribed group of drugs that are mainly used for their analgesic effects. They possess a single common mode of action: inhibition of cyclo-oxygenase, thereby reducing prostaglandin synthesis. This is also the mode of action of paracetamol (acetaminophen) and aspirin.

Recently concern has arisen over the effect of traditional NSAIDs and COX-2 inhibitors on the cardiovascular system, with analysis of the VIGOR ¹ study showing that rofecoxib in particular increases the risk of myocardial infarction (rofecoxib has since been withdrawn from use). While they retain an important role in the treatment of acute gout, inflammatory arthritis, ankylosing spondylitis and dysmenorrhea, long-term prescription should only be undertaken following a full discussion with the patient regarding the balance of risks and benefits.

Mode of action

NSAIDs inhibit cyclo-oxygenase (COX), which catalyses the synthesis of prostaglandins and thromboxane from arachidonic acid (see Fig. 16.1). There are two isoforms of COX:

• COX-1 is constitutively² expressed in most cell types.

• COX-2 is induced when inflammatory cells (fibroblasts, endothelial cells and macrophages) are activated by cytokines such as IL-1β and TNFα. It is also often upregulated in cancer cells, and is constitutively expressed in the kidney and brain.

Both isoforms generate prostaglandins during an inflammatory response, while COX-1 activity is required for prostaglandin synthesis for tissue homeostasis. Thus, many NSAID adverse effects are due to reductions in beneficial prostaglandin production, for example in the gastric mucosa (PGI₂ and PGE₂) and renal medulla. Recognition of this led to the development of COX-2 selective drugs.

NSAIDs can be categorised according to their COX specificity as:

• COX-2-selective compounds (coxibs), which inhibit COX-2 with at least five times greater potency than COX-1. The group includes celecoxib, etoricoxib, lumiracoxib, meloxicam and etodolac.

• Non-COX-2-selective compounds, which comprise all other NSAIDs. These drugs inhibit COX-1 as well as COX-2.

Pharmacokinetics

NSAIDs are absorbed almost completely from the gastrointestinal tract, tend not to undergo first-pass elimination (see p. 87), are highly protein bound and have small volumes of distribution. Their t_½ values in plasma tend to group into short (1–5 h) or long (10–60 h). Differences in t_½ are not necessarily reflected proportionately in duration of effect, as peak and trough drug concentrations at their intended site of action following steady-state dosing are much less than those in plasma. The vast majority of NSAIDs are weak organic acids and localise preferentially in the synovial tissue of inflamed joints (see pH partition hypothesis, p. 80).

Uses

Adverse effects

Gastrointestinal

Dyspepsia is one of the commonest side-effects of NSAIDs. The propensity to gastrointestinal (GI) ulceration may result in occult or overt blood loss. Use of NSAIDs is associated with an approximately four-fold increased incidence of severe gastrointestinal haemorrhage, and such complications account for between 700 and 2000 deaths in the UK each year. In addition, ulceration and stricture of the small intestine can result in anaemia, diarrhoea and malabsorption, similar to Crohn’s disease. The risk of NSAID-induced GI haemorrhage is associated with high doses and prolonged use, age over 65 years, previous history of peptic ulceration, concomitant use of glucocorticoids, anticoagulants or other NSAIDs, heavy smoking and alcohol use, and the presence of Helicobacter pylori infection.

NSAID-associated gastrointestinal disease appears to result from the inhibition of COX–1-mediated production of cytoprotective mucosal prostaglandins, especially PGI₂ and PGE₂, which inhibit acid secretion in the stomach, promote mucus production and enhance mucosal perfusion. Several large randomised controlled trials have investigated the incidence of gastrointestinal adverse effects in traditional NSAIDs compared with coxibs. The VIGOR (rofecoxib versus naproxen), CLASS ³ (celecoxib versus ibuprofen and diclofenac) and TARGET⁴ (lumiracoxib versus ibuprofen and naproxen) studies all indicate that coxib use leads to an approximately 50% reduction of upper gastrointestinal adverse events.

The gastrointestinal toxicity of traditional NSAIDs may be reduced by co-prescription of a proton pump inhibitor, e.g. omeprazole, an H₂-receptor blocker, e.g. ranitidine, or the prostaglandin analogue misoprostol. Proton pump inhibitors are more effective than the other classes of gastroprotective agent and should be considered in all patients with at least one of the above risk factors. In fact, it is now recommended by the UK National Institute for Health and Clinical Effectiveness (NICE) that all patients over 45 years prescribed an NSAID, whether COX-2 selective or not, also receive a proton pump inhibitor.

Cardiovascular

The VIGOR and APPROVE ⁵ trials reported increased thrombotic cardiovascular events in patients treated with rofecoxib, leading to concerns about a class effect of the coxibs. It was suggested that COX-2 selectivity resulted in an imbalance between prostacyclin and thromboxane production, an effect which would not be seen with traditional NSAIDs which inhibited the synthesis of both equally. Subsequent data from the prospective MEDAL⁶ and TARGET trials have not supported a class effect based on COX-2 selectivity. These studies suggest that treatment with either a coxib or an NSAID results in a small increase in cardiovascular risk. The risk is dose-related and rofecoxib, particularly at doses exceeding 50 mg per day, confers the highest cardiovascular risk in the majority of studies. A recent study of more than 1 million patients quantified cardiovascular risk as a composite of coronary death, non-fatal myocardial infarction and fatal and non-fatal stroke, and reported that diclofenac and rofecoxib were associated with the highest cardiovascular risk, while naproxen and perhaps celecoxib at doses ≤ 200 mg per day were the least likely to cause a cardiovascular event.⁷ NICE guidelines recommend that patients with pro-thrombotic risk, coronary artery or cerebrovascular disease should not be prescribed NSAIDs or a coxib. For other patients, treatment decisions should be made on an individual patient basis taking into account both cardiovascular and gastrointestinal risk factors. The medication should be prescribed for the shortest possible time and regularly reviewed.

Renal

NSAIDs decrease renal perfusion in individuals with congestive cardiac failure, chronic renal disease and cirrhosis with ascites: states in which renal perfusion is dependent upon prostaglandin-mediated vasodilatation. NSAIDs may also promote sodium and water retention, causing oedema and hypertension in some individuals. Papillary necrosis and interstitial nephritis are rare complications, often in the context of chronic and excessive NSAID use.

Worsening of asthma

NSAID intolerance in asthmatics probably reflects diversion of arachidonic acid metabolism towards excessive products of the lipo-oxygenase pathway. It is not immune-mediated but clinically may resemble hypersensitivity, with manifestations including vasomotor rhinitis, urticaria, bronchoconstriction, flushing, hypotension and shock.

Other unwanted effects

include headache, confusion, photosensitivity, erythema multiforme, toxic epidermal necrolysis, deranged liver function, cytopenias, haemolytic anaemia and inhibition of ovulation.

Principal interactions

NSAID interactions include:

• Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers: there is a risk of renal impairment and hyperkalaemia.

• Quinolone antimicrobials: convulsions may occur if NSAIDs are co-administered.

• Anticoagulant (warfarin) and antiplatelet agents (dypiridamole, clopidogrel): increased risk of gastrointestinal bleeding with NSAIDs.

• Antihypertensives: their effect is lessened due to sodium retention by inhibition of renal prostaglandin formation.

• Ciclosporin and tacrolimus: nephrotoxic effect is exacerbated by NSAIDs.

• Cytotoxics: renal tubular excretion of methotrexate is reduced by competition with NSAIDs, with risk of methotrexate toxicity (low-dose methotrexate given weekly avoids this hazard).

• Diuretics: NSAIDs cause sodium retention and reduce diuretic efficacy and there is a risk of hyperkalaemia with potassium-sparing diuretics.

• Lithium: NSAIDs delay the excretion of lithium by the kidney and may cause lithium toxicity.

Paracetamol (acetaminophen)

Mode of action and uses

Paracetamol is an effective treatment for mild-moderate pain and for relieving fever. It does not affect platelet function or disrupt the GI mucosal barrier. Paracetamol has analgesic efficacy equivalent to aspirin, but in therapeutic doses it has only weak anti-inflammatory effects, a functional separation that reflects its differential inhibition of enzymes responsible for prostaglandin synthesis.⁸ For this reason, some would not class paracetamol as an NSAID.

Pharmacokinetics

Paracetamol (t_½ 2 h) is well absorbed from the GI tract. It is inactivated in the liver, principally by conjugation as glucuronide and sulphate. Minor metabolites of paracetamol are also formed, of which one oxidation product, N-acetyl-p-benzoquinone imine (NAPQI), is highly reactive chemically. This substance is normally rendered harmless by conjugation with glutathione. The supply of hepatic glutathione is limited and, if the amount of NAPQI formed is greater than the amount of glutathione available, the excess metabolite oxidises thiol (SH-) groups on key enzymes, causing cell death. This is the mechanism of hepatic necrosis in paracetamol overdose.

Dose

The oral dose is 0.5–1 g every 4–6 h; maximum daily dose 4 g.

Adverse effects

Paracetamol is usually well tolerated. Allergic reactions and rash sometimes occur. Maximal, long-term, daily dosing may predispose to chronic renal disease.

Acute overdose

Severe hepatocellular damage and renal tubular necrosis can result from taking 150 mg/kg body-weight (about 10 or 20 tablets) in one dose.⁹ Patients at particular risk include:

• Those whose enzymes are induced as a result of taking drugs or alcohol; their liver and kidneys form more NAPQI.

• Those who are malnourished (chronic alcohol abuse, eating disorders, HIV infection) to the extent that the liver and kidneys are depleted of glutathione to conjugate with NAPQI.

Clinical signs of hepatic damage (jaundice, abdominal pain, hepatic tenderness) and increased liver enzymes do not become apparent for 24–48 h after the overdose. Hepatic failure may ensue 2–7 days later; and is best monitored using prothrombin time.

The plasma concentration of paracetamol is of predictive value; if it lies above a semi-logarithmic graph joining points between 200 mg/L (1.32 mmol/L) at 4 h after ingestion to 50 mg/L (0.33 mmol/L) at 12 h, then serious hepatic damage is likely (plasma concentrations measured earlier than 4 h are unreliable because of incomplete absorption). Patients who are malnourished are regarded as being at risk at 50% of these plasma concentrations.

The general principles for limiting drug absorption apply if the patient is seen within 4 h. Activated charcoal by mouth is effective and should be considered if paracetamol in excess of 150 mg/kg body-weight or 12 g, whichever is the smaller, is thought to have been ingested within the previous hour. The decision to use activated charcoal must take into account its capacity to bind the oral antidote methionine.

Specific therapy involves replenishing stores of liver glutathione, which conjugates NAPQI and so diminishes the amount available to do harm. Glutathione itself cannot be used as it penetrates cells poorly, but N-acetylcysteine (NAC) and methionine are effective as they are precursors for the synthesis of glutathione. NAC is administered intravenously – an advantage if the patient is vomiting. The regimen is: 150 mg/kg in 200 mL 5% dextrose over 15 min; then 50 mg/kg in 500 mL 5% dextrose over 4 h; then 100 mg/kg in 1000 mL 5% dextrose over 16 h. While it is most effective if administered within 8 h of the overdose, evidence shows that continuing treatment for up to 72 h still provides benefit. Methionine alone may be used to initiate treatment when facilities for infusing NAC are not immediately available. The earlier such therapy is instituted the better, and it should be started if:

• a patient is estimated to have taken more than 150 mg/kg body-weight, without waiting for the measurement of the plasma concentration

• plasma concentration indicates the likelihood of liver damage (above), or

• there is uncertainty about the amount taken, or its timing.

Aspirin (acetylsalicylic acid)

In the 18th century, the Reverend Edmund Stone wrote about the value of an extract of bark from the willow tree (of the family Salix) for alleviating pain and fever. The active ingredient was salicin, which is metabolised to salicylic acid in vivo. Sodium salicylate manufactured from salicin proved highly successful in the treatment of rheumatic fever and gout, but it was a gastric irritant. In 1897, Felix Hoffman, a chemist at the Bayer Company, whose father developed abdominal pain with sodium salicylate, succeeded in producing acetylsalicylic acid in a form that was chemically stable. The new preparation proved acceptable to his father and paved the way for the production of aspirin.

Mode of action

The anti-inflammatory, analgesic and antipyretic actions of aspirin are those of NSAIDs in general (see above). The following additional actions are relevant:

• An antiplatelet effect due to permanent inactivation, by acetylation, of COX-1 in platelets, preventing synthesis of thromboxane A₂. Platelets cannot regenerate the enzyme and the resumption of thromboxane A₂ production is dependent on the entry of new platelets into the circulation (platelet lifespan is 7 days). Thus a continuous antiplatelet effect is achieved with low doses.

• Respiratory stimulation is a characteristic of aspirin intoxication and occurs both directly by stimulation of the respiratory centre and indirectly through increased carbon dioxide production.

• Although aspirin in high dose reduces renal tubular reabsorption of uric acid so increasing its elimination, other treatments for hyperuricaemia are preferred. Indeed aspirin should be avoided in gout as low doses inhibit uric acid secretion and on balance its effects on uric acid elimination are adverse.

Uses

The main use of aspirin is as an antiplatelet agent to prevent arterial thrombotic events due to atherosclerosis. It has largely been overtaken by NSAIDs and paracetamol as an analgesic. In high doses it is used to treat inflammation in Kawasaki disease, in combination with intravenous immunoglobulin, but in other inflammatory illnesses it has now been superseded by other, more effective agents with fewer side-effects.

Pharmacokinetics

Aspirin (t_½ 15 min) is well absorbed from the stomach and upper GI tract. Hydrolysis removes the acetyl group, and the resulting salicylate ion is inactivated largely by conjugation with glycine. At low doses this reaction proceeds by first-order kinetics with a t_½ of about 4 h, but at high doses and in overdose the process becomes saturated, i.e. kinetics become zero order, and most of the drug in the body is present as the salicylate. The challenge in overdose is to remove salicylate.

Dose

Doses of 75–150 mg/day are used to prevent thrombotic vascular occlusion; 300 mg as immediate treatment for myocardial infarction; 300–900 mg every 4–6 h for analgesia.

Adverse effects

Gastrointestinal effects are those of NSAIDs in general. Effects particularly associated with aspirin are:

• Salicylism (the symptoms of an excessive dose): tinnitus and hearing difficulty, dizziness, headache and confusion.

• Allergy. Aspirin is a common cause of allergic or pseudoallergic symptoms and signs. Patients exhibit severe rhinitis, urticaria, angioedema, asthma or shock. Those who already suffer from recurrent urticaria, nasal polyps or asthma are more susceptible.

• Reye’s syndrome. Epidemiological evidence relates aspirin use to the development of the rare Reye’s syndrome (encephalopathy, liver injury) in children recovering from febrile viral infections. Consequently, aspirin should not be given to children aged under 15 years.

Acute overdose

A moderate overdose (plasma salicylate 500–750 mg/L) will cause nausea, vomiting, epigastric discomfort, tinnitus, deafness, sweating, pyrexia, restlessness, tachypnoea and hypokalaemia. A large overdose (plasma salicylate concentration above 750 mg/L) may result in pulmonary oedema, convulsions and coma, with severe dehydration and ketosis. Bleeding is unusual, despite the antiplatelet effect of aspirin.

Adults who have taken a single large quantity usually develop a respiratory alkalosis. Metabolic acidosis suggests severe poisoning but a mixed picture is commonly seen. In children under 4 years, severe metabolic acidosis is more likely than respiratory alkalosis, especially if the drug has been ingested over many hours (e.g. mistaken for sweets).

Serial measurements of plasma salicylate are necessary to monitor the course of the overdose, for the concentration may rise in the early hours after ingestion. The general management of overdose applies, but the following are relevant for salicylate overdose:

• Activated charcoal 50 g by mouth prevents salicylate absorption from the GI tract. Gastric lavage or the use of an emetic is no longer recommended.

• Correction of dehydration, using dextrose 5% i.v. is often indicated.

• Acid–base disturbance. Alkalosis or mixed alkalosis/acidosis need no specific treatment. Metabolic acidosis is treated with sodium bicarbonate, which alkalinises the urine and accelerates the removal of salicylate in the urine.

• Haemodialysis may be necessary if renal failure develops or the plasma salicylate concentration exceeds 900 mg/L.

Colchicine

Colchicine is derived from the autumn crocus (Colchicum autumnale). Its anti-inflammatory properties have long been recognised: Alexander of Tralles recommended colchicum for gout in the 6th century AD. Nowadays, in addition to relieving inflammation in acute gout attacks, it is used to treat other inflammatory disorders including Behçet’s syndrome and the hereditary fever syndrome familial Mediterranean fever. The precise way in which colchicine reduces inflammation is not completely understood but relates to its effects on neutrophils (which play a prominent role in the pathology of these conditions). It inhibits the assembly of microtubules, thus interfering with mitotic spindle formation and arresting cell division as well as inhibiting cell migration.

The most common adverse effect of colchicine is diarrhoea, due to its effects on rapidly proliferating gastrointestinal epithelial cells. If this is ignored, severe neutropenia may follow and it is therefore a sign to stop the drug and restart at a lower dose. Agranulocytosis and aplastic anaemia may complicate chronic use.

Immunomodulatory drugs

Immunomodulatory drugs are used both to control symptoms and to retard or arrest the progression of chronic inflammatory diseases. They act to inhibit inflammation in a variety of ways, and reduce the proliferation and activation of lymphocytes.

The terminology surrounding immunomodulatory drugs has evolved separately in different specialties, although the underlying management principles are similar. Rheumatologists use the term ‘disease-modifying anti-rheumatic drugs’ (DMARDs) to describe those agents that reduce inflammatory disease activity and prevent radiologically determined disease progression in illnesses such as rheumatoid or psoriatic arthritis. Treatment regimens for systemic vasculitis or severe organ involvement in the connective tissue diseases make use of terminology drawn from oncology, with ‘remission induction’ followed by ‘maintenance’ phases. Many of these drugs are described as ‘steroid-sparing’ as their concomitant use with glucocorticoids substantially reduces the total cumulative dose of steroid required for disease suppression. Many can be used in combination: with steroids, with each other or with biologic agents. This is discussed in the section on specific disease management at the end of the chapter.

The choice and combination of immunomodulatory agent in an individual patient depends on the following considerations:

• Severity of disease: this determines the risk:benefit ratio. For example, cerebral or renal lupus is more hazardous than rash or arthritis and therefore a more potent but potentially more toxic drug regimen is justified.

• Adverse-effect profile: both the probability and severity of potential adverse effects need to be considered.

• Evidence base: this, disappointingly, is often patchy but where it exists affords greater confidence for the prescribing physician.

• Age: the risk of future malignancy is less significant in elderly patients.

• Co-morbidity: drugs causing hypertension or adverse lipid profiles may be avoided in patients with high cardiovascular risk.

• Pregnancy/breast feeding: an absolute contraindication for many immunomodulatory drugs.

• Importance of future fertility: cyclophosphamide is likely to decrease fertility; leflunomide requires a long washout period prior to pregnancy.

Most conventional immunomodulatory agents act by inhibiting activation or reducing proliferation of lymphocytes. Many have more than one mechanism of action and often the precise way in which they exert their effects is unknown. Moreover, their antiproliferative and cytotoxic effects are in most cases not specific to the immune system but will affect any rapidly dividing cell population. This is one of the major causes of toxicity. Figure 16.4 presents an overview of these drugs and the known mechanisms of action that are relevant to the following discussion.

Fig. 16.4 Overview of action of immunomodulatory drugs. Many conventional immunomodulatory drugs used in rheumatology practice are anti-metabolites, inhibiting de novo synthesis of purines or pyrimidines; pathways upon which activated lymphocytes are particularly dependent. The mechanisms of action of sulfasalazine, hydroxychloroquine and thalidomide appear to involve inhibition of expression of pro-inflammatory cytokines. The calcineurin inhibitors and sirolimus interfere with either the expression of IL-2 or signalling downstream of the IL-2 receptor; these effects target activated T cells. Cyclophosphamide is a cytotoxic agent that indiscriminately targets proliferating cells. Several biological agents block specific pro-inflammatory cytokines. Agents in current use include those targeting TNFα, IL-1 and IL-6.

Methotrexate, azathioprine, mycophenolate mofetil and leflunomide are antimetabolites, interfering with the de novo synthesis of purines and pyrimidines, on which proliferating (but not resting) lymphocytes depend. Methotrexate is thought to have additional anti-inflammatory effects. The calcineurin antagonists (ciclosporin and tacrolimus) and sirolimus selectively inhibit T-cell activation and proliferation, by inhibiting cytokine expression and cytokine-driven proliferation, respectively. Cyclophosphamide is an alkylating agent that is cytotoxic in dividing cells and, in an autoimmune response, is particularly toxic to rapidly proliferating lymphocytes. Intravenous immunoglobulin has immunomodulatory effects through interference with Fcγ receptor signalling, among other mechanisms. The precise mechanisms of action of sulfasalazine, hydroxychloroquine, thalidomide, dapsone and gold are less clear, but they have been shown to influence the expression of a range of pro-inflammatory cytokines.

Immunomodulatory drugs have well recognised and occasionally very serious toxic side-effects but these only occur in a proportion of patients and/or are reversible on cessation of drug. They also often have less impact on quality of life than the inevitable effects of chronic high-dose glucocorticoid.

The complexity of prescribing and monitoring of toxicity with most immunomodulatory drugs demands collaboration between specialists, general practitioners and a well informed patient. All should only be initiated under specialist supervision and all call for close monitoring, for example of bone marrow, liver, kidney or other organs, as known toxicity dictates. Live vaccines in general should not be given to immunosuppressed patients as there is a risk of disseminated infection.

Methotrexate

Methotrexate was first developed as an anticancer drug 50 years ago. Studies in the 1980s demonstrated its efficacy in rheumatoid arthritis and it is now the principal DMARD used in this disease. It is also used to treat many other chronic inflammatory illnesses, particularly psoriatic arthritis, and in the maintenance phase of therapy for systemic vasculitis.

Mechanism of action

As a folate analogue, methotrexate inhibits folate-dependent enzymes involved in purine biosynthesis, thus reducing lymphocyte proliferation, and this was originally thought to be its principal mechanism of action (and is likely to be the source of many of its toxic effects). In recent years, however, it has become clear that methotrexate has a number of other anti-inflammatory effects, and inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, another folate-dependent enzyme, is now thought to be the likely pathway responsible for its efficacy in chronic inflammatory conditions.¹⁰ This results in a rise in intracellular levels of AICAR, which then inhibits adenosine deaminase and prevents the degradation of adenosine. Increased plasma concentrations of adenosine are thought to mediate many anti-inflammatory effects such as decreased TNFα and IFNγ production.

Prescription

Methotrexate is usually prescribed orally, starting at 7.5–10 mg once weekly and increasing as bone marrow and liver function allows, up to 25 mg. Parenteral administration is also possible, but is principally used in paediatric practice. Folic acid is usually prescribed (variably 5 mg weekly, three times weekly or on all days apart from on the methotrexate dosing day), in order to mitigate the adverse effects. This appears to have little effect on the blockade of de novo purine synthesis, unlike folinic acid (tetrahydrofolic acid).

Adverse effects

The most serious adverse effects of methotrexate are bone marrow toxicity, hepatic toxicity and pneumonitis; regular (at least monthly) monitoring of full blood count and liver function testing are recommended and a baseline chest X-ray is performed prior to first prescription. Methotrexate is also embryotoxic (see below). Mouth ulcers and nausea occur commonly but may be improved by co-prescription of folic acid.

Interactions

Methotrexate used with trimethoprim, co-trimoxazole or sulphonamides creates a risk of megaloblastic anaemia and pancytopenia due to the additive antifolate effect. Folinic acid rescue may be effective should this occur.

Contraindications

Methotrexate should not be prescribed to patients with moderate to severe renal impairment, liver disease or an active infection. Because of its teratogenicity it must not be prescribed for women who are or may become pregnant or who are breast feeding. Both men and women should be counselled to use effective contraception while taking methotrexate and for 6 months afterwards.

Azathioprine

Azathioprine is another antimetabolite which acts by inhibiting purine biosynthesis, thus preferentially acting on proliferating lymphocytes. Besides its use to prevent rejection in organ transplant recipients, it has a well established role as a disease-modifiying or steroid-sparing agent in the maintenance phase of treatment of chronic inflammatory diseases, such as SLE, ANCA-associated and large vessel vasculitis, and interstitial lung disease.

Mechanism of action

Azathioprine undergoes reduction in the presence of glutathione to 6-mercaptopurine and then to 6-thioguanine. This forms a false purine nucleotide that is then incorporated into DNA, thus inhibiting DNA replication and cell proliferation. It may also trigger apoptosis. These actions result in a reduction in circulating B and T lymphocytes, reduced IL-2 secretion and reduced IgM and IgG synthesis.

Azathioprine and 6-mercaptopurine are metabolised predominantly by methylation and oxidation in the liver and/or erythrocytes, via thiopurine methyltransferase (TPMT).

Prescription

Azathioprine is taken orally, starting at 25–50 mg and rising over the course of several weeks to a daily dose of 1.5–2.5 mg/kg. Polymorphisms in the gene encoding TPMT are associated with variable catabolism and hence toxicity and in most centres erythrocyte TPMT activity is assessed prior to its prescription, to guide use, dose and escalation.

Adverse effects

The major serious reactions are bone marrow suppression resulting in leucopenia, anaemia and thrombocytopenia; hepatotoxicity; increased susceptibility to infection; and in the long term an increased risk of neoplasia. As with methotrexate, regular monitoring of full blood count and liver function is mandatory. Other side-effects include nausea, alopecia and, rarely, allergy.

Interactions

Xanthine oxidase, the enzyme inhibited by allopurinol and febuxostat to therapeutic effect in the management of gout, is involved in the catabolism of azathioprine. Concomitant use of xanthine oxidase inhibitors and azathioprine may result in profound myelosuppression and should be avoided. If the combination is unavoidable, azathioprine must be decreased to 25–33% of the usual dose. Sulfasalazine and NSAIDs inhibit TPMT and thereby the metabolism of azathioprine, also increasing the risk of myelotoxicity. Lastly, co-prescription of angiotensin-converting enzyme inhibitors and azathioprine increases the risk of myelosuppression; the mechanism is incompletely understood but has assumed greater importance with the recent appreciation that patients with SLE and other chronic inflammatory disorders have an increased risk of cardiovascular disease and are thus more likely to be prescribed both.

Contraindications

Experience with azathioprine in pregnant women with renal transplants indicates that it is relatively safe, probably because the fetus cannot metabolise 6-mercaptopurine. Although a teratogenic metabolite is present in breast milk, its concentration is low and no evidence for harm exists; nevertheless, breast feeding while taking azathioprine is best regarded as unsafe.

Mycophenolate mofetil

Mycophenolate mofetil (MMF) is also an antimetabolite that inhibits purine synthesis. It is licensed for the prophylaxis of acute rejection following organ transplantation and is also used (unlicensed in the UK) as a treatment for SLE nephritis, other connective tissue diseases with severe major organ involvement and systemic vasculitis.

Mechanism of action

MMF is metabolised to mycophenolic acid, which inhibits inosine monophosphate dehydrogenase, an enzyme in the guanine nucleotide synthesis pathway used by lymphocytes. As other cells have salvage pathways, MMF selectively inhibits lymphocyte proliferation.

Adverse effects

Leflunomide

The active metabolite of leflunomide (A77 1726) inhibits dihydro-orotate dehydrogenase, a mitochondrial enzyme required for the synthesis of pyrimidines.¹¹ It arrests the proliferation of activated lymphocytes and is licensed for the treatment of rheumatoid arthritis and psoriatic arthritis.

Adverse effects

Diarrhoea is commonest; other gastrointestinal disturbances, hepatitis, leucopenia, alopecia, hypertension and allergy also occur. In the event of a serious adverse event, the elimination of leflunomide can be accelerated by colestyramine (8 g three times daily).

Contraindications

Leflunomide is contraindicated in liver disease, severe hypoproteinaemia, immunodeficiency, pregnancy, breast feeding or if there is a possibility of future pregnancy. A gap of at least 2 years is recommended between cessation of leflunomide treatment and conception.

Calcineurin inhibitors

The calcineurin inhibitors ciclosporin and tacrolimus inhibit cytokine-driven activation and proliferation of activated T cells by interfering with synthesis of IL-2. Both bind cytosol receptors called immunophilins (ciclophilin and FKBP-12 respectively) and form complexes that inhibit IL-2 production via the calcineurin pathway. They are used orally to prevent rejection after solid organ transplantation and in chronic inflammatory disorders including cutaneous psoriasis, Behçet’s syndrome, systemic vasculitis and, occasionally, rheumatoid arthritis. However, other preparations are also becoming accepted: topical tacrolimus is used in cutaneous SLE and severe atopic dermatitis.

Adverse effects

The use of ciclosporin has in recent years been curtailed a little by the substantial incidence of hypertension and nephrotoxicity associated with long-term use, and the development of more effective, less toxic competitors. Both ciclospoin and tacrolimus can cause myelosuppression and hepatotoxicity and regular blood monitoring is required; gastrointestinal problems are also common, particularly diarrhoea with tacrolimus.

Sirolimus

Sirolimus (rapamycin) is a macrolide antibiotic, structurally very similar to tacrolimus, that is licensed for use in preventing rejection after solid organ transplantation, and is occasionally used (unlicensed) to treat autoimmune inflammatory disorders such as SLE and Behçet’s syndrome. Sirolimus-coated stents are also commonly used in percutaneous coronary artery intervention, as the presence of sirolimus reduces neo-intimal proliferation. It acts by binding FKBP-12, like tacrolimus, but the complex in this case has no effect on the calcineurin pathway and instead binds to and inhibits activation of mTOR (mammalian target of rapamycin), an important signalling kinase. This in turn suppresses cytokine-driven T-cell and B-cell proliferation and antibody production. Adverse effects are similar to those of tacrolimus.

Cyclophosphamide

Cyclophosphamide, an alkylating cytotoxic agent, damages DNA by forming cross-links which trigger apoptosis in dividing cells. In autoimmunity it is particularly toxic to rapidly proliferating lymphocytes and has also been used as a cancer chemotherapy drug. It is used to induce remission in severe inflammatory conditions with life-threatening organ involvement such as SLE nephritis, ANCA-associated vasculitis causing nephritis or pulmonary haemorrhage, or rapidly progressive interstitial lung disease.

Prescription and adverse effects

In rheumatological practice, cyclophosphamide is most commonly given as an intravenous pulse, repeated at 3–4 week intervals, for six pulses. Oral cyclophosphamide is less frequently used due to the larger cumulative dose and thus increased risk of long-term toxicities. A serious consequence is haemorrhagic cystitis, due to the action of acrolein (a drug metabolite) on the urinary tract epithelium. This is minimised by intravenous pre-hydration and oral administration of 2-mercaptoethane sulphonate (mesna), which reacts with and inactivates acrolein. Other adverse effects are highly significant and include bone marrow toxicity and consequent increased risk of opportunistic infection, infertility, teratogenicity, severe nausea and increased incidence of malignancy, especially of the bladder. In male patients, sperm may be stored prior to cyclophosphamide treatment.

Hydroxychloroquine

Hydroxychloroquine, an antimalarial drug, is used commonly for mild manifestations of SLE and other connective tissue diseases, particularly rashes and arthralgia, at doses of 200–400 mg daily. In rheumatoid arthritis, it is used as an adjunct to other disease-modifying agents.

Mechanism of action

It is not well understood how hydroxychloroquine exerts its disease-modifying effects. In vitro studies suggest that chloroquine and hydroxychloroquine can reduce the production of pro-inflammatory cytokines including TNFα and IL-1β, and both are known to be concentrated in lysosomes, inhibiting the metabolism of deoxyribonucleotides.

Adverse effects

Hydroxychloroquine is normally very well tolerated and has a low incidence of side-effects. GI disturbances, rashes, and, rarely, blood dyscrasias may occur. Retinal toxicity may rarely occur with long-term use; measurement of visual acuity initially and at annual intervals is recommended.¹²

Contraindications

Hydroxychloroquine should be used with caution in hepatic or renal impairment, in neurological disorders, in glucose 6-phosphate dehydrogenase deficiency and in porphyria. The manufacturer’s instructions advise against use in pregnancy and breast feeding, but data on over 250 pregnancies in women with connective tissue disease who were taking hydroxychloroquine provide evidence that the treatment is safe in pregnancy, and probably also during breast feeding.¹³

Sulfasalazine

Sulfasalazine (SSZ) is a conjugate of mesalazine (5-aminosalicylic acid, 5-ASA) coupled to sulfapyridine. It is used to treat rheumatoid arthritis, either alone or in combination with methotrexate, and peripheral joint involvement in the spondyloarthropathies, including ankylosing spondylitis and reactive arthritis.

Mechanism of action

SSZ is cleaved by bacterial azoreductases in the colon to release 5-ASA and sulfapyridine (Fig. 16.5). 5-ASA is retained mostly in the colon and excreted, but 30% of intact SSZ and all sulfapyridine are absorbed. Anti-inflammatory effects of mesalazine, both in the colonic epithelial cell and in peripheral blood mononuclear cells, include inhibition of cyclo-oxygenase and lipo-oxygenase, scavenging of free radicals, and inhibition of the production of pro-inflammatory cytokines and immunoglobulins. In the treatment of inflammatory bowel disease, preparations containing 5-ASA alone have efficacy comparable to that of SSZ, but with fewer side-effects. In contrast, the sulfapyridine component appears to be the active moiety in rheumatoid arthritis. SSZ has been shown to reduce rheumatoid factor titres, inhibit IL-2-induced T-cell proliferation and inhibit macrophage IL-1 and IL-12 production, but the relative importance of these effects on its anti-inflammatory activity remains unclear.

Fig. 16.5 Metabolism and activity of sulfasalazine. Sulfasalazine is reduced to sulfapyridine and mesalazine in the colon by bacterial azoreductases. The two components have distinct anti-inflammatory activities.

Adverse effects

Sulfasalazine is associated with a number of adverse effects including cytopenias and hepatitis, which appear to be caused by the sulfapyridine moiety. A lupus-like syndrome may occur; the risk of this is higher in rheumatoid patients who are antinuclear antibody-positive.

Intravenous immunoglobulin

Intravenous immunoglobulin (IvIg) was first used in 1952 to treat primary immune deficiencies. It is composed of pooled IgG extracted from the plasma of 3000–10 000 blood donors, and contains the entire repertoire of naturally occurring antibodies. Besides its uses as a treatment for primary immune deficiencies and hypogammaglobulinaemia, it has immunomodulatory properties, making it an effective therapy for a number of autoimmune conditions. However, it has also been used in scenarios where there is no evidence of efficacy and little theoretical basis to suggest benefit. As there is a national shortage, the UK NHS has recently introduced guidelines to restrict its use only to those conditions in which there is a known benefit.¹⁴

Diseases in which IvIg is known to be of benefit include: Kawasaki disease, immune thrombocytopenic purpura (ITP), dermatomyositis, Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy. There are many others in which it may be used as part of a range of treatments.

Mechanism of action

The immunomodulatory mechanism of action of IvIg is thought primarily to be through the Fc region of the IgG molecule. Binding to Fc receptors and altering Fc receptor signalling in macrophages, other phagocytes and B cells has been shown to be an important effect in ITP and other autoimmune cytopenias. In dermatomysitis and Kawasaki disease, modulation of complement cascade activation is important. IvIg binds C3b and C4b, thus inhibiting formation of the membrane attack complex. Other functions of IvIg such as suppression of autoantibodies and of cytokines and chemokines have also been demonstrated.

Adverse effects

These include infusion reactions during or shortly after treatment, acute renal failure and rarely thrombosis, hyperproteinaemia and disseminated intravascular coagulation. As IvIg contains trace amounts of IgA, IgA-deficient patients may develop a hypersensitivity reaction following repeated infusions, which may progress to anaphylaxis.

Thalidomide

Thalidomide is rightly notorious for its teratogenic effects. In recent years it has re-emerged as a treatment for certain inflammatory dermatoses, including discoid lupus erythematosus, Behçet’s disease, erythema nodosum leprosum, and graft-versus-host disease. The mechanism of action of its anti-inflammatory effects is not fully understood, but it has been shown to inhibit anti-TNFα production and also has anti-angiogenic properties. Apart from the known teratogenicity, the use of thalidomide is limited by cumulative peripheral nerve damage, and nerve conduction studies should be monitored annually.

Dapsone

Dapsone, traditionally used to treat mycobacterial (principally leprosy) and occasionally protozoal infections, also has anti-inflammatory properties. It can be used to treat discoid lupus and other inflammatory dermatological disorders characterised by neutrophil infiltration. Although it is clear that its antimicrobial activity stems from inhibition of folate synthesis, this does not appear to be the mechanism of its anti-inflammatory effects. These are less well understood, but may involve impairing neutrophil chemotaxis and stabilisation of neutrophil lysosomes, thus inhibiting the respiratory burst. Common adverse effects include rashes, haemolysis and liver dysfunction; it may also rarely cause blood dyscrasias and methaemoglobinaemia. It should be avoided in patients suffering from G-6-PD deficiency (see p. 101).

Gold

The main preparations of gold are auranofin (given orally) and sodium aurothiomalate (given parenterally). Although effective in some rheumatoid arthritis patients, gold has been replaced by the more efficacious and less toxic methotrexate and anti-TNFα agents.

Adverse effects

Adverse effects are common and can be severe. They include mouth ulcers, irreversible skin pigmentation, proteinuria, blood dyscrasias, hepatitis, peripheral neuropathy and pulmonary fibrosis. It is contraindicated in hepatic or renal disease, pregnancy, breast feeding and colitis.

Biologic agents

The biggest change in treatment of inflammatory disease over the last 10 years has been the development of monoclonal antibodies and fusion proteins that target a specific component of the inflammatory response. This allows selective modification of the abnormal immune response underlying many chronic inflammatory diseases, resulting in greater efficacy and potentially fewer side-effects than conventional ‘dirtier’ immunosuppressants. The first drugs of this sort to enter widespread clinical use were TNFα antagonists, which now have an established role in the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriasis and Crohn’s disease.

In recent years there has been a dramatic increase in the variety of different biological drugs, and their indications. Their major drawbacks, shared by all, are an increased susceptibility to infection, and price, which in the UK at least severely curtails their use. A brief overview only is given here.

Anti-TNFα therapies

TNFα, a pro-inflammatory cytokine, is produced predominantly by macrophages and in smaller amounts by CD4 + Th1 lymphocytes. It plays an important role in macrophage activation and the eradication of intracellular bacterial and fungal infections. TNFα is also a key mediator of the inflammatory response seen in chronic granulomatous conditions such as rheumatoid arthritis and Crohn’s disease. TNFα blockade by biological agents has proved highly effective for many chronic inflammatory diseases, and there are now several different agents selectively targeting TNFα available, with more in development.

Infliximab

is a chimeric monoclonal IgG1 antibody (Fig. 16.6). In rheumatoid arthritis it is administered by intravenous infusion at 3 mg/kg, repeated 2 and 6 weeks after the initial infusion and then at 8-week intervals. In ankylosing spondylitis, psoriasis and Crohn’s disease, it is used at doses of 5 mg/kg. Methotrexate is co-prescribed to limit the development of neutralising antibodies.

Fig. 16.6 Structure of anti-TNFα biologicals. Infliximab and adalimumab are monoclonal antibodies. Etanercept is a fusion molecule composed of two p75 TNFα receptors coupled to a human immunoglobulin Fc component.

Adalimumab

is a fully human monoclonal IgG1 antibody (Fig. 16.6). The recommended dose is 40 mg by subcutaneous injection fortnightly, in combination with methotrexate. It is licensed for use in rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis.

Etanercept

is a fusion protein consisting of two human p75 TNFα receptors coupled to an Fc component of human IgG1 (Fig. 16.6). It is licensed for weekly subcutaneous injection in adult patients with rheumatoid arthritis (50 mg), for children over 4 years with polyarticular juvenile idiopathic arthritis (400 micrograms/kg; maximum dose 50 mg), psoriasis and ankylosing spondylitis.

The mechanism of action of etanercept differs from that of the monoclonal IgG antibodies in that it:

• does not fix complement and therefore does not cause lysis of cells that express TNFα on their surface

• binds trimeric (active) TNFα only, in contrast with infliximab, which binds both monomeric (inactive) and trimeric (active) TNFα

• also binds lymphotoxin (TNFβ).

There are two further anti-TNFα antibodies that have recently entered clinical practice in the UK. Golimumab is a fully human monoclonal antibody to TNFα which is taken monthly; and certolizumab pegol is a pegylated humanised Fab fragment directed against TNFα.

Adverse effects

The major risk with anti-TNF therapy is increased susceptibility to infection, particularly with intracellular pathogens such as Mycobacteria tuberculosis (M.Tb). In the case of M.Tb this may be reactivation of latent disease, but there is also a risk of new infection with M.Tb, other mycobacteria or intracellular pathogens such as histoplasmosis, coccidiomycosis or nocardiosis. Guidelines for assessing risk and for managing infection with Mycobacterium tuberculosis in the context of anti-TNFα agents are available.¹⁵ Chemoprophylaxis must be started prior to treatment in patients with latent infection.

Antinuclear antibodies develop twice as commonly in rheumatoid arthritis patients taking anti-TNFα agents. The risk of developing anti-double-stranded DNA antibodies is also increased but, in the majority of cases, the clinical significance of these autoantibodies is unclear. Anti-TNFα-induced lupus is a rare complication.

Infusion reactions may occur with infliximab administration, e.g. fever, pruritus, urticaria, chest pain, hypotension and dyspnoea. These usually resolve if the infusion rate is slowed or suspended temporarily and then restarted at a slower rate.

Symptoms and/or radiological evidence of demyelination may be exacerbated, as may severe cardiac failure.

TNFα blockade presents a theoretical risk of increasing the incidence of malignancy. In patients with rheumatoid arthritis, current data do not suggest an overall augmented tumour risk but the chance of developing lymphoma may be increased.

B-cell depletion

Rituximab ¹⁶

is a chimeric monoclonal IgG1 antibody specific for CD20, which is expressed on B cells but not plasma cells. Initially used for B-cell lymphomas, it is now prescribed for a variety of autoimmune disorders, including rheumatoid arthritis and SLE, in which autoantibody production is a significant disease-causing mechanism. Targeting CD20 removes the pathogenic antibody-producing cells, leaving the memory plasma cells needed to mount a response to infection intact. It is administered by intravenous infusion in doses of 1 g 2 weeks apart. The B-cell count is then monitored to check for depletion. Patients can be re-treated if their B-cell count recovers and the disease recurs. The major adverse effects are increased susceptibility to infection, and infusion reactions.

is a fusion protein formed from the extracellular domain of human CTLA4 (cytotoxic T lymphocyte antigen-4) linked to the Fc portion of human IgG1. Normally, CTLA4 on the T-cell membrane binds CD80 and CD86 on antigen presenting cells to provide the co-stimulation signal required for full T-cell activation when it recognises a Class II MHC-antigen complex. Abatacept competes with T-cell-bound CTLA4 and binds CD80 or CD86 itself, thus preventing co-stimulation, and this leads to a reduction in T-cell proliferation and cytokine production. It has been shown to be effective in reducing rheumatoid arthritis activity and is given as an intravenous infusion.

Other biologic anticytokine agents

Interleukin-1 (IL-1) is a pro-inflammatory cytokine with a central role in the activation of an inflammatory response. Anakinra is recombinant IL-1Ra, an endogenous antagonist of the IL-1 receptor. Clinical trials in rheumatoid arthritis, SLE and psoriasis have had disappointing results, but anakinra is dramatically effective in treating rare hereditary fever syndromes characterised by excess IL-1 signalling. These include cryopyrin-associated periodic syndromes (CAPS) such as Muckle–Wells syndrome, and hyper-IgD syndrome. Anakinra is also effective in treating systemic onset juvenile inflammatory arthritis and adult-onset Still’s disease, and may be effective in severe gout.

Interleukin-6 (IL-6) is another pro-inflammatory cytokine that is of critical importance to the mounting of an immune response, and is the most abundant cytokine found in the synovium of rheumatoid arthritis patients. Tocilizumab is a monocloncal antibody that binds IL-6 receptors and inhibits their intracellular signalling. It has been shown to be effective in controlling disease activity in rheumatoid arthritis,¹⁷ and is licensed for use in this condition in the UK. It is given by intravenous infusion on a monthly basis.

Other anticytokine biological agents in development or undergoing clinical trials include agents that block IL-4, IL-5 and IL-13 (mainly to treat allergic asthma), and TGFβ signalling (to treat systemic sclerosis).

Other strategies

Current drug discovery programmes are investigating the potential of protein kinase cascade disruption as a way of modulating the immune system. JAK3, p38 MAPK and Syk have all shown some promise. In particular the JAK3 pathway is a promising candidate, as it is confined to cells of the immune system, thus limiting the potential for adverse effects. A number of small molecule inhibitors of this pathway have demonstrated beneficial effects in small trials for rheumatoid arthritis and psoriasis, but none as yet are in clinical use.

Management of diseases affecting the joints

Osteoarthritis

Osteoarthritis (OA) is the most common form of arthritis, with radiographic evidence of knee OA in up to 15% of people aged over 55 years. It reflects a dynamic bone and cartilage response to joint trauma and ageing. OA is a common cause of disability, particularly in the elderly, and is the major indication for joint replacement.

The aims of management of OA are to control pain, reduce progression of joint damage and minimise disability. The major strategies employed are non-pharmacological; there are no disease-modifying drugs in clinical use. Patient education in pain management is important to minimise the adverse affects of analgesics. NSAIDs have been shown to be marginally more effective but are associated with more adverse effects than paracetamol.¹⁸ Regular paracetamol or co-dydramol should therefore be tried before introducing a NSAID. Other options include topical NSAID gel, which may provide a modest improvement in symptoms at least in the short term. For patients with large-joint OA, occasional intra-articular injection of corticosteroid and local anaesthetic can provide some respite for up to 6 weeks.

Gout

Gout is a recurrent acute inflammatory arthritis caused by monosodium urate (MSU) crystals within synovial joints, affecting 1.4% of the UK population. Hyperuricaemia is due to over-production or under-excretion of uric acid. Both mechanisms may operate in the same patient, but reduced renal clearance is the main cause of hyperuricaemia in most cases. Drugs may influence these processes as follows:

• Over-production of uric acid occurs if there is excessive cell destruction releasing nucleic acids. This may occur when myeloproliferative and lymphoproliferative disorders are first treated.

• Under-excretion of uric acid is caused by thiazide and loop diuretics, low dose aspirin (see earlier), ethambutol, pyrazinamide, nicotinic acid, ciclosporin and alcohol (which increases uric acid synthesis and also causes a rise in serum lactic acid that inhibits tubular secretion of uric acid). Conversely, a small number of drugs have a mild uricosuric effect and increase renal clearance of urate. Losartan and fenofibrate are examples of this.

Patients with gout but no visible tophi have a uric acid pool that is two to three times normal. This exceeds the amount that can be carried in solution in extracellular fluid, so MSU crystals precipitate and form deposits in tissues, including the joints and occasionally in subcutaneous tissues (tophi). These crystals then trigger acute attacks of inflammatory arthritis.

The priority in an acute attack is to relieve the intense pain by reducing the inflammatory response. NSAIDs are most commonly prescribed, but if contraindicated, colchicine (EULAR ¹⁹ guidelines suggest 0.5 mg three times daily) is an alternative. A short course of oral prednisolone or intra-articular corticosteroid is also effective, although the severity of joint pain may preclude intra-articular injection during an acute attack.

Management of chronic gout should include a review of modifiable risk factors for hyperuricaemia, including obesity, hypertension, excessive alcohol consumption, high dietary intake of purines (red meat, game, seafood, legumes) and drugs (see above). If these measures are insufficient, plasma uric acid levels may be reduced by inhibiting the formation of uric acid (allopurinol, febuxostat), or increasing renal excretion (sulfinpyrazone, probenecid or benzbromarone). In treatment-resistant cases, ‘biologic’ therapy with recombinant uricase, which metabolises urate further, can be considered. Rapid lowering of plasma uric acid by any means can precipitate an acute flare, probably by causing the dissolution of crystal deposits. Colchicine prescribed concomitantly for up to 6 months or an NSAID for 6 weeks protect against this.

Allopurinol

inhibits xanthine oxidase, the enzyme that converts xanthine and hypoxanthine to uric acid. Patients taking allopurinol excrete less uric acid and more xanthine and hypoxanthine in the urine. It is readily absorbed from the GI tract, metabolised in the liver to oxypurinol, which is also a xanthine oxidase inhibitor, and excreted unchanged by the kidney. Allopurinol is indicated in recurrent gout and during treatment of myeloproliferative disorders where cell destruction creates a high uric acid load. It prevents the hyperuricaemia due to diuretics and may be combined with a uricosuric agent.

Adverse effects of allopurinol include precipitation of an acute gout attack and the allopurinol hypersensitivity syndrome (AHS) which is rare but can be severe. Features include hepatitis, desquamating erythematous rash, eosinophilia and worsening renal function. For this reason, allopurinol should not be commenced unless the diagnosis is certain, and attacks of gout are frequent despite lifestyle changes. It also interferes with the metabolism of azathioprine and co-prescription may cause severe myelosuppression.

Febuxostat

is a newly licensed non-purine selective xanthine oxidase inhibitor. Although it is at least as effective, if not more, than allopurinol at lowering serum urate levels, its safety in patients who are allergic to allopurinol has not been fully established. Diarrhoea, liver function disturbance and other GI symptoms are the commonest adverse effects. Febuxostat also interferes with azathioprine metabolism.

Sulfinpyrazone

competitively inhibits the active transport of organic anions across the kidney tubule, both from the plasma to the tubular fluid and vice versa. The effect is dose-dependent: at low dose sulfinpyrazone prevents secretion of uric acid into tubular fluid, and at high dose, and more powerfully, it prevents reabsorption, increasing its excretion in the urine. A net beneficial uricosuric action is obtained with an initial dose of 100–200 mg/day by mouth with food, increasing over 2–3 weeks to 600 mg/day, which should be continued until the plasma uric acid level is normal. The dose may then be reduced for maintenance, to as little as 200 mg daily. During initial therapy ensure that fluid intake is at least 2 L/day to prevent uric acid crystalluria. Other adverse effects are mainly gastrointestinal; sulfinpyrazone is contraindicated in peptic ulcer.

Rasburicase

is a recombinant uricase which converts urate into allantoin, a more soluble metabolite which is readily excreted renally. It rapidly and profoundly lowers serum uric acid concentration and is licensed for use in tumour lysis syndrome. It has also been used in small numbers of patients with gout, but antibody development limits its effectiveness with repeated infusions, as would be needed to treat chronic tophaceous gout. A pegylated uricase (pegloticase),²⁰ which has a longer half-life and is less immunogenic, has shown promise in recent trials.

Rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic symmetrical polyarthritis affecting approximately 1% of the UK population. The principal pathology is inflammation within synovial joints, causing pain, swelling and stiffness and progressing to erosion and eventually joint destruction. RA is a systemic autoimmune inflammatory disorder and may cause extra-articular manifestations affecting blood vessels, bone marrow, GI tract, skin, lungs and eyes. Further sources of morbidity reflect the interaction of the disease process with adverse effects of medication and include osteoporosis, gastrointestinal haemorrhage and accelerated atherosclerosis. Mortality in patients with RA is increased up to three-fold compared with the general population; most of the excess is due to cardiovascular disease.

The initial management of a patient presenting with new inflammatory polyarthritis consists of reducing systemic inflammation, joint pain and stiffness while the diagnosis is confirmed.²¹ This may be achieved by short-term glucocorticoids such as Depo-Medrone 120 mg i.m., combined with analgesia and an NSAID (e.g. diclofenac 50 mg three times daily).

Once a diagnosis of RA is made, a DMARD should be initiated. As these reduce the progression of joint damage, it is imperative to start treatment in early disease; it is not acceptable to attempt to treat patients with early RA solely symptomatically. Methotrexate is the most common first-line DMARD. Careful education and counselling of the patient is important to ensure regular monitoring (of bone marrow, liver and lung function) and early detection of adverse effects. Folic acid 5 mg (up to 6 days weekly) is co-prescribed to reduce side-effects such as mouth ulcers.

Hydroxychloroquine is often used as an adjunct DMARD with methotrexate, and combination therapy of methotrexate, sulfasalazine and hydroxychloroquine can have added benefits beyond that of the individual drugs. Where methotrexate is contraindicated, ineffective or toxic, sulfasalazine alone, leflunomide or gold are alternatives. At any point in the disease course, glucorticoids can be used as an adjunct to control flares, administered orally, intra-articularly or intra-muscularly.

If adequate disease control is not achieved after use of two DMARDs, UK guidelines recommend starting anti-TNFα agents: infliximab, etanercept or adalimumab. If this is not effective, current practice involves switching to an alternative anti-TNFα agent with a different mechanism of action, or to the anti-CD20 mAb, rituximab. In 2010, tocilizumab (anti IL-6R) and abatacept (T-cell co-stimulation blockade) were approved for those patients who have not responded to other biologics. Many other biologic agents targeting cytokine expression, immune cell subtypes and intracellular signalling are currently in development.

It is particularly important to address cardiovascular risk reduction in patients with RA, given the increased risk of cardiovascular disease associated with chronic inflammation. Aggressive management of RA with DMARDs may reduce cardiovascular disease incidence at the same time as controlling inflammation. Moreover, atorvastatin has been reported to improve disease activity scores in RA.²²

Protection against osteoporosis is particularly important for patients who receive long-term glucocortocoids; even doses less than prednisolone 7.5 mg daily increase fracture risk. The UK guideline ²³ for the prevention and treatment of glucocorticoid-induced osteoporosis is summarised in Figure 16.7. Bone loss is most rapid in the first few months of treatment, therefore protection must be considered at the onset of treatment, whenever the intention is to continue for more than 3 months, at any dose. Strategies include minimising the dose of corticosteroid, concomitant prescription of vitamin D 800 IU and calcium 1 g daily and advice on smoking cessation, alcohol intake, nutrition and exercise. Bisphosphonates should be prescribed for all patients aged over 65 years, or those with a history of a fragility fracture. Other patients should undergo bone densitometry and should be prescribed a bisphosphonate if the T score is − 1.5 or less²⁴ at either lumbar spine or hip.