Although many of the treatments for inflammatory disease such as RA have been around for several decades, knowledge about the pathogenesis of disease has highlighted several new therapeutic options. This chapter will focus primarily on the treatment of RA, but similar principles apply for psoriatic arthritis; treatment of SLE, vasculitis and crystal arthritis is covered more fully in individual chapters.

Standard analgesics with no anti-inflammatory action (paracetamol, opioids) have a role in controlling pain, but are only used as an adjunct to other therapy and have no impact on disease progression.

NSAIDs inhibit the cyclo-oxygenase (COX) pathway in prostaglandin synthesis. The efficacy of NSAIDs must be balanced against their side effect profile (primarily gastric and renal) due to inhibition of the constitutive COX-1 pathway. The COX-2 isoform of the enzyme is induced at sites of inflammation and the so-called COXIBs (COX-2 inhibitors) target this form more specifically, although all have some residual COX-1 effect. Though they reduce gastric side effects, they are associated with an adverse cardiovascular profile. The persistent use of any NSAID is not only a risk in an aging population with substantial co-morbidity but also should be seen as a marker of treatment failure – escalating DMARD therapy may be a safer option than allowing long-term use of non-steroidal anti-inflammatory agents.

DMARD is an umbrella term for several drugs used to control pain and swelling with evidence of inhibition of disease progression (functionally and/or radiographically). All DMARDs carry some risk of bone marrow suppression and hepatotoxicity; they are initiated in secondary care and require careful monitoring to avoid toxicity. DMARDs should be used as early as possible in active disease, generally with methotrexate as first-line; unfortunately they may take up to three months to reach clinical effect, so patients may require steroids as a ‘bridging’ therapy. Combinations of DMARDs are frequently required to achieve disease control, although this increases the risk of adverse effects.

The advent of monoclonal antibodies directed against key cells or cytokines in inflammatory disease has revolutionised the treatment of refractory arthritis (see Chapter 22, Pathogenesis of rheumatoid arthritis). TNFa inhibition is indicated in patients with active disease (DAS28 score >5.1) despite treatment with two or more DMARDs, one of which must be methotrexate. For those who fail to respond to anti-TNF, or in whom its use is contraindicated, anti-B cell therapy may prove beneficial. Antibody therapy directed against T cells, IL-1 and IL-6 are licensed for use in RA but have not yet received NICE approval; clinical trials looking at the efficacy and safety of IL-17 blockade are underway.

• TNFα inhibitors. TNFα blockers are highly effective in the majority of patients. The greatest risk of TNF inhibition is infection, both common and opportunistic, and re-activation of latent TB. All patients are therefore carefully screened prior to initiation. TNF blockers are usually given in combination with methotrexate, which may reduce the patient’s immune responses to antiTNF (particularly against the mouse chimera infliximab). If low-dose methotrexate is not tolerated, etanercept and adalimumab are licensed as monotherapy in RA.
  
• Anti-B cell therapy. Rituximab, the monoclonal antibody directed against CD20 depletes circulating B cells, thereby impacting on a number of key processes in RA (see figure). Terminally differentiated plasma cells are unaffected. Rituximab is given as two intravenous infusions two weeks apart and may be repeated after 6 months; treatment is frequently limited to 3 or 4 cycles due to concerns about long – term hypogammaglobulinaemia.

Steroids have excellent anti-inflammatory actions, but their long term use is relatively contraindicated due to side effects (e.g. weight gain, peripheral oedema, diabetes and osteoporosis). Steroids may be administered via a number of routes, according to therapeutic demand:

• Oral: low dose to control inflammatory arthritis or polymyalgia rheumatic, high dose for GCA and other vasculitides.
  
• Intramuscular: as ‘bridging’ therapy until DMARDs therapy reaches therapeutic effect; to abort a flare of established disease.
  
• Intra-articular: for isolatedjoint pathology when systemic treatment is not indicated (or to settle a local flare of established disease).

Osteoporosis and bone protection. Bone loss starts early with steroid use. Bisphosphonates and vitamin D/calcium supplementation should be considered in all patients on long term steroids, especially in elderly or those with previous fragility fracture.

Steroid – sparing agents. If long-term steroid use is unavoidable (e.g. in SLE or vasculitis), a steroid-sparing agent such as methotrexate or azathioprine can be used alongside prednisolone to aid dose reduction.

Many inflammatory diseases will require long-term, if not life-long, treatment. Although patients may go into remission on treatment, subsequent withdrawal of therapy carries the risk of disease flare.

There are, however, certain situations in which treatment should be suspended temporarily.

• Intercurrent illness/surgery. In general, DMARD and biologic therapy can continue during mild or moderate intercurrent illness, but the threshold is much lower in the presence of infective illness. Some units will also continue with standard DMARD therapy during an elective surgical period, but schedule operative dates between injections/infusions of biologic agents.
  
• Pregnancy/breastfeeding. Many DMARDs are teratogenic and/or contraindicated in breastfeeding; treatment should be stopped preconception with sufficient ‘wash-out’ time. There are few data on the safety of biologic therapy and pregnancy, but increasing reports of successful pregnancies on antiTNFα are reassuring. The decision to continue biologic therapy in pregnancy is often clinician-specific.