The immune response occurs when immunologically competent cells are activated in response to foreign organisms or antigenic substances liberated during the acute or chronic inflammatory response. The outcome of the immune response for the host may be deleterious if it leads to chronic inflammation without resolution of the underlying injurious process (see Chapter 55). Chronic inflammation involves the release of multiple cytokines and chemokines plus a very complex interplay of immunoactive cells. The whole range of autoimmune diseases (eg, RA, vasculitis, SLE) and inflammatory conditions (eg, gout) derive from abnormalities in this cascade.
The cell damage associated with inflammation acts on cell membranes to release leukocyte lysosomal enzymes; arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized (see Chapter 18). The lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in vascular permeability. During inflammation, stimulation of the neutrophil membranes produces oxygen-derived free radicals and other reactive molecules such as hydrogen peroxide and hydroxyl radicals. The interaction of these substances with arachidonic acid results in the generation of chemotactic substances, thus perpetuating the inflammatory process.
The treatment of patients with inflammation involves two primary goals: first, the relief of symptoms and the maintenance of function, which are usually the major continuing complaints of the patient; and second, the slowing or arrest of the tissue-damaging process. In RA, several validated combined indices are used to define response (eg, Disease Activity Score28 [DAS28], American College of Rheumatology Response Index [ACR Response], Clinical Disease Activity Score [CDAI], Simplified Disease Activity Index [SDAI]). These indices often combine joint tenderness and swelling, patient response, and laboratory data. Reduction of inflammation with NSAIDs often results in relief of pain for significant periods. Furthermore, most of the nonopioid analgesics (aspirin, etc) have anti-inflammatory effects, so they are appropriate for the treatment of both acute and chronic inflammatory conditions.
The glucocorticoids also have powerful anti-inflammatory effects and when first introduced were considered to be the ultimate answer to the treatment of inflammatory arthritis. Although there are data indicating that low-dose corticosteroids have disease-modifying properties, particularly in the early phase of RA, their toxicity makes them less favored than other medications, when it is possible to use the others. However, the glucocorticoids continue to have a significant role in the long-term treatment of arthritis.
Another important group of agents are characterized as disease-modifying anti-rheumatic drugs (DMARDs) including biologics (a subset of the DMARDs). They decrease inflammation, improve symptoms, and slow the bone damage associated with RA. They affect more basic inflammatory mechanisms than do glucocorticoids or the NSAIDs. They may also be more toxic than those alternative medications.
Salicylates and other similar agents used to treat rheumatic disease share the capacity to suppress the signs and symptoms of inflammation including pain. These drugs also exert antipyretic effects.
Since aspirin, the original NSAID, has a number of adverse effects, many other NSAIDs have been developed in attempts to improve upon aspirin’s efficacy and decrease its toxicity.
The NSAIDs are grouped in several chemical classes, as shown in Figure 36–1. This chemical diversity yields a broad range of pharmacokinetic characteristics (Table 36–1). Although there are many differences in the kinetics of NSAIDs, they have some general properties in common. All but one of the NSAIDs are weak organic acids as given; the exception, nabumetone, is a ketone prodrug that is metabolized to the acidic active drug.