Nonsteroidal antiinflammatory drugs in systemic lupus erythematosus

Introduction

Nonsteroidal antiinflammatory drug (NSAID) use in systemic lupus erythematosus (SLE) dates back to the early 1950s, when phenylbutazone, the first nonsalicylate NSAID, was used to treat “subacute” lupus in 1953. Aspirin or acetylsalicylic acid (ASA) was the first NSAID to be introduced in 1899 and later, nonASA NSAIDS were introduced including indomethacin in 1964 and ibuprofen in 1969. NSAIDS to date have different classifications including, but not limited to; salicylates such as ASA and sulfasalazine; propionic acid derivative such as ibuprofen, naproxen; pyarnocarboxylic acids such as etodolac; heteroaryl acetic acid such as diclofenac, ketorolac; indoleacetic indene acetic acids such as indomethacin, sulindac, etodolac; oxicams such as piroxicam, meloxicam; pyrroloppyrrole: ketorolac, mefenamic acid, meclofenamic acid; and COXIBs (diary heterocycles) such as rofecoxib, celecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib.

Despite their common use, NSAIDs are still not approved by the US Food and Drug Administration (FDA) for the management of SLE due to their analgesic, antipyretic and antiinflammatory effects. To date, there are no controlled studies that document the efficacy or side effects of NSAIDs in SLE patients, but use among rheumatologists is popular. A survey among private rheumatologists at Cedars-Sinai Medical Center showed that 84% of 925 SLE patients were prescribed NSAIDs. NSAIDs are thought to help with fever, synovitis, serositis, fatigue, arthritis, and headache. The most commonly prescribed NSAIDs were naproxen (46%), sulindac (29%), indomethacin (13%), and ibuprofen (12%).

Although NSAIDs are commonly used in SLE and nonSLE patients, the data on NSAID-induced adverse events in SLE patients is limited; however, their adverse effects have major health implications given the large number of users. This chapter discusses some of the major adverse effects associated with NSAID use in SLE patients.

Inhibitory role of NSAIDs

NSAIDs collectively inhibit the synthesis of prostaglandins, prostacyclin, and thromboxane (TX), a group of active lipid compounds, via COX enzymes, which usually convert arachidonic acid to prostaglandin (PG) G2, which have effects in various organ systems. Phospholipids are metabolized by phospholipase A into arachidonic acid; arachidonic acid is then further metabolized by cyclooxygenase and peroxidase that metabolizes PGG2 to PGH2, which is then further converted to primary prostanoids or inflammatory mediators: PGD2, PGE2, PGF2, PGI 2, and TXA2. NSAIDs inhibit cyclooxygenase and inhibit the rate-limiting step of prostaglandin synthesis. With these inflammatory mediators blocked, antiinflammatory, antipyretic and analgesic effects are achieved.

Two isoforms of the cyclooxygenase enzyme have been identified—COX-1 and COX-2. The expression of COX-1 is more constitutive compared to COX-2 but the latter is more inducible, with a 20-fold increase compared to a two- to threefold increase in COX-1 enzyme. COX-1 is thought to be ubiquitous throughout the body, alters cell integrity and may cause gastrointestinal (GI) side effects, whereas COX-2 expression is more selective, absent in normal tissues, induced by inflammatory stimuli and is involved mainly in the brain, kidneys, and reproductive system. COX-1 and COX-2 inhibitors have been shown to be equally effective for pain control in rheumatoid arthritis and osteoarthritis patients, but the extent of serious gastrointestinal injury is less with COX-2 inhibitors.