Many rheumatic diseases affect women of childbearing age, and hence, the clinician should be keenly aware of the many possible complications of medications and their effects on fertility, fetal development, and breast-feeding. A frank and thorough discussion with the patient is paramount even before pregnancy is attempted.

Although it is impossible to create absolute rules about the management of medications, the overriding principle will always be to weigh the potential benefits of any drug against its potential risks, which is to be considered on an individual case basis. Although minimizing drug intervention during pregnancy is always desired, there is very strong evidence for discontinuing the use of some drugs such as cyclophosphamide, methotrexate, or leflunomide, both before and during gestation, and effective contraceptive techniques must be implemented when prescribing such drugs to women of childbearing age. For other medications such as azathioprine (AZA) or hydroxychloroquine, the evidence is not as clear, although they are probably relatively safe. Warfarin should be discontinued because of its known teratogenic effects and should be substituted with heparin. Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) should be discontinued in the latter part of pregnancy because of the potential premature closure of the ductus arteriosus, and yet, in the antiphospholipid syndrome, low-dose aspirin is an important treatment option in ensuring a successful pregnancy. Prednisone and methylprednisolone at low to moderate doses will not cross the placenta and are considered to be safe for fetal development. In contrast, the fluorinated corticosteroids (e.g., dexamethasone and betamethasone) will cross the placenta. (See Chapter 38 for further information on this topic.)

NSAIDs exhibit antipyretic, anti-inflammatory, and analgesic properties through their ability to inhibit the production of proinflammatory prostaglandins by the enzyme cyclooxygenase-2 (COX-2). They are used for degenerative musculoskeletal problems, systemic inflammatory illnesses, crystalline diseases, soft-tissue injuries, and certain hypercoagulable states, between other conditions. NSAIDs are essentially equipotent, although responses and tolerances may vary between individual patients. If an inadequate therapeutic response or intolerance occurs, a trial of an alternative agent, especially from a different chemical class, is often worthwhile. Compliance may be related to schedule of administration (Table 1). Concurrent use of multiple NSAIDs does not enhance efficacy and increases toxicities and is not generally recommended. In all patients being treated with NSAIDs for a long term, particularly the older individuals and those with impaired liver or kidney function, regular monitoring of hepatic and renal function is essential.

Traditional NSAIDs, such as ibuprofen and naproxen, also inhibit COX-1, the function of which includes constitutive “housekeeping” functions such as the production of gastroprotective prostaglandins. Accordingly, gastrointestinal toxicities (e.g., bleeding, ulcerations, and perforations) are a major morbidity associated with their use. If NSAIDs are indicated in individuals at a high risk of gastrointestinal complications, gastroprotective agents such as misoprostol or proton pump inhibitors should be concurrently used.

Aspirin and the traditional NSAIDs inhibit platelet function and, in general, should be discontinued before major elective procedures. Because aspirin irreversibly inhibits platelet function, it must be withdrawn for at least 7 to 10 days (the lifespan of a circulating platelet) before such procedures. NSAIDs reversibly inhibit platelets and should be stopped four to five half-lives before surgeries if necessary (approximately 3 to 5 days for medicines that are administered three or more times daily or 5 to 7 days for medicines that are administered
once or twice daily). Intriguingly, ibuprofen, and probably other NSAIDs as well, mitigate the cardioprotective effects of aspirin. If concomitant NSAID and aspirin therapy is desired, it is recommended that the aspirin be administered at least 2 hours before the NSAID is ingested.

Major recent scientific advances have led to the development of a new generation of NSAIDs (known as coxibs) that preferentially inhibit the activity of COX-2. Because of their relative sparing of constitutive COX-1 activity, coxibs have been shown to have fewer adverse gastrointestinal effects than traditional NSAIDs. Clinically, however, this benefit has not been as great as initially hoped for. Moreover, serious concerns have been recently raised over the cardiovascular safety of coxibs. Coxibs appear to actually promote thromboembolic vascular disease (e.g., myocardial infarctions, cerebrovascular accidents) in a dose-dependent manner, probably owing to the unopposed production of thromboxane, which is procoagulant. High and especially supratherapeutic doses of rofecoxib have been associated with an increased risk of myocardial infarctions. The cardiovascular risks are likely enhanced further by aggravated hypertension and fluid retention common to all classes of NSAIDs. Rofecoxib and Valdecoxib have been withdrawn from the market because of these concerns, and there are data that suggest that celecoxib and all NSAIDs may also present considerable dangers in certain high-risk patient populations and should be avoided in patients with significant cardiovascular risk factors (e.g., known coronary artery disease, diabetes, and dyslipidemias). NSAIDs differ in their selectivity for COX-1 and COX-2, and it is possible that adverse effects seen clinically may, in fact, reflect their relative degrees of selectivity (Table 2).

Aspirin, traditional NSAIDs, and coxibs have potential nephrotoxicities. COX-2–mediated prostaglandins have vasodilatory effects on the afferent arterioles in the kidneys and are necessary to maintain renal perfusion, particularly in low-flow states, so NSAIDs are relatively contraindicated in patients with any degree of renal insufficiency. Hypertension and fluid retention are relatively common problems, but frank deterioration of renal function is not rare.

Asthmatic attacks, urticaria, and angioedema may be related to enzymatic inhibition of prostaglandin synthesis in susceptible individuals or to immunoglobulin E (IgE)-mediated reactions. Patients who have these reactions to aspirin or other NSAIDs may be sensitive to all NSAIDs, although some studies indicate that coxibs can be safe in this regard. Rashes are not uncommon, but recent postmarketing surveillance has identified rare, severe, cutaneous reactions to valdecoxib including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, possibly related to sulfonamide reactivity.

Pregnancy is another relative contraindication to the use of NSAIDs because NSAIDs may cause hemorrhagic complications or premature closure of the ductus arteriosus in the third trimester. The benefit of NSAIDs in pregnant women must be weighed very carefully against these risks.

Corticosteroids are potent anti-inflammatory agents capable of quickly suppressing many disease manifestations of systemic, autoimmune, and inflammatory disorders, and are available in forms suitable for topical, locally injectable, and systemic use. Corticotropin or adrenocorticotropic hormone (ACTH) has been used for the treatment of acute crystalline arthritides. Although their ability to modify the ultimate course of disease varies from disease to disease, their side effects with prolonged use are incontrovertible. Among the plethora of adverse effects associated with corticosteroid use, hypertension, weight gain, Cushing’s syndrome, glucose intolerance, osteoporosis, osteonecrosis, emotional lability, premature atherosclerosis, immunosuppression, and others are included. Strong efforts should be made to employ disease-modifying agents to ensure that corticosteroids play as minimal a role as possible in the management of inflammatory arthritis. Similarly, long-term use of agents with long half-lives (e.g., dexamethasone) is generally not favored by rheumatologists because of their increased propensity to cause these adverse effects.

Corticosteroids differ in relative anti-inflammatory (glucocorticoid) potency and relative mineralocorticoid potency. A comparison of the properties of different selected corticosteroids is given in Table 3.

Disease-modifying antirheumatic drugs (DMARDs) are much more readily and promptly utilized for the treatment of systemic rheumatic illnesses than before. Also called slowly acting antirheumatic drugs (SAARDs) or remittive agents in the medical literature, these drugs certainly are slowly acting but probably do not induce indefinite remissions in most cases. In rheumatoid arthritis, for example, the capacity of these agents to modify disease varies greatly from drug to drug and from patient to patient. As a group, their modes of action are quite varied but often poorly understood. Some are clearly immunosuppressive or cytotoxic, whereas others may act on reducing systemic inflammation. Their potential for and spectrum of adverse effects are diverse, so careful monitoring for toxicities is crucial. Although their clinical effect generally becomes apparent only after several weeks to months, they appear capable of ameliorating the course of disease in a significant percentage of patients and reducing cumulative corticosteroid use. Accordingly, DMARDs are also commonly used and known as steroid-sparing agents. Moreover, there appears to be advantages in using combinations of DMARDs to maximize benefit without the development of increasing toxicities.