Chapter 47 Principles of Therapy, Local Measures, and Nonsteroidal Medications

Mariko Ishimori, Michael H. Weisman, Katy Setoodeh, Daniel J. Wallace

Formulation Overview

One of the most difficult and misunderstood aspects of systemic lupus erythematosus (SLE) is its management. Before therapy is initiated, the practitioner must determine which type of lupus is present and, on that basis, formulate a treatment program. Because the prognosis of each clinical subset differs widely, it is essential that the patient database be completed before an educational session is initiated. All blood tests, imaging modalities, and biopsies that provide information and can affect treatment must be performed. Once these prerequisites have been met, the physician should be able to answer the following questions:

1. Does the patient meet the American College of Rheumatology (ACR) criteria for SLE?

a. If not, does the patient meet the biopsy criteria for discoid lupus, subacute cutaneous lupus, or lupus nephritis? If not, is the physician satisfied that the patient has SLE, despite lacking four criteria? (This distinction is a matter of clinical judgment.)

b. If not, does the patient have an undifferentiated connective tissue disease (UCTD)? Some patients with clear-cut inflammatory arthritis, a positive antinuclear antibody (ANA) test, and constitutional symptoms are treated similarly to patients with lupus. Approximately 14% of cases of UCTD evolve into classic SLE.

c. If so, are related disorders such as mixed connective tissue disease, scleroderma, and dermatopolymyositis excluded, or is an overlap syndrome present?

2. If the patient has SLE, is it organ threatening and therefore could potentially shorten lifespan (e.g., cardiopulmonary involvement, renal disease, hepatic involvement, central nervous system vasculitis, thrombocytopenia, or autoimmune hemolytic anemia)? If not, does the patient have non–organ-threatening SLE (e.g., cutaneous, musculoskeletal, serositis, constitutional)?

3. Which subset best describes the disease? Does a particular aspect of the patient’s disease require specific considerations, interventions, or counseling (e.g., antiphospholipid syndrome, Sjögren syndrome antigen A [SSA/Ro] positivity, seizures, concurrent fibromyalgia)?

Occasionally, patients who have been labeled as having SLE do not, in fact, have the disease. The implications of telling a patient that he or she has lupus are tremendous. The emotional and psychological effects of receiving this diagnosis open up new worlds of powerful and expensive medications, which will influence career planning and family life, alter one’s productivity and lifestyle, and, in the United States, make it difficult to obtain health, life, or disability insurance. Physicians should avoid locking themselves into telling a patient that he or she has lupus if any doubt remains.

Educational Session

All patients who are newly diagnosed, as well as those who are new to the treating physician, deserve an educational session that includes concerned family members, friends, and significant others. The session should be supervised by the physician and may involve other health professionals or use audiovisual aids. Several studies have demonstrated that socioeconomic differences account for the widely divergent outcomes in those with SLE (see Chapter 55). It is critical that the patient establish a relationship and rapport with the treating facility or physician, speak a common language, keep appointments, take medication as prescribed, have transportation to the medical office, and have access to medical assistance or advice 24 hours a day. Educational aids, online assistance, and informational literature relating to the various aspects of the disease, including therapy, are available from lupus support organizations such as those listed in the Appendix.

The treatment of SLE includes physical and psychological measures, surgery, and medications. Box 47-1 summarizes the issues that should be discussed with the patient and family during the educational session. (Topics listed in Box 47-1 not covered elsewhere in this textbook are reviewed in the following text, and the reader is also referred to the index.)

Box 47-1

Curriculum for the Educational Session with a Patient Who Is Newly Diagnosed with Lupus or Is New to the Practice Setting

1. What is lupus? What are its causes?

2. Many types of systemic lupus erythematosus (SLE) exist: cutaneous, mild, drug-induced, and organ-threatening, all of which have a (fair, good, excellent) prognosis with treatment.

3. Physical and lifestyle measures to be reviewed:

a. Diet

b. Exercise

c. Rehabilitation (physical, occupational, vocational therapy)

d. Bone mineralization strategies

e. Immunizations

f. Dealing with fevers, infections

g. Sun protection measures

h. Smoking cessation, use of alcohol

i. Climate and barometric pressure

4. Emotional support

a. Fatigue

b. Sleep hygiene

c. Use of mind-body approaches to depression, anxiety, concurrent fibromyalgia, stress reduction

d. Pregnancy

e. Genetic counseling

5. Being current with adjunctive measures:

a. Establishing a regular follow-up system with primary care, gynecologic examinations, mammograms, and colonoscopies, as well as eye examinations for those receiving antimalarial or steroidal medications

b. Screening for accelerated atherogenesis with intervention as needed

c. Importance of keeping appointments, taking medications, and following instructions

d. Managing pain and differentiating inflammatory from noninflammatory pain

6. Medications

a. To treat patients with SLE: topical, nonsteroidal, antimalarial, corticosteroid, immune suppressive, biologic agents

b. To treat lupus subsets (e.g., measures for antiphospholipid syndrome, Raynaud phenomenon, thrombocytopenia, Sjögren syndrome)

c. To treat lupus-related complications related to the disease or its treatment (e.g., hypertension, hyperlipidemia, glaucoma)

7. Information and access

a. Who should be called when for what?

b. Resource listings (e.g., web sites, drug information, lupus advocacy groups)

General Therapeutic Considerations

Rest, Sleep, and the Treatment of Fatigue

Fatigue is present in 50% to 90% of patients with SLE and can be its most disabling symptom.¹ Potentially reversible causes of fatigue should first be ruled out. These include active inflammation, complications from medication, and co-morbid states such as psychosocial stressors. Occasionally, patients with normal examinations, an absence of acute-phase reactants, and normal chemistry panels (other than a positive ANA test) complain of profound fatigue. The administration of certain cytokines is known to induce fatigue.² Reduced muscle aerobic capacity may also play a role.³ Sleep quality in patients with SLE is impaired.⁴ One survey showed that 80% of 172 patients with SLE have disordered sleep, compared with 28% of healthy patients in the control group. Disordered sleep is most likely due to depressed mood, fibromyalgia, steroid therapy, and a lack of exercise.^4,⁵ Fatigue surveys have statistically associated it with aerobic insufficiency, pain, depression, disordered sleep, altered perceived social support, and a higher Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index (SDI).⁶ Fifteen instruments have been evaluated in fatigue-associated SLE in 34 studies, and the fatigue severity scale is regarded as having the best overall results with regard to showing a minimally clinically important difference.⁷

The concept of pacing is paramount in managing fatigue. Total bed rest can worsen fatigue and promote osteoporosis, muscle disuse, atrophy, and contractures. Overexertion and fatigue denial are also counterproductive. Patients are encouraged to pace themselves. Between 1 and 2 hours of morning activity should be followed by a midmorning break. A couple of hours of late-morning activity could be followed by a restful lunch break. Periods of activity followed by periods of rest usually permit most patients with lupus to attain an improved level of functioning and productivity.

Treatment of fatigue requires consideration of the source and contributory factors. Iron deficiency anemia is common because of dietary deficiency, heavy menstrual periods, and/or blood loss resulting from the use of salicylates and nonsteroidal antiinflammatory drugs (NSAIDs). If the fatigue is caused by parenchymal pulmonary disease, then oxygen may be helpful; if it is secondary to inflammation, then antiinflammatory drugs are used. In addition to corticosteroid medications, quinacrine and hydroxychloroquine are cortical stimulants and may decrease fatigue in patients without organ-threatening involvement.⁸ Dehydroepiandrosterone (5-DHEA), modafinil (Provigil), armodafinil (Nuvigil), bupropion, and selective serotonin-reuptake inhibitors can be useful. Depression, fibromyalgia, and emotional stress must be excluded as causes. Several surveys have suggested that fibromyalgia and depression are the most common causes of fatigue in patients with SLE.⁹ Secondary fibromyalgia with a concomitant sleep disorder is not uncommon. Some physicians empirically prescribe low doses of thyroid, vitamin B12 injections, or amphetamines for nonspecific fatigue of SLE; however, the routine use of these agents should be discouraged. In contrast, the use of anxiolytic agents, especially those that promote restorative sleep, should be considered (Box 47-2).

Box 47-2

Fatigue in Systemic Lupus Erythematosus

1. Present in 50% to 90% of patients according to multiple surveys

2. Causes of fatigue:

a. Inflammation

b. Medications (e.g., analgesic, psychotropic, supplemental, antihypertensive agents)

c. Co-morbidities (e.g., anemia, parenchymal scarring, hypothyroidism in those with concurrent Hashimoto thyroiditis, steroid-induced diabetes)

d. Fibromyalgia and psychosocial distress

e. Malnutrition or anorexia, bulimia, or exercise overexertion (observed in 5% of young women)

f. Infection

g. Cytokine dysregulation

h. Hormone imbalances

3. Metrics and fatigue

a. Statistical associations in SLE: depression, fatigue aerobic insufficiency, disordered sleep, high damage scores, inadequate perceived social support, pain

b. Measuring fatigue in clinical trials and surveys (fatigue severity scale is the best of 15 validated instruments for rheumatic diseases)

4. Management of fatigue

a. Treating underlying cause

b. Pacing activities, providing instruction in sleep hygiene and aerobic exercise

c. Offering emotional support

d. Avoiding stimulants unless in a supervised setting

Exercise, Physical Therapy, and Rehabilitation

Six well-designed studies have evaluated aerobic conditioning in patients with SLE. They concluded that aerobic capacity is decreased by 30% to 40% but does not necessarily correlate with disease activity or damage. However, SLE is associated with fatigue, cardiovascular functioning, obesity, bone mineralization, sleep, and quality of life.^10,¹¹ Exercise regimens improve physical functioning and fatigue.¹²^–¹⁴ The patient with SLE should remain physically active and avoid excessive bed rest. Exercises that strengthen muscles and improve endurance while avoiding undue stress to inflamed joints are desirable. Activities such as swimming, walking, low-impact aerobics, and bicycling should be encouraged. Recreational activities involving fine-motor movements and placing stress on certain ligamentous and other supporting structures (e.g., bowling, rowing, weight lifting, golf, tennis, jogging) should be considered on an individual basis. Exercises involving sustained isometric contractions increase muscle strength more than isotonic exercises (e.g., stretching, Pilates). Physical measures, such as the use of local moist heat or cold, decrease joint pain and inflammation. Many patients benefit from a whirlpool bath (Jacuzzi), hot tub, or therapy pool or from merely soaking in a tub of hot water.

Physical therapists instruct patients in strengthening and toning exercises, improved body mechanics, and gait training. No specific measures or treatment approaches are unique for patients with lupus. Joint deformities develop in approximately 10% of patients; physical and occupational therapies to minimize deformities are desirable in this group. Splints are useful for most patients with carpal-tunnel syndrome related to SLE. Corrective-tendon surgery and joint replacement are helpful in advanced cases of SLE.

Occupational therapists instruct patients in the principles of energy conservation and joint protection. They evaluate activities of daily living and suggest the use of devices or aids, such as wrist splints, comb handles, and raised toilet seats, when needed.

Vocational rehabilitation may be important in retraining a patient with SLE who can no longer work in the sun (e.g., farmer, construction worker, fisherman) or perform tasks requiring fine hand-motor function (e.g., computer workstation ergonomics).

Tobacco Smoke and Alcohol

Tobacco use can cause tissue damage by inducing apoptosis, altering cytokine and hormone balances, influencing immunogenesis of self-antigens and lymphocyte function that can, in turn, promote autoimmunity.¹⁵ Clinically, smoking impairs oxygenation, raises blood pressure, promotes the formation of autoantibodies, and worsens Raynaud phenomenon, among other adverse actions (Figure 47-1). Numerous reports correlate tobacco use with worse cutaneous lupus or disease activity than among nonsmokers.¹⁶^–¹⁸ Additional comparisons have confirmed that chronic cutaneous lupus is more common in smokers than in nonsmokers, as is SLE.¹⁹ Two epidemiologic surveys^19,²⁰ associate smoking with 2.3 and 6.69 odds ratios for developing SLE. Because tobacco smoke contains potentially lupogenic hydrazines, abstinence and avoiding second-hand smoke are both important. The efficacy of antimalarial medications may be decreased in smokers, perhaps as a result of the effect of tobacco on the cytochrome P450 enzyme system that metabolizes chloroquines.^21,²²

FIGURE 47-1 Effects of smoking on the immune system. CRP, C-reactive protein; ICAM-1, intracellular adhesion molecule 1; Ig, immunoglobublin; sTNFR, soluble tumor necrosis factor receptor; TNF, tumor necrosis factor.

(Reproduced with permission from Harel-Meir M, Sherer Y, Shoenfeld Y: Tobacco smoking and autoimmune rheumatic diseases. Nat Clin Pract Rheumatol 3:707–715, 2007.)

Although alcohol can worsen reflux esophagitis, which is common in patients with SLE, and is not advised in patients taking methotrexate, approximately 10 studies have addressed the issue with conflicting results. Moderate drinking might be protective for patients with SLE, but a metaanalysis of 7 case-controlled studies and 2 cohort studies found an overall 1.5 odds ratio for developing SLE among those who drink alcohol.^16,^17,^20,^23,²⁴

Weather and Seasons

Changes in barometric pressure can aggravate stiffness and aching in patients with inflammatory arthritis.²⁵ In other words, whether the climate is hot or cold or wet or dry, it does not influence joint symptoms; however, changes in the weather do aggravate joint symptoms (e.g., hot to cold or wet to dry). Patients with lupus are counseled to expect some increased stiffness and aching in these circumstances and not to assume that they have done anything wrong. Several surveys of seasonality and weather in patients with SLE have been conducted, but no conclusions have been independently confirmed other than to suggest that more flares and phototoxicity happen in the summer months and weakness, fatigue, and Raynaud phenomenon more often occur in the winter months.²⁶^–²⁸

Pain Management

Patients with lupus have increased prevalence of problems with pain management.^29,³⁰ Individuals with inflammatory arthritis respond poorly to analgesic medications that have no antiinflammatory effects. The use of morphine and codeine derivatives in patients with SLE should be limited to postoperative management and functionally limiting fixed mechanical deformities. These agents can induce dependence, have short-lived effects, and do not address SLE-related inflammation. Antiinflammatory drugs (e.g., salicylates, NSAIDs, corticosteroids) can be effective in treating pain symptoms in patients with SLE. Some patients with chronic pain that is unresponsive to simple measures should be referred to pain-management centers, which use measures such as acupuncture, electrical stimulation, biofeedback, psychological counseling, and physical therapy to alleviate pain and eliminate narcotic dependence. Anxiolytic measures that work with the mind-body connection are useful as well. Other causes of pain in patients with SLE include avascular necrosis, headache, steroid-induced hyperesthesia, and fibromyalgia.

Role of Stress and Trauma

In a general sense, certain forms of emotional stress, including depression and bereavement, as well as physical trauma can affect the immune system by being associated with decreased lymphocyte mitogenic responsiveness, lymphocyte cytotoxicity, increased natural killer (NK)–cell activity, skin homograft rejection, graft-versus-host response, and delayed hypersensitivity.^31,³² The clinical sequelae of stress are difficult to characterize and quantitate. Could the impairment in T-cell immune functions be responsible for a clinical flare of lupus that is mediated by B-cell hyperreactivity? Acute stress in patients with SLE may correlate with increased urine neopterin levels, interleukin (IL) 4 levels, decreased NK-cell response, and increased numbers of beta-2 adrenergic receptors on mononuclear cells with or without a clinical disease flare.^33,³⁴ However, evidence-based validation of this in a rigorous, reproducible clinical setting is lacking.

Can Stress Induce Lupus?

In 1955, McClary and colleagues ³⁵ first related the onset of disease to significant crises in interpersonal relationships in 13 of 14 patients with SLE. Subsequent reports have reinforced patient perceptions that stress caused their SLE, but the hypothesis remains unproven.

Can Stress Exacerbate Preexisting Systemic Lupus Erythematosus?

Ropes ³⁶ first addressed this question over 50 years ago and observed 45 serious disease flares in her 160-patient cohort study over a 40-year period. Of the 45 patients with serious disease flares, 41 believed that emotional stress precipitated their flare. The development and validation of quality-of-life inventories, fatigue questionnaires, and function scores have correlated disease activity with psychosocial stressors in a general way, but the mechanism by which this correlation may occur has not been elucidated.³⁷^–³⁹ A devastating earthquake was associated with disease improvement in one study, and no change in another.^40,⁴¹

Can Physical Trauma Cause or Exacerbate Systemic Lupus Erythematosus?

No evidence has shown that physical trauma is related to the causation or exacerbation of SLE. Chronic cutaneous lupus erythematosus can develop as a result of physical trauma; King-Smith ⁴² first observed this response to physical trauma in 1926. Approximately 2% of all chronic cutaneous lesions occur in areas of physical trauma.⁴³

In summary, several authors have implicated stress as a factor that can induce or exacerbate SLE. However, a definitive study using a large number of patients and control subjects with similar chronic illnesses is needed before the association can be considered established. Until then, stress reduction is both prudent and important.

How Important ARE Patient Compliance and Treatment Adherence?

Dr. C. Everett Koop, the former Surgeon General of the United States, is reported to have said, “Drugs don’t work in patients who don’t take them.”⁴⁴

Part of the patient educational session with a new patient with lupus must be a discussion relating to compliance. In the LUMINA Texas and Alabama–based cohort study, nearly one half of the patients were noncompliant. They tended to be young, unmarried, African American, and ill.⁴⁵ Adherence to treatment regimens tends to be problematic. One third of 195 patients of Canadian descent with lupus did not participate in mandated annual eye examinations to monitor antimalarial therapies.⁴⁶ Compliance problems among 112 patients with lupus in Detroit were related to depression, medication concerns, physical symptoms, short-term memory problems, and the need for child or elder care.⁴⁷ Other important factors include previous medication experiences, strong beliefs in alternative methods, communication issues, low educational levels, cultural concerns, very high rates of noncompliance in adolescents, and cost. The failure to comply with physician recommendations was shown to be the cause of renal failure in 5 of the 17 patients in a study conducted at the University of Toronto.⁴⁸ In Great Britain, the rate of compliance was treatment specific among 50 women with SLE, ranging from 41% for the use of sun protection to 83% for the use of hydroxychloroquine, 94% for the use of steroids, and 100% for the use of azathioprine therapy.⁴⁹ Ninety-five patients at the University of Cincinnati had a similar outcome when pharmacy refill records were examined using a statistically validated compliance metric.⁵⁰ Adherence to treatment plans is a critical component in managing SLE, and strategies to address this issue need to be more fully developed and implemented.