Lupus: Evolving Treatment Approaches

Jeannette Y. Wick, RPh, MBA, FASCP
Published Online: Monday, May 16, 2011

With its symptoms of nonspecific pain, swelling, and fatigue, lupus can be difficult to diagnose and complicated to treat.


Nonspecific pain, unexplained swelling, profound fatigue—these are symptoms of many disorders, which explains why a definitive diagnosis of lupus can take years to make. Up to 50% of lupus patients see 3 doctors over a 4-year period before a correct diagnosis is made. Some report seeing more than 10 doctors before receiving an accurate diagnosis.1

For many of the one-half million people 2 with lupus, the diagnosis is a relief— because their symptom constellation now has a name—but it’s also a heavy burden, because the disease is agonizingly chronic. Although this Pharmacist to Pharmacist will discuss the most common form of lupus—systemic lupus erythematosus (SLE), which accounts for 70% of all lupus cases—4 other types of lupus are known (see Table 12-5).

Anyone can get lupus, but African American, Hispanic, Asian, and Native American women have 2 to 3 times the risk. Approximately 40% of SLE patients never develop severe system complications, but for the remainder, at least 1 major organ is affected. Additionally, 20% of all SLE sufferers also have comorbid discoid lupus.1,6

Clinical Presentation

SLE’s clinical presentation is usually murky and often complicated by coexistence of acute activity, chronic organ damage, drug-induced side effects, infection, and other conditions. The American College of Rheumatology (ACR) developed and revised criteria for SLE classification,3,4,7 but most experts agree these criteria desperately need revision. Table 23,4,7 lists the 11 criteria that may indicate SLE; patients must have 4 of these to be diagnosed definitively.

The most common symptom at presentation is fatigue; many patients experience generalized arthralgia with early morning stiffness and some will develop mild joint swelling. Other nonspecific symptoms include fever of unknown origin, alopecia, pale or blanching digits, weight loss, headaches, dizziness, depression, and confusion. No specific test confirms lupus, although positive antinuclear antibody (ANA), antiphospholipid antibody, and/ or the antidoublestranded-DNA (antidsDNA) tests are frequently positive.3,4,7

The ACR criteria are more likely to be useful in assessing severe SLE or SLE of longer duration, so clinicians should suspect SLE in patients even if they do not meet 4 of the 11 criteria. Symptoms relapse and flare, and many patients’ symptoms change over time. The average time from diagnosis to death is 20 years. In lupus patients, the leading cause of death is infection, followed by heart disease; deaths due to active lupus are rare.2

In women of reproductive age, presentation may start with recurrent miscarriages. These patients’ offspring are at increased risk of stillbirth, premature delivery, intrauterine growth restriction, (rarely) neonatal lupus syndrome, and congenital heart block. Women with lupus may enter menopause prematurely, and their risk for cardiovascular incident is 50 times higher than for other women.8-10

Treatment

Treatment goals include preventing flares, treating flares promptly as they occur, and reducing organ damage and other problems. Lupus’s symptoms are the result of autoantibodies that can mediate tissue damage in multiple organs. SLE’s etiology is still unknown, but we do know treatments targeting B-cells or limiting their function have provided some degree of therapeutic benefit. Current therapies for SLE target nonspecific sites and include:

• nonsteroidal anti-inflammatory drugs for relief of mild-to-moderate pain

• long-term use of anti-malarials, most often hydroxychloroquine, to lower antibody production, protect against damaging effects of ultraviolet rays, and improve skin lesions

• glucocorticosteroids to stimulate nonspecific immunosuppression

• cytotoxic/immunosuppressive drugs (azathioprine, methotrexate, or cyclophosphamide) in active SLE cases resistant to corticosteroids, again for their nonspecific immunosuppression

Unfortunately, these agents’ well-documented side effect profiles are problematic and can reduce quality of life for lupus patients.

Despite considerable interest in this disease, no new agents have been approved to cure or significantly change the course of SLE. A review article by Daniel F. Wallace 11 summarizes what he calls recent findings about ameliorative agents for symptoms (but not the disease itself) succinctly:

• Low-dose dietary supplementation with omega-3 fish oils in patients with mild SLE activity has a measureable therapeutic effect on disease activity, and improves endothelial function and reduces oxidative stress.12

• Methotrexate can be considered steroid sparing in participants with moderately active lupus by lowering daily prednisone dose and slightly decreasing lupus disease activity.13

• As induction therapy for SLE nephritis, daily oral mycophenolate mofetil is equivalent to intravenous cyclophosphamide and superior to azathioprine for maintenance.14

• Topical pinecrolimus and tacrolimus are safe and effective for chronic cutaneous SLE, and offer an alternative to topical steroids.15

• In very small studies, leflunomide improved SLE arthritis.16,17

• Oral prasterone (dehydroepiandrostrone) has modest effects at best in mild SLE and may diminish fatigue and bone demineralization; it, too, has steroid-sparing properties. The FDA has not approved prasterone for SLE, and research continues.18

The Future: Monoclonal Antibodies

With the growth in researchers’ ability to target therapy against specific antigens, there is hope for more effective treatments for SLE. The FDA is currently reviewing belimumab, the first of a new class of B-cell-targeted biologics known as B-lymphocyte stimulator (BLyS)–specific inhibitors. BLyS-specific inhibitors block a naturally occurring protein (BLyS) involved in autoantibody production, and seem to decrease the number and severity of SLE flares.19

Another experimental monoclonal antibody, epratuzumab, has shown promise in early clinical studies. It binds to the B-cell CD22 protein.20-22

Conclusion

After decades of uncertainty and limited progress in the diagnosis and treatment of SLE, researchers are now making real gains in understanding more about this disease. With several targeted agents in the pipeline at this time, there is greater hope that lupus patients will have more effective therapies available soon. PT


Ms. Wick is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health, Bethesda, Maryland. The views expressed are those of the author and not necessarily those of any government agency.


References

1. Phalen KF. Progress on lupus: new clarity for a baffling disease. www.ama-assn.org/amednews/2002/10/07/hlsa1007.htm. Accessed January 12, 2011.

2. Wallace DJ, Hahn BH, eds. Dubois’ lupus erythematosus. Philadelphia: Lippincott Williams & Wilkins; 2007.

3. Lupus Foundation of America. Lupus fact sheet.  www.lupus.org. Accessed January 12, 2011.

4. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271-1277.

5. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725.

6. Rubin RL. Drug-induced lupus.Toxicology. 2005;209:135-147.

7. Petri M. Review of classification criteria for systemic lupus erythematosus. Rheum Dis Clin North Am.2005;31:245-254, vi.

8. Ruiz-Irastorza G, Khamashta MA. Lupus and pregnancy: integrating clues from the bench and bedside [published online ahead of print December 15, 2010]. Eur J Clin Invest.

9. Smyth A, Oliveira GH, Lahr BD, Bailey KR, Norby SM, Garovic VD. A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol. 2010;5:2060-2068.

10. Haque S, Bruce IN. Therapy insight: systemic lupus erythematosus as a risk factor for cardiovascular disease. Nat Clin Pract Cardiovasc Med. 2005;2:423-430.

11. Wallace DJ. Advances in drug therapy for systemic lupus erythematosus. BMC Med. 2010;8:77.

12. Wright SA, O’Prey FM, McHenry MT, et al. A randomised interventional trial of omega-3-polyunsaturated fatty acids on endothelial function and disease activity in systemic lupus erythematosus. Ann Rheum Dis. 2008;67:841-848.

13. Fortin PR, Abrahamowicz M, Ferland D, Lacaille D, Smith CD, Zummer M; Canadian Network For Improved Outcomes in Systemic Lupus. Steroid-sparing effects of methotrexate in systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2008;59:1796-1804.

14. Appel GB, Contreras G, Dooley MA, et al; Aspreva Lupus Management Study Group. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.J Am Soc Nephrol. 2009;20:1103-1112.

15. Lampropoulos CE, D’Cruz DP. Topical calcineurin inhibitors in systemic lupus erythematosus. Ther Clin Risk Manag. 2010;6:95-101.

16. Remer CF, Weisman MH, Wallace DJ. Benefits of leflunomide in systemic lupus erythematosus: a pilot observational study. Lupus. 2001;10:480-483.

17. Tam LS, Li EK, Wong CK, Lam CW, Szeto CC. Double-blind, randomized, placebo-controlled pilot study of leflunomide in systemic lupus erythematosus. Lupus. 2004;13:601-604.

18. Sánchez-Guerrero J, Fragoso-Loyo HE, Neuwelt CM, et al. Effects of prasterone on bone mineral density in women with active systemic lupus erythematosus receiving chronic glucocorticoid therapy. J Rheumatol. 2008;35:1567-1575.

19. Wiglesworth AK, Ennis KM, Kockler DR. Belimumab: a BLyS-specific inhibitor for systemic lupus erythematosus [published online ahead of print November 16, 2010]. Ann Pharmacother. 2010;44:1955-1961.

20. Traczewski P, Rudnicka L. Treatment of systemic lupus erythematosus with epratuzumab. Br J Clin Pharmacol. 2011;71:175-182.

21. Daridon C, Blassfeld D, Reiter K, et al. Epratuzumab targeting of CD22 affects adhesion molecule expression and migration of B-cells in systemic lupus erythematosus [published online ahead of print November 4, 2010]. Arthritis Res Ther. 2010;12:R204.

22. Mok MY. The immunological basis of B-cell therapy in systemic lupus erythematosus. Int J Rheum Dis. 2010;13:3-11.



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