A Long-Term Study of Hydroxychloroquine Withdrawal on Exacerbations in Systemic Lupus Erythematosus

Abstract

The ability of antimalarials to moderate severe disease activity in systemic lupus erythematosus (SLE) is plausible but undemonstrated. We evaluated the long-term effectiveness of maintaining treatment with hydroxychloroquine sulphate (HCQ) to prevent major flares in quiescent SLE. Forty-seven patients with quiescent SLE who had been randomized to take HCQ (n = 25) or placebo (n = 22) as part of a 24-week withdrawal trial were evaluated for an additional 3 years. The primary outcome was time to a major flare of SLE which resulted in either the institution of or an increase in the current dosage of prednisone of 10 mg/day or more, or institution of therapy with immunosuppressive agents. Secondary outcomes included the specific subtype of these major flares (glomerulonephritis, vasculitis or other) and hospitalization for an exacerbation of SLE. An intent-to-treat analysis was conducted.

Over the 42 months of study, 11 of 22 (50%) patients randomized initially to placebo, and seven of 25 (28%) patients randomized to continue treatment experienced a major flare. The relative risk of major flare for those randomized to continue HCQ compared with controls was 0.43 (95% CI: 0.17, 1.12). The relative risks for subtypes of flares were 0.26 (95% CI: 0.03, 2.54) for nephritis, 0.51 (95% CI: 0.09, 3.08) for vasculitis and 0.65 (95% CI: 0.17, 2.41) for flares characterized by other symptoms. The relative risk of hospitalization for major flare for patients randomized to continue hydroxychloroquine was 0.58 (95% CI: 0.13, 2.60). While the results are not statistically significant, they are compatible with the clinical belief that HCQ has a long-term protective effect against major disease flares in SLE and suggest that on average, HCQ use reduces major flares by 57% (95% CI: 83% reduction to 12% increase).

Keywords

systemic lupus erythematosus hydroxychloroquine nephritis vasculitis major flare

Get full access to this article

View all access options for this article.

References

The Canadian Hydroxychloroquine Study Group . A randomized trial of the effect of withdrawing hydroxychloroquine sulphate in systemic lupus erythematosus . N Engl J Med 1991; 324: 150–154 .

Rudnicki RD , Gresham GE , Rothfield NF . The efficacy of antimalarials in systemic lupus erythematosus . J Rheumatol 1975; 2: 323–330 .

Dubois EL . Antimalarials in the management of discoid and systemic lupus erythematosus . Semin Arthritis Rheum 1978; 8: 33–51 .

Ziff M , Esserman P , McEwan C . Observations on the course and treatment of systemic lupus erythematosus . Arthritis Rheum 1958; 1: 332–350 .

Fox RI , Kang H-I . Mechanism of action of antimalarial drugs: inhibition of antigen processing and presentation . Lupus 1993; 2(Suppl 1): S9–S12 .

Sperber K et al. Selective regulation of cytokine secretion by hydroxychloroquine: Inhibition of IL-1 and IL-6 by monocytes and T-cells . J Rheumatol 1993; 20: 803–808 .

Wallace DJ et al. The effect of hydroxychloroquine therapy on soluble accessory factors and cytokines in systemic lupus erythematosus . J Rheumatol 1994; 21: 375–376 .

Wallace DJ: Antimalarial drugs . In: Wallace DJ , Hahn BH (eds). Dubois' Lupus Erythematosus (4th edn). Philadelphia, Lea 573-573.

Wallace DJ . Antimalarials agents and lupus . Rheum Dis Clin North Am 1994; 20: 243–263 .

10.

Tan EM et al. The 1982 revised criteria for the classification of systemic lupus erythematosus . Arthritis Rheum 1982; 25: 1271–1277 .

11.

Borenstein M . The case for confidence intervals in controlled trials . Controlled Clin Trials 1994; 15: 411–428 .

12.

Kaplan EL , Meier P . Non-parametric estimation from incomplete observations . J Am Stat Assoc 1958; 53: 457–481 .

13.

Cox DR . Regression models and life tables . J R Stat Soc (series B) 1972; 34: 187–220 .

14.

Meenan RF , Gertman PM , Mason JH . Measuring health status in arthritis: the arthritis impact measurement scales . Arthritis Rheum 1989; 23: 146–152 .

15.

Urowitz MB , Gladman DD , Tozman EC , Goldsmith CH . The lupus activity criteria count (LACC) . J Rheumatol 1984; 11: 783–787 .

16.

Bombardier C et al. and the committee on prognosis studies in SLE. Derivation of the SLEDAI: a disease activity index for lupus patients . Arthritis Rheum 1992; 35: 1630–1640 .

17.

Meinão IM et al. Controlled trial with chloroquine diphosphate in systemic lupus erythematosus . Lupus 1996; 5: 237–241 .

18.

Feinstein AR . Clinical Epidemiology. The Architecture of Clinical Research. WB Saunders Co., Philadelphia , 1985.

19.

Swaak et al. Systemic lupus erythematosus II. Observations on the occurrence of exacerbations in the disease course: Dutch experience with 110 patients studied prospectively . Ann Rheum Dis 1989; 48: 455–460 .

20.

Petri M , Genovese M . Incidence of 5 risk factors for hospitalizations in systemic lupus erythematosus: a prospective study of the Hopkins lupus cohort . J Rheumatol 1992; 19: 1559–1565 .

21.

Clarke AE et al. A Canadian study of the total medical care costs for patients with systemic lupus erythematosus and the predictors of costs . Arthritis Rheum 1993; 36: 1548–1559 .

22.

McInnes PM et al. The economic impact of treatment of severe lupus nephritis with prednisone and intravenous cyclophosphamide . Arthritis Rheum 1994; 37: 1000–1006 .