C S L C I E N N I A C R A I L O

1. TREATMENT What conservative SLE therapy will best alleviate cutaneous and rheumatic symptoms, and prevent progression to organ damage in patients with mild SLE? C S L C I E N N I A C R A I L O Search Terms: (PubMed) Population – patients with mild SLE Intervention – conservative therapy Outcome – alleviate symptoms and prevent progression Journal Article: • Systemic Lupus Erythematosus in Three Ethnic Groups: Association of Hydroxychloroquine Use with Reduced Risk of Damage Accrual • by • Barri J. Fessler, Graciela S. Alarcón, Gerald McGwin, Jr., Jeffrey Roseman, Holly M. Bastian, Alan W. Friedman, Bruce A. Baethge, Luis Vilá, and John D. Reveille, for the LUMINA Study Group • From • ARTHRITIS & RHEUMATISM • Vol. 52, No. 5, May 2005, pp 1473–1480 S E A R C H

3. Is the objective of the article on harm similar to your clinical dilemma? Yes. The article’s objective is to examine whether hydroxychloroquine (HCQ) usage is associated with a reduced risk of organ damage in systematic lupus erythematosus (SLE). Given that patient in the case has mild SLE (no organ damage), it can be said that this article is applicable since it explores the benefits and risks of a particular treatment (HCQ) on nonlife-threatening SLE. Moreover, the article can help us to assess whether the said treatment is alleviates the symptoms of the patient and prevents further damage. (page 1473, 1st paragraph) R E L E V A N C E

4. Was it randomized? Was randomization concealed? The study was a retrospective cohort, following the LUMINA (Lupus in Minorities, Nature versus Nurture) project of the University of Alabama, a longitudinal study of outcome in SLE patients. Patients were not randomized into treatment options as this would be unethical in the treatment of SLE. (p.1474, 4th paragraph) However, to address the concern regarding nonrandom treatment assignment, propensity scoring was calculated to adjust for confounding factors that may influence the accrual of damage. (p.1474, 2nd column, 1st paragraph Was the follow-up sufficiently long and complete? V A L I D I T Y G U I D E S • The LUMINA cohort, which was 12 years in operation as of the year the study was made, had a follow-up every 6 months for 1 year after entry, and then annually thereafter. The study reviewed all medical records for these follow-ups. (p.1474, 2nd column, under study population)

6. Was the data analyzed on an intention-to-treat basis? • Randomization of patients into groups was not done. However, the patients were still divided into hydroxychloroquine users at time 0 of the cohort, and nonusers at time 0. The same patients were analyzed in their respective groups all throughout the study. (p.1475, table 1) Was there adequate blinding of subjects and researchers? V A L I D I T Y G U I D E S • Blinding was not done in the study. It was not feasible to blind the patients with SLE to their medications, in this case, hydroxychloroquine. There was no indication in the study that the investigators were blinded to the patients’ exposure.

7. Were there similar baseline characteristics in each group? • Yes. And these baseline characteristics were all accounted for in the analysis of results. (p.1475, table 1) These variables, called covariates, are measured prior to the start of the treatment, and hence unaffected by it. Groups treated equally other than intervention? V A L I D I T Y G U I D E S • As SLE presents with various signs and symptoms in different patients, some patients in the LUMINA cohort has used other treatment drugs. However, these variables (cited in Table 1), also called covariates, were balanced by propensity scoring, which is a device for constructing matched pairs or matched sets / strata in the absence of random assignment (Rosenbaum 1999). Thus, both groups were treated equally other than in the usage of HCQ.

9. How large was the treatment effect? • The treatment goal for a patient with mild SLE is to reduce symptoms without organ damage. Treatment effect was measured in this study using hazard ratio (HR), a type of relative risk that describes the outcome of therapeutic trials to answer to what extent the treatment can shorten the duration of the illness. In the study, HR represented the probability of developing new damage. HR was used as a result of time-to-event curves analyzed by Cox proportional hazards regression to evaluate the effect of several risk factors on damage accrual. With hydroxychloroquine use of all the patients (with or without damage at time 0), the HR for new damage after adjustment for the propensity score was 0.73. (page 1477, 1st column, 1st paragraph; and table 3). The hazard risk reduction was 0.27. C L I N I C A L I M P O R T A N C E How precise is the estimate of the treatment effect? • As seen in Table 3 (page 1477), the confidence interval is 0.52-1.00 with a p value of 0.05. The CI range is quite narrow, suggesting that the result is precise, supported by the p value, which is <0.1.

10. 0.75 0.625 0.625 0.5625 Experimental Group 0.50 0.375 Control Group Baseline

11. RRR As time progresses, RRR increases. The percent reduction of death increases given the duration of tx. ARR As time progresses, ARR increases. Death is prevented more in patients taking HCQ. **CER & EER Patients who are taking HCQ have less propensity to develop new damage due to SLE. NNT As time progresses, NNT decreases. After 8 years, 5 patients must be treated in order to prevent one death.

13. Can the results be applied to my patient care? • Yes. The patients included in the study met the American College of Rheumatology criteria for diagnosis of SLE. Likewise, the demographic (age and sex) and clinical characteristics of the subjects are comparable to the patient in the case. The results of this study can be applied to the patient by the virtue of similarity, both in the diagnosis (SLE) and the different criteria mentioned above. That is, since the patient’s case is similar, if not, identical to the subjects in the study, the results regarding the efficacy of the treatment regimen can be applied to the patient. (p.1476, results, 1st paragraph). There are not much differences between the patient in the case and those in the study except for extent of SLE manifestations. A P P L I C A B I L I T Y Were all clinically important outcomes considered ? • Yes. Results revealed that among the 518 subjects, 56% were treated with HCQ at the study enrolment. The patients who were not treated had higher SLAM and SDI scores which signify that the untreated patients were significantly more likely to have major organ involvement such as renal disease or CNS disease. Thus, both benefits and risks (interpreted in hazard ratio) alike were accounted for in the study.

14. Is treatment feasible? Yes. Hydroxychloroquine is readily available, and is one of the main therapies especially for mild SLE. Patient preferences • As the patient has no life-threatening symptoms yet, she would opt to choose this drug because it alleviates symptoms and prevents organ damage accrual. A P P L I C A B I L I T Y Benefits vs. Harms • The use of HCQ is ideal for her case as it useful in the management of mucocutaneous manifestations and arthritis, and prevents progression to organ damage. It has also been shown to reduce serum cholesterol levels, protect against osteoporosis in corticosteroid-treated patients, and decrease the frequency of lupus flares. However, constant eye check-up is needed because of the risk of retinal toxicity. • .

15. References: • Fauci, Braunwald, et al. 2007. Harrison’s Principles of Internal Medicine, 17th ed. • Rosenbaum PR and Joffe MM. 1999. Invited Commentary: Propensity Scores. American Journal of Epidemiology 150(4):327-333. • Spruance SL, Reid JE, Grace M and Samore M. 2004. Hazard Ratio in Clinical Trials. Antimicrobial Agents and Chemotherapy 48(8):2787-2792. • http://www.lupus.org/webmodules/webarticlesnet/templates/new_magazineback.aspx?articleid=2478&zoneid=67