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Objectives: To analyze the impact of the serum level of hydroxychlroquine (OHCLQ) on the QTc interval of the ECG, in patients with rheumatic systemic autoimmune diseases (SARD), treated with this drug for a long time
Methods: Retrospective study, among patients with SARD, treated with OHCLQ ≥ 1 year, dose 200-400 mg/day. Serum OHCLQ level was measured by liquid chromatography and QTc interval by ECG (Welch Allyn 200; SF, N York, USA). Two control groups for QTc are included: Group-1: patients with SARD not treated with OHCQ; Group-2: healthy subjects without SARD. In both, weight and current treatment and an ECG were recorded.
In patients with SARD was collected: 1) Epidemiological data: age, sex, weight, concomitant diseases, current treatment. 2) SARD: diagnosis, year of diagnosis, disease evolution time, clinical and autoimmunity data, treatment and dose. 3) OHCLQ: time in treatment, toxicity, symptoms (dizziness, syncope) and serum level. 4) ECG; QTc and heart rate (HR).
Results: 65 patients treated with OHCLQ, mean 10.8 (6.5) years are included, diagnosed with SLE: 43 (66%) patients, RA: 15 (23%), palindromic rheumatism: 4 (6%), SS1º: 2 (3 %) and PsA: 1 (1%). 63 (97%) patients are women, with a mean age (SD): 58 (14.7) years, weight: 69 (15) kg. Mean dose of OHCLQ: 221 mcg/L (64), 3.24 (1) mg/kg/day.
Mean serum OHCLQ level: 166 mcg/L (6.5): 18 (28%) patients with level <100 mcg/L (mean: 63 [0.7] mcg/L) and 47 (72%) with level >100 mcg/L L (mean 195 mg/XX [94]). On ECG, mean HR: 69 bpm (10) and mean QTc interval: 429.7 (84) ms, prolonged (>440 ms) in 23 (35%) of the patients.
12 (18%) patients reported dizziness at some time and 29 (45%) were being treated with a drug related to the risk of QTc prolongation: Possible (P: at authorized doses no risk of TdP): 1 (2%) patient, Conditional (C: risk under excessive dose, interactions): 13 (20%), P+C: 4 (8%), C+C: 11 (17%).
When comparing the mean QTc result of the group with OHCLQ and the control groups without OHCLQ (n: 41), the QTc is higher (p=0.062) than the group of healthy subjects (n: 23) and without differences with the control group EASR (n: 18), not treated with OHCLQ (p=0.70). Among patients with OHCLQ level >100 mcg/L (n: 47) vs <100 mcg/L (n: 18), patient weight (p=0.012), level (p<0.0001), and dose in mg /kg (p=0.03), is significantly higher at levels >100 mcg/L. No relationship was observed between the OHCLQ level and the QTc result.
In 6 (9%) patients the OHCLQ dose is >3 mg/kg (mean: 5.35 [1] mg/kg, HR: 73 [14] bpm, OHCLQ dose: 367 [71] mcg/L), no detected significant differences in QTc (1 patient presented QTC >440). In patients with QTc >440 ms, older patient age, QTc result, and heart rate were significant. However, the dose in mg/kg of OHCLQ was lower in the group with QTc <440 ms (p=007).
Conclusion: In patients with SARD treated with maintenance doses of OHCLQ of about 3 mg/kg/day, 1) The serum level of OHCLQ is not associated with QTc prolongation on the ECG. 2) QTc is significantly related to age and heart rate. 3) The EASR per se does not affect the QTc result.
Characteristics of patients with QTc greater than or less than 440 ms and with an OHCLQ level greater than or less than 100 mcg/L.
| QTc >440 ms N: 23 (35%) | QTc ≤440 ms N: 42 (65%) | p | |
|---|---|---|---|
| Age, mean (SD) | 64 (15) | 56 (14.5) | 0.007 |
| Female, n (%) | 22 (96) | 40 (95) | 0.85 |
| QTc, mean (SD) | 454 (23.9) | 416 (23.7) | 0.0001 |
| Symptoms, n (%) | 4 (17) | 4 (10) | 0.77 |
| Heart rate, mean (SD) | 74 (10.3) | 67 (10.3) | 0.016 |
| Weight, mean (SD) | 69 (15.1) | 67 (15.6) | 0.61 |
| Risk factors QTc prolongation | |||
| Concomitant disease, n (%) | 4 (17) | 4 (10) | 0.77 |
| Drugs, n (%) | 14 (61) | 15 (36) | 0.18 |
| OHCLQ; | |||
| Dosis, mean (SD) | 209 (64.5) | 229 (15.8) | 0.15 |
| Mg/kg OHCLQ, media (SD) | 2.91 (1.06) | 3.43 (1.08) | 0.07 |
| Years in treatment, mean (SD) | 9.3 (6.6) | 10.5 (6.5) | 0.48 |
| OHCLQ serum level, media (SD ) | 174.27 (94.6) | 162,4 (80) | 0.51 |
| OHCLQ >100 mcg/L | OHCLQ ≤100 mcg/L | ||
| N: 47 (72% ) | N: 18 (28% ) | p | |
| OHCLQ serum level, mean (SD) | 166 (94) | 63 (96.5) | 0.0001 |
| QTc, mean (SD) | 430 (24) | 431 (23) | 0.87 |
| Dosis mg, mean (SD) | 221 (65) | 208 (66.5) | 0.48 |
| Mg/kg OHCLQ, mean (SD) | 3.32 (1.1) | 2.65 (1.08) | 0.03 |
| Years in OHCLQ, mean (SD) | 10.8 (6.8) | 11.5 (6.9) | 0.71 |
| Weight, mean (SD) | 69 (15.3) | 80 (15.2) | 0.012 |
Acknowledgements: El estudio fue apoyado con una beca de investigación de la Asociación para la Investigación en Reumatología de la Marina Baixa (AIRE-MB).
Disclosure of Interests: None declared