Introduction
Pharmacology
Mechanism of action
Effect on autoantigen presentation and autophagy
Effect on toll-like receptor signaling
Effect on cytokine production
Other effects
HCQ in lupus nephritis
HCQ in IgA nephropathy
Other potential indications for HCQ in nephrology
Adverse effects
Retinopathy
Cardiotoxicity and myopathy
Other side effects
Dosing of HCQ and monitoring of therapy
Evidence gaps, future directions and conclusions
S. No. | Author (year) | Study type | Participants, no | Summary of results |
---|---|---|---|---|
Renal effects | ||||
A. Reduction of proteinuria | ||||
1. | Kasitanon et al. [39] | Retrospective cohort | 29 patients with Class V LN | Patients on HCQ were more likely to achieve remission within 12 months, compared to those not on HCQ (64 vs. 22%, P = 0.036) |
2. | Mejia-Vilet et al. [40] | Retrospective cohort | 60 patients with Class V LN | Patients treated with antimalarials were more likely to achieve complete remission compared to those not on antimalarials (HR 2.46, 95% CI 1.08–5.64; P = 0.032) |
3. | Galindo-Izquierdo et al. [41] | Retrospective cohort | 3575 SLE patients (1092 patients with LN) | Those on antimalarials had higher complete remission rates (OR 1.61, 95% CI 1.10–2.36; P = 0.014) |
4. | Gheet et al. [43] | RCT | 60 children with Class III/IV LN | At 12 months, the cumulative probability of partial and complete remission was 40% and 60% in the HCQ arm, compared to 53.3% and 36.7% in the placebo arm (P = 0.002) |
B. Development of lupus nephritis | ||||
1. | Fessler et al. [37] | Prospective cohort (LUMINA) | 518 SLE patients | HCQ non-users had a higher risk of major organ involvement, such as nephritis (P < 0.0001) and central nervous system disease (P < 0.003) |
2. | Tsang-A-Sjoe et al. [102] | Prospective cohort | 190 SLE patients | Non-use of HCQ was associated with higher risk of LN (P = 0.024) |
3. | Galindo-Izquierdo et al. [41] | Retrospective cohort | 3575 SLE patients (1092 patients with LN) | Patients on antimalarials had lower frequency of lupus nephritis (OR 0.58, 95% CI 0.48–0.70; P < 0.001) |
C. ESKD/CKD progression | ||||
1. | Sisó et al. [45] | Retrospective cohort | 206 patients with LN | Patients on HCQ prior to diagnosis of LN had a lower frequency of creatinine values > 4 mg/dL (2 vs 11%, P = 0.029) and end-stage kidney disease (2 vs 11%, P = 0.044) in comparison with those never treated with HCQ |
2. | Pons-Estel et al. [38] | Prospective cohort | 256 patients with LN | Renal damage defined as eGFR < 50 mL/min, 24 h proteinuria ≥ 3.5 g and/or end-stage renal disease was less likely in those on HCQ (HR 0.12, 95% CI 0.02–0.97; P = 0.046) |
3. | Okpechi et al. [47] | Retrospective cohort | 42 patients with Class V LN | Patients who received HCQ had better renal survival compared with those who did not (P = 0.007) |
4. | Pokroy-Shapira et al. [46] | Prospective cohort | 256 SLE patients | Lower risk of CKD (stage 3 and above) was found with HCQ use (HR 0.4; 95% CI: 0.2–0.9, P = 0.02) |
5. | Kwon et al. [49] | Retrospective study | 52 LN patients | Use of HCQ, both length of treatment with HCQ (adjusted OR 0.974, 95% CI 0.951–0.998, P = 0.036) and cumulative dose of HCQ (log transferred value) (adjusted OR 0.485, 95% CI 0.262–0.896, P = 0.020) were inversely associated with aggravation of tubulointerstitial damage |
6. | Lee et al. [42] | Retrospective longitudinal cohort study | 90 patients with LN | On multivariate analysis, hydroxychloroquine use [odds ratio (OR) = 3.891, 95% confidence interval (CI) 1.196–12.653, P = 0.024], prolonged LN (OR = 0.926, 95% CI 0.874–0.981, P = 0.009) and high-grade tubular atrophy (OR = 0.451, 95% CI 0.208–0.829, P = 0.013) were associated with renal function recovery. During follow up, 25 patients reached end-stage renal disease (ESRD) |
7. | Wu et al. [50] | Retrospective analysis | 783 SLE patients | No significant difference in the risk of developing CKD among those using HCQ for > 90 days, compared to those who used it for < 90 days (HR 1.295, 95% CI 0.40–4.25) |
D. Renal flare | ||||
1. | Tsakonas et al. [44] | RCT | 47 patients with quiescent SLE | HCQ-continuation group, showed a reduced risk of renal flares as compared to the HCQ-withdrawal group (RR 0.26; 95% CI 0.03–2.54) at a follow-up of three years |
Extra-renal benefits | ||||
A. Mortality | ||||
1. | Alarcon et al. [103] | Nested case–control study within the LUMINA cohort | 608 SLE patients | HCQ users had lower mortality, compared to non-users (OR 0.13, 95% CI 0.05–0.30) |
2. | Sisó et al. [45] | Retrospective cohort | 206 patients with LN | HCQ exposure prior to LN diagnosis was associated with lower mortality rates (2 vs 13%, P = 0.029) |
3. | Shinjo et al. [104] | Prospective cohort | 1480 SLE patients | Antimalarial use was associated with lower mortality (HR 0.62, 95% CI 0.39–0.99) |
4. | Zheng et al. [54] | Retrospective cohort | 491 patients with LN | HCQ improved survival of patients with LN (HR for mortality 0.20; 95% CI 0.05–0.82, P = 0.026] |
5. | Mok et al. [53] | Prospective cohort | 803 SLE patients | The use of HCQ had a survival benefit in patients with SLE (HR for mortality 0.59, 95% CI 0.37–0.93) |
B. Infections | ||||
1. | Sisó et al. [45] | Retrospective cohort | 206 patients with biopsy-proven LN | Fewer infections among patients using HCQ before diagnosis of LN, compared to those not on HCQ (11 vs. 29%, P = 0.006) |
2. | Feldman et al. [51] | Retrospective cohort | 33,565 patients with SLE (7113 with LN) | HCQ users had a reduced risk of infection as compared to never users (HR 0.7, 95% CI 0.68–0.77) |
3. | Herrinton et al. [105] | Retrospective cohort | 3030 patients with SLE | On comparison with those on HCQ alone, the HR for infection was 3.9 (95% CI 1.7–9.2) for those on GC at a dose of ≤ 15 mg/day without HCQ (14 infections/252 patient years), while it was 0.0 (0 infections/128 patient-years) for those on a combination of HCQ and GC |
4. | Rúa-Figueroa et al. [106] | Retrospective cohort | 3658 SLE patients | Duration of HCQ use (months) was associated with lower risk of infections (HR = 0.99, 95% CI 0.997–0.999) |
5. | Pimentel-Quiroz et al. [52] | Prospective cohort | 1243 SLE patients | HCQ use was protective against serious infections (HR 0.69; 95% CI 0.48–0.99; P = 0.044) |
6. | Yeo et al. [107] | Case–control | 406 SLE patients; 58 Pneumocystis pneumonia (PCP) cases and 348 non-PCP controls matched by age, sex and disease-duration | Use of higher 3 months cumulative dose of HCQ was associated with a reduced risk of PCP (OR 0.69, 95% CI 0.21–2.24) |
C. Thrombosis | ||||
1. | Sisó et al. [45] | Retrospective cohort | 206 patients with biopsy-proven LN | Lower frequency of thrombosis among patients on HCQ (5 vs. 17%, P = 0.04) |
2. | Mok et al. [108] | Prospective cohort | 272 SLE patients | Patients on HCQ had fewer thrombotic complications (OR 0.17, 95% CI 0.07–0.44; P < 0.0001) |
3. | Ruiz-Irastorza et al. [109] | Prospective cohort | 232 SLE patients | HCQ was protective against thrombotic complications (HR 0.28, 95% CI 0.08–0.90) |
4. | Petri et al. [110] | Prospective cohort | 739 patients with SLE | Thrombosis rates were reduced by 13% for every 200 ng/ml increase in mean HCQ blood level (RR 0.87, 95% CI 0.76–1.00), P = 0.056) |
D. Lipid profile | ||||
1. | Wallace et al. [111] | Cross-sectional | 155 women with SLE or rheumatoid arthritis | HCQ was associated with lower cholesterol (P < 0.001), triglycerides (P < 0.001) and LDL (P < 0.001), irrespective of concomitant steroids |
2. | Kavanaugh et al. [112] | Pilot RCT | 17 SLE patients | HCQ was associated with a significant reduction in total cholesterol in patients with SLE |
3. | Pons-Estel et al. [38] | Prospective cohort | 256 patients with LN | Lower LDL-cholesterol was seen in patients receiving antimalarials (P = 0.016) |
4. | Chong et al. [55] | Cross-sectional study | 100 patients with LN | HCQ was associated with lower levels of total cholesterol (P = 0.025) and LDL (P = 0.045) |
5. | Meng et al. [113] | RCT | 72 SLE patients | Total cholesterol, triglycerides, low-density lipoprotein, and high-density lipoprotein were statistically different (P < 0.05) between the two groups |
E. Pregnancy | ||||
1. | Izmirly et al. [114] | Retrospective cohort | 257 pregnancies of anti-SSA/Ro-positive mothers with SLE | HCQ was significantly associated with a decreased risk of cardiac manifestations of neonatal lupus (OR, 0.23; 95% CI 0.06–0.92; P = 0.037) |
2. | Moroni et al. [56] | Prospective study | 71 pregnancies in 61 women with LN | Among pregnant women with lupus nephritis, HCQ users had an 85% reduction in the odds of having a small-for-gestational-age baby (OR 0.15, 95% CI 0.03–0.77; P = 0.0023) [56] |
3. | Seo et al. [115] | Retrospective cohort | 151 pregnancies in 122 SLE patients | HCQ was associated with lower risk of preeclampsia (OR 0.11, 95% CI 0.02–0.67) |
F. Disease Flares and steroid minimization/withdrawal | ||||
1. | Rothfield et. [116] | Retrospective study | 43 SLE patients | HCQ reduced the required dose of steroids (P < 0.05) and risk of flares (P < 0.05) |
2. | Pons-Estel et al. [38] | Prospective cohort (LUMINA) | 256 patients with LN | Hydroxychloroquine-recipients received lower mean glucocorticoid doses than non-recipients (P = 0.025) |
3. | Jorge et al. [95] | Retrospective cohort | 342 patients with SLE | HCQ dose of ≤ 5 mg/kg/day was associated with an increased risk of lupus flares (adjusted OR 1.98, 95% CI 1.03–3.79) |
4. | Fasano et al. [117] | Prospective cohort | 154 SLE patients | Longer duration of HCQ therapy was associated with a reduced risk of disease flare (HR 0.84, 95% CI 0.72–0.98; P = 0.03) after steroid withdrawal |
5. | Almeida-Brasil et al. [118] | Prospective cohort | 1460 patients with SLE | Higher risk of SLE flare after HCQ reduction (HR 1.20, 95% CI 1.04–1.38) or HCQ discontinuation (HR 1.56, 95% CI 1.31–1.86), compared to HCQ maintenance |
6. | Zen et al. [119] | Prospective cohort | 513 SLE patients (270 with LN) | Patients treated with HCQ had a reduced risk of flares after withdrawal of immunosuppression (OR 0.194, 95% CI 0.038–0.978; P = 0.047) |