Patient demographics and disease characteristics at baseline
Fifty-eight patients were included in the study. Twenty-six patients discontinued HCQ, and 32 patients on HCQ were matched at the time of discontinuation. Baseline characteristics are summarized in Table 1. There were no significant differences between the two groups with regard to age, gender, race/ethnicity, C3 and C4 levels, clinical SLEDAI score, proportion of patients with positive anti-dsDNA antibodies, or history of lupus nephritis. The duration of SLE was longer in the HCQ withdrawal group than in the HCQ continuation group (24.3 ± 10.6 years versus 17.8 ± 11.8 years, p=0.03). Patients who discontinued HCQ had a slightly lower number of accumulated ACR classification criteria than the comparator group (4.6 ± 0.9 vs. 5.4 ± 1.5, respectively, p=0.04). The proportion of patients on prednisone (7.7% versus 15.6%) and other immunosuppressants (15.4% versus 25%) were lower in the HCQ withdrawal group. C3 and C4 levels were marginally higher in the HCQ withdrawal group (108.1 ± 16.4 vs. 100.5±27.6 for C3; 26.0 ± 10.6 vs. 21.3 ± 10.3 for C4) as compared to the comparator group, with the proportion of patients with low C3 or C4 being higher in the HCQ continuation than in HCQ withdrawal group (14/32 [43.8%] vs. 3/25 [12%], respectively; p=0.02). The proportion of patients with type 2 diabetes mellitus (T2DM) at baseline was similar between the groups (7.7% of patients in the HCQ withdrawal group vs. 6.3% in the comparator group). A higher proportion of patients on statins in the HCQ withdrawal group was taking statins at baseline compared to the HCQ continuation group (5/26 [19.2%] vs. 3/32 [9.4%]).
Table 1. Baseline characteristics of the study subjects per group.
|
HCQ Withdrawal (N=26)
|
HCQ Continuation (N=32)
|
P value
|
Age (HCQ discontinued or matched)
|
60.4 ± 4.1
|
59.8 ± 4.3
|
0.53
|
Female gender
|
25 (96.2%)
|
31 (96.9%)
|
1.00
|
Race/Ethnicity
|
|
|
0.94
|
White
|
7 (26.9%)
|
11 (34.4%)
|
|
Black
|
8 (30.8%)
|
9 (28.1%)
|
|
Asian
|
6 (23.1%)
|
6 (18.8%)
|
|
Hispanic
|
5 (19.2%)
|
6 (18.8%)
|
|
Duration of SLE, yr*
|
24.3 ± 10.6 (n=25)
|
17.8 ± 11.8 (n=28)
|
0.03
|
Duration of HCQ use, yr**
|
13.0 (8-23, n=23)
|
14.0 (6-22, n=27)
|
0.70
|
Number of ACR criteria met*
|
4.6 ± 0.9
|
5.4 ± 1.5
|
0.04
|
History of arthritis
|
20 (76.9%)
|
23 (71.9%)
|
0.89
|
History of lupus nephritis
|
11 (42.3%)
|
14 (43.8%)
|
1.00
|
History of serositis
|
8 (30.8%)
|
10 (31.3%)
|
1.00
|
Complement, C3
|
108.1 ± 16.4 (n=20)
|
100.5 ± 27.6
|
0.12
|
Complement, C4
|
26.0 ± 10.6 (n=21)
|
21.3 ± 10.3
|
0.09
|
Low C3 or C4*
|
3/25 (12.0%)
|
14/32 (43.8%)
|
0.02
|
Presence of anti-dsDNA Ab
|
7 (28.0%, n=25)
|
9 (29.0%, n=31)
|
1.00
|
Immunosuppressive Use
|
4 (15.4%)
|
8 (25.0%)
|
0.52
|
AZA only
|
0
|
2 (6.3%)
|
|
MMF only
|
0
|
3 (9.4%)
|
|
MTX only
|
1 (3.8%)
|
1 (3.1%)
|
|
Other only†
|
2 (7.7%)
|
1 (3.1%)
|
|
Combination‡
|
1 (3.8%)
|
1 (3.1%)
|
|
Prednisone Use
|
2 (7.7%)
|
5 (15.6%)
|
0.44
|
Statin Use
|
5 (19.2%)
|
3 (9.4%)
|
0.45
|
Clinical SELENA-SLEDAI score
|
0.2 ± 0.8
|
0.2 ± 0.8
|
0.70
|
SELENA-SLEDAI score
|
0.9 ± 1.4
|
1.8 ± 1.8
|
0.08
|
Values are expressed as n (%) for categorical variables, mean ± SD (standard deviation) or median (interquartile range [IQR]) for continuous variables.
* Statistically significant difference by T-test or Mann Whitney U test, p<0.05
** Median (IQR)
† Any patient on a single immunosuppressant other than systemic steroids, azathioprine, mycophenolate mofetil and methotrexate.
‡ Any patient on combination therapy, excluding antimalarials and topical or systemic steroids.
ACR, American College of Rheumatology; Anti-dsDNA Ab, anti-double stranded DNA antibodies; AZA, azathioprine; HCQ, hydroxychloroquine; MMF, mycophenolate mofetil; MTX, methotrexate; SELENA-SLEDAI, Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index; SLICC, Systemic Lupus International Collaborating Clinics.
Withdrawal of HCQ does not significantly increase the risk of flares in patients over 55 with quiescent SLE
Five out of 26 patients in the HCQ withdrawal group (19.2%) and 5 out of 32 patients in the HCQ continuation group (15.6%) experienced a flare of any severity, corresponding to an estimated odds ratio of 1.28 (95% CI: 0.31, 5.30; p=0.73). After adjusting for years since diagnosis of SLE, low C3 or C4, number of ACR criteria, and SELENA-SLEDAI score (i.e., the baseline characteristics that differed between the HCQ withdrawal and continuation groups at the p <0.10 level in Table 1), results were similar (OR = 1.31 95% CI: 0.18, 9.49, p=0.78). The estimated odds ratio for flare from the propensity score analysis was lower (OR = 1.18; 95% CI: 0.23, 6.16, p=0.84). The Kaplan-Meier plots of time to flare for both the HCQ continuation and withdrawal groups are shown in Figure 1 (log-rank=0.67).
There were no severe flares during the 12 months following HCQ discontinuation or continuation. The rate of moderate flares was lower in the HCQ withdrawal group than in the HCQ continuation group (7.7% vs. 15.6%), corresponding to an unadjusted odds ratio of 0.45 (95% CI: 0.10, 2.72; p=0.37). After adjusting for propensity score, the estimated odds ratio for moderate flare was 0.50 (95% CI: 0.07, 3.82; p=0.50).
The clinical manifestations and treatment of flares are described in Table 2. Four patients in the HCQ withdrawal group developed cutaneous manifestations, including alopecia, pernio, discoid or malar rash. One of these patients also developed arthritis, and another patient had polyarthritis requiring methotrexate. In the HCQ continuation group, there were three patients with cutaneous flares (discoid rash and alopecia), two of which also had polyarthritis. One additional patient who continued HCQ had polyarthritis as the only clinical manifestation, and another patient had pericarditis in this group. No patient in either group developed new manifestations of lupus during the study period.
Table 2. Clinical manifestations and treatment of flares according to study group.
Patient
|
Time to flare (months)
|
Clinical manifestations
|
Flare (rSFI)
|
SELENA-SLEDAI score
|
Treatment
|
HCQ withdrawal group
|
1
|
2.5
|
Localized rash (discoid)
|
Mild
|
5
|
HCQ 400 mg/day
|
2
|
2.5
|
Localized rash (pernio) and arthritis (<3 joints)
|
Mild
|
8
|
None for 1 year, followed by HCQ
|
3
|
3
|
Arthritis (>3 joints)
|
Moderate
|
4
|
MTX 7.5-10 mg/week
|
14
|
6
|
Localized rash (malar) and alopecia
|
Mild
|
4
|
HCQ 400 mg/day
|
26
|
6
|
Extensive rash (discoid)
|
Moderate
|
2
|
HCQ 200 mg/day, followed by HCQ 400 mg/day
|
HCQ continuation group
|
28
|
5
|
Serositis (pericarditis)
|
Moderate
|
4
|
Pred 30 mg/day + MMF increased to 2 g/day
|
30
|
11
|
Arthritis (>3 joints)
|
Moderate
|
4
|
NSAIDs followed by Pred 20 mg/day
|
43
|
4
|
Alopecia and arthritis (>3 joints)
|
Moderate
|
6
|
HCQ 600 mg/day
|
49
|
3.5
|
Extensive rash (discoid) and alopecia
|
Moderate
|
7
|
HCQ 600 mg/day, followed by CQ 250 mg/TIW
|
54
|
8
|
Extensive rash (discoid) and arthritis (>3 joints)
|
Moderate
|
6
|
MTX 7.5 mg/week
|
CQ, chloroquine; HCQ, hydroxychloroquine; MMF, mycophenolate mofetil; MTX, methotrexate; NSAID, Non-steroidal anti-inflammatory drugs; Pred, prednisone; rSFI, revised version of the SELENA-SLEDAI Flare composite index; SELENA-SLEDAI, Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index; TIW, three times per week.
Reasons for HCQ discontinuation
The most common reason for HCQ discontinuation was retinal toxicity (11/26, 42.3%), followed by patient’s preference (9/26, 34.6%), other confirmed or suspected adverse effects (4/26, 15.4%), and ophthalmologist recommendation for macular degeneration (1/26, 3.8%) and rheumatologist recommendation for quiescent SLE (1/26, 3.8%). One patient discontinued HCQ for biopsy-proven cardiac toxicity. No lupus flares occurred in the patients who discontinued HCQ due to maculopathy or cardiotoxicity. Two patients in the HCQ continuation group developed maculopathy after the 12-month post-matching period, requiring discontinuation of the drug. As maculopathy was diagnosed after matching and chart reviewing process, and due to lack of follow-up after HCQ discontinuation, these patients were maintained in the HCQ continuation group.
Metabolic, cardiovascular, thrombotic outcomes and mortality
No patients in the HCQ withdrawal group (excluding patients with T2DM at baseline), and only one out of 30 patients in the comparator group developed T2DM during the 12 months following HCQ discontinuation or time of matching. There were no acute coronary syndromes, strokes, or other events associated with arterial thrombosis in either group during the 12-month study period. In the HCQ withdrawal group, one patient developed a postsurgical episode of unilateral lower extremity deep venous thrombosis and pulmonary embolism that was managed as a provoked venous thromboembolic event with 3 months of anticoagulation. One patient in the HCQ discontinuation group was started on a statin during the study period. There were no deaths during the 12-month post-matching period in any of the groups.