Discussion
In this retrospective cohort study, we assessed the effect of HCQ on
platelet counts in children with chronic ITP, in the context that HCQ
was usually used in patients with positive ANA and in combination with
other treatments. Our findings supported that HCQ was associated with
increased platelet counts in children with chronic ITP and suggested
that the baseline ANA positivity may be not associated with the efficacy
of HCQ.
Data from our study showed potential benefits from HCQ in treating
children with chronic ITP. Compared with patients who don’t receive HCQ
during the course, patients who received HCQ had a higher response rate
at the latest follow-up (69.0% vs. 48.3%; odds ratio, 2.39; 95% CI,
1.15 to 4.95). In our study, at 3 months from HCQ initiation, 21
(56.8%) patients responded, and 15 (40.5%) achieved CR/R at 1 year
from HCQ initiation. Previously, a study from Roche et al. reported a
1-year response rate of 56.5% in children with ITP10,
and a study from Brik-Simon et al. reported a higher response rate of
82.4% (14/17) in children with SLE-related ITP at 1-year after HCQ
initiation 9, 15. For adults, a study from Khellaf et
al. reported an overall response rate of 60% (24/40) with a median
follow-up of 64 months in ITP patients with ANA titer ≥
1:16016. Of note, results from above studies showed
that patients with manifestation associated with autoimmune diseases may
have a better response to HCQ, which was usually explained by the effect
of HCQ on immunomodulatory and the previously successful experience of
treating SLE patients with HCQ. However, our results showed that there
was no difference in symptoms and markers associated with autoimmune
diseases between chronic ITP patients with response to HCQ and those
without, indicating other potential mechanism of HCQ in treating
patients with ITP such as its effect on the autophagy and apoptosis of
megakaryocytes17, 18.
In patients who received monotherapy of HCQ, 10 of 14 (71.4%) had no
response to the treatment at 3 months after initiation, while in
patients who received HCQ combined with corticosteroids, 14 of 18
(77.8%) achieved response. Considering the failure of corticosteroids
in maintaining platelet counts before receiving HCQ and the low response
rate of HCQ used as a monotherapy in our study, we speculate that the
effectiveness of HCQ needs the facilitation of corticosteroids, which
was also noted by Mohammadpour et al. whose review noticed the role of
HCQ as a steroid-sparing agent in the treatment of ITP19. Furthermore, to assess the effect of HCQ in
treating ITP in the context that some patients receive HCQ combined with
other drugs, we conducted mixed-effect models and results revealed that
HCQ could facilitate increasing platelet counts after considering the
potential influence of concomitant treatments, sex, age, and ANA level
on platelet counts (mean difference between HCQ and non-HCQ groups:
23.82×109/L; 95% CI: 7.44 ~ 40.21).
Previously, researchers paid more attention to patients with positive
ANA and few studies analyzed the association between ANA and the effect
of HCQ in patients with ITP. In this study, we did not find interaction
effect of initial ANA level on the treatment efficacy of HCQ through
mixed-effect models. And there was no difference in ANA positivity
between patients with response to HCQ and those without. These findings
remind us that ANA positivity is not a completely reliable indicator for
the introduction of HCQ in patients with chronic ITP. And this might
support the use of HCQ in patients with ANA at a titer of less than
1:160 because they may also benefit from the treatment. However, the
insignificant interaction result should be interpreted with caution
because this study was not powered to find a significant interaction
effect. Larger sample studies are needed to explore the efficacy of HCQ
in ANA-negative ITP children and discuss its mechanism.
HCQ associated side effects were recorded in 6 patients (6/42, 14.3%),
and most of them (4/6,66.7%) received HCQ more than 2 years. Thus, we
should take caution when using HCQ for long-term treatment of children
with ITP. In children with proliferative lupus nephritis who were
treated with HCQ, Gheet et al. found that 3.3% of patients experienced
mucocutaneous alopecia, 10% of patients experienced hyperpigmentation,
and 6.7% of patients experienced retinopathy.20Cutaneous side effects due to HCQ can disappear within few weeks of
discontinuation,21 while retinopathy due to HCQ can be
irreversible.22, 23 In this study, we noticed that one
patient had no ophthalmologic monitoring after the discontinuation of
HCQ, reminding clinicians of the importance of patient education and
long-term follow-up. Besides, searching for effective monitoring means
of side effects will be helpful for the use of HCQ in a safe and
rational way.
This study had some limitations. Firstly, the dosage of drugs was not
taken into consideration in mixed-effects models due to missing data,
which was mainly restricted by its retrospective nature. Also, the
missing value of platelet counts at certain time made it difficult to
evaluate the response time of HCQ. In addition, the dosage of HCQ was
not consistent in each patient, which may lead to a potential bias when
we assessed the effect of HCQ on platelet counts.