Clinical efficacy of intravenous ferric carboxymaltose in restless legs syndrome patients: An observational study

INTRODUCTION

Willis–Ekbom disease is a sensorimotor disorder that is commonly addressed as restless legs syndrome (RLS). Although RLS primarily affects legs, but in some cases the symptoms can also occur in arms, neck, trunk etc.^[1] RLS presents with varied presentations and levels of morbidity and thus is often misdiagnosed.^[1] According to population-based studies, the prevalence of 5–10% has been reported in Western countries, while it is much lower in India and many Asian countries.^[2-5]

Genetic variations, abnormalities of iron metabolism, dysfunction of the dopaminergic system, and involvement of the central opiate system have been suggested as a pathophysiological basis for the occurrence of RLS.^[6] Dopaminergic dysfunction due to central iron deficiency is one of the popular hypotheses for RLS pathophysiology.^[6] Iron is a cofactor for tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis it is deficiency causes malfunctioning of the dopamine transporter system, leading to a reduction in dopamine production in the brain which further manifests as symptoms of RLS.^[6] Although dopaminergic agonists are the first-line treatment for RLS, almost 30% of patients experience augmentation. Studies by Trenkwalder et al. and Frauscher et al. have shown that low ferritin levels can worsen augmentation during dopaminergic therapy.^[7,8] An association between low cerebrospinal fluid ferritin levels with RLS symptomatology is proven in several trials demonstrating the effect of oral and intravenous (IV) iron showing variable results.^[9] Nordlander first demonstrated that IV iron therapy results in remission of symptoms for RLS patients with iron deficiency.^[10] Various studies have used IV dextran, IV sucrose, and IV carboxymaltose to treat RLS.^[11-13] Oral iron therapy is associated with various side effects, which include bloating, diarrhea, heartburn, nausea, and constipation. These side effects often result in poor compliance. Parenteral iron formulations include iron sucrose, iron dextran, and the latest new parenteral formulation is ferric carboxymaltose (FCM), which is a dextran-free type 1 iron complex. Iron sucrose is safe but its use is limited as the maximum permissible dose is 300 mg per sitting or up to 600 mg per week. Hence, iron sucrose needs to be administered multiple times during the treatment period. FCM offers an advantage as large dose up to 1000 mg can be given in a single sitting. Needs of fewer infusions and that also for short duration offer the advantage of using FCM over other formulations. FCM is convenient to use and offers potentially good compliance. Allergic reactions are less with FCM as compared to iron dextran. FCM is more expensive than other formulations, but as lesser number of infusions are required, so overall leads to cost savings only. Also, because of its macromolecular structure, i.e., ferric hydroxide carbohydrate complex, it results in slow and controlled release of the iron in the brain without associated risk of release of large amounts of ionic iron in the serum. Although IV iron supplementation has been used to treat symptoms of RLS, the precise timeline for symptom improvement and the optimal dosage required to achieve a therapeutic response remain unclear. The present study was conducted to determine the impact of a single dose of 500 mg of IV FCM on RLS severity, sleep, and quality of life (QoL). The study also endeavored to assess the duration over which there was a maximum change in the severity of RLS symptoms.

MATERIALS AND METHODS

RESULTS

Fifty individuals with low ferritin levels (24.31 ± 20.93) enrolled in the study were administered a single dose of IV FCM at the initial visit and were followed for changes in symptoms at 1 month (n = 49) and 3 months (n = 47). No major infusion reaction was noticed in any of the patients. 74% (37) of participants were females. Mean body mass index was 26.45 ± 3.25, and mean age was 45.86 ± 15.6 years with 24% (12) of participants being in their 4^th decade [Table 1]. Mean duration of RLS symptoms before diagnosis of RLS was 5.01 ± 7.47 years and 36% (18) individuals had a positive family history of RLS [Table 1].

Change in status of sleep quality, daytime sleepiness, and QOL

Similar improvement was observed in daytime sleepiness, sleep quality, and QOL at follow-up visits [Table 4]. 70% (35) of patients had excessive daytime sleepiness at baseline; however, at the 3^rd visit, only 4 patients had an ESS score>10 [Figure 1 and Table 4]. 90% (45) of participants were poor sleepers at baseline with a mean PSQI of 10.42 ± 4.93; however, after IV iron, 59.57% (28) reported being good sleepers with PSQI score improving to 5.51 ± 4.68 and 5.17 ± 4.65, respectively, at the second and third visit [Figure 1]. Significant improvement was also registered in QOL (P = 0.0001) with a mean RLSQoL score of 59.05 ± 23.88 at baseline, improving to 86.28 ± 21.58 at the third visit [Table 4]. No worsening of symptoms was noted in any of the patients in this study.

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Figure 1:

(a) Comparison of international restless legs syndrome rating scale score at baseline and 1 month and 3 months of single dose of 500 mg intravenous (IV) ferric carboxymaltose (FCM), (b) Daytime sleepiness scores on Epworth sleepiness scale at baseline and 1 month and 3 months of administration of single dose of 500 mg IV FCM, (c) Sleep quality at baseline and 1 month and 3 months after administration of 500 mg IV FCM.

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DISCUSSION

RLS is a sensorimotor disorder with a suggested pathophysiology of altered brain iron homeostasis.^[17] RLS remains an underdiagnosed, misdiagnosed, and undertreated clinical entity that has a negative effect on individuals’ sleep as well as QoL.^[18] The RLS-H (Hindi version) screening tool can be used as a screening tool for early detection of RLS among susceptible patients.^[19] This will help in early and correct diagnosis of RLS patients and avoid unnecessary treatment in the form of multivitamins for these patients. Despite normal body iron stores, it is the central iron deficiency that has been suggested to be associated with the severity of RLS symptoms.^[6] Studies have shown a 6 times higher prevalence of RLS in iron-deficient patients compared to the general population.^[20] In our study, >50% of participants with RLS had low serum ferritin levels, and RLS severity had a negative correlation with serum ferritin levels (r = −0.098). The level of Hb also showed a negative correlation with disease severity; however, it could not reach statistical significance. Mean hemoglobin was 12.29 ± 1.45 and 44% (22) of patients had anemia as per the WHO criteria.^[14]

Studies have shown that even in the absence of decreased hemoglobin or serum iron levels, serum ferritin levels <50 ng/mL are associated with RLS.^[21] An Indian study on RLS patients with iron-deficiency anemia showed an increased prevalence of RLS of about 37.37% (21); mean hemoglobin and total iron binding capacity (TIBC) were 6.04 g/dL; 519.47 μg/dL in males and 6.55 g/dL; 457.16 μg/dL in females.^[22] However, RLS was not correlated with any derangements in hematological parameters such as hemoglobin and TIBC in this study, while serum ferritin levels were not evaluated.^[22] In the present study, RLS severity showed a negative correlation with Hb, serum iron, and serum ferritin. Studies have shown that augmentation during treatment is associated with low serum ferritin levels, which is a severe complication of RLS.^[7] Connor et al reported low serum ferritin (<50 mcg/L) in only 10–20% of patients.^[23] One recent case–control study has shown high serum hepcidin levels in RLS patients.^[24] Further studies are needed on a larger sample size to confirm the association of various hematological parameters with RLS.

70.4% (50) patients with low ferritin were given IV FCM in our study as per the evidence-based consensus clinical guidelines, which recommend IV iron if serum ferritin is <100 μg/L with transferrin saturation of 45%.^[25] Significant efficacy in reducing RLS severity was observed within the 1^st month of follow-up, with an overall reduction of mean RLS severity score by 19.59 points. Further, a reduction of 1.2 points in score was observed in the next 2 months of follow-up. Cho et al in their study of 32 RLS patients reported that a single 1000 mg FCM injection resulted in significant clinical improvement in non-anemic RLS patients at 6 weeks after injection, with a mean reduction of 8.4 points in IRLSS score compared to baseline, which was significantly better than the placebo group.^[26] He also registered significant improvement on the Visual Analog Scale (−40.6 ± 22.7 vs. −21.3 ± 20.0 (P = 0.001)).^[26] Allen et al in a multi-centered placebo-controlled trial proved the safety and efficacy of carboxymaltose in 24 RLS patients with a significant difference between the FCM and placebo group at 4 weeks and a reduction in mean IRLSS score of 8.9 points.^[27] In the present study, improvement in symptoms continued for 3 months of follow-up compared to other studies which followed for 6 weeks and 4 weeks.^[26,27]

Our study shows that early diagnosis and timely intervention can lead to significant improvement not only in RLS symptomatology but also in various aspects of life. There was an improvement of 27.23 points in the RLS QOL questionnaire at the subsequent visit. Hornyak et al. in their study on 20 RLS patients on the absolute or functional iron deficiency or low normal serum ferritin levels (<45 µg/L) showed a reduction in IRLSS score from 28.3 (6.1) to 18.3 (8.0) (P = 0.002) after a dose of 500 mg of FCM.^[13] After receiving a single dose of 500 mg FCM injection, 19 pregnant women experienced a reduction in IRLS score from 35 ± 26 to 25 ± 20 (P = 0.001) and registered an improvement in sleep quality (P = 0.029).^[28] Allen et al. also observed that the group that received FCM had greater improvement in RLSQOL score (56.5 ± 49.1) compared to the placebo group (19.5 ± 51.7, P = 0.024).^[27] Although not statistically significant (P = 0.094), the MOS sleep score also improved in the FCM group (75.8 ± 79) compared to the placebo group (35.1 ± 75.2).^[27] Significant reduction in daytime sleepiness with improvement in sleep quality, QOL, and reduction in RLS severity were all observed in our study at 1 month and improved further at 3 months, after a single dose of IV carboxymaltose [Table 3].

Trotti and Becker in their systematic review on iron for the treatment of RLS showed improvement in RLS severity with treatment at an interval of 12 weeks.^[29] Assessment of secondary outcomes was limited as a small number of trials have assessed these outcomes.^[29] There was no difference in subjective sleep quality between the iron and placebo groups (SMD 0.19, 95% CI −0.18 to 0.56; I² = 9%, 3 studies, 128 participants). Iron did not improve sleepiness compared to placebo, as measured on ESS but did improve daytime tiredness (item of RLS-6) compared to placebo (SMD-1.5, 95% CI −2.5 to −0.6; 1 study, 110 participants).^[29] Our study is one of the few studies assessing secondary outcomes such as daytime sleepiness, sleep quality, and QOL along with the status of RLS severity after a single IV dose of carboxymaltose.

Various studies on the efficacy of iron FCM in RLS, including Cho et al.,^[26] Allen et al.,^[25] Hornyak et al.,^[13] Schneider et al.,^[28] and the present study, show a positive treatment effect; however, studies by Earley et al.,^[12] and Grote et al.^[30] using iron sucrose has shown minimal treatment effect. FCM has an advantage as it has a slower dissociation of iron compared to iron sucrose, with decreased anaphylaxis risk compared to iron dextran.^[26] The efficacy and safety of FCM in correcting iron deficiency are proven, and now, it stands as a potential safer treatment option in RLS patients.^[26-28] Our study showed significant clinical efficacy of a single FCM injection in RLS patients, which may help in avoiding or postponing the use of other medications.

There is a paucity of data on RLS from India. Ours is the first hospital-based study from central India that used standardized assessment criteria, i.e., International Restless Study Group for diagnosing RLS and assessed the efficacy of a single dose of IV FCM on RLS at subsequent intervals for 12 weeks. Our study not only explored its effect on RLS severity but also assessed its impact on daytime sleepiness, sleep quality, and QOL; these parameters have been explored in limited studies.

Although our study followed the patients of RLS for 12 weeks after a single IV FCM, we could not record the change in levels of serum iron, serum ferritin, and other hematological parameters of interest on subsequent visits, which could have given us better objective insight into the continued improvement in RLS symptomatology as well as severity. Other limitations other than failure to repeat investigations in follow-up visits, include a small sample size and a follow-up duration of only for 3 months. A future long-term follow-up study (>6 months) could be done to assess the severity of symptoms with changes in ferritin levels after controlling for multiple comorbidities.

CONCLUSION

While the causal relationship between iron and RLS remains unproven, the present study has observed that a single 500 mg dose of IV FCM can significantly improve not only RLS symptoms but also sleep quality and sleepiness in individuals who have ferritin deficiency. This improvement can lead to an overall better QOL for RLS patients. Subsequent large-scale studies may be conducted in the future to identify the subgroup of the population that will respond the most to IV iron treatment.