Hydroxocobalamin: An Effective Treatment for Flushing and Persistent Erythema in Rosacea

J Clin Aesthet Dermatol. 2022;15(6):42-45.

by Yi-Wei Huang, MD and Hui-Peng Huang, MD; Chao-Kai Hsu, MD, PhD; and Julia Yu-Yun Lee, MD

Dr. Yi-Wei Huang is with the Department of Dermatology at National Taiwan University Hospital in Taipei, Taiwan. Dr. Hui-Peng Huang is with Huang Hui-Peng Dermatology Clinic in Tainan, Taiwan. Drs. Hsu and Lee are with the Departments of Dermatology at National Cheng Kung University Hospital and College of Medicine in Taiwan.

FUNDING: No funding was provided for this article

DISCLOSURES: The authors report to conflicts of interest relevant to the content of this article.

ABSTRACT: Background. Expression of inducible nitric oxide synthase (NOS) is higher in rosacea skin samples than in normal skin controls. Hydroxocobalamin is a potent inhibitor of all isoforms of NOS, capable of reducing the vasodilatations induced by nitric oxide.

Objective: We aimed to evaluate the role of hydroxocobalamin in treating facial flushing and persistent erythema of rosacea. Methods: Thirteen patients  with rosacea who displayed facial flushing and persistent erythema received 1 to 4 weekly intramuscular injections of hydroxocobalamin 1 to 2 mg. The outcomes were measured using the Clinician’s Erythema Assessment (CEA) by photography and an infrared thermometer to evaluate the difference in skin surface temperature (SST) of the cheeks before and after treatment. Results: Thirty minutes after the first dose of intramuscular injection of hydroxocobalamin, the mean CEA significantly reduced from 2.2± 0.6 to 1.2±0.4 (p<0.001), and average SST also significantly reduced from 36.7±0.70°C to 36.2±0.61°C (p<0.001) on the cheeks. Conclusion: In our patient sample, intramuscular administration of hydroxocobalamin was effective for immediate reduction of facial erythema associated with rosacea.

Keywords: Hydroxocobalamin, vitamin B12, nitric oxide synthase, rosacea, erythema, flushing


Rosacea is a chronic inflammatory facial disorder with diagnostic phenotype of fixed centrofacial erythema in a characteristic pattern that may periodically intensify, or phymatous changes.1 The presence of two or more major features, including papules/pustules, facial flushing, telangiectasia, and eye manifestations, is also considered diagnostic.2 Although the exact pathogenesis of rosacea remains to be fully elucidated, various triggering factors, such as Demodex infestation, microbiota, ultraviolet radiation, heat, psychological stress, and skin barrier disruption are associated with the development or worsening of rosacea.3 Abnormal innate immunity and neurovascular dysregulation can contribute to and augment the inflammatory cascade, vasodilation, and angiogenesis in rosacea.4 Immunohistochemical staining of skin samples has shown increased expression of inducible nitric oxide synthase (NOS) in patients with rosacea compared to controls.4

Treatment modalities of rosacea demonstrated various efficacies; however, effective control of persistent facial erythema in some patients remains challenging for clinicians.5 Selective α-adrenergic receptor agonists with potent vasoconstricting activity, for example, brimonidine tartrate 0.5% gel and oxymetazoline hydrochloride 1% cream, have been approved for treatments of facial erythema.6 Topical ivermectin cream has been reported to be effective in reducing facial erythema associated with rosacea.7 β-blockers like propranolol can suppress flushing reactions, but the side effects of hypotension and bradycardia can pose problems.8 Carvedilol, a nonselective β-adrenergic blocker with α1 blocking activity and potent antioxidant activity, is effective in persistent erythema of rosacea, but is contraindicated in patients with low blood pressure or asthma.9 Some patients with persistent erythema are responsive to pulsed dye laser and intense pulsed light.10 Despite these treatment options, an unmet need remains for refractory facial erythema. Herein, we report 13 rosacea patients whose persistent facial erythema responded to hydroxocobalamin, a nitric oxide (NO) scavenger.

Methods

Thirteen patients with rosacea exhibiting persistent erythema and facial flushing from Huang Hui-Peng Dermatology Clinic, were enrolled in the study from April to June 2021. The study was performed in accordance with the Helsinki Declaration. At each patient’s visit, clinical photos were taken after the patients had rested for 15 minutes. The skin surface temperatures (SST) of both cheeks were measured with an infrared thermometer, and blood pressure was checked before intramuscular injection of hydroxocobalamin (1 or 2 mg). Another set of photography was taken 30 minutes after injection, along with measurement of skin temperature and blood pressure. Clinical erythema severity was assessed by Clinician Erythema Assessment (CEA) using a 5-point scale: 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), 4 (severe). For patients with clinical improvement, further doses of hydroxocobalamin were given weekly in the following 1 to 3 weeks. Concomitant medications were recorded.

Results

This study included 12 female patients and one male patient, aged 20 to 65 years. The disease duration ranged from six months to 30 years. The demographic data, clinical features, preceding and concomitant treatments, and the clinical response to hydroxocobalamin injection are listed in Table 1. Seven patients did not receive any treatment for rosacea in the previous two months. Two patients had been treated with methylcobalamin 500 μg one month prior to receiving hydroxocobalamin. The dose of hydroxocobalamin at the first session was 1mg for 11 patients and 2mg for two patients. SST was not measured in one patient. Twelve out of 13 patients experienced significant clinical improvement within one hour of injection. One patient exhibited an increase in SST from 35.4°C to 35.7°C with no change in erythema. The CEA grade reduced significantly from 2.2±0.6 to 1.2±0.4 (p<0.001) (Figure 1). Among the 12 patients with documentation of SST, the reduction of temperature of right and left cheeks was from 36.7±0.68°C to 36.2±0.58°C (p=0.001) and from 36.7±0.76°C to 36.2±0.66°C (p=0.001), respectively. As shown in Figure 2, when combining the SST results from both cheeks, the temperature significantly dropped from 36.7±0.70°C to 36.2±0.61°C (p<0.001). Four patients were lost to follow-up after the first treatment session. The remaining eight patients with clinical improvement received additional weekly injections of hydroxocobalamin, and showed similar rapid improvement with reduced facial erythema and flushing lasting 2 to 6 days. Neither significant side effects nor changes in blood pressure were noted during the follow up period of two weeks to four months. Concomitant treatments included carvedilol, oral isotretinoin, doxycycline, minocycline, levocetirizine, fexofenadine, ivermectin cream, permethrin cream, metronidazole gel, and clindamycin gel. 

Discussion

The underlying mechanisms for increased cutaneous blood flow after whole body heating to increase the core temperature, measured in the human forearm, may be explained by cotransmitters, possibly vasoactive intestinal peptide, of cholinergic sympathetic fibers.11–13 On the contrary, thermoregulation of cutaneous local heating is initiated by fast-responding vasodilation mediated by afferent axon reflexes, followed by slow-responding vasodilation that relies on local production of NO.11,12,14 The vasodilation response to whole body heating can be blocked by botulinum toxin A,11,14 which had been reported to be effective in reducing erythema of rosacea patients.15,16 To the best of our knowledge, the present study is the first one to evaluate the erythema-reducing effect of hydroxocobalamin for rosacea patients.

There are three isoforms of NOS, including neuronal NOS, endothelial NOS, and inducible NOS. Neuronal NOS and endothelial NOS are constitutively active, generally producing low levels of NO. Inducible NOS is induced by cytokines and microbial factors, and produces high levels of NO, which controls smooth muscle contraction and causes vasodilation.16 In rosacea skin samples, expression of inducible NOS was higher than that of normal skin controls.4 The cobalamin compounds contain a central cobalt (Co), usually Co3+.17 A study by Rochelle, et al18 revealed that the addition of NO to hydroxocobalamin resulted in oxidation of Cb(II) to Cb(III) by NO and a reversible complex in which NO is liganded to the Cb(III). Furthermore, hydroxocobalamin has been shown to be a potent inhibitor of all isoforms of NOS, more potent than methylcobalamin.16 These studies suggest that hydroxocobalamin possesses an NO binding effect as well as a potent NOS inhibition effect, which might explain the efficacy of hydroxocobalamin in treating facial erythema in our patients.

The biological half-life of vitamin B12 in the plasma is approximately six days.19 The effect of one single injection of hydroxocobalamin for reducing facial erythema lasted 2 to 6 days in the present study. Daily oral hydroxocobalamin might be a good option for continuous symptom control, but more research is needed in this area.

Hydroxocobalamin is generally safe and used widely in different medical conditions.20,21 High dose vitamin B6 and B12 supplement has been reported to trigger rosacea fulminans or pyoderma faciale,22 clinically similar to rosacea but is mostly regarded as a separate entity. In our case series, no significant rebound or flare up was observed. Theoretically, the prior and/or concomitant medications may help to reduce erythema of rosacea in our patients. However, none of the medications were taken one hour before the injection of hydroxocobalamin. Therefore, the rapid clinical improvement of erythema within 30 to 50 minutes observed in our patients could be attributed to hydroxocobalamin. 

Limitations. The limitation of the present study is that it was not a randomized, controlled study, and hence, the results could have assessor bias. A larger, controlled study will help in validating the results from this study.

Conclusion

In our small series, intramuscular injection of hydroxocobalamin improved facial erythema of rosacea with rapid onset and minimal adverse effects. These results are encouraging, but further studies are warranted to determine the optimal dosage, efficacy of oral form, treatment duration, and long-term therapeutic effect and side effects. 

References

  1. Buechner SA. Rosacea: an update. Dermatology. 2005;210(2):100-8.
  2. Tan J, Almeida LM, Bewley A, Cribier B, Dlova NC, Gallo R, et al. Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel. Br J Dermatol. 2017;176(2):431-8.
  3. Woo YR, Lim JH, Cho DH, Park HJ. Rosacea: molecular mechanisms and management of a chronic cutaneous inflammatory condition. Int J Mol Sci. 2016;17(9):1562.
  4. Moura AKA, Guedes F, Rivitti-Machado MC, Sotto MN. Inate immunity in rosacea. Langerhans cells, plasmacytoid dentritic cells, Toll-like receptors and inducible oxide nitric synthase (iNOS) expression in skin specimens: case-control study. Arch Dermatol Res. 2018;310(2):139-46.
  5. van Zuuren EJ, Fedorowicz Z, Tan J, van der Linden MMD, Arents BWM, Carter B, et al. Interventions for rosacea based on the phenotype approach: an updated systematic review including GRADE assessments. Br J Dermatol. 2019;181(1):65-79.
  6. Del Rosso JQ. Topical a-agonist therapy for persistent facial erythema of rosacea and the addition of oxmetazoline to the treatment armamentarium: where are we now? J Clin Aesthet Dermatol. 2017;10(7):28-32.
  7. Mendieta Eckert M, Landa Gundin N. Treatment of rosacea with topical ivermectin cream: a series of 34 cases. Dermatol Online J. 2016;22(8):6.
  8. Logger JGM, Olydam JI, Driessen RJB. Use of beta-blockers for rosacea-associated facial erythema and flushing: A systematic review and update on proposed mode of action. J Am Acad Dermatol. 2020;83(4):1088-1097.
  9. Hsu CC, Lee JY. Carvedilol for the treatment of refractory facial flushing and persistent erythema of rosacea. Arch Dermatol. 2011;147(11):1258-1260.
  10. Chang HC, Chang YS. Pulsed dye laser versus intense pulsed light for facial erythema of rosacea: a systematic review and meta-analysis. J Dermatolog Treat. 2021:1-3.
  11. D. L. Kellogg J. In vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans during thermoregulatory challenges. J Appl Physiol. 2006;100(5):1709–1718.
  12. Wong BJ, Hollowed CG. Current concepts of active vasodilation in human skin. Temperature (Austin). 2017;4(1):41–59.
  13. Kellogg DL, Jr., Pérgola PE, Piest KL, Kosiba WA, Crandall CG, Grossmann M, et al. Cutaneous active vasodilation in humans is mediated by cholinergic nerve cotransmission. Circ Res. 1995;77(6):1222–1228.
  14. Minson CT, Berry LT, Joyner MJ. Nitric oxide and neurally mediated regulation of skin blood flow during local heating. J Appl Physiol (1985). 2001;91(4):1619–1626.
  15. Scala J, Vojvodic A, Vojvodic P, Vlaskovic-Jovicevic T, Peric-Hajzler Z, Matovic D, et al. Botulin toxin use in rosacea and facial flushing treatment. Open Access Maced J Med Sci. 2019;7(18):2985–2987.
  16. Weinberg JB, Chen Y, Jiang N, Beasley BE, Salerno JC, Ghosh DK. Inhibition of nitric oxide synthase by cobalamins and cobinamides. Free Radic Biol Med. 2009;46(12):1626–1632.
  17. Obeid R, Fedosov SN, Nexo E. Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl-cobalamin in prevention or treatment of cobalamin deficiency. Mol Nutr Food Res. 2015;59(7):1364–1372.
  18. Rochelle LG, Morana SJ, Kruszyna H, Russell MA, Wilcox DE, Smith RP. Interactions between hydroxocobalamin and nitric oxide (NO): evidence for a redox reaction between NO and reduced cobalamin and reversible NO binding to oxidized cobalamin. J Pharmacol Exp Ther. 1995;275(1):48–52.
  19. Adams JF. Biological half-life of vitamin B12 in plasma. Nature. 1963;198:200.
  20. Kira J, Tobimatsu S, Goto I. Vitamin B12 metabolism and massive-dose methyl vitamin B12 therapy in Japanese patients with multiple sclerosis. Intern Med. 1994;33(2):82–86.
  21. Bodian M. Neuroblastoma: an evaluation of its natural history and the effects of therapy, with particular reference to treatment by massive doses of vitamin B12. Arch Dis Child. 1963;38(202):606–619.
  22. Jansen T, Romiti R, Kreuter A, Altmeyer P. Rosacea fulminans triggered by high-dose vitamins B6 and B12. J Eur Acad Dermatol Venereol. 2001;15(5):484–485.