Vasodilators for primary Raynaud's phenomenon

Su, Kevin Y. C.; Sharma, Manik; Kim, Hyunjun Jonathan; Kaganov, E.; Hughes, Ian; Abdeen, Mohamed Hashim; Ng, Jennifer

doi:10.1002/14651858.cd006687.pub4

Cited by 14 publications

(8 citation statements)

References 74 publications

(119 reference statements)

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“…For mild cases, avoidance of triggers like cold or emotional stress might be sufficient, but severe vasospastic attacks require pharmacological interventions with calcium channel blockers as first line response 6 . However, overall effectiveness of calcium channel blockers 5 or alternative vasodilatory medications such as angiotensin receptor blockers, selective serotonin reuptake inhibitors, or phosphodiesterase-5 inhibitors is limited 6,7 and much hope put in selective α 2C -adrenoreceptors inhibitors has not been supported by a recent trial 36 . A staggering characteristic of the ADRA2A locus was the specificity in phenome-wide screens and comprehensive database lookups, which indicated a RP-specific effect.…”

Section: Discussionmentioning

confidence: 99%

“…Management of RP is predominantly limited to avoidance of triggers and evidence for medical treatment is generally weak. Repurposed vasodilators are the first line treatment if pharmacological intervention is required due to progressive frequency of vasospastic attacks 6 , although only calcium channel blockers have so far been shown to lead to a significant and reproducible reduction in the frequency of vasospastic attacks 7 . However, use of systemic drugs for localized symptoms puts patients at risk of generalised adverse effects, such as hypotension.…”

Section: Introductionmentioning

confidence: 99%

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ADRA2AandIRX1are putative risk genes for Raynaud’s phenomenon

Hartmann

Yasmeen

Denaxas

et al. 2022

Preprint

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BackgroundRaynaud’s phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers in fingers and toes triggered by cold or emotional stress. Despite its high reported heritability, no causal genes have been robustly identified, limiting mechanistic understanding and treatment options.AimTo investigate the genetic architecture of RP to better understand its aetiology and identify new potential therapeutic targets.MethodsWe conducted a genome-wide association study including 9,084 RP cases and 435,357 controls, based on diagnoses from electronic health records, among participants of the UK Biobank study. We identified candidate causal variants and genes using Bayesian fine-mapping and colocalization with gene expression across 49 tissues. We performed phenome-wide association analyses for all significant RP loci and computed genetic correlations followed by latent causal variable analyses between RP and a total of 205 selected phenotypes.ResultsWe identified eight unreported genomic regions associated with the risk of RP atp<5×10−8and assignedADRA2A(rs7090046, odds ratio (OR) per allele: 1.27; 95%-CI: 1.23-1.31; p<2.52×10−47) andIRX1(rs11748327, OR: 1.20; 95%-CI: 1.16-1.23, p<9.71×10−28) as the candidate causal genes at the two strongest loci. Higher expression ofADRA2Ain tibial artery andIRX1in skeletal muscle was thereby associated with a higher RP risk. We identified a likely causal detrimental effect of low fasting glucose levels on RP risk (rG=-0.12; p-value=0.01), while significant positive genetic correlations with reported comorbidities like migraine, depression, or peripheral artery disease are likely explained by shared risk factors.ConclusionOur results provide the first robust evidence for a strong genetic contribution to RP, highlighting a so far underrated role of α2A-adrenoreceptor signalling, encoded atADRA2A, as an important mechanism for hypersensitivity to catecholamine-induced vasospasms even at thermoneutral conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ADRA2AandIRX1are putative risk genes for Raynaud’s phenomenon

Hartmann

Yasmeen

Denaxas

et al. 2022

Preprint

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“…Although it is generally uncertain whether cilostazol is safe and effective for use in children, a clinical trial testing the effects of cilostazol for the treatment of juvenile Raynaud’s Phenomenon, a blood vessel disorder in children, has been completed with no significant beneficial effects discovered [67]. On the other hand, cilostazol has been tested effective in a rat model of prenatal valproic acid-induced autism spectrum disorder [68] and hence proposed as an adjunctive therapy for the children with autism spectrum disorder [69].…”

Section: Discussionmentioning

confidence: 99%

The anti-platelet drug cilostazol enhances interrenal steroidogenesis and exerts a scant effect on innate immune responses in zebrafish

Chang

Chen

Chuang

et al. 2022

Preprint

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Rationale: Cilostazol, an anti-platelet phosphodiesterase-3 inhibitor used for the treatment of intermittent claudication, is known for its pleiotropic effects on platelets, endothelial cells and smooth muscle cells. However, how cilostazol impacts the endocrine system and the injury-induced inflammatory processes remains unclear. Methods: We used the zebrafish, a simple transparent model that demonstrates rapid development and a strong regenerative ability, to test whether cilostazol influences steroidogenesis, and the temporal and dosage effects of cilostazol on innate immune cells during tissue damage and repair. Results: While dosages of cilostazol from 10 to 100 uM did not induce any noticeable morphological abnormality in the embryonic and larval zebrafish, the heart rate and adrenal/interrenal steroidogenesis in larval zebrafish was increased in a dose-dependent manner. During larval fin amputation and regeneration, cilostazol treatments did not affect the immediate injury-induced recruitment of either neutrophils or macrophages, followed by a subtle yet significant effect on reducing the neutrophil retention at the lesion site. Conclusions: Our results indicate that cilostazol has a significant effect on the growth and endocrine function of steroidogenic tissue; and a limited effect on the neutrophil retention without affecting neutrophil and macrophage recruitment during tissue damage and repair.

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“…3 Although calcium channel blockers have been shown to improve symptoms, the evidence for second-line treatment options is less convincing. [4][5][6] Refractory cases of RP are common, often leading patients to seek procedural interventions.…”

Section: Introductionmentioning

confidence: 99%

“…First-line management is lifestyle modifications, followed by medical interventions such as calcium channel blockers, and second-line options are phosphodiesterase 5 inhibitor inhibitors, angiotensin receptor blocker / angiotensin converting enzyme inhibitor inhibitors, selective serotonin receptor inhibitor, and alpha channel blockers 3 . Although calcium channel blockers have been shown to improve symptoms, the evidence for second-line treatment options is less convincing 4–6 . Refractory cases of RP are common, often leading patients to seek procedural interventions.…”

Section: Introductionmentioning

confidence: 99%

Medium- and Long-Term Outcomes of Autologous Fat Grafting to Hands and Feet for Patients With Raynaud Phenomenon

Haravu,

Bond,

Hendren-Santiago

et al. 2023

Ann Plast Surg

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Background Autologous fat grafting (AFG) has emerged as a promising treatment option for Raynaud phenomenon. However, existing studies are limited by short follow-up, and there is little evidence regarding predictive factors for successful outcomes. Methods A retrospective chart review and standardized phone interviews were performed for all patients (n = 17, 65% response rate) treated with AFG to the hands or feet at our institution for primary or secondary Raynaud from 2010 to 2021. Each occurrence of AFG was defined as a separate surgery (n = 23), with an average follow-up of 3.7 years. Results At follow-up, patients reported a 31% reduction in cold attack frequency, a 45% reduction in the intensity of individual attacks, a 29% reduction in the duration of attacks, and a 40% improvement in overall Raynaud Condition Score (P < 0.01). Although initial AFG to an extremity significantly improved symptoms, subsequent attempts were not shown to statistically improve outcomes. Digital ulcers were present in 65% of cases, and AFG resulted in ulcer healing in 87% of those cases. Median duration of maximum symptom relief was 1 year postoperatively, with 74% of patients reporting diminishing symptom relief by 4 years postoperatively. Those with a BMI ≥25, with primary Raynaud phenomenon or without preoperative ulcers experienced significantly longer symptom relief (P < 0.05). Average patient satisfaction was 7.7 of 10, and 91% would recommend the procedure to others. Conclusions Autologous fat grafting is an effective, albeit sometimes temporary, treatment for Raynaud and digital ulcers. Certain patients may be more likely to experience lasting symptom relief beyond 1 year.

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Vasodilators for primary Raynaud's phenomenon

Abstract: 5. Art. No.: CD006687.. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the Review.

Cited by 14 publications

References 74 publications

ADRA2AandIRX1are putative risk genes for Raynaud’s phenomenon

ADRA2AandIRX1are putative risk genes for Raynaud’s phenomenon

The anti-platelet drug cilostazol enhances interrenal steroidogenesis and exerts a scant effect on innate immune responses in zebrafish

Medium- and Long-Term Outcomes of Autologous Fat Grafting to Hands and Feet for Patients With Raynaud Phenomenon

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