Patients' perspectives on systemic sclerosis-related Raynaud's phenomenon in the feet: A qualitative study from the OMERACT Foot and Ankle Working Group.

OBJECTIVE: To explore, from patients' perspectives, the symptoms and impact of Raynaud's phenomenon (RP) on the feet of patients with systemic sclerosis (SSc-RP), and to identify which foot-related domains are important to patients. METHODS: Forty participants (34 women) with SSc-RP took part in one of six focus groups held in the United Kingdom or United States. Participants were purposively sampled to ensure diversity in disease type, duration, and ethnicity. The topic guide included questions on RP impact, self-management, and treatment expectations. Qualitative content analysis was employed to identify key concepts in the data relating to foot-specific symptoms and their impact. Themes were organized by corresponding domains of potential importance. RESULTS: Twenty-eight participants (70 %) reported experiencing RP in their feet. Five themes were identified corresponding to domains of potential importance: temperature changes, pain, cramping and stiffness, numbness, and color changes. These issues negatively affected participants' lives, impairing walking, driving, and socializing, and causing issues with footwear and hosiery. CONCLUSIONS: This large qualitative study exploring the experiences of patients with SSc-RP in the feet identified several key domains of high importance to patients. SSc-RP is common in the feet, presents in several patterns, and impacts multiple aspects of patients' lives. These findings indicate where future foot-specific interventions for RP could be targeted. Findings from this study improve understanding of what domains are important to patients with SSc-RP affecting the feet and will contribute to the development of a core outcome set for foot and ankle disorders in rheumatic and musculoskeletal diseases.

Mottled Raynaud's phenomenon and hand-arm vibration syndrome: followed up for 10 years.

Vibration white finger is a form of secondary Raynaud's phenomenon (RP) caused by the use of handheld vibrating tools. RP usually appears on the extremities of the fingers, and its borders are well recognised. No reports have been published on 'mottled' RP in continuous observation from the onset to the disappearance of RP. A man in his 60s who had been using vibrating tools such as jackhammers and tampers for 30 years presented with sensations of coldness, burning and numbness. Whole-body cold exposure was performed outdoors in winter, and RP was photographed continuously. 'Mottled' RP can be defined as triphasic colour changes: white, blue and red. The patient was taken off work, kept warm and medicated. His symptoms improved slightly after 10 years of follow-up, but the RP did not disappear. 'Mottled' RP is rare and refractory and should be recognised as a form of RP.

Cold Finger: Raynaud Phenomenon Following Snakebite Envenoming by Nikolsky's Viper (Vipera berus nikolskii).

A field biologist was bitten by a female Nikolsky's viper (Vipera berus nikolskii) in Kharkiv Oblast, Ukraine. Two months later, the patient began to experience cold-induced vasospasm of the affected digit diagnosed as acquired Raynaud phenomenon. The patient had more than 30 occurrences during the single winter following the bite, but the signs and symptoms of Raynaud phenomenon disappeared with the end of winter. This report describes the case and puts it into context with the literature on the topic of toxin-induced peripheral vasospastic disorders and their potential importance in snakebite envenoming.

Cold Hands or Feet: Is It Raynaud's or Not?

Raynaud's phenomenon is an exaggerated response to cold stimuli that may be primary or secondary. The diagnosis relies on patient history and physical examination to distinguish RP from other vasomotor dysfunction (e.g. acrocyanosis, pernio, small fiber neuropathy with vasomotor symptoms, and complex regional pain syndrome). Achenbach syndrome, or spontaneous venous hemorrhage, may also be mistaken for RP but is a self-limiting phenomenon. Laboratory evaluation and vascular diagnostic testing may identify SRP causes. Regardless of etiology, treatment includes warming with trigger avoidance, and consideration of vasodilators (eg. calcium channel, alpha-1 blockers). SRP with digital ulceration may require PDE5i, endothelin-1 receptor blockers, and prostanoids. Refractory cases may require pneumatic arterial pumps, botulinum toxin administration, or surgical sympathectomy.

Raynaud phenomenon and microvasculopathy in systemic sclerosis: multi-modality imaging for diagnosis and evaluation.

PURPOSE OF REVIEW: To describe the clinical significance of and the diagnostic approach to Raynaud phenomenon (RP) in the peripheral extremities and the heart. RECENT FINDINGS: Nailfold capillaroscopy has recently been standardized in an expert consensus paper. Abnormal capillaroscopy in combination with specific autoantibody profiles and clinical signs are highly predictive of progression of RP to systemic sclerosis (SSc). Magnetic resonance imaging (MRI) can also perform tissue characterization of both the extremities and the heart. Microvascular wall abnormalities detected using nailfold capillaroscopy in patients with SSc may lead to deposition of erythrocyte-derived iron, due to microhemorrhages, which may predispose to fibrosis. MRI can assess the presence of iron using T2∗ measurements. SUMMARY: RP is a hallmark of the microvasculopathy in SSc and can affect both the peripheral extremities and the heart. Nailfold capillaroscopy is the current gold standard for the evaluation of the peripheral microvasculature. Other imaging modalities include thermography, laser Doppler-derived methods, 99m Tc-pertechnetate hand perfusion scintigraphy, power Doppler ultrasonography, dynamic optical coherence tomography, MRI, and photoacoustic imaging, but these are currently not widely used. Cardiac RP can be investigated with positron emission tomography or cardiovascular magnetic resonance, with the latter offering the additional possibility of tissue characterization and iron content quantification secondary to microhemorrhages.

The Use of Botulinum Toxin in Raynaud Phenomenon: A Comprehensive Literature Review.

BACKGROUND: Raynaud phenomenon (RP) is a vasospastic condition of the digits that can be primary or secondary to systemic disease. Symptoms are triggered by cold or stress and can cause pain and skin color changes. The chronic ischemia may lead to necrosis, ulceration, and amputation. There are no Food and Drug Administration-approved treatments and cases refractory to pharmacologic and surgical treatments are difficult to control. Local botulinum toxin injections have been increasingly used in the treatment of Raynaud disease and have shown promising results. AIM OF THE STUDY: To examine the outcomes, techniques, and complications of botulinum toxin use for the treatment of Raynaud disease. METHODS: The PubMed database was queried using "botulinum toxin" AND "Raynaud phenomenon" as title key words. Preferred reporting items for systematic reviews and meta-analysis criteria were used. Additional articles were selected while reviewing the references of the articles from PubMed. No time restrictions were followed. Articles of all languages were included. Articles were analyzed for study type, demographics, diagnosis/inclusion criteria, treatment methods, outcome measures, length of follow-up, results, and complications. A positive outcome was defined as subjective improvement in symptoms and/or improvement in the outcome measures. A poor outcome was defined as harm done to the patient by the injection that would not have occurred otherwise. RESULTS: Forty-two clinical studies describing the use of botulinum toxin for Raynaud's phenomenon were found. A total of 425 patients with primary or secondary Raynaud's were treated, with ages ranging from 14 to 91 years. There were 342 women and 81 men, with a female-to-male ratio of 38:9. Outcomes were positive in 96.2% of patients. There were 14.2% of the studies that reported 3.5% of all patients showing no subjective improvement. A single study reported a poor outcome for 1 patient. There were 40.5% of the studies that reported complications, affecting 20.2% of all patients. The most frequently reported complication was transient hand weakness, affecting 44.2% of patients with complications and 8.9% of total patients. Weakness resolved in hours to months after injection. Pain at the injection site lasting minutes to days was reported in 40.7% of patients with complications, and 8.2% of total patients. CONCLUSIONS: Botulinum toxin treatment for RP is effective. Complications are minor and self-limiting.

Patient With Pulmonary Symptoms, Dysphagia, and Raynaud Disease.

A nonsmoking patient with gastroesophageal reflux disease and Raynaud disease had 4 weeks of dysphagia and a 4.54-kg weight loss over 3 months, cough productive of yellow sputum, and dyspnea on exertion. White blood cell count and creatine kinase and aldolase levels were elevated; antinuclear antibody assay findings were positive; and chest CT showed bibasilar pulmonary consolidations and ground glass opacities. What is the diagnosis and what would you do next?

Preliminary Clinical and Laser Speckle Contrast Analysis Data on Selexipag Efficacy for the Treatment of Digital Vasculopathy in Systemic Sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is burdened by Raynaud phenomenon (RP) and digital ulcers (DUs), and sometimes standard vasoactive therapies are ineffective or contraindicated. Selexipag is an oral selective IP prostacyclin receptor agonist approved for the treatment of SSc-related pulmonary arterial hypertension. We aimed to evaluate the clinical and instrumental efficacy of selexipag in SSc digital vasculopathy. METHODS: Patients with SSc with severe digital vasculopathy refractory or with contraindication to all other vasoactive therapies were administered selexipag. RP- and DU-related clinical outcomes were evaluated, and digital perfusion was assessed by laser speckle contrast analysis (LASCA), all at baseline and after 3 months. RESULTS: Selexipag was administered to 9 patients with SSc (66.6% female, mean age 52.3 [SD 16.6] yrs). One patient had to stop the drug because of adverse effects. After 3 months of selexipag administration, there was a significant reduction in RP daily episodes (P = 0.01) and RP mean duration (P = 0.04). The number of DUs decreased from 10 to 4 without reaching statistical significance. A significant improvement in mean perfusion of the fingers (P = 0.02) was observed with LASCA. CONCLUSION: Selexipag showed good potential for the treatment of SSc digital vasculopathy. Our results are certainly preliminary, yet quite encouraging. New trials for the evaluation of selexipag efficacy in SSc digital vasculopathy are needed.

[What's new in the management of systemic sclerosis]. / Nouveautés dans la prise en charge de la sclérodermie systémique.

This review of the literature highlights the results of the recent randomized controlled trials about the management of systemic sclerosis (SSc) and its complications. The latest randomized studies have failed to demonstrate the utility against placebo of the injections of botulinum toxin A to achieve a better control of Raynaud's phenomenon and the efficacy of the adipose-derived cell transplantation for the treatment of hand dysfunction. Rituximab allows a significant improvement of cutaneous induration. The injections of mesenchymal stromal cells are well tolerated and should encourage future randomized trials to evaluate their efficacy. Finally, nintedanib and tocilizumab allow a reduction in the rate of decline of lung function, as well as a possible stabilization with tocilizumab.

Cet article expose les résultats des essais randomisés et contrôlés récents concernant la prise en charge de la sclérodermie systémique (SSc) et ses complications. Les études discutent l'utilité des injections de la toxine botulinique pour le contrôle du phénomène de Raynaud, et des injections de cellules dérivées du tissu adipeux pour améliorer la fonctionnalité de la main. Le rituximab permet une amélioration significative de l'induration cutanée, et les injections de cellules stromales mésenchymateuses, en plus d'être bien tolérées, ouvrent la voie à d'éventuels essais randomisés en vue d'évaluer leur efficacité. Finalement, le nintédanib et le tocilizumab permettent une réduction du taux de déclin de la fonction pulmonaire, jusqu'à une éventuelle stabilisation de cette dernière observée avec le tocilizumab.

Associations between nailfold capillary aberrations and autoantibodies in children and adults with Raynaud's phenomenon.

OBJECTIVE: To characterise associations between individual nailfold capillary aberrations with autoantibodies in a cross-sectional study on children and adults with Raynaud's phenomenon (RP). METHODS: Consecutive children and adults with RP and without previously known connective tissue disease (CTD) systemically underwent nailfold capillaroscopy and laboratory tests for the presence of antinuclear antibodies (ANA). The prevalence of individual nailfold capillary aberrations and ANA was assessed, and the associations between individual nailfold capillary aberrations and ANA were analysed separately in children and adolescents. RESULTS: In total, 113 children (median age 15 years) and 2858 adults (median age 48 years) with RP and without previously known CTD were assessed. At least one nailfold capillary aberration was detected in 72 (64%) of included children and in 2154 (75%) of included adults with RP (children vs adults p<0.05). An ANA titre ≥1:80, ≥1:160 or≥1:320 was observed in 29%, 21% or 16% of included children, and in 37%, 27% or 24% of screened adults, respectively. While the occurrence of individual nailfold capillary aberrations was related to the presence of an ANA titre of ≥1:80 in adults (reduced capillary density, avascular fields, haemorrhages, oedema, ramifications, dilations and giant capillaries: each p<0.001), no comparable association between nailfold capillary aberrations and ANA was observed in children with RP without previously known CTD. CONCLUSION: In contrast to adults, the association between nailfold capillary aberrations and ANA might be less pronounced in children. Further studies are warranted to validate these observations in children with RP.

Simultaneous bilateral distal venous arterialization between redial artery and cephalic vein in dorsal hand for Raynaud's phenomenon in both hands: A case report.

Raynaud's phenomenon (RP) is characterized by episodic vasospasm in peripheral vessels and ischemia of the fingers. Venous arterialization is thought to induce neovascularization and increased oxygen tension. In this report, we describe a patient with RP in the fingers of both hands in whom venous arterialization achieved an acceptable result in both hands. The patient was a 62-year-old woman with a 10-year history of worsening pain and cold sensation in the tips of the index, middle, ring, and little fingers on both sides. The venous arterialization procedure was performed on both hands simultaneously at the level of the anatomical snuff box between radial artery and cephalic vein in dorsal hand. There was no need for valvectomy in the level of hands. To prevent development of the steal phenomenon in the arterialized veins, the superficial basilic and median veins of the forearm were ligated via 1 cm skin incisions. The pain and cold sensation in the fingertips of both hands remained decreased, and the nonhealing ulcers on the fingertips healed without the need for amputation. The observation period was 14 months, and the surface temperature of the fingers was increased after venous arterialization, as was the temperature of the palm and forearm. There was no problem when administering intravenous infusion into the forearm on either side postoperatively. The case showed venous arterialization was effective for RP without increasing intravenous pressure in the affected limb, and further investigation is necessary.

Arm heating to relieve Raynaud's phenomenon in systemic sclerosis: A single-arm multicentre prospective clinical trial.

OBJECTIVES: Raynaud's phenomenon, one of the major symptoms of systemic sclerosis (SSc), is difficult to treat. Although it is empirically considered that warming is a beneficial technique, there is no supportive evidence. We conducted a multicentre study to evaluate whether continuous heating of the arm alleviates Raynaud's phenomenon in SSc. METHODS: A pair of disposable warmers was applied to the upper arm near the elbow of patients with SSc. Two weeks of non-warmer application were followed by 2 weeks of warmer application, which was repeated twice. The Raynaud Condition Score (RCS), number of episodes, and duration of Raynaud's phenomenon were recorded. The differences in the mean RCS, frequency, and duration of Raynaud's phenomenon between the warmer application and non-application periods were analysed. RESULTS: Twenty-eight patients were included in the analysis. The average RCS was 1.98 and 2.66 during the warmer application and non-application periods, respectively. The change between the two periods was statistically significant by paired t-test. In addition, the frequency and total duration of Raynaud's phenomenon in the warmer application period were significantly lower than those in the non-application period. CONCLUSIONS: Heating of the upper arm near the elbow is effective in alleviating Raynaud's phenomenon in SSc.

Repeatability of high-resolution laser Doppler images of the hands in patients with systemic sclerosis and secondary Raynaud's phenomenon.

OBJECTIVES: The objective of the study was to establish the repeatability of baseline diagnostic images of the dorsum of the hands acquired using a high-resolution laser Doppler imager in patients with Raynaud's phenomenon secondary to systemic sclerosis (SSc). METHODS: The dorsal side of the hands of 22 patients (8 male 14 female), age range 29-73, median 62, with SSc and secondary Raynaud's phenomenon were imaged over two consecutive days at approximately the same time using a Moor Instruments' high-resolution laser Doppler imaging unit. The images were analysed by taking regions of interest at discrete locations in the images to calculate dimensionless values of flux (PU). Repeatability of the diagnostic investigation was assessed using methods described by Bland and Altman and by also plotting the results from visit 1 against visit 2 and calculating the line of best fit. RESULTS AND CONCLUSIONS: Based on the criteria that 95% of all measurement differences should be within a factor of 1.96 of the standard deviations of the mean values, then high-resolution laser Doppler imaging technique is probably repeatable when acquiring and analysing baseline images of patients with Raynaud's phenomenon secondary to SSc. However, a larger study with more patients is required to prove this conclusively-as only data from 19 patients were analysed (3 patients were not included due to technical issues)-and was therefore susceptible to marked clinical variations in patients presenting on different days for the investigations.

A phase 2 trial investigating the effects of the angiotensin II type 2 receptor agonist C21 in systemic sclerosis-related Raynaud's.

OBJECTIVE: Our main aim was to investigate the effect of a single oral dose of C21, a selective angiotensin II type 2 receptor agonist, on cold-induced vasoconstriction in SSc-related RP. METHODS: This was a phase IIa, randomized, double-blind, cross-over, single-dose, placebo-controlled, single-centre study. Twelve female patients with SSc (median age 58.5 years, median duration of RP 19.0 years) attended on four occasions: screening, treatment visits 1 and 2 (separated by 3-7 days) and follow-up. At the first treatment visit, patients were randomized to receive either a single oral dose of C21 (200 mg) or placebo, then the opposite treatment on the second visit. Forty min after each treatment, each patient underwent a standard hand cold challenge. The primary end point was the area under the curve (AUC) for rewarming for each finger (eight fingers) over 15 min. Secondary end points included the maximum finger temperature after rewarming (MAX). Statistical analyses were performed by multiplicative ANCOVA models. RESULTS: For all eight fingers combined, mean AUC for rewarming was higher after treatment with C21 than after placebo (geometric mean 20 046°C*s vs 19 558°C*s), but not significantly (P = 0.380) and MAX (at 15 min) was also higher (geometric mean 23.5°C vs 22.5°C; P = 0.036). C21 was well tolerated. CONCLUSION: Despite the small trial size, a signal emerged suggesting that even in patients with established SSc, C21 may confer benefit for RP and deserves further investigation. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT04388176.

Efficacy and Safety of Botulinum Toxin in Adults with Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: To determine whether a single session of botulinum toxin type A (BTA) injections into both hands more effectively decreases the frequency of systemic sclerosis-associated Raynaud's phenomenon (SSc-RP) episodes than placebo. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group phase III trial in patients with SSc-RP assessed the effect of 50-unit BTA or placebo injections into the palms of both hands around each neurovascular bundle during 1 session in winter. The primary end point was the between-group difference in the median change in the number of RP episodes from baseline (day 0) to 4 weeks postinjection. Values between the groups were compared with the Wilcoxon rank-sum test. RESULTS: The intent-to-treat analysis included 46 BTA-treated patients and 44 placebo recipients. At 4 weeks after assigned treatment injections, the median number of daily RP episodes decreased comparably in the BTA and placebo groups (median change -1 episode/day [interquartile range (IQR) -1.5, 0 episodes/day] and -1 episode/day [IQR -2.5, 0 episodes/day], respectively) (P = 0.77 versus placebo). Moreover, change in Raynaud's Condition Score, quality of life assessed by Health Assessment Questionnaire disability index, and hand function assessed by shortened Disabilities of the Arm, Shoulder, and Hand (QuickDASH) and Cochin Hand Function Scale from baseline to follow-up weeks 4, 12, and 24 did not differ significantly between groups. The BTA group experienced transient hand muscle weakness significantly more frequently (P = 0.003). CONCLUSION: Neither the primary nor secondary end points were reached, and our results do not support any beneficial effect of palmar BTA injections to treat SSc-RP.

Assessment of the Systemic Sclerosis-Associated Raynaud's Phenomenon Questionnaire: Item Bank and Short-Form Development.

OBJECTIVE: To develop, refine, and score a novel patient-reported outcome instrument to assess the severity and impact of Raynaud's phenomenon (RP) in systemic sclerosis (SSc). METHODS: The Assessment of Systemic Sclerosis-Associated Raynaud's Phenomenon (ASRAP) questionnaire items were developed with patient insight partner support and grounded in the lived patient experience of SSc-RP. ASRAP items underwent formal qualitative assessment and linguistic testing. An international multicenter study was undertaken to field test the preliminary ASRAP questionnaire. RESULTS: A preliminary 37-item ASRAP questionnaire was supplemented with 2 additional items following expert review to enhance content coverage before undergoing formal linguistic testing to optimize readability. Patient cognitive debriefing interviews were undertaken to enhance comprehension, ambiguity, cognitive difficulty, relevance, and content coverage of both the ASRAP items and instructions. We enrolled 420 SSc patients from scleroderma centers in the UK and US over 2 consecutive winters. Factor analysis with item response theory was undertaken to remove redundant and poorly fitting items. The retained 27-item long-form ASRAP questionnaire was calibrated and scored using the graded response model. A fixed 10-item short-form ASRAP questionnaire was developed using computerized adaptive testing simulations. CONCLUSION: The ASRAP questionnaire has been developed with extensive SSc patient input, with items grounded in the lived experience of SSc-RP to ensure strong content validity, with a focus on how patients feel and function. An advanced psychometric approach with expert input has removed redundant and/or poorly fitting items without eroding content validity. Long- and short-form ASRAP questionnaires have been calibrated and scored to permit formal validation.