Dynamic blood flow imaging with 99mTc-hydroxymethylene diphosphonate as a therapeutic response marker in patients with Raynaud's phenomenon.

We evaluated the predictive value of dynamic blood flow scintigraphy with 99mTc-HDP (hydroxymethylene diphosphonate) for therapeutic response in patients with Raynaud's phenomenon (RP). Eighty patients who underwent dynamic blood flow scintigraphy using the one-hand chilling method were enrolled. We analyzed the quantitative variables as the ratio of chilled fingers to ambient fingers (CAfinger), that of the chilled hand to ambient hand (CAhand), and that of chilled fingers to ambient palm (FPR) (CAFPR) at 15 and 30 s after 99mTc-HDP bolus injection. Total cumulative radioactivity counts for 180 s were obtained. We evaluated the clinical utility of these quantitative parameters with other clinical variables, including RP severity, therapeutic compliance, types of RP, and scintigraphic interpretation of findings in patients with RP. Fifty-two patients showed poor therapeutic response. There were significant differences between good- and poor-therapeutic responder groups in RP intensity (p = 0.003), CAfinger15s (p = 0.008), CAfinger30s (p = 0.002), CAfinger180s (p = 0.011), CAhand15s (p = 0.008), CAhand30s (p = 0.007), CAhand180s (p = 0.017), CAFPR30s (p = 0.004), and CAFPR180s (p = 0.002). After multivariate logistic regression analysis, only CAfinger30s (p = 0.002) had an independent predictive value of the therapeutic response. 99mTc-HDP dynamic blood flow scintigraphy could be helpful in predicting the therapeutic response in patients with RP.

Una paciente con fenómeno de Raynaud del pezón e hipertiroidismo / A patient with Raynaud's phenomenon of the nipple and hyperthyroidism

Introducción: el fenómeno de Raynaud del pezón es una patología poco frecuente. Puede presentarse asociada a hipertiroidismo o enfermedades autoinmunes del tejido conectivo. Presentamos un caso asociado a hipertiroidismo.Caso clínico: mujer, de 39 años, que consulta por dolor en pezón que se agrava con la lactancia 1 mes después del parto. Se diagnosticó fenómeno de Raynaud del pezón, que mejoró con la toma de nifedipino. Tres meses después, la paciente presentó fiebre. El análisis de sangre mostró hormona estimulante del tiroides (TSH) 0,0008 mU/L (normal: 0,55-4,75 mU/L) y T4 libre 48 pg/mL (normal: 2,30-4,20 pg/mL). Los anticuerpos antitiroglobulina fueron > 500 UI/mL. La T3, los anticuerpos antiperoxidasa (TPO) y la inmunoglobulina estimulante del tiroides fueron normales. Se diagnosticó tiroiditis posparto (TPP). Dos meses después, los niveles de TSH y T4 libre volvieron a la normalidad.Conclusión: nuestra paciente presenta una TPP asociada a un fenómeno de Raynaud.(AU)

Introduction: Raynaud's phenomenon of the nipple is a rare pathology. It can occur associated with hyperthyroidism or autoimmune connective tissue diseases.We report a case associated with hyperthyroidism.Case study: a 39-year-old woman consulted for nipple pain, which worsened with breastfeeding, one month after childbirth. Raynaud's phenomenon of the nipple was diagnosed, which improved with nifedipine. Three months later the patient developed fever. Blood test revealed thyroid stimulating hormone (TSH) 0.0008 mU/L (normal 0.55-4.75 mU/L) and free T4 48 pg/mL (normal 2.30-4.20 pg/mL). Antithyroglobulin antibodies were >500 IU/mL. T3, antiperoxidase antibodies (TPO), and thyroid-stimulating immunoglobulin were normal. Postpartum thyroiditis (PPT) was diagnosed. Two months later, TSH and free T4 levels returned to normal.Conclusion: our patient presented PPT associated with Raynaud's phenomenon.(AU)

Proposed Response Parameters for Twelve-Month Drug Trial in Juvenile Systemic Sclerosis: Results of the Hamburg International Consensus Meetings.

OBJECTIVE: Juvenile systemic sclerosis (SSc) is an orphan disease, associated with high morbidity and mortality. New treatment strategies are much needed, but clearly defining appropriate outcomes is necessary if successful therapies are to be developed. Our objective here was to propose such outcomes. METHODS: This proposal is the result of 4 face-to-face consensus meetings with a 27-member multidisciplinary team of pediatric rheumatologists, adult rheumatologists, dermatologists, pediatric cardiologists, pulmonologists, gastroenterologists, a statistician, and patients. Throughout the process, we reviewed the existing adult data in this field, the more limited pediatric literature for juvenile SSc outcomes, and data from 2 juvenile SSc patient cohorts to assist in making informed, data-driven decisions. The use of items for each domain as an outcome measure in an open label 12-month clinical trial of juvenile SSc was voted and agreed upon using a nominal group technique. RESULTS: After voting, the domains agreed on were global disease activity, skin, Raynaud's phenomenon, digital ulcers, musculoskeletal, cardiac, pulmonary, renal, and gastrointestinal involvement, and quality of life. Fourteen outcome measures had 100% agreement, 1 item had 91% agreement, and 1 item had 86% agreement. The domains of biomarkers and growth/development were moved to the research agenda. CONCLUSION: We reached consensus on multiple domains and items that should be assessed in an open label, 12-month clinical juvenile SSc trial as well as a research agenda for future development.

Botulinum Toxins for the Treatment of Raynaud Phenomenon: A Systematic Review With Meta-analysis.

OBJECTIVE: Botulinum toxin (Btx) therapy has emerged as a potential treatment for patients with Raynaud phenomenon (RP) in recent years. This study aimed to investigate the efficacy and safety of Btx treatment for RP. METHODS: Databases of PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from their inception up to August 2022. Studies that reported Btx use for the treatment of RP were included. A meta-analysis was conducted for the Shortened version of the Disabilities of the Arm, Shoulder, and Hand (Quick DASH) score and visual analog scale pain score using a random-effects model. RESULTS: Thirteen full-text studies were included. The pooled standard mean changes for the visual analog scale pain score and QuickDASH score were -3.82 (95% confidence interval, -6.62 to -1.02) and 0.83 (95% confidence interval, -1.47 to -0.19), respectively. The 2 most common complications were injection site pain and intrinsic hand weakness. CONCLUSIONS: The effect of Btx treatment on RP is promising based on current evidence. Nevertheless, more studies and randomized clinical trials with larger sample sizes are needed to confirm the current results.

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.

Botulinum toxin for refractory Raynaud's phenomenon: A "how to" guide for pediatric patients.

Raynaud's phenomenon describes symptoms caused by digital vascular spasm and is classically induced by cold exposure. Severe cases can result in ulceration, necrosis, and digital autoamputation. When standard and adjunctive medical therapies fail or are contraindicated, botulinum toxin A (BTX-A) is an effective treatment option that can be added to existing regimens and should be considered before utilizing rescue therapies associated with higher risk and often higher cost. This report describes our technique, highlights considerations relevant to pediatric patients, and provides photos and videos of the procedure performed on a 16-year-old girl.

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.

Placebo response in Raynaud's Phenomenon clinical trials: The prominent role of regression towards the mean: Placebo response in Raynaud's Phenomenon.

BACKGROUND: Substantial placebo response has been observed in trials assessing treatments in Raynaud's Phenomenon (RP), which makes any treatment effect difficult to detect. However, whether this response is due to a real placebo effect or to other nonspecific effects, such as regression towards the mean (RTM), has not been explored. Our objectives were to explore and quantify placebo response in RP, and to evaluate the magnitude of RTM contribution. METHODS: We combined trial-level and individual-level data from a series of n-of-1 trials and a network meta-analysis, respectively. Main outcomes were the daily frequency and the mean duration of RP attacks, as well as the Raynaud's Condition Score (RCS). We estimated the placebo response by the mean difference between the placebo period (or arm) and the baseline. RTM was estimated by the relationship between placebo response and baseline, and with Galton squeeze plots. Finally, we simulated the effect of the threshold used for inclusion in clinical trials on RTM. FINDINGS: We observed a large and significant placebo response from both individual and trial data for RCS [-1.20 (-1.63, -0.77) and -0.65 (-0.89, -0.41)] and the daily frequency of RP [-0.61 (-0.85, -0.37) and -0.75 (-0.95, -0.54)]. Outcome at baseline was significantly associated with placebo response, suggesting the presence of RTM. The latter was confirmed on individual data, through Galton squeeze plots. INTERPRETATION: Placebo response is large in RP trials, and likely due to regression towards the mean rather than 'true' placebo effect. This should be carefully considered when designing future trials. FUNDING: This work has been partially supported by MIAI @ Grenoble Alpes (ANR-19-P3IA-0003).

Treatment of resistant Raynaud's phenomenon with single-port thoracoscopic sympathicotomy: One-year follow-up.

OBJECTIVE: Follow-up of patients with treatment-resistant Raynaud's phenomenon (RP) one-year after single-port thoracoscopic sympathicotomy (SPTS). METHODS: Eight patients (six males, two females, median age of 45 years) with treatment-resistant RP underwent left-sided SPTS at the third rib (R3), unilaterally. Questionnaires were taken, and number and duration of RP attacks were reported over a 2-week period. Perfusion was assessed with a cooling and recovery procedure at baseline and one year after SPTS. Furthermore, laser speckle contrast analysis, pulse wave velocity, heart rate variability and nailfold capillary microscopy were performed. RESULTS: One year after SPTS the duration of the attacks of was reduced with 1.9 h in the left hand versus 0.3 h in the right hand. Furthermore, three aspects of the questionnaire showed a significant improvement (role limitations due to physical health (p = 0.017), pain (p = 0.027) and physical functioning (p = 0.025)). The total area under the curve of the total cooling and recovery procedure of the left hand was larger one year after surgery (101 (75-140) at baseline versus 118 (95-190) one year post-operatively, p = 0.012), implying a better perfusion in the fingers. This was mainly due to the improvement during the recovery phase (21 (1-41) at baseline versus 38 (24-43) one year post-operatively, p = 0.028). CONCLUSION: One year after unilateral R3 SPTS the benefit with regard to the majority of outcome variables persisted, though some effects seem to attenuate. Long-term effects and long-term follow-up results will be investigated in an on-going study. CLINICAL TRIAL REGISTRATION NUMBER: NCT02680509.

The safety and persistence of intravenous iloprost in systemic sclerosis.

INTRODUCTION: Vasculopathy is a crucial feature of systemic sclerosis (SSc). It occurs in almost every patient with SSc, with Raynaud's phenomenon (RP) and digital ulcers (DU) having a great impact on the quality of patients' lives. Intravenous (IV) iloprost, a synthetic analogue of prostacyclin, is broadly used to treat RP and DU secondary to SSc. Currently, there is no standard protocol defined for the iloprost treatment of SSc-associated RP and DU, and, consequently, the management of this treatment is largely based on each centre's experience. OBJECTIVE: The objective of this study is to evaluate the safety profile of a particular scheme of IV iloprost used in our centre as the standard treatment of SSc-related vascular complications. METHODS: We retrospectively evaluated the clinical records of SSc patients, classified according to the 2013 European Alliance of Associations for Rheumatology (EULAR) criteria (31) with SSc-related DU and/or severe RP not responsive to CCB, receiving or who have received IV iloprost infusions from January 1st 2011 to March 31st 2021 Results: Within this time frame, 60 patients (n=44 for DU; n=16 for severe RP) were treated with a monthly 10-hour IV iloprost perfusion with a dosing regimen adapted to individual tolerance. Forty-nine of these 60 patients (81.7%) were on iloprost for more than one year. Within 12 months of therapy, 40 patients have healed the DUs (90.9%), with only 4 patients maintaining active DUs. A significant clinical improvement in RP at 12 months was observed in 87.5% (n=14/16) of SSc patients with severe RP. Eleven AE implying treatment dose/frequency adjustments or suspension were recorded (18.3% of patients): severe headache (n=5), hypotension (n=3), tachycardia (n=1), flushing (n=1) and generalised erythroderma (n=1). In all patients, the perfusion rate was reduced in the following treatment sessions with good tolerance, with the exception of the patient with the generalised erythroderma reaction, who suspended the perfusion and was later switched to bosentan. After a mean follow-up time of 6.9 (+/-) 4.0 years of treatment (range 0.06-22), 24 patients (40%) stopped the therapy, 14 (58.3%) of whom due to clinical improvement. The overall 5-, and 10-year survival rates of IV iloprost were 68.2% and 55.6%, respectively. CONCLUSION: SSc patients who received this flexible IV iloprost regimen achieved clinical improvement, reflected in the high persistence rate of the drug, with a good tolerability profile. In addition, most side effects were mild and easily managed.